Toxicological _/ l
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for

CHLORFENVINPHOS 1

Draft for Public Comment

Commeni Period Ends: February 20, 19%

 

U.S. DEPARTMENT OF HEALTH & HUMAN SERVICES
Public Health Service
Agency for Toxic Substances and Disease Registry

 

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DRAFT
TOXICOLOGICAL PROFILE FOR
CHLORFENVINPHOS

Prepared by:

Research Triangle Institute
Under Contract No. 205-93-0606

Prepared for:

US. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Agency for Toxic Substances and Disease Registry

August 1995

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CHLORFENvtNPHOS

DISCLAIMER

“I”?

The use of company or product nume(s) is for identification only and does not imply endorsement by
the Agency for Toxic Substances and Disease Registry.

 

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CHLORFENVINPHOS Ill

UPDATE STATEMENT

Toxicological profiles are revised and republished as necessary, but no less than once every three
years. For information regarding the update status of previously released profiles, contact ATSDR at:

Agency for Toxic Substances and Disease Registry
Division of Toxicology/Toxicology Information Branch
1600 Clifton Road NE, E—29
Atlanta, Georgia 30333

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FOREWORD

This toxicological profile is prepared in accordance with guidelines developed by ATSDR and EPA.
The original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised
and republished as necessary.

The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects
information for the hazardous substance being described. Each profile identifies and reviews the key literature
(that has been peer-reviewed) that describes a hazardous substances toxicologic properties. Other pertinent
literature is also presented. but described in less detail than the key studies. The profile is not intended to be an
exhaustive document; however, more comprehensive sources of specialty information are referenced.

Each toxicological profile begins with a public health statement, that describes in nontechnical language,
a substance’s relevant toxicological properties. Following the public health statement is information concerning
levels of significant human exposure and, where known. significant health effects. The adequacy of information
to determine a substance’s health effects is described in a health effects summary. Data needs that are of
significance to protect public health will be identified by ATSDR and EPA. The focus of the profiles is on
health and toxicologic information; therefore. we have included this information in the beginning of the
document.

Each profile must include the following:

(A) The examination. summary, and interpretation of available toxicologic information and epidemiologic
evaluations on a hazardous substance in order to ascertain the levels of significant human exposure for
the substance and the associated acute, subacute, and chronic health effects.

(B) A determination of whether adequate information on the health effects of each substance is available
or in the process of development to determine levels of exposure that present a significant risk to human
health of acute. subacute, and chronic health effects.

(C) Where appropriate, identification of toxicologic testing needed to identify the types or levels of
exposure that may present significant risk of adverse health effects in humans.

The principal audiences for the toxicological profiles are health professionals at the federal. state. and
local levels. interested private sector organizations and groups, and members of the public. We plan to revise
these documents in response to public comments and as additional data become available. Therefore. we
encourage comments that will make the toxicological profile series of the greatest use.

Comments should be sent to:

Agency for Toxic Substances and Disease Registry
Division of Toxicology

Mail Stop E-29

Atlanta, Georgia 30333

Foreword

The toxicological profiles are developed in response to the Superfund Amendments and Reauthorization
Act (SARA) of 1986 (Public Law 99-499) which amended the Comprehensive Environmental Response.
Compensation. and Liability Act of 1980 (CERCLA or Superfund). This public law directed the Agency for
Toxic Substances and Disease Registry (ATSDR) to prepare toxicological profiles for hazardous substances most
commonly found at facilities on the CERCLA National Priorities List and that pose the most significant potential
threat to human health. as determined by ATSDR and the Environmental Protection Agency (EPA). The
availability of the revised priority list of 275 hazardous substances was announced in the Federal Register on
Febniary 28. 1994 (59 FR 9486). For prior versions of the list of substances. see Federal Register notices dated
April 17. 1987 (52 FR 12866); October 20. 1988 (53 FR 41280): October 26. 1989 (54 FR 43619); October 17.
1990 (55 FR 42067); and October 17. 1991 (56 FR 52166): and October 28. 1992 (57 FR 48801).

Section 104(i)(3) of CERCLA. as amended. directs the Administrator of ATSDR to prepare a
toxicological profile for each substance on the list.

This profile reflects our assessment of all relevant toxicologic testing and information that has been peer
reviewed. It has been reviewed by scientists from ATSDR. the Centers for Disease Control and Prevention
(CDC). and other federal agencies. It has also been reviewed by a panel of nongovemment peer reviewers and

is being made available for public review. Final responsibility for the contents and views expressed in this
toxicological profile resides with ATSDR.

W

David Satcher. M.D.. PhD.
Administrator
Agency for Toxic Substances and
Disease Registry

 

 

 

 

CHLORFENVINPHOS Vii

CONTRIBUTORS

CHEMICAL MANAGER(S)/AUTHORS(S):

Alfred S. Dorsey, Jr., D.V.M.
ATSDR, Division of Toxicology, Atlanta, GA

Steven S. Kueberuwa, MS.

Research Triangle Institute, Research Triangle Park, NC

THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS:

1. Green Border Review. Green Border review assures consistency with ATSDR policy.

2. Health Effects Review. The Health Effects Review Committee examines the health effects
chapter of each profile for consistency and accuracy in interpreting health effects and
classifying end points.

3. Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to
substance—specific minimal risk levels (MRLs), reviews the health effects database of each
profile, and makes recommendations for derivation of MRLs.

4. Quality Assurance Review. The Quality Assurance Branch assures that consistency across

profiles is maintained, identifies any significant problems in format or content, and establishes
that Guidance has been followed.

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CHLORFENVINPHOS ix

PEER REVIEW

A peer review panel was assembled for chlorfenvinphos. The panel consisted of the following
members:

1. Dr. Frederick Oehme. Professor, Kansas State University. Manhattan. KS:
2. Dr. Casey Robinson. Professor of Phannacology and Toxicology, University of Oklahoma.

Oklahoma City, OK; and

3. Dr. Syed Naqvi. Professor of Biology. Southem Universin Department of Biological Sciences.
Baton Rouge, LA.

These experts collectively have knowledge of chlorfenvinphos‘ physical and chemical properties.
toxicokinetics, key health end points. mechanisms of action. human and animal exposure. and
quantification of risk to humans. All reviewers were selected in confomtity with the conditions for
peer review specified in Section 1()4(i)(13) of the Comprehensive Environmental Response.
Compensation, and Liability Act. as amended.

Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the
peer reviewers‘ comments and detennined which comments will be included in the profile. A listing
of the peer reviewers' comments not incorporated in the profile. with a brief explanation of the
rationale for their exclusion. exists as part of the administrative record for this compound. A list of
databases reviewed and a list of unpublished documents cited are also included in the administrative
record.

The citation of the peer review panel should not be understood to itnply its approval of the profile‘s
final content. The responsibility for the content of this profile lies with the ATSDR.

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CHLORFENVINPHOS Xi
CONTENTS
CONTRIBUTORS ......................................................... vii
PEER REVIEW .......................................................... ix
LIST OF FIGURES ....................................................... xv
LIST OF TABLES ...................................................... xvii
1. PUBLIC HEALTH STATEMENT ........................................... l
1.] WHAT IS CHLORFENVINPHOS? ...................................... l
1.2 WHAT HAPPENS TO CHLORFENVINPHOS WHEN IT ENTERS THE
ENVIRONMENT? .................................................. 2
13 HOW MIGHT I BE EXPOSED TO CHLORFENVINPHOS? .................... 2
1.4 HOW CAN CHLORFENVINPHOS ENTER AND LEAVE MY BODY? ............ 3
1.5 HOW CAN CHLORFENVINPHOS AFFECT MY HEALTH? ................... 3
16 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN
EXPOSED TO CHLORFENVINPHOS? ................................... 4
1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH? ........................................ 5
1.8 WHERE CAN I GET MORE INFORMATION? ............................. 6
2. HEALTH EFFECTS ..................................................... 7
2.1 INTRODUCTION .................................................. 7
22 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE .............. 7
2.2.1 Inhalation Exposure ........................................... 9
2.2.1.1 Death .............................................. 9
2.2.1.2 Systemic Effects ...................................... 9
2.2.1.3 Immunological and Lymphoreticular Effects .................. 14
2.2.1.4 Neurological Effects .................................. 15
2.2.1.5 Reproductive Effects .................................. 16
2.2.1.6 Developmental Effects ................................. 16
2.2.1.7 Genotoxic Effects .................................... 17
2.2.1.8 Cancer ............................................ 17
2.2.2 Oral Exposure .............................................. 18
2.2.2.1 Death ............................................. 18
2.2.2.2 Systemic Effects ..................................... 19
2.2.2.3 Immunological and Lymphoreticular Effects .................. 36
2.2.2.4 Neurological Effects .................................. 38
2.2.2.5 Reproductive Effects .................................. 44
2.2.2.6 Developmental Effects ................................. 45
2.2.2.7 Genotoxic Effects .................................... 47
2.2.2.8 Cancer ............................................ 47
2.2.3 Dermal Exposure ............................................ 48
2.2.3.1 Death ............................................. 48
2.2.3.2 Systemic Effects ..................................... 48
2.2.3.3 Immunological and Lymphoreticular Effects .................. 49
2.2.3.4 Neurological Effects .................................. 49

 
   
      
      
        
       
   
     
   
       
   
     
   
       
   
   
       
       
       
   
      
         
    
     
      
      
    

 

         
      
      
   

CHLORFENVINPHOS
2.2.3.5 Reproductive Effects .................................. 50
2.2.3.6 Developmental Effects ................................. 50
2.2.3.7 Genotoxic Effects .................................... 50
2.2.3.8 Cancer ............................................ 50
2.3 TOXICOKINETICS .......................................... 52
2.3.1 Absorption ................................................ 52
2.3.1.1 Inhalation Exposure ................................... 52
2.3.1.2 Oral Exposure ....................................... 52
2.3.1.3 Dermal Exposure ..................................... 53
2.3.2 Distribution ................................................ 54
2.3.2.1 Inhalation Exposure ................................... 54
2.3.2.2 Oral Exposure ....................................... 54
2.3.2.3 Dermal Exposure ..................................... 55
2.3.3 Metabolism ................................................ 56
2.3.3.1 Inhalation Exposure ................................... 56
2.3.3.2 Oral Exposure ....................................... 56
2.3.3.3 Dermal Exposure ..................................... 63
2.3.4 Elimination and Excretion ...................................... 63
2.3.4.1 Inhalation Exposure ................................... 63
2.3.4.2 Oral Exposure ....................................... 63
2.3.4.3 Dermal Exposure ..................................... 64
2.3.4.4 Other Exposure ...................................... 64
2.3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models 64
2.4 MECHANISMS OF ACTION ......................................... 67
2.4.1 Pharmacokinetic Mechanisms ................................... 67
2.4.2 Mechanisms of Toxicity ....................................... 7|
2.4.3 Animal—to-Human Extrapolations ................................. 73
2.5 RELEVANCE TO PUBLIC HEALTH ................................... 73
2.6 BIOMARKERS OF EXPOSURE AND EFFECT ............................ 92
2.6.1 Biomarkers Used to Identify or Quantify Exposure to Chlorfenvinphos ...... 93
2.6.2 Biomarkers Used to Characterize Effects Caused by Chlorfenvinphos ....... 95
2.7 INTERACTIONS WITH OTHER CHEMICALS ............................ 96
2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ................... 97
2.9 METHODS FOR REDUCING TOXIC EFFECTS ........................... 99
2.9.1 Reducing Peak Absorption Following Exposure ....................... 99
2.9.2 Reducing Body Burden ........................................ 100
2.9.3 Interfering with the Mechanism of Action for Toxic Effects .............. 100
2.10 ADEQUACY OF THE DATABASE .................................... 101
2.10.1 Existing Information on Health Effects of Chlorfenvinphos ............... 101
2.10.2 Identification of Data Needs .................................... 104
2.10.3 Ongoing Studies ............................................ 117

  
      
 

3. CHEMICAL AND PHYSICAL INFORMATION ................................ 1 19
3.1 CHEMICAL IDENTITY ............................................. 1 19
3.2 PHYSICAL AND CHEMICAL PROPERTIES ............................. 1 19

     
  

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ....................... 123
4.1 PRODUCTION ................................................... 123
4.2 IMPORT/EXPORT ................................................. 123

 
   
 

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CHLORFENVINPHOS xiii

4.3 USE ........................................................... 124

4.4 DISPOSAL ...................................................... 128

5. POTENTIAL FOR HUMAN EXPOSURE ..................................... 129

5.1 OVERVIEW ..................................................... 129

5.2 RELEASES TO THE ENVIRONMENT .................................. 130

5.2.1 Air ...................................................... 132

5.2.2 Water .................................................... 132

5.2.3 Soil ..................................................... 132

5.3 ENVIRONMENTAL FATE ........................................... 133

5.3.1 Transport and Partitioning ...................................... 133

5.3.2 Transformation and Degradation ................................. 138

5.3.2.1 Air ................................ ~ ............... 138

5.3.2.2 Water ............................................. 138

5.3.2.3 Sediment and Soil .................................... 140

5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ............ 144

5.4.1 Air ...................................................... 144

5.4.2 Water .................................................... 144

5.4.3 Sediment and Soil ........................................... 146

5.4.4 Other Environmental Media .................................... 147

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ............... 148

5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .................. 149

5.7 ADEQUACY OF THE DATABASE .................................... 150

5.7.1 Identification of Data Needs .................................... 150

5.7.2 Ongoing Studies ............................................ 154

6. ANALYTICAL METHODS ............................................... 155

6.1 BIOLOGICAL SAMPLES ............................................ 155

6.2 ENVIRONMENTAL SAMPLES ....................................... 157

6.3 ADEQUACY OF THE DATABASE .................................... 160

6.3.1 Identification of Data Needs .................................... 162

6.3.2 Ongoing Studies ............................................ 164

7. REGULATIONS AND ADVISORIES ....................................... 165

8. REFERENCES ........................................................ 167

9. GLOSSARY ......................................................... 183
APPENDICES

A. MINIMAL RISK LEVEL (MRL) WORKSHEETS ........................... A-1

B. USER’S GUIDE .................................................. 8-]

C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS ........................ C-l

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CHLORFENVINPHOS xv

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LIST OF FIGURES

Levels of Significant Exposure to Chlorfenvinphos - Inhalation ...................... l 1
Levels of Significant Exposure to Chlorfenvinphos - Oral ......................... 28
Proposed Mammalian Metabolic Pathway for Chlorfenvinphos ...................... 57
Conceptual Representation of the Physiologically-based Pharmacokinetic (PBPK) Model for a

Hypothetical Chemical Substance .......................................... 66
Existing Information on Health Effects of Chlorfenvinphos ....................... 102
Frequency of NPL Sites With Chlorfenvinphos Contamination ..................... I31
Hydrolysis Pathways for Chlorfenvinphos in Water ............................. 139
Environmental Degradation Pathways for Chlorfenvinphos in Soil ................... 142
Environmental Transformation Pathways for Chlorfenvinphos in Plants ............... I45

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CHLORFENVINPHOS xvii

6-4

7—1

LIST OF TABLES

Levels of Significant Exposure to Chlorfenvinphos — Inhalation ...................... 10
Levels of Significant Exposure to Chlorfenvinphos - Oral ......................... 20
Genotoxicity of Chlorfenvinphos In Vitro ..................................... 91
Chemical Identity of Chlorfenvinphos ...................................... 120
Physical and Chemical Properties of Chlorfenvinphos ........................... 121
Previously Registered Uses of Chlorfenvinphos ............................... 125
Canceled Chlorfenvinphos Registrations in the United States ...................... 126
Analytical Methods for Determining Chlorfenvinphos in Biological Samples ........... 156
Analytical Methods for Determining Chlorfenvinphos in Environmental Samples ........ 158

Analytical Methods for Determining Environmental Degradation Products

of Chlorfenvinphos ................................................... 161
Analytical Methods for Determining Biomarkers for Chlorfenvinphos ................ 163
Regulations and Guidelines Applicable to Chlorfenvinphos ........................ 166

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CHLORFENVINPHOS 1

1. PUBLIC HEALTH STATEMENT

This public health statement tells you about Chlorfenvinphos and the effects of exposure.

The Environmental Protection Agency (EPA) has identified 1,416 hazardous waste sites as the
most serious in the nation. These sites make up the National Priorities List (NPL) and are
targeted for long—term federal cleanup. Chlorfenvinphos has been found in at least one NPL
site. However, it is unknown how many NPL sites have been evaluated for this substance.
As EPA looks at more sites, the sites with Chlorfenvinphos may increase. This is important
because exposure to this substance may harm you and because these sites may be sources of

exposure.

When a substance is released from a large area, such as an industrial plant, or from a
container, such as a drum or bottle, it enters the environment. This release does not always
lead to exposure. You can be exposed to a substance only when you come in contact with it

by breathing, eating, touching, or drinking.

If you are exposed to Chlorfenvinphos, many factors determine whether you’ll be harmed.
These factors include the dose (how much), the duration (how long), and how you come in
contact with it. You must also consider the other chemicals you’re exposed to and your age,

sex, diet, family traits, lifestyle, and state of health.

1.1 WHAT IS CHLORFENVINPHOS?

Chlorfenvinphos is the common name of an organophosphorus insecticide used to control
insect pest on livestock. It was also used to control household pests such as flies, fleas, and
mites. This chemical is synthetic and does not occur naturally in the environment.
Chlorfenvinphos was sold under common trade names including Birlane®, Dermaton®,

Sapercon®, Steladone®, and Supona®.

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CHLORFENVINPHOS 2

1. PUBLIC HEALTH STATEMENT

The pure chemical (100% Chlorfenvinphos) is a colorless liquid with a mild odor.
Preparations commonly used in insecticides sold in stores were usually 90% Chlorfenvinphos.
Most of Chlorfenvinphos was used in liquid form. The substance easily mixes with acetone,

ethanol, and propylene glycol. It is slowly broken down by water and is corrosive to metal.

1.2 WHAT HAPPENS TO CHLORFENVINPHOS WHEN IT ENTERS THE ENVIRONMENT?

Chlorfenvinphos may enter the environment only from runoff after rainfall and leaching from
hazardous waste sites. After it has run off or leached, it may be present in the soil, surface
(rivers and ponds), and underground water (wells). On soil, it may also be washed into
surface waters by rain. It may also move from soil to the air by evaporation or by being
absorbed by plants. No information is presently available to show that it can be found in fish

or other freshwater produce, or seafood, or plants that are eaten by people.

1.3 HOW MIGHT I BE EXPOSED TO CHLORFENVINPHOS?

The most common way for people to be exposed to Chlorfenvinphos is by eating imported
agricultural products and by using lanolin—containing pharmaceutical products. Lanolin is a
fatty substance that is used as a base for many medications that are rubbed on the skin to
keep the skin from drying. Lanolin is also used as a base for many cosmetic skin lotions and
creams. In areas surrounding hazardous waste disposal or treatment facilities, you could be
exposed to the substance by contact with soils or runoff water, or surface or groundwater
contaminated as a result of spills or leaks of material on the site. People who work in the
disposal of Chlorfenvinphos or its wastes are more likely to be exposed. You are most likely
to be exposed to this substance if you live near chemical plants where Chlorfenvinphos was
manufactured, or near dairy farms, cattle or sheep holding areas, or where poultry was
produced and where the substance was used, or if you live near hazardous waste sites that

contain the substance.

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CHLORFENVINPHOS 3

1. PUBLIC HEALTH STATEMENT

1.4 HOW CAN CHLORFENVINPHOS ENTER AND LEAVE MY BODY?

If you breathe air containing chlorfenvinphos, you may absorb it into your body through your
lungs. If you eat food or drink water containing this substance, it may be absorbed from your
stomach and intestines. The substance may also enter your body through the skin. Once in
the body, it is rapidly broken down and eliminated from the body, mostly when you urinate.

It does not build up in your tissues.
1.5 HOW CAN CHLORFENVINPHOS AFFECT MY HEALTH?

Most cases of unintentional chlorfenvinphos poisoning have resulted from short exposures to
very high concentrations of this substance. Usually this occurs when people unintentionally
swallow the substance or when workers, who do not properly protect themselves when using
it, inhale, swallow, or contaminate their skin with a large amount of the substance. This
chemical affects the nervous system. In animals and people, high doses of the substance
produce effects on the nervous system similar to those produced by high doses of muscarine
and pure nicotine. Some mild symptoms of exposure are headache, dizziness, weakness,
feelings of anxiety, confusion, runny nose, constriction of the pupils of the eye, and inability
to see clearly. More severe symptoms may include nausea and vomiting, abdominal cramps,
slow pulse, diarrhea, pinpoint pupils, difficulty in breathing, and passing out (coma). These
signs and symptoms may start to develop within 30 to 60 minutes and reach their maximum
effect after 6 to 8 hours. Very high exposure to chlorfenvinphos has killed people who
swallowed it by accident or who swallowed large amounts of the substance to commit suicide.
We do not know if longer term breathing of the substance at lower amounts can produce
damage to the immune system in people. In almost all cases, complete recovery occurred
when exposure stopped. There is no evidence that long-term exposure to small amounts of
the chlorfenvinphos causes any other harmful health effects in people. The substance has not
been shown to cause birth defects or to prevent conception in people. The International
Agency for Research on Cancer, the Environmental Protection Agency, and the National

Toxicology Program have not studied chlorfenvinphos for cancer in people and animals.

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CHLORFENVINPHOS 4

1. PUBLIC HEALTH STATEMENT

studies, high doses of chlorfenvinphos produced effects on the nervous system similar to

those seen in people.

To protect the public from the harmful effects of toxic chemicals and to find ways to treat
people who have been harmed, scientists use many tests. One way to see if a chemical will
hurt people is to learn how the chemical is absorbed, used, and released by the body; for
some chemicals, animal testing may be necessary. Animal testing may also be used to
identify health effects such as cancer or birth defects. Without laboratory animals, scientists
would lose a basic method to get information needed to make wise decisions to protect public
health. Scientists have the responsibility to treat research animals with care and compassion.
Laws today protect the welfare of research animals and scientists must comply with strict

animal care guidelines.

1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED
TO CHLORFENVINPHOS?

Most of the signs and symptoms resulting from chlorfenvinphos poisoning are due to the
inhibition of an enzyme called acetylcholinesterase in the nervous system. This enzyme is
also found in your red blood cells and a similar enzyme (pseudocholinesterase) is found in
blood plasma. The most common test for exposure to many pesticides containing the element
phosphorus, which include chlorfenvinphos, is to determine the level of cholinesterase activity
in the red blood cells or plasma. This test requires only a small amount of blood and can be
done in your doctor’s office. It takes weeks for this enzyme to completely recover to normal
levels following exposure; therefore, a valid test may be conducted a number of days
following the suspected exposure. This test indicates only exposure to a chemical substance
of this type. It does not specifically show exposure to chlorfenvinphos. Other chemicals or
disease states may also alter the activity of this enzyme. There is a wide range of normal
cholinesterase activity among individual people in the general population. If you have not
established your normal or baseline value through a previous test, you might have to repeat

the test several times to determine if your enzyme activity is recovering.

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CHLORFENVINPHOS

1. PUBLIC HEALTH STATEMENT

Specific tests are available to determine the presence of chlorfenvinphos or the other
chemicals to which it breaks down in the body in blood, body tissue, and urine. These tests
are not usually available through your doctor’s office and require special equipment and
sample handling. If you need the specific test, your doctor can collect the sample and send it
to a special laboratory for analysis. Chlorfenvinphos is rapidly broken down to other
chemicals and removed from the body (in urine), so this test can only be done in the first few
days after exposure to make sure that you have really breathed, swallowed, or got

chlorfenvinphos on your skin.

1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO
PROTECT HUMAN HEALTH?

The federal govermnent has no set standards or guidelines to protect people from the possible
harmful health effects of chlorfenvinphos because its use has not been allowed in the United

States for a long time.

The federal government develops regulations and recommendations to protect public health.
Regulations 9% be enforced by law. Federal agencies that develop regulations for toxic
substances include the Environmental Protection Agency (EPA), the Occupational Safety and
Health Administration (OSHA), and the Food and Drug Administration (FDA).
Recommendations provide valuable guidelines to protect public health but M be enforced
by law. Federal organizations that develop recommendations for toxic substances include the
Agency for Toxic Substances and Disease Registry (ATSDR) and the National Institute for
Occupational Safety and Health (NIOSH).

Regulations and recommendations can be expressed in not—to-exceed levels in air, water, soil,

or food that are usually based on levels that affect animals, then are adjusted to help protect

people. Sometimes these not-to—exceed levels differ among federal organizations because of

different exposure times (an 8-hour workday or a 24-hour day), the use of different animal

studies, or other reasons.

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CHLORFENVINPHOS 6

1. PUBLIC HEALTH STATEMENT

Recommendations and regulations are also periodically updated as more information becomes
available. For the most current information, check with the federal agency or organization

that provides it.

1.8 WHERE CAN I GET MORE INFORMATION?

If you have any more questions or concerns, please contact your community or state health or

environmental quality department or:

Agency for Toxic Substances and Disease Registry
Division of Toxicology

I600 Clifton Road NE, Mailstop E-29

Atlanta, GA 30333

* Information line and technical assistance

Phone: (404) 639—6000

Fax: (404) 639-6315 or 6324
ATSDR can also tell you the location of occupational and environmental health clinics.
These clinics specialize in recognizing, evaluating, and treating illnesses resulting from

exposure to hazardous substances.

* To order toxicological profilechontact:

National Technical Information Service
5285 Port Royal Road

Springfield. VA 22161

Phone: (800) 553—6847 or (703) 487—4650

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CHLORFENVINPHOS

2. HEALTH EFFECTS

2.1 INTRODUCTION

The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and
other interested individuals and groups with an overall perspective of the toxicology of

chlorfenvinphos. It contains descriptions and evaluations of toxicological studies and epidemiological
investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic

data to public health.

A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile.

2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE

To help public health professionals and others address the needs of persons living or working near
hazardous waste sites, the information in this section is organized first by route of
exposure—inhalation, oral, and dermal; and then by health effect—death, systemic, immunological,
neurological, reproductive, developmental, genotoxic, and carcinogenic effects. These data are
discussed in terms of three exposure periods—acute (14 days or less). intermediate (15—364 days). and

chronic (365 days or more).

Levels of significant exposure for each route and duration are presented in tables and illustrated in
figures. The points in the figures showing no—observed—adverse-effect levels (NOAELs) or lowest-
observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the
studies. LOAELS have been classified into "less serious" or "serious" effects. "Serious" effects are
those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute
respiratory distress or death). "Less serious" effects are those that are not expected to cause significant
dysfunction or death, or those whose significance to the organism is not entirely clear. ATSDR
acknowledges that a considerable amount of judgment may be required in establishing whether an end
point should be classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some
cases, there will be insufficient data to decide whether the effect is indicative of significant
dysfunction. However, the Agency has established guidelines and policies that are used to classify

these end points. ATSDR believes that there is sufficient merit in this approach to warrant an attempt

"'DRAFT FOR PUBLIC COMMENT'"

CHLORFENVINPHOS 8

2. HEALTH EFFECTS

at distinguishing between "less serious" and "serious" effects. The distinction between "less serious"
effects and "serious" effects is considered to be important because it helps the users of the profiles to
identify levels of exposure at which major health effects start to appear. LOAELs or NOAELs should
also help in determining whether or not the effects vary with dose and/or duration. and place into

perspective the possible significance of these effects to human health.

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and
figures may differ depending on the user’s perspective. Public health officials and others concerned
with appropriate actions to take at hazardous waste sites may want information on levels of exposure
associated with more subtle effects in humans or animals (LOAEL) or exposure levels below which no
adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans

(Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike.

Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have
been made for chlorfenvinphos. An MRL is defined as an estimate of daily human exposure to a
substance that is likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a
specified duration of exposure. MRLs are derived when reliable and sufficient data exist to identify
the target organ(s) of effect or the most sensitive health effect(s) for a specific duration within a given
route of exposure. MRLs are based on noncancerous health effects only and do not consider
carcinogenic effects. MRLs can be derived for acute, intermediate, and chronic duration exposures for
inhalation and oral routes. Appropriate methodology does not exist to develop MRLs for dermal

exposure.

Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990),
uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional
uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an
example, acute inhalation MRLs may not be protective for health effects that are delayed in
development or are acquired following repeated acute insults. such as hypersensitivity reactions.
asthma, or chronic bronchitis. As these kinds of health effects data become available and methods to

assess levels of significant human exposure improve, these MRLs will be revised.

A User’s Guide has been provided at the end of this profile (see Appendix B). This guide should aid

in the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs.

"’DRAFT FOR PUBLIC COMMENT'"

 

 

CHLORFENVINPHOS

2. HEALTH EFFECTS

2.2.1 Inhalation Exposure

2.2.1.1 Death

There are no reports of deaths in humans exposed by acute-, intermediate—, or chronic—duration

inhalation to chlorfenvinphos.

No studies were located regarding lethality in animals after intermediate— or chronic—duration inhalation
exposure to chlorfenvinphos. A study investigated whether the difference in the route of absorption or
the mode of lethality is responsible for the higher lethality of the micron-sized (>l um) aerosols in
male rats. The study reported 0, 60, and 100% mortality in rats at the 83, I44, and 236 mg/m3 dose
levels, respectively. The deaths occurred 3 and 4 hours after initiation of the exposure to micron-sized
chlorfenvinphos aerosols. There was 0, 80, and 100% mortality in rats at the 254, 47], and

l,065 mg/m3 dose levels, respectively. LC,0 values calculated from the mortality data were 130 mg/m3
for the micron-sized aerosols and 5l0 mg/mJ for the submicron—sized aerosols, indicating that the
micron—sized aerosols were about 4 times more potent in producing lethality than the submicron-sized
aerosols. Elapsed time from the start of exposure to death was not changed by the cannulation in both

the micron-sized and the submicron-sized aerosols. However, the LC50 value of the micron-sized

aerosols was markedly increased from 130 mg/m’l to 490 mg/m3 by the cannulation, while that of the

submicron-sized aerosols was hardly changed by cannulation (510—480 mg/m’l), suggesting that the
mode of lethality is not different between two types of aerosol. The authors surmised that death from
acute exposure to chlorfenvinphos aerosols probably derives from inhibition of erythrocyte
cholinesterase (ChE) activity (Takahashi et al. 1994). In another study with rats, the acute lethality of
chlorfenvinphos was indifferent in male rats in snout—only or whole body exposures (Tsuda et al.

I986).

The LCi0 values and doses associated with death in each species and duration category are shown in

Table 2—l and plotted in Figure 2-1.

2.2.1.2 Systemic Effects

No studies were located regarding the respiratory, hematological, cardiovascular, gastrointestinal,

musculoskeletal, hepatic, renal, endocrine, dermal, ocular, body weight, or other systemic effects in

"'DFlAFT FOR PUBLIC COMMENT'“

 

10

CHLORFENVINPHOS

2. HEALTH EFFECTS

 

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"'DRAFT FOR PUBLIC COMMENT'“

CHLORFENVINPHOS 12

2. HEALTH EFFECTS

humans following acute-, intermediate-, or chronic—duration inhalation exposure to chlorfenvinphos.
Existing human data on the metabolic effects of the substance are limited to chronic—duration exposure.
Similarly, no studies were located regarding the hematological, gastrointestinal, musculoskeletal,
hepatic, renal, endocrine, metabolic, dermal, ocular, body weight, or other systemic effects of the
substance in animals following acute, intermediate-, or chronic-duration inhalation exposure to
chlorfenvinphos. Existing animal data on the respiratory and cardiovascular effects are limited to

acute-duration exposure.

The highest NOAEL value and all LOAEL values for adverse systemic effects in each reliable study

for each species and duration category are shown in Table 2—1 and plotted in Figure 2-1.

Respiratory Effects. Acute-duration exposure of rats to inhalation aerosol chlorfenvinphos doses
produced cardiorespiratory changes in the treated rats at high doses. Male Fischer 344 rats exposed to
the micron-sized (>1 pm) or submicron-sized (<1 um) chlorfenvinphos aerosols for 4 hours suffered
cardiorespiratory effects. Rats exposed to the lethal concentration of 1,220 mg/m3 of the submicron-
sized aerosols showed a progressive increase in blood pressure followed by an apnea during which the
blood pressure was maximally increased. Rats exposed to 390 mg/m3 of the micron-sized aerosols
also exhibited cardiorespiratory changes similar to those of the submicron-sized aerosols (data were not
shown in the report). No significant qualitative difference was observed in cardiorespiratory changes
between the micron—sized and the submicron-sized aerosols, suggesting that the mode of lethality is not
different between the two types of aerosols. A LOAEL of 390 mg/m3 for apnea was established in
this study (Takahashi et al. 1994). In a previous study (Takahashi et al. 1991), Sprague-Dawley rats
exhibited similar signs at a dose of 16 mg/m3 following intravenous administration of the

chlorfenvinphos.

Cardiovascular Effects. Acute exposure of rats to inhalation aerosol chlorfenvinphos doses
produced cardiorespiratory changes in the treated rats at high doses. Adult male Fischer 344 rats
exposed to the micron-sized (>1 um) or submicron-sized (<1 um) chlorfenvinphos aerosols for 4 hours
suffered cardiorespiratory effects. Rats exposed to the lethal concentration of 1,220 mg/m3 of the
submicron-sized aerosols showed a progressive increase in blood pressure followed by apnea during
which the blood pressure was maximally increased. Bradycardia was observed in electrocardiograms
(ECG) at the pressor period, which was characterized by a prolonged TP time without a change in PQ,

QRS, and ST time. Rats exposed to 390 mg/m3 of the micron-sized aerosols also exhibited cardio-

"'DRAFT FOR PUBLIC COMMENT'"

 

 

 

 

CHLORFENVINPHOS

2. HEALTH EFFECTS

 

respiratory changes similar to those of the submicron-sized aerosols (data were not shown in the
report). No significant qualitative difference was observed in cardiorespiratory changes between the
micron-sized and the submicron-sized aerosols, suggesting that the mode of lethality is not different
between the two types of aerosols. A LOAEL of 390 mg/m3 for progressive increased blood pressure
and bradycardia was established in this study (Takahashi et al. 1994). In a previous study (Takahashi
et al. 1991), Sprague-Dawley rats exhibited similar signs at a dose of 16 mg/m3 following intravenous

administration of the chlorfenvinphos.

It has also been suggested that the cholinergic action of organophosphates, like chlorfenvinphos, may
interfere with the pathways controlling the secretory activity of the anterior pituitary lobe and the
adrenal cortex whose hormones influence the activities of many enzymes, including aromatic amino
acid transferases (Puzynska 1984). Inhibition of the activity of neurotransmitters, like acetylcholine, in
the adrenal cortex by chlorfenvinphos may interfere with the secretory activity of the adrenal cortex.
Interference with the secretory activity of the adrenal cortex may, in turn, lead to disturbance in one or

more components of the renal blood pressure regulatory systems (Klaassen et al. I986).

Metabolic Effects. The information on the metabolic effects of chronic-duration inhalation
exposure to chlorfenvinphos provide only inconclusive evidence. Examinations of 31 manufacturing
workers who directly handled the organophosphoric pesticide chlorfenvinphos (and other compounds)
for l9~53 years revealed significantly lowered nitrobllue tetrazolium (NBT)-dye reduction in both
stimulated and non-stimulated cells, as well as a significant decrease of the spontaneous E rosette
formation (not influenced by exposure time) in the blood (early E rosettes, 52%; late E rosettes, 57%)
as compared to controls (early E rosettes, 57%; late E rosettes, 63%). No correlation was found
between the spontaneous E rosette formation and cholinesterase activity. The authors of this study
concluded that depressed NBT-dye reduction and diminished spontaneous E rosette formation may be
regarded as a probable mode of the effect of organophosphoric chemicals on metabolic and membrane
damage of human cells. About half of the subjects in the study were smokers (Wysocki et al. l987).
However, the data from this study are not reliable for evaluating the inhalation toxicity of
chlorfenvinphos because the workers in this study were also concurrently exposed to greater

concentrations of other known toxic substances.

Evidence from rat studies indicates that the alteration of brain and liver activities of the aromatic

amino acid transferases by chlorfenvinphos may be due to the inhibitory effect of the substance on

"'DRAFT FOR PUBLIC COMMENT'"

CHLORFENVINPHOS

2. HEALTH EFFECTS

noradrenaline activity, since noradrenaline has been shown to affect amino acid transferase (L-tyrosine
aminotransferase) activity in another study (Puzynska 1984). It has also been suggested that the
cholinergic action of organophosphates, like chlorfenvinphos, may interfere with the pathways
controlling the secretory activity of the anterior pituitary lobe and the adrenal cortex whose hormones
influence the activities of many enzymes, including aromatic amino acid transferases (Puzynska I984).
Interference with the secretory activity of the adrenal cortex may lead to a disruption in the normal
activities of one or more components of the renal blood pressure regulatory systems (Klaassen et al.

1986).

2.2.1.3 Immunological and Lymphoreticular Effects

No studies were located regarding the immunological and lymphoreticular effects in humans following
acute- or intermediate—duration inhalation exposure to chlorfenvinphos. However, chronic-duration
inhalation exposure to organophosphoric pesticides caused altered immune response and, consequently,
produced damage to humoral mechanisms in humans. Examinations of 31 manufacturing workers who
directly handled the organophosphoric pesticide chlorfenvinphos (and other compounds) for

1953 years revealed significantly lowered NBT-dye reduction in both stimulated and non-stimulated
cells, and a decreased percentage of phagocytic cells (P<0.00], 0.05, and 0.002, respectively) in

pesticide workers occupationally exposed to an estimated average ambient chlorfenvinphos

concentration of 0.21 mg/m'l. These analyses parameters of the NBT test showed a positive linear

correlation with the degree of cholinesterase activity reduction. The exposure time had no effect on
NBT reduction test parameters, but there was a negative linear correlation with the phagocytic index of
the NBT test (r = —0.4879, P<0.0l). A significant decrease of the spontaneous E rosette formation
(not influenced by exposure time) was found in the blood of the exposed workers (early E rosettes,
52%; late E rosettes, 57%), as compared to controls (early E rosettes, 57%; late E rosettes, 63%). No
correlation was found between the spontaneous E rosette formation and cholinesterase activity. The
number of white blood cells, mainly neutrophils, did not show any significant differences in both
examined subgroups, but the absolute lymphocyte count in the peripheral blood of the exposed
subjects was lower when compared to controls (1,941.9 versus 2,380 cells/mm", P<0.05). The authors
of this study concluded that depressed NBT-dye reduction and diminished spontaneous E rosette
formation may be regarded as a probable mode of action of organophosphoric chemicals on metabolic
and membrane damage to human cells. Cholinesterase activity, which showed a time-independent

positive linear relationship to lowered NBT—dye reduction in the subjects, was above 2 umol in 17 of

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CHLORFENVINPHOS 15

2. HEALTH EFFECTS

the subjects (with an average age of 38.5 years). Eighteen (58.1%) of the subjects examined showed
symptoms of chronic bronchitis; seven (23.3%) subjects in the control group also had anamnestic
symptoms of chronic bronchitis. It is generally understood that chronic bronchitis stems from changes
in humoral rather than cellular immune response. About half of the subjects were smokers. The
maximal estimated airborne concentrations of substances in the workplace were estimated as

0654 mg/m" (formothion), 0.483 mg/m3 (sumithion), trace (DDVP), 0.213 mg/m“ (chlorfenvinphos),
and 1.09 mg/m3 (malathion) (Wysocki et al. 1987). The data from this study are not reliable for
evaluating the inhalation toxicity of chlorfenvinphos because the workers in this study were also

concurrently exposed to greater concentrations of other known immunotoxic substances.

No studies were located regarding immunological and lymphoreticular effects in animals after acute—,

intermediate, or chronic-duration inhalation exposure to chlorfenvinphos.

2.2.1.4 Neurological Effects

In humans, chlorfenvinphos inhibits cholinesterase activity in the central and peripheral nervous system
when administered by the oral (Cupp et al. 1975; Pach et al. 1987) or inhalation route in acute—
duration exposures (Kolmodin—Hedman and Eriksson 1987). In animals, chlorfenvinphos inhibits
cholinesterase activity in the central and peripheral nervous system when administered by the oral
(Barna and Simon 1973; Osicka—Koprowska et al. 1984; Takahashi et al. 1991), or dermal route in
acute—duration exposures. In addition, chlorfenvinphos inhibits noradrenaline activity in the central
adrenergic mechanism in acute oral exposures in animals (Brzezinski 1978; Osumi et al. 1975).
Inhibition of cholinesterase activity results in accumulation of choline at muscarinic and nicotinic
receptors leading to peripheral and central nervous system effects. These effects usually appear within

a few minutes to a few hours after exposure depending on the extent of exposure.

No studies were located regarding neurological effects in humans after acute— or intermediate-duration
inhalation exposure to chlorfenvinphos. The single study that reported neurological effects in humans
from inhalation exposure to chlorfenvinphos involved occupational exposure. A group of nine
gardeners (pesticide mixers) who worked with the organophosphates (dimethoate, formothion,
isofenphos and occasionally chlorfenvinphos) for an unspecified duration complained of headaches.
The gardeners had a mean difference (before and after exposure) of 0.56 nmol/mL for cholinesterase

and 2.67 nmol/mL for butyrylcholinesterase. Since the symptoms could result from exposure to the

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CHLORFENVINPHOS 16

2. HEALTH EFFECTS

other organophosphates (dimethoate. formothion, isofenphos) to which the workers were also exposed.
the role of chlorfenvinphos exposure in this incident is not certain. In addition, no data were given on

air concentrations of the organophosphate pesticides (Kolmodin—Hedman and Eriksson 1987).

No studies were located regarding neurological effects in animals after intermediate— or chronic—
duration inhalation exposure to chlorfenvinphos. Acute exposure of rats to inhalation aerosol
chlorfenvinphos doses produced neurological signs indicative of cholinergic response stemming from
inhibition of cholinesterase activity. Surviving adult male Fischer 344 rats (27 of 60) exposed to the
micron—sized (>l pm) or submicron—sized (<l um) chlorfenvinphos aerosols for 4 hours (0. 83, I30,
144. 236. 254, 322. 471. (123, 1.019. or 1.065 mg/m") exhibited cholinergic signs. including salivation.
urination. exophthalmos. twitches. and tremors. at 283 mg/kg. The inhalation experiments were
conducted using a nose—only inhalation chamber. To examine the toxicological significance of
swallowed chlorfenvinphos. a drain cannula was placed in the esophagus under penmbarbital sodium
anesthesia. Toxic signs were not assessed in detail during the exposure because the rats were in the
animal holder. There were no differences in toxic signs between the micron—sized and the submicron—

sized aerosols (Takahashi et al. 1994).

The highest NOAEL value and all LOAEL values for neurological effects in each reliable study for

each species and duration category are shown in Table 2—l and plotted in Figure 2—l.

2.2.1.5 Reproductive Effects

No studies were located regarding the reproductive effects in humans or animals following acute—.

intermediate—. or chronic—duration inhalation exposure to chlorfeiwinphos.

2.2.1.6 Developmental Effects

No studies were located regarding the developmental effects in humans or animals following acute-.
intermediate, or chronic-duration inhalation exposure to chlorfenvinphos. However, a statistical
system for hazard identification was developed for use in predicting the developmental toxicity of
175 chemicals, including chlorfenvinphos. The data used in this system included the results of any
developmental toxicity testing in up to 14 animal species as well as reports of mutagenicity or

carcinogenicity. The compounds were categorized with respect to their human developmental toxicity

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CHLORFENVINPHOS 17

2. HEALTH EFFECTS

potential as: 7| .0 testing negative, ()0 not tested (unknown). 0.5 tested with equivocal results, and
|.() testing positive. Chlorfenvinplms scored —l .0 for rat: 0.0 for primate, mouse, dog. cat, pig, ferret,
sheep, goat, cow, and opossum; and l.() for hamster and rabbit. This method correctly classified the
study compounds 63- 91% of the time. The models had a sensitivity of 0277570, a positive predictive
value of 75—10070, and a negative predictive value of ()4—-9l ‘/n indicating that these statistical models

are not optimal for hazard identification (.lelovsek et al. 1989).

2.2.1.7 Genotoxic Effects

No studies were located regarding the genotoxic effects of chlorfenvinphos in humans following

inhalation exposure.

Other genotoxicity studies for chlorfenvinphos are described in Section 2.5.

2.2.1.8 Cancer

No studies were located regarding the cancer effects in humans or animals after inhalation exposure to

chlorfenvinphos.

However, a study to determine the ability of vinyl phosphate esters, like chlorfenvinphos, to form
methylated bases in DNA of calf thymus failed to detect 6—methyl guanine, a known mutagen. In both
the reaction with double—stranded DNA (dsDNA) and single-stranded DNA (ssDNA). 7-methyl
guanine was the main methylation product. However, all methyl derivatives of adenine constituted
about 40% and 50% of all methylation products in the case of dsDNA and ssDNA, respectively.
3-Methylcytosine was the only methyl derivative of pyrimidine identified (Wiaderkiewicz et al. 1986).
The production of electrophilic metabolic intermediates or epoxides in the metabolism of
chlorfenvinphos, which could react with nucleophilic cellular components (DNA, RNA, and proteins)
leading to carcinogenesis, was considered unlikely by a theoretical analysis (Akintonwa 1985). In
another study, tetrachlorvinphos (Gardonam) was evaluated for potential to induce chromosomal
aberrations and sister—chromatid exchanges (SCEs) in vim) in a primary culture of Swiss mice spleen
cells at concentrations of 0.25, 0.50, 1.0. or 2.0 ug/mL. 'l‘etrachlorvinphos (Gardonam’) induced a high
percentage of metaphases with chromosomal aberrations in the mouse spleen cells after four hours of

treatment in a dose-dependent manner. According to the authors, the results indicate that tetra-

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CHLORFENVINPHOS 18

2. HEALTH EFFECTS

chlorvinphos in the tested concentrations is mutagenic in mouse spleen cell cultures (Amer and Aly
1992). In both of these studies, structural analogs of chlorfenvinphos (methylbromophenvinphos and
tetrachlorvinphos, respectively) were used; therefore, the data are difficult to relate to chlorfenvinphos
without extensive structure-activity relationship analysis. In a mutagenicity study, the dose-response
curve, at doses of 0, 50, 500, and 5,000 ug/plate, for the mutagenic activity of chlorfenvinphos for the
Salmonella typhimurium strain TA100 was reduced by the S9 mix (metabolic activation). At present,
no mutagenic pesticide the decreases of which in the presence of the S9 mix is carcinogenic except

captan (F—28) (Moriya et al. 1983).

A theoretical analysis that predicted the mammalian biotransformation products based on the
recognition of the structure of chlorfenvinphos, understanding of Types I and II metabolism of foreign
compounds, and mechanistic biochemistry found that cytochrome P—450 monooxygenase (an inducible
enzyme) is the relevant enzyme which mediates the biotransformation of chlorfenvinphos. The author
of this study postulated that the 2,4-dichlorobenzoy1 glycine (2,4-dichlorohippuric acid) was produced
in the rat by this mechanism. The production of electrophilic metabolic intermediates or epoxides in
the metabolism of chlorfenvinphos, which could react with nucleophilic cellular components (DNA,
RNA, and proteins) leading to carcinogenesis, was considered unlikely by this theoretical approach

(Akintonwa 1984).

2.2.2 Oral Exposure

2.2.2.1 Death

There are no reports of deaths in humans exposed by intermediate— or chronic-duration ingestion of
chlorfenvinphos. A 16-month—old child who accidentally drank an unspecified amount of
chlorfenvinphos, used for flea treatment in the home, died despite treatment in a hospital (Felthous

1978).

Chlorfenvinphos is extremely toxic to rodents and dogs by the oral route in acute doses. The oral
LD50 values for rats, rabbits, and dogs have been estimated as 9.7, 300, 50.5 mg/kg, respectively
(Ambrose et al. 1970). After prolonged (105 minutes) exhibition of cholinergic signs, death occurred
at the 20 mg/kg dose levels animals when Sprague—Dawley rats were orally administered single doses

of 1.25. 5, or 20 mg/kg chlorfenvinphos (Takahashi et al. 1991). The acute oral LD50 of

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CHLORFENVINPHOS 19

2. HEALTH EFFECTS

chlorfenvinphos given to male rats as a single dose in olive oil was estimated to be 15.4 mg/kg.
Animals that died from the effects of chlorfenvinphos did so within 12 hours of dosing; no further
deaths were noted up to 72 hours after dosing. The chlorfenvinphos LDSO value for the rats pretreated
with dieldrin (0.2 mg/kg) was estimated to be 157 mg/kg; thus, dieldrin pretreatment induced a lO—fold
protective effect against the acute toxicity of the organophosphate (Hutson and Wright 1980). Using
Probit analysis, the acute oral LDSO, calculated from the mortality data of male Wistar rats dosed with
varying concentrations (19.7—29.6 mg/kg) of chlorfenvinphos orally, was 22.8 mg/kg (Hutson and
Logan 1986). In another study with Wistar rats, the acute oral toxicity of chlorfenvinphos, LD50 was
significantly decreased in rats fed a protein-deficient (4.5%) diet during the 60 days of administration.
The 60-day rat LD50 value was reduced from a control value of 23.0 mg/kg to 7.4 mg/kg in males and
25.5 mg/kg to 10.2 mg/kg in females (Puzynska 1984). Pretreatment of male Fischer 344 rats with

15 mg/kg chlorfenvinphos followed by a further 15 mg/kg dose significantly reduced the male oral
LD50 for chlorfenvinphos from a positive control value of 34.5 mg/kg to 105.6 mg/kg; about 3.08-fold
(p<0.05). Deaths occurred between 8 hours and 1 day after oral administration of chlorfenvinphos

(Ikeda et al. 1992).

Chlorfenvinphos appears to be less toxic in the mouse than in the rat. In a lethality study with BDFl
mice of both sexes, the oral LD50 and maximum tolerated dose (MTD) for chlorfenvinphos (suspended
in methylcellulose) were estimated as 148 mg/kg and 109 mg/kg, respectively. The mice were
evaluated 5 days after intragastric administration of the chlorfenvinphos doses (Kowalczyk—Bronisz et

al. 1992).
In prolonged exposures, no significant effect on mortality and survival was reported for rats and dogs
given chlorfenvinphos in the diet at doses as high as 90 mg/kg/day for 12 weeks or 24 mg/kg/day for

104 weeks (Ambrose et al. 1970).

The LD50 values and doses associated with death in each species and duration category are shown in

Table 2-2 and plotted in Figure 2-2.

2.2.2.2 Systemic Effects

No studies were located regarding the hematological, cardiovascular, gastrointestinal, musculoskeletal,

hepatic, renal, endocrine, dermal, ocular, body weight, or other systemic effects in humans following

““DRAFT FOR PUBLIC COMMENT'“

20

CHLORFENVINPHOS

2. HEALTH EFFECTS

 

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CHLORFENVINPHOS 31

2. HEALTH EFFECTS

acute-, intermediate-, or chronic-duration oral exposure to chlorfenvinphos. Existing human data on
the respiratory and neurological effects are limited to acute-duration exposures. Similarly, no studies
were located regarding the respiratory, musculoskeletal, metabolic, dermal, ocular, body weight, or
other systemic effects animals following acute-, intermediate-, or chronic-duration oral exposure to
chlorfenvinphos. Existing animal data are limited to acute-duration exposures for gastrointestinal.
hepatic and endocrine effects; intermediate—duration exposures for respiratory, hematological,
cardiovascular, gastrointestinal, hepatic, renal, metabolic, and body weight effects; and chronic-
duration exposures for cardiovascular, gastrointestinal, hepatic, renal, metabolic, and body weight

effects.

The highest NOAEL value and all LOAEL values for adverse systemic effects in each reliable study

for each species and duration category are shown in Table 2—2 and plotted in Figure 2—2.

Respiratory Effects. A 29-year-old male was admitted with severe respiratory distress and
bronchial tree hypersecretion. The patient had ingested about 50 mL of the preparation Enolofos‘”,
which contains 50% chlorfenvinphos, in a suicide attempt. These symptoms subsided after he was

given hemoperfusion and drug treatment for anticholinesterase poisoning (Pach et al. 1987).

In animal studies, necropsy examination of rabbits administered 10 mg/kg of chlorfenvinphos orally
for 90 days showed no signs of poisoning nor gross lesions in the lungs in an intermediate-duration

study (Roszkowski 1978).

Hematological Effects. Information on the hematological effects from oral chlorfenvinphos
exposure is limited. Investigations conducted on 4 groups of rabbits (13 each) of both sexes at a dose
of 10 mg/kg for 90 days to evaluate the serological effects of chlorfenvinphos reported significant
increases of hemolysin and hemagglutinin serum titers as compared to controls. Hemagglutinin and
hemagglutinin IgG titers were increased by l6 and 18%, respectively, while hemolysin and hemolysin

IgG titers were elevated by 66 and 102%, respectively (Roszkowski 1978).

Cardiovascular Effects. Evidence from animal studies indicates that chlorfenvinphos is not
directly toxic to the cardiovascular system but may modulate the function of the cardiovascular system
via its effect on the central nervous system. In an intermediate-duration study, necropsy examination

of rabbits administered 10 mg/kg of chlorfenvinphos orally for 90 days showed no signs of poisoning

"’DRAFT FOR PUBLIC COMMENT'"

CHLORFENVlNPHOS 32

2. HEALTH EFFECTS

or gross lesions in the heart (Roszkowski 1978). Relative heart weight ratios of weanling albino
(Wistar) rats administered daily chlorfenvinphos doses of 0, 0.27, 0.9, 2.7, 9, or 90 mg/kg/day (males):
0, 0.3, l, 3, 10, or 100 mg/kg/day (females) in the diet for 12 weeks were not significantly altered at
any of the doses tested. Similarly, no effects on relative heart weight ratios were reported for this
strain of rats given chlorfenvinphos at doses of 0, 0.7, 2.1, 7, or 21 mg/kg/day (males) or 0, 0.8. 2.4,
8, or 24 mg/kg/day (females) in the diet for 104 weeks in another part of the same study (Ambrose et
al. 1970). However, cardiovascular function was not assessed in these studies. No gross or
microscopic histopathology in heart tissues or changes in relative heart weights were evident in
mongrel dogs administered daily chlorfenvinphos doses of 0, 0.01, 0.1, 1, or 10 mg/kg/day (males) or
0, 0.05, 0.5, 5, or 50 mg/kg/day (females) for 12 weeks (Ambrose et al. 1970). However.
cardiovascular function was not assessed in this study. Similarly, no effects on heart—to-body weight
(bw) ratios were reported for Beagle dogs given chlorfenvinphos at doses of 0, 0.7, 2.1, 7, or

21 mg/kg/day (males) or 0, 0.8, 2.4, 8, or 24 mg/kg/day (females) in the diet for 104 weeks in another

part of the same study (Ambrose et al. 1970)

Other evidence from rat studies indicates that the alteration of brain and liver activities of the aromatic
amino acid transferases by chlorfenvinphos may be due to the inhibitory effect of the substance on
noradrenaline activity since noradrenaline has been shown to affect amino acid transferase (L—tyrosine
aminotransferase) activity in another study (Puzynska 1984). It has also been suggested that the
cholinergic action of organophosphates like chlorfenvinphos may interfere with the pathways
controlling the secretory activity of the anterior pituitary lobe and the adrenal cortex whose hormones
influence the activities of many enzymes, including aromatic amino acid transferases (Puzynska 1984).
Interference with the secretory activity of the adrenal cortex may lead to a disruption in the normal
activities of one or more components of the renal blood pressure regulatory systems (Klaassen et al.

1986).

Gastrointestinal Effects. The gastrointestinal absorption of glucose was increased by 30% over
control values, while Na+ absorption was decreased by 32% below control values in adult female
albino (Wistar) rats orally administered Birlane® (chlorfenvinphos) at a dose of 0 or 2.4 mg/kg/day in
the diet for 10 days. Gastrointestinal absorption of Ca2+ and body weight increases were unaffected by
chlorfenvinphos exposure. Similarly, gastrointestinal absorption of glucose was increased by 12% over
control values while Na‘ absorption was decreased by 23% below control values following orally

administered Birlane"O (chlorfenvinphos) at a dose of 0 or 0.8 mg/kg/day in the diet to this strain of

"'DRAFT FOR PUBLIC COMMENT'"

 

 

CHLORFENVINPHOS 33

2. HEALTH EFFECTS

rats for 30 days. Gastrointestinal absorption of Ca2+ was, likewise, unaffected by chlorfenvinphos
exposure in this intermediate exposure to oral chlorfenvinphos. The changes in glucose and Na+
absorption were not considered statistically significant (P>0.05) by the investigators (Barna and Simon
I973). The LOAEL of 2.4 mg/kg/day from the 10-day dosing protocol of this study, based on adverse
neurological effects in rats, was used to derive an acute oral MRL of 0.002 mg/kg/day for
chlorfenvinphos. In another intermediate—duration study. necropsy examination of rabbits administered
l0 mg/kg of chlorfenvinphos orally for 90 days showed no signs of poisoning or gross lesions in the
gastrointestinal tract (Roszkowski 1978). No gross or microscopic histopathology were evident in the
stomach, and small and large intestine of weanling albino (Wistar) rats of both sexes chronically

(104 weeks) given daily dietary chlorfenvinphos doses of 0, 0.7, 2.], 7, or 2] mg/kg/day (males) or 0,
0.8, 2.4, 8, or 24 mg/kg/day (females) (Ambrose et al. I970).

Hepatic Effects. The limited information on the hepatic effects of chlorfenvinphos indicates that
the substance is not significantly hepatotoxic by the oral route in acute- or intermediate-duration
exposure. No changes in liver weight (relative to body weight) were reported in Fischer 344 rats
given a single oral chlorfenvinphos dose of 15 mg/kg. A NOAEL 15 mg/kg for hepatic effects was
determined in this study (Ikeda et al. l99l). Mature Wistar rats of both sexes kept on diets containing
4.5% of casein (low-protein diet), 26% of casein (optimal-protein diet), or standard (Murigran) diet
and 30 mg/kg/day of chlorfenvinphos for 30 days to evaluate the effects of oral chlorfenvinphos
exposure on serum activity of sorbitol dehydrogenase (SDH), and on brain and liver activities of the
aromatic amino acids transferases L—phenylalanine aminotransferase (Phen AT), L-tyrosine amino-
transferase (Tyr AT), and L—tryptophan amino—transferase (Try AT), exhibited disturbances in the
activities of these enzymes. Chlorfenvinphos significantly decreased the activities of Phen AT (males
= 4l%, p<0.01), Tyr AT (males 2 30, p<0.01), and Try AT (males = 20%, females : 42%, p<0.0l) in
the brain of the rats. Concomitantly, chlorfenvinphos significantly increased the activities of Phen AT
(males = 37%, females = 54%, p<0.0l ). Tyr AT (males = 75, female = 150%, p<0.001)), and Try AT
(males 2 109%. females = 62%, p<0.00l) in the liver of the rats, and developed a rise in the activity
of sorbitol dehydrogenase (SDH) in serum (45% protein diet, males = NS, females 2 94%; standard
diet, males = 51%, females = l05%). This change was more pronounced in female rats fed standard

Murigran diet. However, no changes in protein levels were reported in the study (Puzynska 1984).

In animal studies, necropsy examination of rabbits administered 10 mg/kg of chlorfenvinphos orally

for 90 days showed no signs of poisoning or gross lesions in the liver (Roszkowski 1978). No gross

“"DRAFT FOR PUBLIC COMMENT‘"

CHLORFENVINF’HOS

 

2. HEALTH EFFECTS

or microscopic histopathology in liver tissues was evident in weanling albino (Wistar) rats
administered daily chlorfenvinphos doses of 0, 0.27, 0.9, 2.7, 9, or 90 mg/kg/day (males): 0, 0.3, 1, 3,
10, or 100 mg/kg/day (females) in the diet for 12 weeks. However, relative liver weights were
significantly and irreversibly decreased at the 2.7 mg/kg/day (males) or 3 mg/kg/day (females) dose
levels. In a chronic study (104 weeks) in which both sexes for this strain of rats were given daily
dietary chlorfenvinphos doses of 0, 0.7, 2.1, 7, or 21 mg/kg/day (males) or 0, 0.8, 2.4, 8. or

24 mg/kg/day (females), increased relative liver weights were observed in males at the 7 mg/kg/day
dose level. No gross or microscopic histopathology in the liver tissues examined or changes in
relative liver weights were reported at any dose level (Ambrose et al. 1970). Hepatic function was not

assessed in this study.

No gross or microscopic liver histopathology or changes in relative liver weights were evident in
mongrel dogs administered daily chlorfenvinphos doses of 0, 0.01, 0.1, l, or 10 mg/kg/day (males) or
0, 0.05, 0.5, 5, or 50 mg/kg/day (females) for 12 weeks (Ambrose et al. 1970). Similarly, no gross or
microscopic liver histopathology or significant changes in relative kidney weights were evident in
Beagle dogs (2 per sex) fed daily dietary chlorfenvinphos doses of 0, 0.3, 2, or 10 mg/kg/day (males),
or 0, 1.5, 10, or 50 mg/kg/day (females) for 104 weeks. No adverse effects on liver function as
indicated by alterations in serum BSP, SGOT, and SAP or in BUN levels were reported for the test

animals (Ambrose et a1. 1970).

Renal Effects. The relative kidney weight ratios of weanling albino (Wistar) rats administered
daily chlorfenvinphos doses of 0, 0.27, 0.9, 2.7, 9, or 90 mg/kg/day (males): 0, 0.3, l, 3, 10, or

100 mg/kg/day (females) in the diet for 12 weeks were significantly and irreversibly decreased at the
2.7 mg/kg/day (males) or 3 mg/kg/day (females) dose levels (Ambrose et al. 1970). However, no
quantitative data on the reduction of relative kidney weight were provided in the study. In a chronic
study (104 weeks) in which both sexes of this strain of rats were given daily dietary chlorfenvinphos
doses of 0, 0.7, 2.1, 7, or 21 mg/kg/day (males) or 0, 0.8. 2.4, 8, or 24 mg/kg/day (females), no gross
or microscopic histopathology in the kidney and urinary bladder tissues examined or changes in
relative kidney weights were evident (Ambrose et al. 1970). Renal function was not assessed in these

studies.

No gross or microscopic histopathology in kidney tissues or changes in relative kidney weights were

evident in mongrel dogs administered daily chlorfenvinphos doses of 0, 0.01, 0.1, l, or 10 mg/kg/day

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CHLORFENVINPHOS 35

2. HEALTH EFFECTS

(males) or 0, 0.05, 0.5, 5, or 50 mg/kg/day (females) for 12 weeks (Ambrose et al. 1970). Similarly,
no gross or microscopic renal histopathology or significant changes in relative kidney weights were
evident in Beagle dogs (2 per sex) fed daily dietary chlorfenvinphos doses of 0, 0.3, 2, or

10 mg/kg/day (males), or 0, 1.5, 10, or 50 mg/kg/day (females) for 104 weeks (Ambrose et al. 1970).

However, renal function was not assessed in these studies.

Endocrine Effects. A significant increase (>300%) of plasma corticosterone was observed at

1 and 3 hours and plasma aldosterone from 1 to 6 hours after treatment of male Wistar rats with a
single chlorfenvinphos dose of 6.15 mg/kg (50% LDSO) by stomach tube. Maximal increase in plasma
corticosteroid levels occurred within 1 hour, while the brain cholinesterase activity was only slightly
inhibited at that time. The authors surmised that changes in plasma corticosteroids are not related to
the decrease of cholinesterase activity in the brain (Osicka—Koprowska et al. 1984). The toxicological

significance of these findings is uncertain.

Metabolic Effects. No significant effect on food consumption was observed in weanling albino
(Wistar) rats administered daily chlorfenvinphos doses of 0, 0.27, 0.9, 2.7, 9, or 90 mg/kg/day (males):
0, 0.3, 1, 3, 10, or 100 mg/kg/day (females) in the diet for 12 weeks (Ambrose et a1. 1970).

Similarly, in a chronic study (104 weeks) in which weanling albino (Wistar) rats of both sexes were
given daily dietary chlorfenvinphos doses of 0, 0.7, 2.1, 7, or 21 mg/kg/day (males) or 0, 0.8, 2.4, 8,
or 24 mg/kg/day (females), no consistent difference in food consumption was evident at all dose levels
tested, as compared to undosed controls (Ambrose et al. 1970). In dog studies, no significant effect on
food consumption was observed in mongrel dogs given dietary chlorfenvinphos doses of 0, 0.01, 0.1,
1, or 10 mg/kg/day (males) or 0, 0.05, 0.5, 5, or 50 mg/kg/day (females) for 12 weeks (Ambrose et a1.
1970). Similarly, no significant changes in food consumption were evident at all dose levels tested in
a chronic study (104 weeks) in which Beagle dogs (2 per sex) were given daily dietary
chlorfenvinphos doses of 0, 0.3, 2, or 10 mg/kg/day (males), or 0, 1.5, 10, or 50 mg/kg/day (females)
(Ambrose et al. 1970).

Body Weight Effects. A significant but slightly reversible depression of growth was observed in
weanling albino (Wistar) rats (10 per sex) administered daily chlorfenvinphos doses of 0, 0.27, 0.9,
2.7, 9, or 90 mg/kg/day (males): 0, 0.3, 1, 3, 10, or 100 mg/kg/day (females) in diet for 12 weeks at
the 9 mg/kg/day (males) or 10 mg/kg/day (females) (Ambrose et al. 1970). In an accompanying

chronic study (104 weeks) in which both sexes of this strain of rats were given daily dietary

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chlorfenvinphos doses of 0, 0.7, 2.1, 7, or 21 mg/kg/day (males) or 0, 0.8, 2.4, 8, or 24 mg/kg/day
(females), no consistent difference in body weight gains in males was evident at all dose levels tested,
as compared to undosed controls. However, chlorfenvinphos significantly decreased body weight gain
of females at the 8 and 24 mg/kg/day dose groups from the 26th week until near the end of the study,
although the decreased body weight gain became statistically insignificant at the end of the study.
(Ambrose et a1. 1970). In another rat study, body weight increases in adult female albino (Wistar) rats
were unaffected following orally administered Birlanew (chlorfenvinphos) at a dose of 0 or

2.4 mg/kg/day in the diet for 10 days or 0 or 0.8 mg/kg/day in the diet for 30 days (Barna and Simon
1973).

Likewise, no significant effect on body weight was observed in mongrel dogs following dietary
chlorfenvinphos doses of 0, 0.01, 0.1, l, or 10 mg/kg/day (males), or 0, 0.05, 0.5, 5, or 50 mg/kg/day
(females) for 12 weeks (Ambrose et a1. 1970). In a chronic study (104 weeks) in which Beagle dogs
(2 per sex) were given daily dietary chlorfenvinphos doses of 0, 0.3, 2, or 10 mg/kg/day (males), or 0,
1.5, 10, or 50 mg/kg/day (females), no significant changes in body weight were evident at all dose

levels tested, as compared to undosed controls (Ambrose et a1. 1970).

2.2.2.3 Immunological and Lymphoreticular Effects

No studies were located regarding the immunological and lymphoreticular effects in humans following

acute—, intermediate—, or chronic-duration oral exposure to chlorfenvinphos.

The limited information on the immunological and lymphoreticular effects of chlorfenvinphos indicates
that the substance is moderately immunotropic to the rodent immune system in oral exposures. The

gastrointestinal absorption of glucose was increased by 30% over control values in adult female albino
(Wistar) rats orally administered Birlane® (chlorfenvinphos) at a dose of 0 or 2.4 mg/kg/day in the diet

for 10 days. Similarly, gastrointestinal absorption of glucose was increased by 12% over control

values following orally administered Birlane‘") (chlorfenvinphos) at a dose of 0 or 0.8 mg/kg/day in the

diet to this strain of rats for 30 days. The changes in glucose and Na+ absorption were not considered
statistically significant (P>0.05) by the investigators (Barna and Simon 1973). It has been observed in
other studies that an increased metabolic activity of neutrophils and monocytes during phagocytosis is

accompanied by higher consumption of glucose and oxygen. Hydrogen peroxide is then derived from

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CHLORFENVINPHOS 37

2. HEALTH EFFECTS

the pentosc cycle, NAD-, and NADP-oxidase action (Kolanoski 1977). The relationship between

increased gastrointestinal absorption of glucose and increased glucose utilization is not clear.

In an intermediate—duration dietary study with albino (Wistar) rats, there was a significant and
irreversible reduction in relative spleen weight of female rats given 23 mg/kg/day Chlorfenvinphos for
12 weeks. However, no gross or microscopic histopathologies were evident in the spleen and bone
marrow tissues of the rats upon examination (Ambrose et a1. 1970). In dogs, relative spleen weights
were unaffected following dietary doses of 10 mg/kg/day (males) or 50 mg/kg/day (females) to
mongrel dogs (2 per sex) for 12 weeks. In addition, no gross or microscopic histopathology was
evident in the spleen and bone marrow tissues of the dogs upon examination (Ambrose et al. 1970).

No quantitative data on the reduction of relative spleen weights were provided in these studies.

A study was undertaken to evaluate selected serological and cytoimmunological reactions in rabbits
subjected to a long-term intoxication with subtoxic oral doses (10 mg/kg in a soya oil solution with a
small amount of food) of Chlorfenvinphos for 90 days (shortened chronic poisoning). Both control
group (soya oil) and treatment group rabbits were immunized with sheep red blood cells six days prior
to ending the experiment. Chlorfenvinphos treatment significantly elevated serum hemagglutinin level
(16%) and hemolysin activity (66%, p<0.05) as well as increased the number of nucleated lymphoid
cells producing hemolytic antibody to sheep erythrocytes as compared to controls (treated 906,

p<0.05 and controls 618). Spleen cytomorphology changes, manifested mainly as transformation of
primary follicles into secondary ones with well developed germinal centers, were also observed
(Roszkowski 1978). After 90 days of oral intoxication of C57BL/6 mice and (C57BL/6xDBA/2)Fl
(BDFl/Iiw) hybrid mice (6—8 weeks old) with Chlorfenvinphos (suspended in 1% methylcellulose
solution). a dose-related decrease in number of hemolysin-producing cells was observed. Plaque-
l‘orming cells (PFC) were 58% at the 6 mg/kg dose group and 85% at the 3 mg/kg dose level, as
compared to control values. Chlorfenvinphos treatment also caused reduction in E rosettes-forming
cell numbers by 30% at the 6 mg/kg dose level, 25% at the 3 mg/kg dose level, and 45% at the

6 mg/kg dose level. Spleen colonies were stimulated as evidenced by the increase of endogenous
spleen colonies, and exogenous spleen colonies (CFU—S) increased 190% at the 1.5 mg/kg dose level,
137% at the 6 mg/kg dose level, 162% at 1.5 mg/kg dose level, and 70% at the 6 mg/kg dose level,
respectively). When the IgM PFC number was tested 3 weeks later, after the exposure to
chlorfenvinphos in the small dose (1.5 mg/kg), an increase (about 40%) in plaque number was

observed. There was a 50% reduction in thymus weight at the 1.5 mg/kg dose level, as compared to

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CHLORFENVINPHOS 38

2. HEALTH EFFECTS

controls, as well as significant involution of the thymus. IgM levels returned to normal values.
indicating the reversible nature of the immunotropic effect of chlorfenvinphos. Increases in
lnterlukin-l (ll-l) activity and DTH reaction were observed 24 hours after challenge was observed in a
separate in vitro study (Kowalczyk-Bronisz et al. 1992). The LOAEL of 1.5 mg/kg/day, based on
adverse immunolgical/lymphoreticular effects in this study, was used to derive an intermediate oral

MRL of 0.002 mg/kg/day for chlorfenvinphos.

In a chronic—duration (104 weeks) dietary study in which weanling albino (Wistar) rats of both sexes
were given daily dietary chlorfenvinphos doses of 0, 0.7, 2.1, 7, or 21 mg/kg/day (males) or 0, 0.8,
2.4, 8, or 24 mg/kg/day (females), no histopathological changes in the spleen or bone marrow were
evident at all dose levels tested, as compared to undosed controls. In addition, no changes in absolute
or relative spleen weights were reported (Ambrose et al. 1970). Likewise, no histopathological
changes in the spleen or bone marrow were evident in Beagle dogs (2 per sex) given daily dietary
chlorfenvinphos doses of 0, 0.3, 2, or 10 mg/kg/day (males), or 0, 1.5, 10, or 50 mg/kg/day (females)
for 104 weeks. In addition, no changes in absolute or relative spleen weights were reported (Ambrose

et al. 1970).

The highest NOAEL values and all reliable LOAEL values for immunological and lymphoreticular

effects in each species and duration category are presented in Table 2—2 and plotted in Figure 2—2.

2.2.2.4 Neurological Effects

In humans, chlorfenvinphos inhibits cholinesterase activity in the central and peripheral nervous system
when administered by the oral (Cupp et al. 1975; Pach ct al. 1987) or inhalation route in acute—
duration exposures (Kolmodin-Hedman and Eriksson 1987). In animals, chlorfenvinphos inhibits
cholinesterase activity in the central and peripheral nervous system when administered by the oral
(Barna and Simon 1973; Osicka-Koprowska et al. 1984; Takahashi et al. 1991), or dermal route in
acute-duration exposures. In addition, chlorfenvinphos inhibits noradrenaline activity in the central
adrenergic mechanism in animals (Brzezinski 1978; Osumi et al. 1975). Inhibition of cholinesterase
activity results in accumulation of choline at muscarinic and nicotinic receptors leading to peripheral
and central nervous system effects. These effects usually appear within a few minutes to a few hours

after exposure depending on the extent of exposure.

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CHLORFENVINPHOS 39

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No studies were located regarding the neurological effects in humans following acute-, intermediate-.
or chronic—duration oral exposure to chlorfenvinphos. A 16—year-old white male mistakenly took a full
swallow of a mange-mite medication (identified as Dermaton“), containing 25% organophosphate, like
chlorfenvinphos, as an active ingredient) prescribed by a veterinarian for his dog. Approximately

90 minutes later, he was hospitalized with symptoms of abdominal cramps, nausea, vomiting,
generalized weakness, cold dry skin, constricted pupils, fine generalized muscular twitching, and
apprehension. On physical examination, his blood pressure was 152/102, pulse was 96 and irregular.
respiration was 24, and rectal temperature was 94.2 °F. While in the emergency room, gastric lavage
of 4 L was done and 1 mg of atropine given intravenously. On transfer to the intensive care unit
(ICU), respiration had increased in rate and depth; skin was warm and slightly diaphoretic, muscle
twitching increased and he complained of double vision. Emesis persisted. The patient developed
hypothermia which lasted for 2 hours. Four and one-half hours after admission, the patient was
listless, apathetic, but oriented. Blood analysis showed a plasma and erythrocyte cholinesterase level
of 0.3 and 1.1 umol/minute, respectively. Twenty-four hours later, plasma and erythrocyte
cholinesterase levels were 0.8 and 12.7 pmol/minute, respectively. He was given 1 gram of
pralidoxime intravenously over a 15-minute period, repeated in 1 hour. Forty-eight hours after
admission, signs of improvement were evident. The patient was discharged 5 days after admission

without residual effects (Cupp et al. 1975).

The existing information on neurological effects in animals following acute-. intermediate—, and
chronic—duration oral exposures to chlorfenvinphos indicates that the substance causes disruptions in
the central and peripheral nervous system in rats. When chlorfenvinphos was evaluated for acute
lethality in animals, death, which occurred within 12 hours in tested rats, rabbits, and dogs, was
usually preceded by the characteristic signs of cholinergic response—salivation, lacrimation, muscle

fasciculation, and diarrhea, and emesis (Ambrose et al. 1970).

In acute-duration studies, plasma and erythrocyte cholinesterase activities were inhibited by 52% and

(no

30%, respectively, at the only tested Birlane (chlorfenvinphos) dietary dose of 2.4 mg/kg/day
administered to adult female albino (Wistar) rats for 10 days. However, the changes in glucose and
Na+ absorption were not considered statistically significant (P>0.05) by the investigators (Barna and
Simon 1973). The LOAEL of 2.4 mg/kg/day from the 10-day dosing protocol of this study, based on
adverse neurological effects in rats, was used to derive an acute oral MRL of 0.002 mg/kg/day for

chlorfenvinphos. Brain, erythrocyte, and plasma cholinesterase activities were reduced by about 90%

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2. HEALTH EFFECTS

or more, or by 50%, respectively, following acute oral treatment of male Sprague-Dawley rats with
chlorfenvinphos. Rats administered chlorfenvinphos orally attained maximum inhibition of
cholinesterase activity in less than two hours. The rats also exhibited cholinergic signs that included
fasciculations, twitches, convulsions, chromodacryorrhea, exophthalmos, gasping, lacrimation,
prostration, salivation, Straub tail reflex, and urination. The clinical signs lasted for eight hours. No
effects were observed at the 1.25 mg/kg dose level. Inhibitory activity of chlorfenvinphos on brain
cholinesterase activity was confirmed in vitro; the concentration producing 50% inhibition (ICm) of the

activity was 68 ng/mL of chlorfenvinphos (Takahashi et al. 1994). Cholinesterase activity in the brain

of male Wistar rats was unaffected 3 hours after oral administration of l mg/kg of chlorfenvinphos.

However, at a doses of 2 and 4 mg/kg, oral chlorfenvinphos produced a marked decrease in the brain
cholinesterase activity to 38% and 18% of the control (p<0.00l ), respectively. The maximum
inhibition occurred three hours after the administration, after which the cholinesterase activity elevated
gradually. Activity in the brain decreased steadily with time and, at 72 hours, still remained 67% that
of the control. Erythrocyte cholinesterase activity also decreased after 4 mg/kg of chlorfenvinphos: the
lowest level (20%, p<0.001) was attained 3 hours after treatment (Osumi et al. l975). This study was
not used to calculate an acute oral MRL because it was deemed less appropriate because of the gavage
(oral) route of administration; an oral feeding study is preferred for this purpose by the ATSDR MRL

Workgroup.

Acute oral chlorfenvinphos exposure was also associated with reversible sleep disturbance in male
Wistar rats. Chlorfenvinphos doses up to 1 mg/kg did not affect the awake-sleep cycle in the rats. but
spontaneous electroencephalogram (EEG) showed a prominent arousal pattern and appearance of slow
wave sleep, and parasleep was markedly depressed in doses over 2 mg/kg. The duration of arousal
pattern was proportional to the doses, but the awake-sleep cycle returned to control values on the
second day; a rebound increase in parasleep occurring on the third day at a doses over 4 mg/kg.
Atropine at a dose of 2 mg/kg (administered to l rat 2 hours after chlorfenvinphos administration) was
antidotal to the chlorfenvinphos-induced disturbance of EEG arousal pattern, depressing the EEG
arousal pattern without affecting cholinesterase activity in the brain. As a positive control.
physostigmine, a reversible cholinesterase inhibitor, in doses of 0.05 and 0.l mg/kg. produced an
increase in wakefulness during the first hour. Thereafter, the arousal pattern was reduced, and slow
wave sleep and parasleep patterns increased, as compared with the control, 3—5 hours after the
administration of chlorfenvinphos. According to these investigators, appearance of EEG- arousal

pattern after treatment with chlorfenvinphos may be derived from central cholinergic activation. A

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CHLORFENVINPHOS 41

2. HEALTH EFFECTS

LOAEL of 2 mg/kg with a NOAEL of 1 mg/kg for 38% decrease in brain cholinesterase activity and
reversible sleep disturbances was determined in this study (Osumi et al. 1975). This study was not
used to calculate an acute oral MRL because it was deemed less appropriate due to the gavage (oral)
route of administration. An oral feeding study is preferred for this purpose by the ATSDR MRL
Workgroup.

In intermediate—duration studies, plasma and erythrocyte cholinesterase activities were inhibited by
36% and 3%, respectively, at a chlorfenvinphos dose of 0.8 mg/kg/day following dietary

(to

administration of 0 or 08 mg/kg/day Birlane (chlorfenvinphos) to adult female albino (Wistar) rats
for 30 days (Barna and Simon 1973). However, the changes in erythrocyte cholinesterase activity
were not considered significant and were, therefore, not used to derive an intermediate MRL.
Similarly, the changes in plasma cholinesterase were not used to derive an intermediate MRL because,
while plasma cholinesterase (pseudocholinesterase) inhibition may have some physiological
significance, alteration in the levels of this enzyme is generally regarded more as a biomarker of
exposure to organophosphate compounds than as an adverse neurological effect. In other intermediate—
duration rat studies, mature rats of both sexes kept on diets containing 4.5% of casein (low—protein
diet), 26% of casein (optimal—protein diet), or standard (Murigran) diet for 30 days exhibited altered
cholinesterase activities following acute poisoning with chlorfenvinphos. These alterations consisted of
significant inhibition in cholinesterase activity in the serum (4.5% protein diet: males = 97%, females
= 96%; standard diet: males 2 87%, females = 93%) and brain (4.5% protein diet: males 2 83%,
females = 87%; standard diet: males 2 58%, females = 39%), with more pronounced effects in the
brain of female rats fed low-protein diets (87%). The activity of this enzyme returned to normal
values 14 days after dosing (Puzynska I984). Blood and plasma cholinesterase activity was depressed
at 29 mg/kg/day (males) or 2l0 mg/kg/day (females) with a NOAEL of 2.7 mg/kg/day (males) or

3 mg/kg/day (females) following dietary administration of chlorfenvinphos doses of 0, 0.27, 0.9, 2.7,
9, or 90 mg/kg/day (males), or 0, 0.3, l, 3, [0, or 100 mg/kg/day (females) in the diet to weanling
albino (Wistar) rats for 12 weeks. Essentially, no gross or microscopic histopathology was evident in
the brain tissues examined (Ambrose et al. 1970). Similarly, plasma cholinesterase activity was
consistently depressed, while erythrocyte cholinesterase activity was sporadically depressed in all dose
groups in mongrel dogs (2 per sex) administered daily chlorfenvinphos doses of 0, 0.0], 0.1, l, or

10 mg/kg/day (males) or 0, 0.05, 0.5, 5, or 50 mg/kg/day (females) in the diet for 12 weeks. No gross
or microscopic histopathology was evident in the brain and spinal cord tissues examined (Ambrose et

al. 1970). Due to incomplete reporting of this study, it was not clear if there was a NOAEL for the

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CHLORFENVINPHOS 42

2. HEALTH EFFECTS

inhibition of erythrocyte cholinesterase activity. Also, no quantitative data on the depression of

plasma or erythrocyte cholinesterase activity were provided in these studies.

In another intermediate—duration study in which Sprague-Dawley rats were fed diets containing

[0.5 mg/kg/day for 4—9 months, whole blood cholinesterase activity was markedly inhibited (0.9 and
0.6; control, 2.4 and 1.9, respectively; p<0.001) at 3 and 6 months of exposure to chlorfenvinphos. At
3 and 6 months of exposure to chlorfenvinphos, plasma cholinesterase activity was also markedly
inhibited (0.4 and 0.4; control, 1.9 and 1.6, respectively; p<0.001). At 3—6 months, all 36 Sprague-
Dawley rats in this study had repetitive and increasingly diminishing muscle fiber depolarizations
when given double stimuli. The greatest reduction in peak depolarization occurred with an interval of
4 muscle action potential amplitude (ms) and a large but slightly smaller reduction at 7 ms. These
phases probably coincide with refractoriness of some muscle fibers due either to repetitive activity (at
4 ms) or reflex activity (at 7 ms). Double and repetitive stimulation at rates even as low as 0.5 Hz
reduced or abolished the prolonged negative potential and repetitive activity. These abnormalities
became more marked with time, even on constant dosing. Spike potentials were recorded between the
direct response (M) and reflex responses with latency similar to the repetitive activity potential

(Maxwell and LeQuesne 1982).

In chronic—duration studies, chlorfenvinphos significantly inhibited both plasma and erythrocyte
cholinesterase activities in a dose-dependent manner in weanling albino (Wistar) rats (30 rats per sex
per group) fed daily chlorfenvinphos doses of 0, 0.7, 2.], 7, or 21 mg/kg/day (males) or 0, 0.8, 2.4, 8,
or 24 mg/kg/day (females) mg/kg/day in the diet for 104 weeks. Plasma and erythrocyte
cholinesterase activities were inhibited by 48% in females and 45% in males in the first week of
treatment and by 20% in females and 33% in males in the fourth week of treatment, respectively, at
the lowest dose tested (0.7 mg/kg/day for males and 0.8 mg/kg/day for females). Essentially, no gross
or microscopic histopathology was evident in the brain tissue examined (Ambrose et al. l970). The
LOAEL of 0.7 mg/kg/day, based on adverse neurological effects in rats in this study, was used to

derive a chronic oral MRL of 0.0007 mg/kg/day for chlorfenvinphos.

Similarly, chlorfenvinphos significantly inhibited both plasma and erythrocyte cholinesterase activities
in Beagle dogs (2 per sex) fed daily chlorfenvinphos doses of 0, 0.3, 2, or 10 mg/kg/day (males), or 0,
LS, 10, or 50 mg/kg/day (females) in the diet (moist) for 104 weeks. Plasma cholinesterase activities

were significantly inhibited at all dietary levels through week 39 of the study; 49% inhibition at the

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CHLORFENVINPHOS 43

2. HEALTH EFFECTS

0.3 mg/kg/day (males) and 1.5 mg/kg/day (females) dose levels. Erythrocyte cholinesterase activity
was significantly and consistently inhibited (36%) during the first 12 weeks only in the 10 mg/kg/day
(males) and 50 mg/kg/day (females) dose levels. No gross or microscopic histopathology was evident

in the brain and spinal cord tissues examined.

Besides its cholinergic action. chlorfenvinplms may also act on the central noradrenergie mechanism in
rats by accelerating the noradrenaline tumover in the brain in viva. Three hours after oral
administration of 4 mg/kg of chlorfenvinphos. the brain noradrenaline level of male Wistar rats was
reversibly altered by l6% (Osumi et al. 1975). In another study with male Wistar rats, 13 mg/kg of
oral chlorfenvinphos decreased cerebral noradrenaline level by 20% as compared to the control rats.
Other rats that received oral chlorfenvinphos 30 minutes after pretreatment with disulfiram injection
(400 mg/kg intrapentoneally) as positive controls exhibited a 50% decrease of cerebral noradrenaline;
the level was observed in time intervals of 1—3 hours. peaking at 89% decrease after 6 hours. Based
on these observations, it was suggested that chlorfenvinphos accelerates the rate of noradrenaline
disappearance from the rat brain in viva. Thus. besides being a cholinergic agent. chlorfenvinphos
may also act on the central noradrenergie mechanism. disturbing the dynamic equilibrium between the
rate of t‘onnation and utilization of noradrenaline. It was postulated that this action on the central
noradrenergie mechanism by chlorfenvinphos may be responsible for the changes in blood pressure

observed in other studies after chlorfenvinphos intoxication (Brzezinski 1978).

lntraperitoneal administration of daily doses of 0, 100, 150, 200, or 300 mg/kg/day chlorfenvinphos to
White Leghom hens for 10 days or until death resulted in cholinergic signs. Typical cholinergic signs,
including inability to stand. salivation. and relching. and some deaths. were observed immediately after
the administration of all dose levels of chlorfenvinphos, with or without atropine coadministration. No
signs of delayed neurotoxicity or evidence of neurological lesions suggestive of demyelination or

neural damage were observed in the brain and sciatic nerve tissues examined (Ambrose et al. 1970).

The highest NOAEL values and all reliable LOAEL values for neurological effects in each species and

duration category are presented in Table 2-2 and plotted in Figure 2-2.

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CHLORFENVINPHOS 44

2. HEALTH EFFECTS

2.2.2.5 Reproductive Effects

No studies were located regarding the reproductive effects in humans following acute-, intermediate-,

or chronic-duration oral exposure to chlorfenvinphos.

No studies were located regarding the reproductive effects in animals following acute-duration oral
exposure to chlorfenvinphos. The limited information on the reproductive toxicity of chlorfenvinphos
indicates that chlorfenvinphos may interfere with the reproductive competence of rats. In a
3-generation reproductive study, chlorfenvinphos induced adverse reproductive effects (decreased
fertility and maternal body weight gain) at a LOAEL of 2.7 mg/kg/day in albino (Wistar) rats (15 rats
per sex per group) given chlorfenvinphos at at doses of 0. 2.7, 9, or 27 mg/kg/day (males) or 0, 3, 10,
or 30 mg/kg/day (females) in the diet for l 1 weeks. The chlorfenvinphos-dosed rats were mated for
20 days to produce an F/la generation and remated 10 days after weaning of the F/la pups to produce
an F/lb generation. Each generation was fed the chlorfenvinphos doses for 11 weeks before mating.
The study reported decreased maternal body weights of 3, 5, and l 1%, respectively, for F/0 parental
generation animals fed 0, 3, or 10 mg/kg/day; 9, 2, and 19%, respectively. for F/I parental generation
animals fed 0, 3, or 10 mg/kg/day; and 14 and 10%, respectively, for F/2 parental generation animals
fed 0 or 3 mg/kg/day chlorfenvinphos. The changes in maternal body weight gain were not considered
significant. However, fertility (pregnancy/mating x 100) was decreased by 49% in the F/lb parents at
the 10 mg/kg/day dose level. In the F/2b parents, fertility was decreased by 50% at the 3 mg/kg/day
dose level and by 84% in the 10 mg/kg/day dose level. No gross or microscopic histopathology was
evident in male and female gonads examined. No adverse effects on gestation by chlorfenvinphos

exposure was noted at all exposure levels (Ambrose et al. 1970).

In intermediate—duration studies, chlorfenvinphos had no effect on relative testes weight at all the doses
tested in weanling albino (Wistar) rats (10 per sex) administered daily chlorfenvinphos doses of
90 mg/kg/day (males) or 100 mg/kg/day (females) in diet for 12 weeks. Essentially, no gross or

microscopic histopathology was evident in all the gonads (Ambrose et al. 1970).

In chronic—duration studies, no gross or microscopic gonad histopathology in either sex or changes in
the relative weights of the testes in males were reported in albino (Wistar) rats (30 rats per sex per
group) administered daily chlorfenvinphos doses of 21 mg/kg/day (males) or 24 mg/kg/day (females)

in the diet for 104 weeks (Ambrose et al. 1970). Similarly, no gross or microscopic gonad

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2 ‘2
CHLORFENVINPHOS 45

2. HEALTH EFFECTS

histopathology in either sex or changes in the relative weights of the testes were reported in male
mongrel dogs (2 per sex) administered daily chlorfenvinphos doses of 0, 0.01, 0.1, l, or 10 mg/kg/day
(males) or 0, 0.05, 0.5, 5, or 50 mg/kg/day (females) in the diet for 12 weeks (Ambrose et al. 1970).

Reproductive function was not evaluated in these studies.

The highest NOAEL values and all reliable LOAEL values for reproductive effects in each species and

duration category are presented in Table 2-2 and plotted in Figure 2-2.

2.2.2.6 Developmental Effects

No studies were located regarding the developmental effects in humans following acute-, intermediate-,

or cln‘onic-duration oral exposure to chlorfenvinphos.

The limited information on the developmental toxicity of chlorfenvinphos indicates that acute exposure
to chlorfenvinphos may interfere with the normal development of rats. Acute—duration oral exposure
to chlorfenvinphos inhibited cellular respiration in developing juvenile White rats. In this study, rats
of both sexes aged 4, 8, l6, 32, 42, and 56 days, originating from an inbred culture (presumed to be
Wistar) and randomly paired, were dosed with chlorfenvinphos (Birlane®, 94%) at concentrations of 0,
29, 58, and 300 mg/kg. Inhibition of respiratory state 3 (in the presence of adenosine triphosphate,
ADP) was observed at concentrations of 29, 58, and 300 mg/kg, of chlorfenvinphos in a concentration
dependent manner. The degree of inhibition by chlorfenvinphos (58 mg/kg) increased with the age of
the animals. amounting to 25% (aged 4 days) and 55% (aged 32 days) in the presence of glutamate
with malate as substrate. Chlorfenvinphos in the highest concentration (300 mg/kg) completely
arrested respiration in state 3 of the rat brain mitochondrial fractions in animals aged 16, 32, and

56 days. whereas, in fractions from 4-day—old animals, the degree of stimulation of oxygen uptake by
ADP doubled. Similar results were obtained with chlorfenvinphos when succinate was used as
respiratory substrate (Skonieczna et al. l98l). A statistical system for hazard identification was
developed for use in predicting the developmental toxicity of 175 chemicals, including
chlorfenvinphos. The data used in this system included the results of any developmental toxicity
testing in up to 14 animal species as well as reports of mutagenicity or carcinogenicity data. The
compounds were categorized with respect to their human developmental toxicity potential as:

V] .0 testing negative, 0.0 not tested (unknown), 0.5 tested with equivocal results, and 1.0 testing

positive. Chlorfenvinphos scored —l.0 for rat; 0.0 for primate, mouse dog, cat, pig, ferret, sheep, goat,

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CHLORFENVINPHOS 46

2. HEALTH EFFECTS

cow, and opossum; and 1.0 for hamster and rabbit. This method correctly classified the study
compounds 63—91% of the time. The model had a sensitivity of 62—75%. a positive predictive value
of 75—100%, and a negative predictive value of 64—91%, indicating that the statistical model is not

optimal for hazard identification (Jelovsek et al. 1989).

In intermediate— and chronic-duration, and multigeneration exposures, chlorfenvinphos also gave
indications of interference with development. Weanling albino (Wistar) rats (10 per sex) administered
daily dietary chlorfenvinphos doses of 0, 0.27, 0.9, 2.7, 9, or 90 mg/kg/day (males): 0, 0.3, 1, 3, 10, or
100 mg/kg/day (females) in the diet for 12 weeks exhibited a significant but slightly reversible
depression of growth at the 9 mg/kg/day (males) or 10 mg/kg/day (females). No quantitative data on
the depression of growth were provided in the study (Ambrose et al.1970). In a chronic feeding study
(104 weeks) in which weanling albino (Wistar) rats (30 rats per sex per group) were given
chlorfenvinphos in the diet at a doses of 0, 0.7, 2.1, 7, or 21 mg/kg/day (males) or 0, 0.8, 2.4, 8, or
24 mg/kg/day (females) for 104 weeks, chlorfenvinphos significantly decreased body weight gain of
females at the 8 and 24 mg/kg/day dose groups from the 26th week till toward the end of the study.
However, the decreased body weight gain became not statistically significant at the end of the study.
An increased relative liver weight was observed in males at the 7 mg/kg/day dose level, but no other
signs of hepatopathology were reported. No consistent differences in body weight gains in males,
survival of the test animals, food consumption, or mortality were evident at all dose levels tested, as
compared to undosed controls. Essentially, no gross or microscopic histopathology was evident in any
of the tissues (heart, lungs, liver, kidney, urinary bladder, spleen, stomach, small and large intestine,
skeletal muscle, skin, bone marrow, pancreas, thyroid, adrenal, pituitary) examined to indicate
teratogenicity. No changes in organ—to-body weight were observed in the heart and kidney (Ambrose
et al. 1970). In a 3-generation reproductive study, albino (Wistar) rats (15 rats per sex per group)
were given chlorfenvinphos in the diet at a doses of O, 2.7, 9, or 27 mg/kg/day (males) or 0, 3, 10, or
30 mg/kg/day (females) in the diet for l 1 weeks. The chlorfenvinphos—dosed rats were mated for

20 days to produce an F/la generation and remated 10 days after weaning of the F/la pups to produce
an F/lb generation. Each generation was fed the chlorfenvinphos doses for l 1 weeks before mating.
The pup viability index (pups surviving 5 days/pups born alive x 100) decreased by 66% for F/lb
pups at a maternal dose of 10 mg/kg/day. No offspring in the 27 mg/kg/day (males) or 30 mg/kg/day
(females) dose group survived beyond the F1 generation. The lactation index was also decreased by

46% in the F/lb offspring at the 10 mg/kg/day dose level. No gross or microscopic histopathology

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CHLORFENVINPHOS 47

2. HEALTH EFFECTS

was evident in any of the tissues examined. There were no gross signs of teratogenicity (Ambrose et

al. 1970).

The highest NOAEL values and all reliable LOAEL values for developmental effects in each species

and duration category are presented in Table 2-2 and plotted in Figure 2—2.

2.2.2.7 Genotoxic Effects

No studies were located regarding the genotoxic effects in animals after oral exposure to

chlorfenvinphos. Other genotoxicity studies are discussed in Section 2.5.

2.2.2.8 Cancer

No studies were located regarding the cancer effects in humans or animals after oral exposure to

chlorfenvinphos.

However, in a mutagenicity study, the dose-response curve, at a doses of 0, 50, 500, 5,000 ug/plate,
for the mutagenic activity of chlorfenvinphos for the S. rypliimurium strain TAlOO was reduced by the
SQ mix (metabolic activation). At present, no mutagenic pesticide, the activity of which decreases in
the presence of the $9 mix. is carcinogenic except captan (F-28) (Moriya et al. 1983). Additionally, a
theoretical analysis that predicted the mammalian biotransformation products based on the recognition
of the structure of chlorfenvinphos, understanding of Types I and Il metabolism of foreign compounds,
and mechanistic biochemistry also acknowledged that cytochrome P—450 monooxygenase (an inducible
enzyme) is the relevant enzyme which mediates the biotransformation of chlorfenvinphos, The author
of this study postulated that the 2.4—dichlorobenzoyl glycine (2,4-dichlorohippuric acid) was produced
in the rat by this mechanism. It is noteworthy that the production of electrophilic metabolic
intermediates or epoxides in the metabolism of chlorfenvinphos, which could react with nucleophilic
cellular components (DNA, RNA, and proteins) leading to carcinogenesis. was considered unlikely by
this theoretical approach (Akintonwa 1984). A study that used methylbromophenvinphos (a structural
analog to chlorfenvinphos) was conducted to determine the ability of vinyl phosphate esters (like
chlorfenvinphos) to form methylated bases in DNA of calf thymus. The study failed to detect
6-methyl guanine, a known mutagen. In both the reaction with dsDNA and ssDNA, 7-methyl guanine

was the main methylation product. All methyl derivatives of adenine constituted about 40% and 50%

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CHLORFENVINF’HOS 48

2. HEALTH EFFECTS

of all methylation products in the case of dsl)NA and ssDNA, respectively; 3-methylcytosine was the
only methyl derivative of pyrimidine identified (Wiaderkiewicz et al. 1986). From a slightly different
perspective. a theoretical analysis considered probability of the formation of electrophilic metabolite
intermediates or epoxides of chlorfem'inphos and the possible reaction of these metabolites with
nucleophilic cellular components (DNA. RNA. and proteins) leading to genotoxic carcinogenesis. The
analysis concluded that the formation of such metabolites in mammalian metabolism is unlikely

(Akintonwa l985).

In contrast, tetrachlorvinphos (Gardonaw). a structural analog to chlorfenvinphos. was evaluated for
potential to induce chromosomal aberrations and SCHs in vim) in a primary culture of Swiss mice
spleen cells at concentrations of 0.25. 0.50, l.(), or 2.0 ug/mL. Tetrachlorvinphos induced a high
percentage of metaphases with chromosomal aberrations in the mouse spleen cells after four hours of
treatment in a dose—dependent manner, According to the authors. the results of this evaluation indicate
that tetrachlorvinphos. in the tested concentrations. is mutagenic in mouse spleen cell cultures (Amer
and Aly I992). However. in both of these studies, structural analogs of chlorfenvinphos (methyl—
bromophenvinphos, tetrachlorvinphos) were used; therefore. the data are difficult to relate to

chlorfenvinphos without extensive structure—activity relationship analysis.

2.2.3 Dermal Exposure

2.2.3.1 Death

No- studies were located regarding death in humans after acute—, intermediate—, or chronic—duration

dermal exposure to chlorfenvinphos.

The dermal Ll)” values in rabbits for undiluted chlorfenvinphos and emulsifiable concentrate have

been estimated as 400 and l,087 mg/kg, respectively (Ambrose et al. I970).
2.2.3.2 Systemic Effects
No studies were located regarding the respiratory. cardiovascular, gastrointestinal, hematological,

hepatic, musculoskeletal, hepatic. renal, endocrine. dermal, or ocular effects in humans or animals

following acute-. intermediate—. or chronic-duration dermal exposure to chlorfenvinphos.

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CHLORFENVINPHOS 49

2. HEALTH EFFECTS

2.2.3.3 Immunological and Lymphoreticular Effects

No studies were located regarding the immunological and lymphoreticular effects in humans or

animals after acute—. intermediate. or chronic-duration dermal exposure to chlorfenvinphos.

2.2.3.4 Neurological Effects

No studies were located regarding neurological effects in humans after intermediate—, or chronic—
duration dermal exposure to chloi‘fenvinphos. l)ermally~applied chlorl'envinplios formulations
significantly inhibited plasma cholinesterase activity in healthy human volunteers without prior
occupational exposure to the substance. Three different chlorfenvinphos formulations were used in
this study: 80% weight per volume (w/v) emulsifiable concentrate (EC), mainly chlorfenvinphos and
emulsifiers; 24% w/v EC, mainly isometric trimetliyl benzencs with Ill/2% w/v emulsifiers; 25% w/w
wettable powder (WP), mainly colloidal silica, florisil. triphenylphosphate. sodium triphosphates,
empicol LZ and tamal. The formulations were administered separately in single applications to the
forearm skin of 9 adult human males for periods up to 4 hours in doses of 4~l() mg/kg/bw
chlorfenvinphos. The 80% EC and 25% EC formulations had no effect on cholinesterase activity
levels in the volunteers. ()1in plasma and erythrocyte cholinesterase activities of volunteers who
received a single application of the 24% einulsifiable concentrate (5 and l() mg/kg/bw chlorfenvinphos
equivalent to a dermal dose of 5 mg/cml) were inhibited by 5.176% and 9%, respectively (Hunter

1969).

No studies were located regarding neurological effects in animals after intermediate— or chronic—
duration dermal exposure to clilorfenvinphos. Acute—duration dermal exposure of laboratory animals to
Chlorfenvinphos resulted in the depression of plasma cholincsterase Without clinical symptoms. Two
dogs of unspecified sex treated with a daily dose of 0.3% chlorfenvinphos applied topically to the
spinal area from head to tail for 7 days (3 consecutive days, I day skipped, then 4 consecutive days)
suffered 28% depression in plasma Cholinesterase activity by day 8. No clinical signs resulting from

Cholinesterase depression were observed in any of the dogs (Vestweber and Kruckenberg I972).
Although all doses of chlorfenvinphos elicited cholinergic responses (leg weakness. salivation, and

retching) from hens given 100, 150, 200. or 300 mg/kg by intraperitoneal injection. the hens showed

no signs of delayed neurotoxicity after 20 days of observation (Ambrose et al. l‘)70).

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CHLORFENVINPHOS 50

2. HEALTH EFFECTS

2.2.3.5 Reproductive Effects

No studies were located regarding the reproductive effects in humans or animals after acute-,

intermediate-. or chronic-duration dermal exposure to chlorfenvinphos.

2.2.3.6 Developmental Effects

No studies were located regarding the developmental effects in humans or animals after acute-,
intermediate—. or chronic-duration dermal exposure to chlorfenvinphos. However, a statistical system
for hazard identification concluded that chlorfenvinphos is likely to interfere with development in
rabbits and hamsters but not in rats. This system did not evaluate the adverse reproductive effects
potential of chlorfenvinphos in primates, mice, and dogs. This method correctly classified the study
compounds 63~9l ”/0 of the time. The models had a sensitivity of 62—75%, a positive predictive value
of 75—10070. However, the model had a negative predictive value of 64—91%, indicating the model is

not optimal for hazard identification (Jelovsek et al. 1989).

2.2.3.7 Genotoxic Effects

No studies were located regarding the genotoxic effects of chlorfenvinphos in humans or animals
following dermal exposure. Other genotoxicity studies for chlorfenvinphos are described in

Section 2.5.

2.2.3.8 Cancer

No studies were located regarding the cancer effects in humans or animals after dermal exposure to

chlorfenvinphos.

However. the dose—response curve at doses of 0, 50, 500, and 5,000 pg/plate for the mutagenic activity
of chlorfenvinphos for the S. ijwhimurium strain TAl00 was reduced by the S9 mix (metabolic
activation). At present, no mutagenic pesticide, the activity of which decreases in the presence of the
8‘) mix. was carcinogenic except captan (F—28) (Moriya et al. 1983). Additionally, a theoretical
analysis that predicted the mammalian biotransformation products based on the recognition of the

structure of chlorfenvinphos, understanding of Types I and II metabolism of foreign compounds, and

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CHLORFENVINPHOS 51

2. HEALTH EFFECTS

mechanistic biochemistry also acknowledged that cytochrome P-450 monooxygenase (an inducible
enzyme) is the relevant enzyme which mediates the biotransformation of chlorfenvinphos. The author
of this study postulated that the 2,4-dichlorobenzoyl glycine (2,4-dichlorohippuric acid) was produced
in the rat by this mechanism. It is noteworthy that the production of electrophilic metabolic
intermediates or epoxides in the metabolism of chlorfenvinphos, which could react with nucleophilic
cellular components (DNA, RNA, and proteins) leading to carcinogenesis, was considered unlikely by
this theoretical approach (Akintonwa 1984). A study that used methylbromophenvinphos (a structural
analog to chlorfenvinphos) to determine the ability of vinyl phosphate esters like chlorfenvinphos to
form methylated bases in the DNA of calf thymus failed to detect 6-methyl guanine, a known
mutagen. In the reactions with both dsDNA and ssDNA, 7-methyl guanine was the main methylation
product. All methyl derivatives of adenine constituted about 40% and 50% of all methylation products
in the case of dsDNA and ssDNA, respectively; 3—methylcytosine was the only methyl derivative of
pyrimidine identified (Wiaderkiewicz et al. 1986). From a slightly different perspective, a theoretical
analysis considered probability of the formation of electrophilic metabolite intermediates or epoxides
of chlorfenvinphos and the possible reaction of these metabolites with nucleophilic cellular
components (DNA, RNA, and proteins) leading to genotoxic carcinogenesis. The analysis concluded

that the formation of such metabolites in mammalian metabolism is unlikely (Akintonwa 1985).

In contrast, tetrachlorvinphos (Gardona®), a structural analog to chlorfenvinphos, was evaluated for its
potential to induce Chromosomal aberrations and SCEs in vitro in a primary culture of Swiss mice
spleen cells at concentrations of 0, 0.25, 0.50, 1.0, or 2.0 pg/mL. Tetrachlorvinphos induced a high
percentage of metaphases with chromosomal aberrations in the mouse spleen cells after four hours of
treatment in a dose-dependent manner. For tetrachlorvinphos doses of 0, 0.25, 0.50, 1.0, and

2.0 ug/m, the corresponding number of metaphases were 150, 590, 590, 600, and 600. According to
the authors, the results of this evaluation indicate that tetrachlorvinphos (in the tested concentrations) is
mutagenic in mouse spleen cell cultures (Amer and Aly 1992). However, in both of these studies,
structural analogs of chlorfenvinphos (methylbromophenvinphos and tetrachlorvinphos, respectively)
were used; therefore, the data are difficult to relate to chlorfenvinphos without extensive structure-

activity relationship analysis.

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2.3 TOXICO KIN ETICS
2.3.1 Absorption

2.3.1.1 Inhalation Exposure

No studies were located regarding the absorption of chlorfenvinphos after inhalation exposure in

humans or animals.
2.3.1.2 Oral Exposure

A 29—year—old male was admitted with severe respiratory distress and bronchial tree hypersecretion.
The patient had ingested about 50 mL of the preparation Enolofosm, which contains 50%
chlorfenvinphos, in a suicide attempt. The concentration of chlorfenvinphos in the serum was

300 ng/mL upon admission. This was the only human chlorfenvinphos poisoning case in which
hemoperfusion intervention was employed. The mean clearance of chlorfenvinphos during
hemoperfusion was low (68 mL/min) and only 0.42 mg of the poison was recovered. The poison level
in the serum was low (15 ng/mL) immediately before the procedure, and gradually rose in successive
blood samples indicating that chlorfenvinphos passes fairly easily from the tissues into blood. Perhaps
this is related to secondary resorption from the digestive tract. The highest value of clearance was
observed in the fourth hour of hemoperfusion, in contrast to the observations during hemoperfusion
performed for other drug poisoning, when the value of the clearance was lowest in the last hour. The
serum chlorfenvinphos levels decreased temporarily within a few hours even prior to the beginning of
hemoperfusion, either due to rapid inactivation or to rapid passage into the tissues where the

organophosphates accumulate (Pach et al. 1987).

In animal studies, pairs of Carworth Farm E strain male rats administered [”C]chlorfenvinphos orally
at doses of 2.5 or 13.3 mg/kg in olive oil (with or without prior monooxygenase induction with
dieldrin) exhibited minimal changes in the metabolic profiles. The authors suggested that the
relatively low amount of radioactivity eliminated within 0—32 hours via the urine of high—dose

dieldrin—untreated rats was probably due to limited absorption/metabolism (Hutson and Wright 1980).

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CHLORFENVINPHOS 53

2. HEALTH EFFECTS

2.3.1.3 Dermal Exposure

A study conducted to assess the potential dermal absorption of chlorfenvinphos for man (since the
most likely route of entry is through the skin in occupational exposures) applied the substance to the
forearm skin of nine healthy human volunteers who had no prior occupational exposure to the
substance. Three different chlorfenvinphos formulations were used in this study: 80% w/v EC,
mainly chlorfenvinphos and emulsifiers: 24% W/V EC, mainly isometric trimethyl benzenes with 4.5%
w/v emulsifiers; and 25% weight per weight (w/w) (WP), mainly colloidal silica. florisil,
triphenylphosphate, sodium triphosphates, empicol L2 and tamal. The formulations were administered
separately in single applications to the forearm skin of nine adult human males for periods up to

4 hours in doses of 4—10 mg/kg/bw chlorfenvinphos. The 80% EC formulation was applied at doses
of 4, 5, 10, or 10 mg/kg/bw for periods of 4, 3.7, 3.8, or 4 hours on approximate skin areas of 36, 38,
320, or 336 cml, respectively. The 24% EC formulation was applied at doses of 5, 5, 10. 10, or

10 mg/kg/bw for periods of 4, 3.8, 4.1, 4, or 4 hours on approximate skin areas of 272, 420, 800, 600,
or 880 cml, respectively. The 25% WP formulation was applied at doses of 5 or 5 mg/kg/bw for
periods of 4.2 or 3.8 hours on approximate skin areas of 80 or 70 cml, respectively. The extent and
ease of absorption or permeability factor of the applied doses depended on the formulation, relating to
solvents in the preparation. The dermal absorption of the 80% EC formulation was 1.43, 1.81, 0.06,
or 0.32 mg/cmZ/hour, corresponding to applied doses of 4, 5. 10. or 10 mg/kg/bw for periods of 4. 3.7,
3.8, or 4 hours on approximate skin areas of 36. 38. 320, or 336 cmz. respectively. The dermal
absorption of the 24% EC formulation was 0.18. 0.12. 0.14, 0.20. or 0.08 mg/cml/hour corresponding
to applied doses of 5, 5, 10, 10. or 10 mg/kg/bw for periods of 4, 3.8, 4.1. 4, or 4 hours on
approximate skin areas of 272, 420, 800, 600, or 880 cml, respectively. The dermal absorption of the
25% WP formulation was 0.35 mg/CmZ/hour corresponding to applied doses of 5 mg/kg/bw for periods
of 4.2 hours on approximate skin areas of 80 cml. Concentrations of intact chlorfenvinphos of 14.4,
12.0, or 0.5 pg/L were found in the blood of volunteers 24 hours post-exposure for which absorbed
chlorfenvinphos of 0.20, 0.14, or 0.08 mg/cmZ/hour had been estimated, respectively. Concentrations
of intact chlorfenvinphos of 22, 3.8, <2.8, 2.9, 2.6. 0.2, or <0.7 pg/L were found in the blood of
volunteers 8 hours later for which absorbed chlorfenvinphos of 1.81. 1.43, 0.32, 0.18, 0.12, and

0.06 mg/cml/hour had been estimated. respectively (Hunter 1969).

No studies were located regarding the absorption of chlorfenvinphos after dermal exposure in animals.

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CHLORFENVINPHOS 54

2. HEALTH EFFECTS

2.3.2 Distribution

2.3.2.1 Inhalation Exposure

Although chlorfenvinphos is a hydrophilic substance, it has hitherto not been widely found in human
tissues because it is not expected to persist in these tissues. As an organophosphorus compound,
chlorfenvinphos is not expected to accumulate in the body tissues because of its expected short half—
life. However, Chlorfenvinphos was found in some of the 41 specimens of cervical mucus, follicular—
and sperm fluids, and human milk that were examined. Chlorfenvinphos levels of 13.66, 1.69, 2.02,
and 1.89 ug/kg were detected in 4 of the 1 l samples of cervical mucus. Chlorfenvinphos levels of
0.42 ug/kg were detected in l of the 10 sperm fluid samples and 1 of the IO human milk samples,
respectively. The detection of chlorfenvinphos in the cervical mucus, which showed the highest levels,
was unexpected because it is the most unlikely site for accumulation in the body. It was suggested
that a connection exists between the gland activities and the appearance of some pesticides in the
cervical mucus which might show a new way for accumulation. Accordingly, the data indicate that
new environmental pollutants like Chlorfenvinphos can appear in the human reproductive organs,
exposing even germ-cells, presenting a risk of interference with the process of reproduction (Wagner et
al. 1990). Since the data were generated from environmental exposure, the combined route of

exposure possibly includes the inhalation.

No studies were located regarding the distribution of Chlorfenvinphos after inhalation exposure in

animals.

2.3.2.2 Oral Exposure

Although Chlorfenvinphos is a hydrophilie substance, it has not hitherto been widely found in human
tissues because it is not expected to persist in these tissues. As an organophosphorus compound,
chlorfenvinphos is not expected to accumulate in the body tissues because of its expected short half—
life. However, chlorfenvinphos was found in some of the 41 specimens of cervical mucus, follicular
and sperm fluids, and human milk that were examined. Chlorfenvinphos levels of 13.66, 1.69, 2.02,
and 1.89 g/kg were detected in 4 of the 11 samples of cervical mucus. Chlorfenvinphos levels of
0.42 ug/kg were detected in 1 of the 10 sperm fluid samples and 1 of the 10 human milk samples,

respectively. The detection of Chlorfenvinphos in the cervical mucus, which showed the highest levels,

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CHLORFENVINPHOS 55

2. HEALTH EFFECTS

was unexpected because it is the most unlikely compartment for an accumulation in the body. It was
suggested that a connection exists between the gland activities and the appearance of some pesticides
in the cervical mucus, which might show a new way for accumulation. Accordingly, this data indicate
that new environmental pollutants like chlorfenvinphos can appear in the human organs, contacting
even germ-cells, presenting risk of adverse effects on reproduction (Wagner et al. 1990). Since the
data were generated from environmental exposure, the combined route of exposure possibly includes

oral.

A 29-year-old male was admitted with severe respiratory distress and bronchial tree hypersecretion.
The patient had ingested about 50 mL of the preparation Enolofos“), which contains 50%
chlorfenvinphos, in a suicide attempt. The concentration of chlorfenvinphos in the serum was

300 ng/mL upon admission. This is the only human chlorfenvinphos poisoning case in which
hemoperfusion intervention was employed. The mean clearance of chlorfenvinphos during
hemoperfusion was low (68 mL/minute) and only 0.42 mg of the poison was recovered. The poison
level in the serum was low (15 ng/mL) immediately before the procedure, and gradually rose in
successive blood sampling indicating that chlorfenvinphos passes fairly easily from the tissues into
blood. Perhaps this is related to secondary resorption from the digestive tract. The highest value of
clearance was observed in the fourth hour of hemoperfusion, in contrast to the observations during
hemoperfusion performed for other drug poisoning, when the value of the clearance was lowest in the
last hour. The serum chlorfenvinphos levels decreased temporarily within a few hours even prior to
the beginning of hemoperfusion, either due to rapid inactivation or to rapid passage into the tissues

where the organophosphates accumulate (Pach et al. 1987).

No studies were located regarding the distribution of chlorfenvinphos in animals after oral exposure.

2.3.2.3 Dermal Exposure

No studies were located regarding the distribution of chlorfenvinphos after dermal exposure in humans

or animals.
Although chlorfenvinphos is a hydrophilic substance, it has hitherto not been widely found in human

tissues because it is not expected to persist in these tissues. As an organophosphorus compound,

chlorfenvinphos is not expected to accumulate in the body tissues because of its expected short half—

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CHLORFENVINPHOS 56

2. HEALTH EFFECTS

life. However. chlorfenvinphos was found in some of the 41 specimens of cervical mucus, follicular
and sperm fluids. and human milk that were examined. Chlorfenvinphos levels of 13.66. 1.69, 2.02.
and [.89 g/kg were detected in 4 of the l 1 samples of cervical mucus. Chlorfenvinphos levels of
0.42 pg/kg were detected in l of the 1() sperm fluid samples and l of the 10 human milk samples.
respectively. The detection of chlorfenvinphos in the cervical mucus. which showed the highest levels.
was unexpected because it is the most unlikely compartment for an accumulation in the body. It was
suggested that a connection exists between the gland activities and the appearance of some pesticides
in the cervical mucus, which might show a new way for accumulation. Accordingly, this data indicate
that new environmental pollutants, like chlorfenvinphos. can appear in the human organs. contacting
even germ-cells and, thus. present risk of adverse effects on reproduction (Wagner et al. 1990). Since
the data were generated from environmental exposure. the combined route of exposure possibly

includes dermal.

2.3.3 Metabolism

An adapted scheme for the mammalian metabolic pathway of chlorfenvinphos (Akintonwa 1984. 1985;
Akintonwa and Itam 1988; Hunter et al. 1972; Hutson and Millburn 1991; Hutson and Wright 1980) is

presented in Figure 2-3.

2.3.3.1 Inhalation Exposure

No studies were located regarding the metabolism of chlorfenvinphos after inhalation exposure in

humans or animals.

2.3.3.2 Oral Exposure

In humans, the rates of chlorfenvinphos de—ethylation by liver microsomal fractions are

0.36 nmol/minute per mg protein (range (1.1 14182) without induction and 1.03 nmol/minute per nmol
of cytochrome P—450 (range 0.42—1.78) with induction (Hutson and Logan 1986).

In animal studies. pairs of Carworth Farm E strain male rats administered [”C]chlorfenvinphos orally

at doses of 2.5 or 13.3 mg/kg in olive oil (with or without prior monooxygenase induction with

dieldrin) exhibited minimal changes in the metabolic profiles. Urine samples were collected at 12 and

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CHLORFENVINPHOS
2. HEALTH EFFECTS

Figure 2-3. Proposed Mammalian Metabolic Pathway for Chlorfenvinphos

[' = "C-labeled]
OH

I
CH3CHO\ 4°

H
CH3CH20’ \O—C‘

C/

‘Ci
Cl

cszo \ 40
/P\
cszo 0-0'

Liver microsomes.
NADP H, 02

Cl Cl

Chlorolenvinphos
[2-chloro-1-(2‘.4'-dichloro
phenyl)viny| diethylphosphate]

Hemiacetal

020-04201

cszojJ

P —OH (:1
/

Cszo
Dielhylphosphoric acid
CI

2.4-Dichlorophenacylchlonde

Reduclase/NADH
liver microsomes

C'H(OH)CHZCI
Cl

Cl
2-Chloro-1-(2‘,4'-dichloro-
phenyl) ethanol

Cl
2,4-Dichloromandelic
acid glucuronide

T

Cl 002

2,4-Dichloromandelic acid
(rat, dog)

cszo \ 40
Ho’ \O-C‘=C<
Cl
Cl

H

{oxidative de-ethyletion]

O
4
CH3C c'
\
H
2-Chloro-1-(2',4'-dichlorophenyl)
vinyl elhylhydrogen phosphate
(ral. dog)

Acetylaldehyde

O=C'—CH3
cu

glunathione-S translatase

Cl
2,4-Dichloroacelophenone

l

C‘H(OH)CH3

$0

1-(2',4‘-Dichlorophenyl)

ethanol
jtranslerase
UDPGA

GO—CH-CH3

(Elm

1-(2',4--Dichlorophenyl)
ethanol glucuronide
(rat. dog)

Fleductasel

C'H(OH)CH20H
NADH

Cl

CI
2.4-Dichloro-

lip [“40pr
”We've 2
0m
6s

phenyl ethanediol

Glucuronyl

UDPGA ‘imnslerase

Glucuronyl
C'H(OH)CHZOG

<96.

1-(2',4'-Dichlorophenyl)
ethanediol-Z-glucuronide
(rat. dog)

CONHCHZCOOH
Cl

Cl Cl

2, 4«Dichloro
benzoyl glycine

2,4-Dichloro-
benzotc acid

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CHLORFENVINPHOS 58

2. HEALTH EFFECTS

32 hours and analyzed for metabolites of chlorfenvinphos using authentic standards: de—ethyl—
chlorfenvinphos or 2-chloro-l~(2',4'-dichlorophenyl) vinylethylhydrogen phosphate, l—(2’,4’-dichloro-
phenyl) ethanol, l-(2’,4’—dichlorophenyl) ethanediol, 2,4-dichloromandelic acid, and 2,4-dichloro-
benzoyl glycine. The metabolites 2-chloro—l—(2,4-dichlorophenyl) vinylethylhydrogen phosphate,
l-(2,4—dichlorophenyl) ethanol, l-(2,4-dichlorophenyl) ethanediol, 2,4-dichlor0mandelic acid, and
2,4-dichlorobenzoyl glycine were identified in the urine by chromatography. Increased
monooxygenase induction (dieldrin pretreatment) favored the production of the glucuronide of
l-(2,4—dichlorophenyl) ethanol and decreased yield of 2,4-dichloromandelic acid and 2,4—dichloro—
benzoyl glycine at a low dose level. At the high-dose level, an increased yield of l~(2,4-dichloro—
phenyl) ethanol, an increase in the relative yield of 2,4-dichloromandelic acid and 2,4-dichlorobenzoyl
glycine, and a doubling in the relative yield of de-ethylchlorfenvinphos occurred with a concomitant
reduction in the relative yields of the glucuronides. The authors suggested that the relatively low
amount of radioactivity eliminated within 0—32 hours via the urine of high-dose dieldrin—untreated rats
was probably due to limited absorption/metabolism. The results support the conclusion that the effect
of enzyme induction on the metabolism of substrates of that enzyme are dose-dependent with respect
to enzyme saturation. Therefore, alterations in metabolism are not necessarily a consequence of

enzyme induction alone (Hutson and Wright 1980).

Based on data from animal studies, the level of activity of cholinesterases in the livers of mammalian
species and the distribution of these enzymes has been suggested as an important factor in accounting
for species specificity of some phosphate triester anticholinesterase agents, including chlorfenvinphos.
The acute oral LD50 values of chlorfenvinphos for the rat, mouse, rabbit, and dog are 10, l00, 500,
and l,200 mg/kg, respectively. The relative rates of chlorfenvinphos O-dealkylation in the rat, mouse,
rabbit, and dog as compared to the oral LD50 values for chlorfenvinphos in these species are l, 8, 24,
and 88, respectively. The relative in vivo chlorfenvinphos-induced altered rates of hexobarbital
metabolism in the rat, mouse, rabbit, and dog as compared to the oral LD50 values for chlorfenvinphos
in these species are 4, l7, 5, and 1, respectively. The oral LD50 values for the rat, mouse, rabbit, and
dog were given as 10, 100, 500, and 12,000 mg/kg, respectively, in this study. The enzyme system
responsible for this reaction was found to be microsomal and required molecular oxygen and NADPH2
for activity. The activity of this enzyme system in isolated washed rat, mouse, and dog liver
microsomes had rates of product formation of 0.02, 0.65, and 2.00 nmol (per mg of microsomal
protein per minute), respectively. The activity of this enzyme system in isolated washed rabbit liver

microsomes had a rate of product formation similar to the other species used in this study. The

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maximum specific activity of liver microsomes with respect to the dealkylation of chlorfenvinphos

achieved in dieldrin—treated and phenobarbital-treated mice was 3.6 nmol at 1.6 mg/kg of daily for

62 weeks and 6.0 nmol at 12 mg/kg daily for 40 weeks, respectively. The maximum specific activity
of liver microsomes with respect to the dealkylation of chlorfenvinphos achieved in dieldrin-treated
and phenobarbital-treated dogs was 4.1 nmol (per mg of microsomal protein per minute) at 2.0 mg/kg
daily for 4 weeks and 9.2 nmol (per mg of microsomal protein per minute) at 20 mg/kg daily for

4 weeks, respectively. The activity of the enzyme system oxygenzNADPH2 oxidoreductase (with
chlorfenvinphos as substrate) in isolated washed monkey liver microsomes had a rate of product
formation of 1.00 nmol (per mg of microsomal protein per minute). The maximum specific activity of
liver microsomes with respect to the dealkylation of chlorfenvinphos achieved in dieldrin—treated
monkeys was 1.8 nmol (per mg of microsomal protein per minute) at 0.03 mg/kg/day for 6.15 years.
The mechanism of this reaction has been proposed to be mediated by oxidative dealkylation of
chlorfenvinphos to the relatively nontoxic metabolite, 2-chloro-l-(2,4-dichlorophenyl) vinyl ethyl-
hydrogen phosphate and acetaldehyde. The enzyme system was readily inducible, especially in the rat,
by the administration of phenobarbital or dieldrin. The maximum specific activity of liver microsomes
with respect to the dealkylation of chlorfenvinphos achieved in dieldrin~treated and phenobarbital-
treated rats was 12.4 nmol at 8 mg/kg/day for 4 weeks and 5.7 nmol at 14 mg/kg/day for 4 weeks,
respectively. A 600-fold increase in specific activity was observed in the liver of dieldrin—pretreated
rats. In rats pretreated with dieldrin at 200 ppm in the diet for 12 days, the acute LD50 for
chlorfenvinphos was increased by a factor of 6—8. A quantitative study of the species distribution of
phosphate esterases and glutathione S—alkyl transferase found that these enzymes are significantly less
in the pig than all the other species studied, suggesting a significantly varied distribution among some
mammalian species. The author of the study concluded that the distribution of these enzymes is an
important factor in accounting for the species specificity of at least some anticholinesterase agents and
that the glutathione—dependent alkyl transferase is predominantly a methyl transferase; the contribution
of these two enzyme systems to the detoxification of any particular phosphate triester is dependent on

the structure and solubility of the molecule (Donninger 1971).

These findings were confirmed by three other reports. In one of the reports, the oral LDSO values for
rat, mouse, rabbit, and dog are 10—30 mg/kg, 150, 500, and >5.000 mg/kg, respectively. The oral
LD50 in the rabbit has been reported to be as high as >12,000 mg/kg in some studies. The difference
in toxicity in rats and dogs was found to be due to several pharmacokinetic and pharmacodynamic

factors. These factors include the rates of absorption and metabolism, bioavailability in blood, and

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rates ol‘ uptake by the brain. as well as the sensitivity of brain cholinesterase to the phosphorylating
action of the compound. In studies using rats and dogs. the most important reaction in detoxification
is the conversion ol‘ chlorl'envinphos to dc—ethylchlorl'envinphos by oxidative de—ethylation. The
reaction is catalyzed by a hepatic microsomal monooxygenase. probably cytochrome P-450. The
relative rates ol' de-‘ethylation in liver slices were I. 8. '24. and 88 for the rat. mouse, rabbit, and dog,
respectively. Thus. an excellent inverse correlation between oral LI)i0 and rate of de—ethylation was
established. Also evidence for the significance of the reaction in vim was provided from experiments
in which rats were protected 7—fold from the action of chlorl‘envinphos by pie—treatment with dieldrin
in the diet for l2 days. This treatment induces cytochrome I’-45() microsomal monooxygenase and,
thus. chlorl‘envinphos de-ethylation. 'I‘he de»ethylation was induced about 40—fold measured in virro
and as expressed relative to cytochrome I’—450 concentration. However, the author cautioned that
species dil‘l‘ercnces in toxicity response are ol’ten mulli-l‘actorial, and metabolism can be a minor

component (Hutson and Millburn l‘)‘)l).

In the second report, the metabolism of chlorl'envinphos in kidney subcellular traction and in the
serum ol‘ liischer 344 rats (orally pretreated with chIorl‘envinphos l'ollowed by oral treatment with a
similar chlorl‘envinphos dose or 50 mg/kg phenobarbital in 24 hours). with or without the NADPH—
generating system. was found to be negligible. Metabolism ol‘ chlorl'cnvinphos in the liver subcellular
l‘raction without the NADI’II—generating system was also practically negligible. However, when the
NADPII—generating system was added to the liver subcellular l‘raction, chlorl‘envinphos metabolism
increased significantly (203% in the 9.000 gram l‘raction and l78% in the mierosomes) in the
chlorl‘enviiiphos-pretreated animals and in the phenobarbital-pretreated animals (565%). Additionally,
chlorl'envinphos pretreatment increased cytochrome P-450 content (30%) in the hepatic microsomal
fraction; phenobarbital pretreatment caused a lb’tm increase. Hepatic microsomal cytochrome

b5 content and cytochrome P450 reductase activity were also increased by chlorl'envinphos and
phenobarbital pretreatment (Ill and I307“ respectively. for chlorl‘envinphos; and [26 and l39%,
respectively. for phenobarbital). Both chlorl‘envinphos and phenobarbital pretreatment significantly
increased protein content (p<0.00l) in the microsomal traction. (‘hlorl‘envinphos treatment did not
increase liver weight (relative to body weight). Increases were also noted in cytochrome P—450-linked
activities such as aminopyrine N—demethylase (40%) and aniline hydroxylase (27%) content in the
hepatic microsomal l'raction and hexobarbital sleeping time and zoxazolamine paralysis time. Both
chlorl‘envinphos and phenolmrbital are potent inducers of cytochrome P—450, which is involved in the

metabolic detoxication ol‘ chIorl‘envinphos. 'I'hns. the authors concluded that the increase in hepatic

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chlorfenvinphos metabolism may be due to the induction of the hepatic cytochrome P-45() system
caused by the single oral short-term treatment with chlorfenvinphos. Also. this induction may be one
of the reasons for the decrease in plasma chlorfenvinphos concentration which may be responsible for

the reduction in toxicity of subsequent exposure to chlorfenvinphos (lkeda et al. 199l ).

The third report was a theoretical analysis that predicted the mammalian biotransformation products
based on the recognition of the structure of chlorfenvinphos. understanding of Types 1 and 11
metabolism of foreign compounds. and mechanistic biochemistry. This analysis also acknowledged
that cytochrome P-450 monooxygenase (an inducible enzyme) is the relevant enzyme which mediates
the biotransformation of chlorfenvinphos. Cytochrome P-450 monooxygenase will mediate the
oxidative dealkylation of chlorfenvinphos to the relatively nontoxic metabolite. 2—chloro—
l—(2,4-dichlorophenyl) vinyl ethylhydrogen phosphate or de-ethylchlorfenvinphos. Since
chlorfenvinphos is active per se, suppression of P—450 monooxygenase would increase the mammalian
half-life and thus, the toxicity of chlorfenvinphos. Conversely. induction of P-450 monooxygenase
suppression would decrease the mammalian toxicity of chlorfenvinphos. Thus. pre— or co—exposure to
inhibitors of P—450 monooxygenase activity inhibitors such as metyrapone (phenobarbital type). alpha-
naphthoflavone (methyicholanthrene type), and tetrahydrofuran (ethanol type). Thirteen metabolites of
chlorfenvinphos were predicted from theoretical biotransformation as justified by known structure of
Chlorfenvinphos and understanding of biochemical reactions of monooxygenation. reduction,
hydrolysis, glucuronidation, glutathione-S—transferase conjugation. and amino acid conjugation. The
13 metabolites predicted are: 2-chloro—l-(2'.4'—dichlorophenyl) vinyldiethyl phosphate; acetaldehyde;
2-chloro-l-(2‘,4'-dichlorophenyl) vinylethylhydrogen phosphate; 2.4-dichlorophenaeylchloride:
2-chloro—l-(2'.4‘-dichlorophenyl) ethanol; 2,4-dichloromandelic acid; 2.4-dichloromandelic acid ester
glueuronide; 2,4-dichloroacetophenone; 1-(2’,4'-dichlorophenyl) ethanol: 1-(2'.4'—dichlorophenyl)
ethanediol; 1—(2'.4‘-dichlorophenyl) ethanediol—2—glucuronide; l-hydroxy-l—(2',4‘—dichlorophenyl) acetyl
glycine; and l-(2',4‘-dichlorophenyl) ethanediol. 2-Chloro—l—(2'.4‘-dichlorophenyl) vinylethylhydrogen
phosphate. 2,4-dichloromandelic acid, l-(2'~4'-dichlorophenyl) ethanediol-Z-glucuronide, and
l-(2',4'—dichlorophenyl) ethanediol are predicted for the dog and rat. l-Hydroxy-l—(2',4'-dichloro-
phenyl) acetyl glycine (the glycine conjugate of 2.4-dichloromandelic acid) was not confirmed in the
rat, while 2,4—dichlorohippuric acid was present in the dog but not in the rat. While the theoretical or
predictive approach to metabolites identification elucidates all the possible mechanistic pathways in the
derivation of each metabolite and identifies all toxic or hazardous intermediates. only actual

experimentation, which begins with theoretical prediction, can provide species differences in the

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proportion of metabolites and the toxicity of these metabolites. Thus, the theoretical approach to
chlorfenvinphos metabolism in mammals effectively reveals that the monooxygenation of the vinyl
group would produce an unstable epoxide (2—hydroxyl groups attached to a carbon) to yield
2,4-dichlorophenyl glyoxylate and 2,4-dichlorobenzoic acid through decarboxylation and oxygenation.
The author of this study postulated that the 2,4-dichlorobenzoyl glycine (2,4—dichlorohippuric acid)
was produced in the rat by this mechanism. The production of electrophilic metabolic intermediates or
epoxides in the metabolism of chlorfenvinphos, which could react with nucleophilic cellular
components (DNA, RNA. and proteins) leading to carcinogenesis, was considered unlikely by this

theoretical approach (Akintonwa 1984).

2,4-Dichlorophenacyl chloride an intermediary metabolite of chlorfem'inphos and dimethylvinphos. is
excreted from mammals mainly as l-(2,4-dichlorophenyl)ethyl glucuronide (Hutson et al. 1977). The
authors assumed that this arose via the reductive dechlorination of the phenacyl halide to the
acetophenone, which was then reduced to the alcohol and conjugated. A further investigation of the
proposed reductive dechlorination step (using subcellular fractions of rat liver) led the authors to
conclude that it is likely that the mechanism of reaction is a nucleophilic attack by sulphur (of the
second GSH) on sulphur (of the conjugate) with the expulsion of the phenacyl anion as leaving group.

The enzyme may be regarded as one of the glutathione transferases (Hutson et al. l977).

An assay developed for determining monooxygenase activity in human fetal livers, as a measure of the
rate of decrease in substrate concentration, was found reliable for incubations at 37 r’C for periods up
to ID minutes. Incubations in excess of 10 minutes were unreliable due to an unexpected increase in
E246 nm readings. The investigators concluded that hydrolysis, rather than monooxygenation, of
chlorfenvinphos, was probably responsible for the observed increase in readings. Using 5- and
IO—minute incubations, specific activity values for monooxygenase in l3— and lo—week—old human
fetuses were determined to be (14710.84 and 5.26:0.46. respectively; no monooxygenase could be
detected in 24-week—old fetuses. The authors concluded that, similar to in vim observations, the
mechanism for oxidative dealkylation of chlorl‘envinphos proceeds initially via monooxygenation of
the alpha—carbon atom of the alkoxy group to produce an unstable hemiacetal, which breaks down by
oxidative 0- and N-alkylation mechanisms to acetaldehyde and 2—chloro-l-(2.4—dichlorophenyl) vinyl-

ethylhydrogen phosphate (Akintonwa and Itam 1988).

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2.3.3.3 Dermal Exposure

No studies were located regarding metabolism of chlorfenvinphos after dermal exposure in humans or

animals.

2.3.4 Elimination and Excretion

2.3.4.1 Inhalation Exposure

No studies were located regarding excretion of chlorfenvinphos after inhalation exposure in humans or

animals.

2.3.4.2 Oral Exposure

A male patient, aged 29, was admitted to the hospital 3 hours after a suicide attempt during which he
drank about 50 mL of the preparation Enolofos® which contains 50% chlorfenvinphos. The
concentration of chlorfenvinphos in the serum was 300 ng/mL upon admission. In this, the only
human chlorfenvinphos poisoning in which hemoperfusion intervention was employed, the mean
clearance of chlorfenvinphos during hemoperfusion was low, 68 mL/minute; and only 0.42 mg of the
poison was recovered. The level of the poison in the serum was low (15 ng/mL) immediately before
the procedure and gradually rose in successive blood sampling. At all times in successive blood
samples during the procedure, there was an increase of chlorfenvinphos level in the serum, indicating
that chlorfenvinphos passes fairly easily from the tissues into blood. Perhaps this is related to
secondary resorption from the digestive tract. The highest value of clearance was observed in the
fourth hour of hemoperfusion, in contrast to the observations during hemoperfusion performed for
other drug poisoning, when the value of the clearance was lowest in the last hour. The serum
chlorfenvinphos levels decreased temporarily within a few hours even prior to the beginning of
hemoperfusion, either due to rapid inactivation or to rapid passage into the tissues where the

organophosphates accumulate (Pach et al. 1987).
In animal studies, pairs of Carworth Farm E strain male rats administered [”C]chlorfenvinphos orally

at doses of 2.5 or l3.3 mg/kg in olive oil (with or without prior monooxygenase induction with

dieldrin) exhibited minimal changes in the metabolic profiles. About 50% of the administered

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radioactivity was eliminated in the urine in the first 12 hours, 9—13% in the next 12 hours, 3.543% in
the subsequent 16 hours, and 4.2—5% in the final 42 hours of monitoring. A total of 67.l~72.5‘7r of
the administered [”C]chlorfenvinphos was recovered from the urine of this dose group animals. ()1in
15.2—16.9% 0f the administered radioactivity was eliminated in the urine in the first 12 hours.
25—82% in the next 12 hours, 6.1—6.6% in the subsequent 18 hours, and 0.7—1.4% in the final

42 hours of monitoring. Only 26.2—31.7% of the total dose was recovered in the urine in the high-
dose animals. Dieldrin pretreatment resulted in a more rapid elimination as well as a greater

percentage elimination of the administered [”C]chlorfenvinphos doses (Hutson and Wright 1980).

2.3.4.3 Dermal Exposure

No studies were located regarding excretion of chlorfenvinphos after dermal exposure in humans or

animals.

2.3.4.4 Other Exposure

Following an intravenous injection of [”C]-chlorfenvinphos to female Beagle dogs. approximately 58%
of the radioactivity was recovered in the urine within 24 hours, primarily as diethyl phosphorothioic
acid (42%) and diethyl phosphoric acid (16%). No intact chlorfenvinphos was excreted (Iverson et al.
1975).

2.3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models

Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake
and disposition of chemical substances to quantitatively describe the relationships among critical
biological processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue
dosimetry models. PBPK models are increasingly used in risk assessments, primarily to predict the
concentration of potentially toxic moieties of a chemical that will be delivered to any given target
tissue following various combinations of route, dose level, and test species (Clewell and Andersen
1985). Physiologically based pharmacodynamic (PBPD) models use mathematical descriptions of the
dose—response function to quantitatively describe the relationship between target tissue dose and toxic

end points.

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PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to
delineate and characterize the relationships between: (I) the external/exposure concentration and target
tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen et al.
1987; Andersen and Krishnan 1994). These models are biologically and mechanistically based and
can be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low
dose, from route to route, between species, and between subpopulations within a species. The
biological basis of PBPK models results in more meaningful extrapolations than those generated with

the more conventional use of uncertainty factors.

The PBPK model for a chemical substance is developed in four interconnected steps: (1) model
representation, (2) model parametrization, (3) model simulation, and (4) model validation (Krishnan
and Andersen 1994). In the early l990s, validated PBPK models were developed for a number of
toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen
I994; Leung 1993). PBPK models for a particular substance require estimates of the chemical
substance-specific physicochemical parameters, and species—specific physiological and biological
parameters. The numerical estimates of these model parameters are incorporated within a set of
differential and algebraic equations that describe the pharmacokinetic processes. Solving these
differential and algebraic equations provides the predictions of tissue dose. Computers then provide

process simulations based on these solutions.

The structure and mathematical expressions used in PBPK models significantly simplify the true
complexities of biological systems. If the uptake and disposition of the chemical substance(s) are
adequately described, however, this simplification is desirable because data are often unavailable for
many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty.
The adequacy of the model is, therefore, of great importance, and model validation is essential to the

use of PBPK models in risk assessment.

PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the
maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan
1994). PBPK models provide a scientifically-sound means to predict the target tissue dose of
chemicals in humans who are exposed to environmental levels (for example, levels that might occur at
hazardous waste sites) based on the results of studies where doses were higher or were administered in

different species. Figure 2—4 shows a conceptualized representation of a PBPK model.

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Figure 2-4. Conceptual Representation of a Physiologically Based
Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance

‘ ‘ ‘ ‘ * Exhaled chemical

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

lngesfion
/ Lungs :
a Liver ‘ .
V I A i A
E R
N Vmax Km GI _ T
O Tract E
U Fat ‘ R
S l
A
Slowly L
penused
B tissues
L . B
o Richly L
O ‘ perfused O
D tissues 0
D
< Kidney ~
-/
Urine
~ Skin V
A
1- - - -Chemical in air

contacting skin

Source: adapted from Krisnan et al. 1992

Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a
hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by
inhalation, or by ingestion, metabolized in the liver, and excreted in the urine or by exhalation.

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If PBPK models for chlorfenvinphos exist, the overall results and individual models are discussed in
this section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species

extrapolations.

A physiologically based pharmacokinetic (PBPK) analysis used data from a study with 8-week old
Fischer 344 rats as a model to study the mechanism of protection by initial chlorfenvinphos exposure
against the toxicity of a subsequent exposure. The analysis concluded that, contrary to expectation, the
body burden of chlorfenvinphos decreased after the initial exposure upon subsequent challenge
exposure. The model predicted that decreased body burden of oral chlorfenvinphos dose might be due
to the decrease in the plasma concentration after a challenge dose of chlorfenvinphos. In the rat study
on which the model is based, the acute oral toxicity of chlorfenvinphos was reduced by the oral
pretreatment of rats with chlorfenvinphos after a subsequent challenge dose. This was accompanied by
reduction in brain cholinesterase, liver, and plasma concentrations of chlorfenvinphos (by one-third and
4—10 times, respectively). Unbound fractions of chlorfenvinphos in blood and liver were estimated by
the in vitro experiments and pretreatment did not change the unbound fraction of chlorfenvinphos.

The authors stated that, according to the PBPK model, the decrease in body burdens of the oral
chlorfenvinphos dose may be caused mainly by an increase in intrinsic clearance of chlorfenvinphos by
the liver and a decrease in the partition coefficient of chlorfenvinphos between the emergent blood and
the liver. The increase in the intrinsic clearance was suggested to be related to the metabolic induction
of P—450 observed in vitro. Additionally, pretreatment decreased the absorption rate constant of the
oral chlorfenvinphos dose. Essentially, this is responsible for the protection afforded against toxicity

of subsequent exposure to chlorfenvinphos (Ikeda et al. 1992).

2.4 MECHANISMS OF ACTION

2.4.1 Pharmacokinetic Mechanisms

The level of activity of cholinesterases in the livers of mammalian species livers and the distribution of
these enzymes have been suggested to be imponant factors in accounting for species specificity of
some phosphate triester anticholinesterase agents, including chlorfenvinphos. It may account for the
great variation in the toxicity of chlorfenvinphos among different animal species. The acute oral LD,”

values of chlorfenvinphos for the rat, mouse, rabbit, and dog are 10, 100, 500, and 1,200 mg/kg,

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respectively. The relative rates of conversion of chlorfenvinphos (by 0-dealkylation) to the diester by
liver slices from the rat, mouse, rabbit, and dog are l, 8, 24, and 80 hours, respectively, evidently
correlating with the published acute oral LDSO values for the species. The enzyme system responsible
for this reaction was found to be microsomal and required molecular oxygen and NADPH2 for activity.
The activity of this enzyme system in isolated rat, mouse, and dog liver (washed) microsomes had
rates of product formation of 0.02, 0.65, and 2.00 nmol (per mg of microsomal protein per minute),
respectively. The activity of this enzyme system in isolated washed rabbit liver microsomes had a rate

of product formation similar to the other species used in this study.

The maximum specific activity of liver microsomes with respect to the dealkylation of chlorfenvinphos
achieved in dieldrin- treated and phenobarbital- treated mice was 3. 6 nmol at l .6 mg/kg/day for

62 weeks and 6.0 nmol at 12 mg/kg/day for 40 weeks respectively. The maximum specific activity of
liver microsomes with respect to the dealkylation of chlorfenvinphos achieved in dieldrin- and
phenobarbital-treated dogs was 4.1 nmol (per mg of microsomal protein per minute) at 2.0 mg/k/day
for 4 weeks and 9.2 nmol (per mg of microsomal protein per minute) at 20 mg/kg/day for 4 weeks,
respectively. The activity of the enzyme system oxygenzNADPH2 oxidoreductase (with
chlorfenvinphos as substrate) in isolated washed monkey liver microsomes had a rate of product
formation of 1.00 nmol (per mg of microsomal protein per minute). The maximum specific activity of
liver microsomes with respect to the dealkylation of chlorfenvinphos achieved in dieldrin—treated
monkeys was 1.8 nmol (per mg of microsomal protein per minute) at 003 mg/kg/day for 6.l5 years.

It has been proposed that the mechanism of this reaction is mediated by oxidative dealkylation of
chlorfenvinphos t0 the relatively nontoxic metabolite, 2-chloro-l-(2,4—dichlorophenyl) vinyl ethyl-
hydrogen phosphate and acetaldehyde. The enzyme system was readily inducible, especially in the rat,

by the administration of phenobarbital or dieldrin.

The maximum specific activity of liver microsomes with respect to the dealkylation of chlorfenvinphos
achieved in dieldrin- and phenobarbital—treated rats was 12.4 nmol at 8 mg/kg/day for 4 weeks and

5.7 nmol at 14 mg/kg/day for 4 weeks, respectively. A 600-fold increase in specific activity was
observed in the liver of dieldrin—pretreated rats and, in rats pretreated with dieldrin at 200 ppm in the
diet for 12 days, the acute LDso for chlorfenvinphos was increased by a factor of 6—8. A quantitative
study of the species distribution of phosphate esterases and glutathione S—alkyl transferase found that
these enzymes are significantly less in the pig than all the other species studied, suggesting a

significantly varied distribution among some mammalian species. The author of the study concluded

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CHLORFENVINPHOS 69

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that the distribution of these enzymes is an important factor in accounting for the species specificity of
at least some miticholinesterase agents and that the glutathione-dependent alkyl transferase is
predominzmtly a methyl transferase; the contribution of these two enzyme systems to the detoxification
of any particular phosphate triester is dependent on the structure and solubility of the molecule

(Donninger 1971).

These findings were confinned by two other reports. In one. the oral LD50 values for rat, mouse.
rabbit. and dog were ltk30 trig/kg. lSO. 500. and >5,()()0 mg/kg. respectively; it can be

>12.000 mg/kg in the rabbit. The difference in toxicity in rats and dogs was found to be due to rates
of absorption and metabolism. bioavailability in blood, and rates of uptake by the brain and sensitivity
of brain cholinesterase to the phosphorylating action of the compound. In studies using rats and dogs.
the most importzmt reaction in detoxification is the conversion of chlorfenvinphos to de-ethyl-
chlorfenvinphos by oxidative de-ethylation. The reaction is catalyzed by a hepatic microsomal mono-
oxygenase. probably cytochrome P-450. The relative rates of de-ethylation in liver slices were 1, 8.
24. tuid 88 for the rat. mouse. rabbit. and dog. respectively. Thus. an excellent inverse correlation
between oral LDfin and rate of de-ethylation was established. Also evidence for the significance of the
reaction in viva was provided from experiments in which rats were protected 7-fold front the action of
chlorfenvinphos by pre-treatment with dieldrin in the diet for 12 days. This treaunent induces
cytochrome P-450 tnicrosomal monooxygenase and, thus, chlorfenvinphos de—ethylation. The
de-ethylation was induced about 40-fold measured in vitro and as expressed relative to cytochrome
P—450 concentration. However, the author cautioned that species differences in toxicity response are

often tnulti-factorial tmd metabolism can be a minor component (Hutson and Millbum 1991).

In the second report. the metabolism of chlorfenvinphos in kidney subcellular fraction and in the
serum of Fischer 344 rats (orally pretreated with chlorfenvinphos followed by an oral treatment with a
similar chlorfenvinphos dose or 50 mg/kg phenobarbital in 24 hours), with or without the NADPH-
generating system. was found to be negligible. Metabolism of chlorfenvinphos in the liver subcellular
fraction without the NADPH-generaling system was also practically negligible. However. when the
NADPH-generaling system was added to the liver subcellular fraction. chlorfenvinphos metabolism
increased significtmtly (203% in the 9.000 gram fraction and l78% in the microsomes) in the
chlorfenvinphos-pretreated animals and in the phenobarbital-pretreated animals (565%). Additionally,
chlorfenvinphos pretreatment increased cytochrome P-450 content (30%) in the hepatic microsomal

fraction; phenobarbital pretreatment caused a 180% increase. Hepatic microsomal cytochrome

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b5 content and cytochrome P—450 reductase activity were also increased by chlorfenvinphos and
phenobarbital pretreatment (121 and 130%, respectively, for chlorfenvinphos and 126 and 139%.
respectively, for phenobarbital). Both chlorfenvinphos and phenobarbital pretreatment significantly
increased protein content (p<0.00l) in the microsomal fraction. Chlorfenvinphos treatment did not
increase liver weight (relative to body weight). Increases were also noted in cytochrome P—450-linked
activities such as aminopyrine N—demethylase (40%) and aniline hydroxylase (27%) content in the
hepatic microsomal fraction and hexobarbital sleeping time and zoxazolamine paralysis time. Both
chlorfenvinphos and phenobarbital are potent inducers of cytochrome P-450, which is involved in the
metabolic detoxication of chlorfenvinphos. Thus, the authors concluded that the increase in hepatic
chlorfenvinphos metabolism may be due to the induction of the hepatic cytochrome P-450 system
caused by the single oral short-term treatment. Also this induction may be one of the reasons for the
decrease in plasma chlorfenvinphos concentration, which may be responsible for the reduction in

toxicity of subsequent exposure to chlorfenvinphos (Ikeda et al. 1991 ).

A theoretical analysis concluded that the pharmacokinetics of delayed neurotoxicants vary from the
pharmacokinetics of neurotoxic organophosphates like chlorfenvinphos. Delayed neurotoxicants tend
to be more lipophilic and distribute rapidly to well-perfused tissues from the blood, readily partition
into membranes, and effectively penetrate the blood/brain barrier. Some of the major sites and enzyme
systems involved in the detoxication of direct»acting neurotoxic organophosphates, like
chlorfenvinphos, are NADPH—P—450, GSH transt‘erase, FAD-monooxygenase and esterases; the most
important of which is monooxygenase. The major activation step for microsomal monooxygenases is
of critical importance for the toxicity of organophosphate compounds like chlorfenvinphos. The
relative rates of chlorfenvinphos O—dealkylation in rats, mice, rabbits, and dogs as compared to the oral
LDin values for chlorfenvinphos in these species are l, 8, 24, and 88, respectively. The relative in
viva chlorfenvinphos-induced altered rates of hexobarbital metabolism in rats, mice, rabbits, and dogs
as compared to the oral LDi0 values for chlorfenvinphos in these species are 4, l7, 5, and l,
respectively. The oral LD50 values for rats, mice, rabbits, and dogs were given as 10, 100. 500, and
l2,000 mg/kg, respectively, in this study. According to the author, the potential for oxidative
0—dealkylation P-450 pathway varies widely with species, and the activity toward chlorfenvinphos
correlates well with species selectivity. The author concluded that the biotransformation of delayed
neurotoxicants will certainly influence relative potencies, but the distinction between a delayed
neurotoxicant and the neurotoxicity of organophosphate compounds, which is mainly limited to acute

effects, depends more heavily on pharmacodynamic than pharmacokinetic considerations. The

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understanding of the syndrome of delayed neurotoxicity will come from receptor/mechanism studies

(Hansen 1983).

2.4.2 Mechanisms of Toxicity

Most chlorfenvinphos toxicity results from the inhibition of cholinesterase activity in the central and
peripheral nervous system when administered by the oral (Cupp et al. 1975; Pach et al. 1987) or
inhalation route in acute—duration exposures in humans (Kolmodin-Hedman and Eriksson 1987) and
when administered by the oral (Barna and Simon 1973; Osicka-Koprowska et al. 1984; Takahashi et
al. 1991), or dermal route in acute—duration exposures. Inhibition of cholinesterase activity results in
accumulation of choline at muscarinic and nicotinic receptors leading to peripheral and central nervous
system effects. These effects usually appear within a few minutes to a few hours after exposure
depending on the extent of exposure. The enzyme is responsible for terminating the action of the
neurotransmitter choline in the synapse of the pre— and post-synaptic nerve endings or in the
neuromuscular junctions. On arrival of a nerve impulse at the synaptic gutter between the pre- and
post—synaptic nerve endings or effector muscle fiber endplates, there is a release of choline from the
pre-synaptic terminals. At the post-synaptic nerve—ending, choline acts as a chemical mediator to
perpetuate the action potential. However, the action of choline does not persist long as it is

hydrolyzed by the enzyme cholinesterase and rapidly removed.

Chlorfenvinphos, an anticholinesterase organophosphate, inhibits the activity of cholinesterase enzyme
by reacting with the esteratic sites of the enzyme to form a stable phosphorylated complex which is
incapable of destroying choline at the synaptic gutter between the pre— and post-synaptic nerve endings
or neuromuscular junctions of skeletal muscles, resulting in accumulation of choline at these sites.
This leads to continuous or excessive stimulation of cholinergic fibers in the post—ganglionic
parasympathetic nerve endings, neuromuscular junctions of the skeletal muscles, and cells of the
central nervous system, and results in hyperpolarization of nerve or muscle fibers and receptor
desensitization. In the parasympathetic system, stimulation of postganglionic fibers on the effector
organs is mimicked by muscarine, and the receptors for the transmitters are called muscarinic
receptors. They are found primarily in smooth muscle, the heart, and the exocrine glands. Stimulation
of these receptors by inhibition of cholinesterase activity produces signs and symptoms of cholinergic
poisoning that include bronchoconstriction and bronchial secretions, increased salivation and

lacrimation, exophthalmos, increased sweating, increased gastrointestinal tone and peristalsis, nausea,

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vomiting, abdominal cramps, diarrhea, hypotension, and bradycardia that can increase to heart block,
involuntary urination caused by contraction of the smooth muscle of the bladder, and constriction of

the pupils or miosis.

At the autonomic ganglia and neuromuscular junctions, stimulation of transmission is mimicked by the
action of nicotine, and the receptors are called nicotinic receptors. Inhibition of cholinesterase activity
leads to abnormal continuous or excessive stimulation of the receptor muscle fibers. causing weakness
of the muscles, involuntary twitching, fasciculations, cramps, and eventual paralysis of the muscles.
Paralysis of the respiratory muscles leads to respiratory failure and death. The central nervous system
effects are due to accumulation of choline at various cortical, subcortical, and spinal levels (primarily
in the cerebral cortex, hippocampus, and extrapyramidal motor system). Accumulation of choline in
the central nervous system causes tension, anxiety, restlessness, insomnia. headache. emotional
instability, neurosis, excessive dreaming and nightmares, apathy, drowsiness, confusion, slurred speech.
tremor, ataxia, convulsions, depression of respiratory and circulatory centers, and coma. The most
likely cause of death in fatal organophosphate poisoning is paralysis associated with respiratory failure

(Cupp et al. 1975; Klaassen et al. 1986; Takahashi et al. 1991; Williams and Burson I985).

Organophosphate-induced hypotension (reported for chlorfenvinphos only in rats receiving intravenous
doses) (Takahashi et al. 1991) has been suggested to be due to factors other than inhibition of
Cholinesterase activity (Kojima et al. 1992) and may be due to a central adrenergic mechanism of
toxicity (Brzezinski 1978; Osumi et al. I975). Evidence from studies with rats indicates that
chlorfenvinphos induces alterations in the brain, liver, and circulatory levels of aromatic amino acid
transferase (Phen AT, Tyr AT, and Try AT) as well as inhibits noradrenaline activity in rim in rats at
doses as low as 4 mg/kg in 3 hours (Brzezinski I978: Osumi et al. 1975', Puzynska 1984). Evidence
from other studies also indicates that the alteration of brain and liver activities of the aromatic amino
acid transferases by chlorfenvinphos may be due to the inhibitory effect of chlorfenvinphos on
noradrenaline activity, since noradrenaline has been shown to affect amino acid transferase (L—tyrosine
aminotransferase) activity (Puzynska I984). It has also been suggested that the cholinergic action of
organophosphates like chlorfenvinphos may interfere with the pathways controlling the secretory
activity of the anterior pituitary lobe and the adrenal cortex whose hormones influence the activities of
many enzymes, including aromatic amino acid transferases (Puzynska I984). Interference with the
secretory activity of the adrenal cortex may lead to a disruption in the normal activities of one or more

components of the renal blood pressure regulatory systems (Klaassen et al. 1986).

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2.4.3 Animal-to-Human Extrapolations

In one study, the rates of chlorfenvinphos de-ethylate by human liver microsomal fractions were

0.36 nmol/minute per mg protein (range ().1 1—082) without induction and 1.03 nmol/minute per nmol
of cytochrome P-45() (range 0.42—1.78) with induction. The rates of chlorfenvinphos de—ethylation by
liver microsomal fractions were 0.62 nmol/minute/mg protein (range 0.36—0.93) and

1.30 nmol/minutc/nmol cytochrome P-45() (range 0.81—1.74) for uninduced rabbits. The rabbit is
considered relatively resistant to the acute toxic action of the chlorfenvinphos with an LD50 of
5()()—l,()()() mg/kg (provided in zmother study). These results demonstrate that human hepatic
cytochrome P—450 is almost as active as that of rabbits. However, the authors stressed that these
results refer to the total cytochrome P-45() complement of the cells and take no account of the several
forms known to exist which differ from species to species, and with environmental factors, and the
other factors involved in the acute toxicity of chlorfenvinphos in humans. Based on the findings in
this study. it appears that humans may de-ethylate chlorfenvinphos more like rabbits or mice than rats

(Hutson and Logan I986).
2.5 RELEVANCE TO PUBLIC HEALTH

Overview.

Chlorfenvinphos is an insecticide with broad-based use in both agriculture and control of pests in
residential dwellings, gardens. and on household pets. The pesticide is not currently registered for use
in the United States. Additionally, there is no evidence that chlorfenvinphos was ever registered for
use as a pesticide by the US. EPA (EPA l994a). Like most organophosphate pesticides,
chlorfenvinphos is rapidly hydrolyzed to non-toxic products. The greatest potential for significant
exposure to this compound is found in occupational settings (i.e., manufacture and application of
chlorfenvinphos). Currently, the most common exposure scenario for the general population comes
from home use of imported foods and lanolin-containing pharmaceutical products. Workers involved
in disposal of chlorfenvinphos-contaminated wastes are at a higher risk of exposure. Populations
living in the vicinity of plants where chlorfenvinphos was manufactured, or living near dairy farms,
cattle- or sheep-holding areas, or poultry-producing facilities where chlorfenvinphos was used, as well
as populations living near hazardous waste sites containing chlorfenvinphos, are potentially at higher

risk of exposure. Adverse health effects in humans or animals resulted from inhalation, ingestion, or

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CHLORFENVINPHOS 74

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dermal exposure to Chlorfenvinphos. No association has been reported between Chlorfenvinphos

toxicity and low—level environmental contamination.

The principal toxic effect of Chlorfenvinphos, an anticholinesterase organophosphate, is the inhibition
of cholinesterase activity in the central and peripheral nervous system when administered by the oral
(Cupp et al. 1975; Pach et al. 1987) or inhalation route in acute-duration exposures in humans
(Kolmodin-Hedman and Eriksson 1987); and the inhibition of cholinesterase activity in the central and
peripheral nervous system when administered by the oral (Bama and Simon 1973; Osicka-Koprowska
et al. I984; Takahashi et al. I991) or dermal route in acute-duration exposures. In addition,
Chlorfenvinphos inhibits noradrenaline activity in the central adrenergic mechanism in animals
(Brzezinski I978; Osumi et al. I975). Chlorfenvinphos also inhibits noradrenaline activity in the
central adrenergic mechanism in animals (Brzezinski 1978; Osumi et al. 1975). Inhibition of
cholinesterase activity results in the accumulation of choline at choline receptors leading to cholinergic
responses in the peripheral (muscarinic and nicotinic) and central nervous system and neuromuscular
junctions. Severe inhibition of cholinesterase activity often leads to cholinergic symptoms in humans
and laboratory animals, including excessive glandular secretions (salivation, lacrimation, rhinitis),
miosis, exophthalmos, bronchoconstriction, vasodilation, hypotension, diarrhea, nausea, vomiting,
urinary incontinence, and bradycardia. Tachycardia, mydriasis, fasciculations, cramping, twitching,
muscle weakness, and muscle paralysis are associated with nicotinic receptor stimulation. Central
nervous system toxicity may be mediated by either muscarinic or nicotinic receptors and includes
respiratory depression, anxiety, insomnia, headache, apathy, drowsiness, dizziness, loss of
concentration, confusion, tremors, convulsions, and coma (Williams and Burson I985; Chambers and
Levi I992; Cupp et al. I975; Klaassen et al. 1986; Takahashi et al. 1991, 1994). In non-fatal
exposures, the effects are transient and recovery is rapid and complete following cessation of exposure
(Williams and Burson I985; Chambers and Levi 1992). In sufficiently high doses, Chlorfenvinphos
exposure has resulted in death of humans (Felthous 1978), rats (Hutson and Logan 1986; Hutson and
Wright 1980; Puzynska I984; Takahashi et al. 1991, I994; Tsuda et al. 1986), and mice (Kowalczyk-
Bronisz et al. 1992). These effects usually occur within a few minutes to a few hours after dosing,

depending on the extent of exposure.

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Minimal Risk Levelsfor Chlorfenvinphos.
Inhalation MRLs.

Inhalation MRLs for acute-, intermediate—, or chronic-duration exposure to chlorfenvinphos have not
been calculated because adequate data for developing these MRLS are not available. The available

human reports involve mixed exposures. The available animal studies reported serious effects.

A human study reported immunological effects at a LOAEL of 0.21 mg/mg3 following prolonged
occupational exposure to chlorfenvinphos by the inhalation route. However, the subjects of this study
were also concurrently exposed to greater concentrations of other potentially immunotoxic substances
such as formothion, sumithion, and malathion (Wysocki et al. 1987). In another human study, a group
of nine gardeners (pesticide mixers) exposed to unknown concentrations of a mixture of pesticides
(chlorfenvinphos, dimethoate, formothion, isofenphos), complained of headaches and had a mean
difference (before and after exposure) of 0.56 nmol/mL for cholinesterase and 2.67 nmol/mL for
butyrylcholinesterase (Kolmodin-Hedman and Eriksson 1987). However, since these symptoms could
also result from exposure to the other organophosphate pesticides in the mixture, the etiology for these

symptoms is uncertain. Therefore the study was not useful for developing inhalation MRLs.

The available animal inhalation studies reported only serious effects (mortality, apnea, salivation,
urination, exophthalmos, twitches, and tremors) (Takahashi et al. 1994; Tsuda et al. 1986) following
exposure to chlorfenvinphos. Therefore, the data from these studies are not appropriate for use in the

calculation of MRLs.
Oral MRLs.

0 An MRL of 0.002 mg/kg/day has been developed for acute—duration oral exposure (14 days or

less) to chlorfenvinphos.

This MRL for chlorfenvinphos is based on a LOAEL of 2.4 mg/kg/day for neurological effects (30%
erythrocyte cholinesterase inhibition) in female rats (Barna and Simon l973). In the study, two groups
(55 per group) of adult female albino (Wistar) rats weighing 208 gram were orally administered

Birlane” (chlorfenvinphos) at dose of 0 or 2.4 mg/kg/day in the diet for 10 days. The study was

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designed to investigate the effects of oral chlorfenvinphos on body weight increase, the gastrointestinal
absorption of glucose, Na", and Ca3+, as well as the effects of oral chlorfenvinphos on plasma and
erythrocyte cholinesterase activity levels. Plasma cholinesterase activity was inhibited by 52% while
erythrocyte cholinesterase activity level was inhibited by 30% at a dose of 2.4 mg/kg/day (the only
dose tested). Gastrointestinal absorption of glucose was increased by 30% over control values while
Na+ absorption was decreased by 32% below control values. Gastrointestinal absorption of Ca2+ and
body weight increases were unaffected by chlorfenvinphos exposure. These changes in the
gastrointestinal absorption of glucose and Na+ were not considered statistically significant (P>0.05) by

the investigators.

Adverse neurological effect is the principal toxic effect from exposure to chlorfenvinphos.
Chlorfenvinphos, an anticholinesterase organophosphate, inhibits cholinesterase activity in the central
and peripheral nervous system in humans and animals (Cupp et al. I975; Gralewicz et al.1990; Hunter
I969; Maxwell and LeQuesne I982; Osicka-Koprowska et al. 1984; Osumi et al. I975; Pach et al.
I987; Takahashi et al. 1991; Vestweber and Kruckenberg I972). Chlorfenvinphos also inhibits
noradrenaline in the central nervous system in animals (Brzezinski I978; Osumi et al. I975). Human
subjects exposed to large acute doses of chlorfenvinphos exhibited severe cholinergic signs. These
cholinergic signs were relieved by the administration of atropine and/or pralidoxime, indicating
cholinesterase inhibition etiology (Cupp et al. 1975; Pach et al. 1987). In rats, relatively moderate to
low doses (2.4—30 mg/kg) of oral chlorfenvinphos significantly inhibited cholinesterase activities in a
number of tissues, including the brain, erythrocyte, and plasma (Bama and Simon 1973; Osicka-
Koprowska et al. I984; Puzynska 1984). An acute—duration oral study also found alterations in
noradrenaline levels in rat brain following exposure to chlorfenvinphos. A chlorfenvinphos dose of

13 mg/kg decreased noradrenaline levels in rat brains by 20%, as compared to control rats. According
to the investigators, chlorfenvinphos accelerated the rate of NA disappearance from the brain
(Brzezinski 1978). Therefore, it is appropriate to base the acute oral MRL for chlorfenvinphos on

cholinesterase inhibition.

It should be noted that a study by Osumi et al. (I975) which determined a NOAEL of I mg/kg/day
and a LOAEL of 2 mg/kg/day for 38% inhibition of brain cholinesterase in rats was not used to
calculate an acute oral MRL. It was deemed less appropriate because of the gavage (oral) route of
administration of the test substance. An oral feeding study is preferred by the ATSDR MRL
Workgroup.

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0 An MRL of 0.002 mg/kg/day has been developed for intermediate-duration oral exposure
(15—364 days) to chlorfenvinphos.

The MRL is based on a LOAEL of 1.5 mg/kg/day for adverse immunological/lymphoreticular effects
in mice (Kowalczyk-Bronisz et a1. 1992). In this study, male and female inbred C57BL/6 mice and
(C57BL/6xDBA/2)Fl (BDFl/Iiw) hybrids mice (6—8 weeks old) were orally dosed with
chlorfenvinphos (suspended in 1% methylcellulose solution) and evaluated for 5 days for the effect of
chlorfenvinphos exposure on the mouse immune system. The rats were exposed to oral
chlorfenvinphos doses of 0, 1.5, 3, or 6 mg/kg (0, 1 of 100, 1 of 50 or 1 of 25 LDSO) daily for

3 months; the control group was given 1% methylcellulose. Exposed and control mice were then
immunized by intraperitoneal injections of 0.2 mL 10% sheep red blood cells. The IgM-PFC (plaque-
forming or antibody—producing cells) number in spleen cell suspension was tested on day 4 after
immunization and the procedure repeated 3 weeks after the exposure to chlorfenvinphos had ceased.
Exposed and control groups were subjected to immunological tests and hematological examinations.
Lymphatic organs were histologically examined. A dose—related decrease in the number of hemolysin-
producing cells was observed: plaque—forming cells (PFC) were 58% at the 6 mg/kg dose group and
85% at the 3 mg/kg dose level as compared to control values. Chlorfenvinphos treatment also caused
reduction in the number of E rosette-forming cells by 30% at the 6 mg/kg dose level and by 25% at
the 3 mg/kg dose level. Increases in 11-] activity and DTH reaction were observed 24 hours after
challenge. Spleen colonies were stimulated, as evidenced by the increase of endogenous spleen
colonies and exogenous spleen colonies (CFU-S). CFU-S increased 190% at the 1.48 mg/kg dose
level; 137% at the 6 mg/kg dose level; 162% at 1.5 mg/kg dose level; and 70% at the 6 mg/kg dose
level. When the IgM PFC number was tested 3 weeks later, after the exposure to chlorfenvinphos in
the small dose (1.5 mg/kg), an increase (about 40%) in number of plaques was observed. There was a
50% reduction in thymus weight at the 1.5 mg/kg dose level, compared to controls; significant

involution of thymus was also noted.

In other studies, adverse immunological/1ymphoreticular effects have been associated with exposure to
oral chlorfenvinphos. In an intermediate-duration dietary study with albino (Wistar) rats, there was a
significant and irreversible reduction in relative spleen weight of female rats given 23 mg/kg/day
chlorfenvinphos for 12 weeks (Ambrose et a1. 1970). A study was undertaken to evaluate selected
serological and cytoimmunological reactions in rabbits subjected to a long-term poisoning with

subtoxic oral doses (10 mg/kg in a soya oil solution with a small amount of food) of chlorfenvinphos

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for 90 days. Chlorfenvinphos treatment significantly elevated serum hemagglutinin levels (16%) and
hemolysin activity (66%, p<0.05), and also increased the number of nucleated lymphoid cells
producing hemolytic antibody to sheep erythrocytes compared to controls (treated 906, p<0.05 and
controls 618). Spleen cytomorphology changes, manifested mainly as transformation of primary
follicles into secondary ones with well developed germinal centers, were also observed (Roszkowski
I978). Therefore, it is appropriate to base the intermediate oral MRL for chlorfenvinphos on

immunological effects.

- An MRL of 0.0007 mg/kg/day has been derived for chronic-duration oral exposure (365 days or

more) to chlorfenvinphos.

This MRL for chlorfenvinphos was developed from a LOAEL of 0.7 mg/kg/day for adverse
neurological effects in rats (Ambrose et al. I970). In this study, four matched groups of weanling
albino (Wistar) rats (30 rats per sex per group) were culled to a narrow starting weight range and fed
daily GC—4072 (technical chlorfenvinphos) doses of 0, 0.7, 2.l, 7, or 2I mg/kg/day (males) or 0, 0.8,
2.4, or 8, or 24 mg/kg/day (females) in the diet for 104 weeks. An additional group of non-littermate
rats (30 per sex) was administered 2] mg/kg/day (males) or 24 mg/kg/day (females) chlorfenvinphos
for 104 weeks. Plasma and ChE activity levels were obtained from 4 rats of each sex per dose group
at I, 4, 8, and 12 weeks. At 13 weeks, 4 rats per sex per dose group were sacrificed for
histopathologic examination. At 13 weeks, 4 rats per sex per dose group were sacrificed for
histopathologic examination. The rats in the 21 mg/kg/day (males) and 24 mg/kg/day (females) were
sacrificed on the 95th week, while all other dose group animals were sacrificed on the end of the study
(104 weeks). At each autopsy, relative organ weights were determined for heart and kidneys. All
animals sacrificed in moribund condition as well as those sacrificed at weeks I3, 95, and 104 were
examined grossly and microscopically, and organs (heart, lungs, liver, kidney, urinary bladder, spleen,
stomach, small and large intestine, skeletal muscle, skin, bone marrow, pancreas, thyroid, adrenal,
pituitary) from these animals were histopathologically examined. Chlorfenvinphos significantly
decreased body weight gain of females at the 8 and 24 mg/kg/day dose groups from the 26th week
until near the end of the study, although the decreased body weight gain became statistically
insignificant at the end of the study. Increased relative liver weights were observed in males at the

7 mg/kg/day dose level, but no other signs of hepatopathology were reported. No consistent difference
in body weight gains in males, survival of the test animals, food consumption, or mortality was

evident at all dose levels tested, as compared to undosed controls. Essentially, no gross or

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CHLORFENVINPHOS

2. HEALTH EFFECTS

microscopic histopathology was evident in all the organs (heart, lungs, liver, kidney, urinary bladder,
spleen, stomach, small and large intestine, skeletal muscle, skin, bone marrow, pancreas, thyroid,
adrenal, pituitary) and tissues examined. No changes in organ—to-body weight were observed in the

heart, kidney, spleen and testes (Ambrose et al. 1970).

Although the neurological effects of prolonged human exposure to low oral doses of chlorfenvinphos
are not known due to a lack of studies, acute-duration exposure data indicate that neurological effects,
mediated by cholinesterase inhibition, are the most sensitive toxicological consequences of human
exposure to chlorfenvinphos (Cupp et al. 1975; Pach et al. 1987). Similarly, chlorfenvinphos
significantly inhibited both plasma and erythrocyte cholinesterase activities in Beagle dogs (2 per sex)
fed daily chlorfenvinphos doses of 0, 0.3, 2, or 10 mg/kg/day (males), or 0, 1.5, 10, or 50 mg/kg/day
(females) in the diet (moist) for 104 weeks. Plasma cholinesterase activities were significantly
inhibited at all dietary levels through week 39 of the study; 49% inhibition at the 0.3 mg/kg/day
(males) and 1.5 mg/kg/day (females) dose levels (Ambrose et al. 1970).

Death. Data are not available to estimate the lethal dose of chlorfenvinphos in any route or for any
duration of exposure in humans. However, one study reported the death of a 16-year-old victim

following unintentional ingestion of an unspecified amount of chlorfenvinphos (Felthous 1978). In

animal studies, the acute inhalation LC50 for rats is estimated as 130 mg/m3 (Tsuda et al. 1986). The

acute oral LD50 for technical chlorfenvinphos for both sexes of rat is variously estimated as

15.4 mg/kg (Hutson and Wright 1980); 22.8 mg/kg (Hutson and Logan 1986); 34.5 (Ikeda et al.

1992); 9.7 mg/kg/day (Ambrose et al. 1970). The acute oral LD50 values for male and female rats
have been given as 23 mg/kg and 25.5 mg/kg, respectively (Puzynska 1984). Chlorfenvinphos appears
to be less acutely toxic to mice, with an estimated LD50 values of 148 mg/kg and 109 mg/kg,
respectively, for male and female mice (Kowalczyk-Bronisz et al. 1992). The LD50 for rabbits has
been estimated to be 300 mg/kg (Ambrose et al. 1970) and SOD-1,000 mg/kg (Hutson and Logan
1986); the estimated LDSO for dogs is 50.5 mg/kg/day (Ambrose et al. 1970).

The dermal LD50 values for undiluted chlorfenvinphos and emulsifiable concentrate for rabbits have
been estimated as 400 and 1,087 g/kg, respectively (Ambrose et al. 1970). No reports of human
deaths resulting from dermal exposure to chlorfenvinphos were located, but evidence from non—lethal
human data and animal studies (Hunter 1969; Vestweber and Kruckenberg 1972) indicates that human

lethality by this route of exposure is unlikely.

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CHLORFENVINPHOS 80

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Systemic Effects.

Respiratory Effects. No studies were located regarding the respiratory effects in humans following
acute—, intermediate-, or chronic-duration inhalation or dermal exposure, or following intermediate- or
chronic—duration oral exposure to chlorfenvinphos. A male patient, aged 29, was admitted 3 hours
after a suicide attempt during which he drank about 50 mL of Enolofosu‘), which contains 50%
chlorfenvinphos, was implicated in respiratory failure and bronchial tree hypersecretion. These
symptoms subsided after he was given hemoperfusion and drug treatment for anticholinesterase
poisoning (Pach et al. 1987). Animal data indicate that acute-duration inhalation exposure to high
doses of chlorfenvinphos (16—390 mg/m") may be accompanied by transient apnea (Takahashi et al.
I991, I994). Necropsy examination of rabbits administered IO mg/kg of chlorfenvinphos orally for
90 days showed no signs of poisoning or gross lesions in the lungs in an intermediate-duration study
(Roszkowski I978). Due to inadequate data, it is unknown whether human exposure to environmental

concentrations of chlorfenvinphos could result in adverse respiratory effects.

Hematological Effects. The hematological effects from inhalation exposure to chlorfenvinphos are not
known due to lack of data in humans and laboratory animals. Similarly. the hematological effects of
oral chlorfenvinphos exposure are not certain because of limited and inconclusive data in animals.
Uncorroborated investigations conducted on 4 groups of male and female rabbits (13 each) at a dose of
IO mg/kg for 90 days to evaluate the serological effects of chlorfenvinphos reported significant
increases of hemolysin and hemagglutinin serum titers as compared to controls. Hemagglutinin and
hemagglutinin IgG titers were increased by 16 and 18%, respectively, while hemolysin and hemolysin

IgG titers were elevated by 66 and 102%, respectively (Roszkowski I978).

Cardiovascular Effects. No studies were located regarding the cardiovascular effects in humans
following acute-, intermediate-, or chronic-duration inhalation, oral, or dermal exposure to
chlorfenvinphos. Animal data indicate that acute—duration inhalation exposure to high doses of
chlorfenvinphos (16—390 mg/m3) may be preceded by an initial hypotension followed by steadily
increasing hypertension and abnormal cardiac conductivity (Takahashi et al. l99l. I994). Evidence
from animal studies also indicates that oral chlorfenvinphos is not directly toxic to the cardiovascular
system, but may modulate the function of the cardiovascular system via its effect on the central

nervous system (Ambrose et al. 1970; Klaassen et al. I986; Puzynska 1984). Due to inadequate data.

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CHLORFENVINPHOS 81

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it is unknown whether human exposure to environmental concentrations of chlorfenvinphos could

result in adverse cardiovascular effects.

Gastrointestinal Effects. No studies were located regarding the gastrointestinal effects in humans
following acute-, intermediate—, or chronic—duration oral exposure to chlorfenvinphos. Acute- and
intermediate—duration oral exposures to chlorfenvinphos increased gastrointestinal absorption of
glucose, while decreasing the gastrointestinal absorption of Na*; Ca2+ absorption was unaffected in
adult Wistar rats. However, the changes in glucose and Na+ absorption were not considered
statistically significant (P>0.05) by the investigators (Barna and Simon 1973). In another intermediate—
duration study, necropsy examination of rabbits administered 10 mg/kg of chlorfenvinphos orally for
90 days showed no signs of poisoning or gross lesions in the gastrointestinal tract (Roszkowski I978).
Likewise, weanling albino (Wistar) rats of both sexes chronically administered daily dietary
chlorfenvinphos doses of 2] mg/kg/day (males) or 24 mg/kg/day (females) exhibited no gross or
microscopic histopathology in the stomach, and small and large intestines at autopsy (Ambrose et al.
1970). Based on the available information, human exposure to chlorfenvinphos at hazardous waste

sites in not likely to result in any significant adverse gastrointestinal effects.

Hematological Effects. No studies were located regarding the gastrointestinal effects in humans or
animals following acute-, intermediate, or chronic—duration oral exposure to chlorfenvinphos. In one
study, necropsy examination of rabbits administered ll) mg/kg of chlorfenvinphos orally for 90 days
showed no signs of poisoning or gross lesions in the gastrointestinal tract (Roszkowski 1978). Due to
the paucity of data on the hematological effects on chlorfenvinphos in humans and animals, the

hematological effects of human exposure to chlorfenvinphos are not known.

Musculoskeletal Effects. No musculoskeletal effects were reported in humans or animals from
exposure to chlorfenvinphos by any route or duration; therefore, the musculoskeletal effects from

exposure to chlorfenvinphos by any route or duration are not known.

Hepatic Effects. Based on the currently available data, chlorfenvinphos exposure at environmental
levels is not likely to present risk of liver injury to humans. No hepatic effects were reported in
humans from exposure to chlorfenvinphos by any route. Although chlorfenvinphos proved to be
porphyrinogenic in tissue culture without induction and markedly porphyrinogenic with induction

(Koeman et al. 1980), no such evidence was found in the currently available in vim studies. The

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limited information on the hepatic effects of chlorfenvinphos indicates that the substance is not
significantly hepatotoxic by the oral route in acute-, intermediate-, or chronic-duration exposures. No
changes in liver weight (relative to body weight) were reported in Fischer 344 rats given a single oral
chlorfenvinphos dose of 15 mg/kg (Ikeda et al. 1991). Although intermediate oral administration of
chlorfenvinphos induced alterations in serum sorbitol dehydrogenase, and brain and liver levels of
aromatic amino acids transferases Phen AT, Tyr AT, and Try AT in mature Wistar rats (Puzynska
1984). necropsy examination of rabbits administered 10 mg/kg of chlorfenvinphos orally for 90 days
showed no signs of poisoning or gross lesions in the liver (Roszkowski 1978). Likewise, no gross or
microscopic histopathology in liver tissues was evident in weanling albino (Wistar) rats administered
daily dietary chlorfenvinphos doses of 90 mg/kg/day (males) or 100 mg/kg/day (females) or in
mongrel dogs given daily dietary doses of 10 mg/kg/day (males) or 50 mg/kg/day (females) for

12 weeks. However, relative liver weights were significantly and irreversibly decreased in the rats at a
dose of 2.7 mg/kg/day (males) or 3 mg/kg/day (females) (Ambrose et al. 1970). In chronic

(104 weeks) feeding studies, increased relative liver weights were observed in males at a dose of

7 mg/kg/day following dietary administration of chlorfenvinphos to both sexes. No liver
histopathological or adverse liver function effects were reported in Beagle dogs (2 per sex) fed daily
dietary chlorfenvinphos doses of 10 mg/kg/day (males) or 50 mg/kg/day (females) for 104 weeks
(Ambrose et al. 1970). The Puzynska study (1984) concluded that the alteration of brain and liver
activities of the aromatic amino acid transferases may be due to the inhibitory effect of
chlorfenvinphos on noradrenaline activity, since noradrenaline has been shown to affect amino acid
transferase (L—tyrosine aminotransferase) activity in another study. Chlorfenvinphos has been shown
independently to inhibit noradrenaline activity in vivo in rats at doses as low as 4 mg/kg in 3 hours,

and also in other studies (Brzezinski 1978; Osumi et al. 1975).

Endocrine Effects. There are no reports of endocrine effects in humans exposed by acute-,
intermediate—, or chronic-duration ingestion of chlorfenvinphos. No studies were located regarding
endocrine effects in animals after intermediate- or chronic—duration oral exposure to this insecticide.
Although a significant increase (>300%) of plasma corticosterone was observed at 1 and 3 hours and
plasma aldosterone from 1 to 6 hours after treatment of male Wistar rats with a single chlorfenvinphos
dose of 6.15 mg/kg (50% LDSO) by stomach tube (Osicka—Koprowska et al. 1984), the toxicological

significance of these findings and relevance to human health is unknown.

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CHLORFENVINPHOS

2. H EALTH EFFECTS

Renal Effects. No studies were located regarding the renal effects in humans or animals following

acute-, intermediate—, or chronic—duration oral exposure to chlorfenvinphos. In one study, necropsy
examination of rabbits administered 10 mg/kg of chlorfenvinphos orally for 90 days showed no signs
of poisoning or gross lesions in the kidney (Roszkowski 1978). Likewise, no gross or microscopic
histopathology in kidney tissues was evident in weanling albino (Wistar) rats administered daily
dietary chlorfenvinphos doses of 90 mg/kg/day (males) or 100 mg/kg/day (females) or in mongrel dogs
given daily dietary doses of 10 mg/kg/day (males) or 50 mg/kg/day (females) for 12 weeks. However.
relative kidney weights were significantly and irreversibly decreased in the rats at a dose of

2.7 mg/kg/day (males) or 3 mg/kg/day (females) (Ambrose et a1. 1970). In chronic (104 weeks)
feeding studies, no gross or microscopic histopathology in the kidney and urinary bladder tissues
examined or changes in relative kidney weights were evident in this strain of rats following daily
doses of 21 mg/kg/day (males) or 24 mg/kg/day (females) (Ambrose et a1. 1970). No kidney
histopathological or adverse kidney function effects were reported in Beagle dogs (2 per sex) fed daily
dietary chlorfenvinphos doses of 10 mg/kg/day (males) or 50 mg/kg/day (females) for 104 weeks
(Ambrose et a1. 1970). No renal function was assessed in these studies. Due to the lack of adequate
data on the renal effects on chlorfenvinphos in humans and animals, the renal effects of human

exposure to chlorfenvinphos are not known.

Dermal Effects. No studies were located regarding the dermal effects in humans or animals following
acute—, intermediate—, or chronic-duration inhalation, oral, or dermal exposure to chlorfenvinphos.
Consequently, it is not known whether human exposure to environmental concentrations of

chlorfenvinphos could result in adverse dermal effects.

Ocular Effects. No studies were located regarding the ocular effects in humans or animals following
acute-, intermediate-, or chronic-duration inhalation, oral, or dermal exposure to chlorfenvinphos.
Consequently, it is not known whether human exposure to environmental concentrations of

chlorfenvinphos could result in adverse ocular effects.

 

Metabolic Effects. No studies were located regarding the metabolic effects in humans following
acute-, intermediate-, or chronic—duration oral exposure to chlorfenvinphos. In animal studies, no
significant effect on food consumption was evident in weanling albino (Wistar) rats administered daily
dietary chlorfenvinphos doses of 90 mg/kg/day (males) or 100 mg/kg/day (females) or in mongrel dogs
given daily dietary doses of 10 mg/kg/day (males) or 50 mg/kg/day (females) for 12 weeks. Similarly,

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2. HEALTH EFFECTS

in chronic (104 weeks) feeding studies, no significant effect on food consumption was evident in rats
and Beagle dogs following daily doses of 21 mg/kg/day (tnales) or 24 mg/kg/day (females) and

IO mg/kg/day (males) or 50 mg/kg/day (females), respectively (Ambrose et a1. 1970). Based on the
available information. human exposure to environmental concentrations of chlorfenvinphos is not likely

to result in any significant adverse metabolic effects.

Body Weight Effects. No studies were located regarding the body weight effects in humans following
acute—, intermediate-, or chronic-duration inhalation, oral, or dermal exposure to chlorfenvinphos. In
animal studies, acute—duration exposure of adult rats to oral Birlane” (chlorfenvinphos) at a dose of
2.4 mg/kg/day in the diet for 10 days did not affect body weight increases. Body weight increases
were also unaffected following oral doses of 0.8 mg/kg/day in the diet for 30 days (Barna and Simon
1973). Similarly, no body weight changes were seen in mongrel dogs exposed to dietary
chlorfenvinphos at a dose of 10 mg/kg/day (males) or 50 mg/kg/day (females) for 12 weeks (Ambrose
et al. 1970). However, oral exposure of weanling rats for the same duration was associated with a
significant but slightly reversible depression of growth, observed at a dose of 9 mg/kg/day (males) or
IO mg/kg/day (females). In an accompanying chronic-duration oral study (104 weeks),
chlorfenvinphos also significantly and reversibly decreased body weight gain of female weanlings at
dose levels of 28 mg/kg/day. Beagle dogs given daily dietary chlorfenvinphos doses of 10 mg/kg/day
(males) or 50 mg/kg/day (females) for the same duration (104 weeks) exhibited no significant changes
in body weight (Ambrose et al. 1970). Based on the available information, human exposure to
environmental concentrations of chlorfenvinphos is not likely to result in any significant adverse body

weight effects.

Other Systemic Effects. No studies were located regarding other systemic effects in humans or
animals following acute—, intermediate, or chronic-duration inhalation, oral, or dermal systemic effects
resulting from exposure to chlorfenvinphos. Consequently, it is not known whether human exposure

to environmental concentrations of chlorfenvinphos could result in other adverse systemic effects.

Immunological and Lymphoreticular Effects. Only one study was located that reported

immunological effects in humans. In this report. occupational exposure to inhaled chlorfenvinphos for
an average of 15 years was associated with damage to humoral mechanisms in humans. In this study,
the subjects exhibited significant decrease of the spontaneous E rosette formation and lowered absolute

lymphocyte count in the peripheral blood. However, the subjects of this study were also concurrently

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CHLORFENVINPHOS 85

2. HEALTH EFFECTS

exposed to greater concentrations of other potentially immunotoxic substances such as formothion,
sumithion, and malathion (Wysocki et al. 1987). In animal studies. the gastrointestinal absorption of
glucose was increased by 30% over control values in adult female albino (Wistar) rats orally
administered Birlane“) (chlorfenvinphos) at a dose of 0 or 2.4 mg/kg/day in the diet for IO days.
Similarly, gastrointestinal absorption of glucose was increased by 12% over control values following
orally administered Birlanew (chlorfenvinphos) at a dose of 0 or 0.8 mg/kg/day in the diet to this strain
of rats for 30 days. However, the changes in glucose and Na” absorption were not considered
statistically significant (P>0.05) by the investigators (Barna and Simon 1973). It has been observed in
other studies that an increased metabolic activity of neutrophils and monocytes during phagocytosis is
accompanied by higher consumption of glucose and oxygen. Hydrogen peroxide is then derived from
the pentose cycle, NAD-, and NADP—oxidase action (Kolanoski 1977). However, the relationship
between increased gastrointestinal absorption of glucose and increased glucose utilization is not clear.
In other animal studies, rabbits orally exposed to chlorfenvinphos for 90 days also exhibited
significantly elevated serum hemagglutinin level (16%) and hemolysin activity (66%, p<0.05) as well
as increased numbers of nucleated lymphoid cells producing hemolytic antibodies to sheep
erythrocytes. Spleen cytomorphology changes, manifested mainly as transformation of primary
follicles into secondary ones with well developed germinal centers, were also observed (Roszkowski
1978). Intermediate—duration dietary exposure of rats resulted in a significant and irreversible
reduction in relative spleen weight of female rats given 23 mg/kg/day chlorfenvinphos for 12 weeks.
However, no gross or microscopic histopathology was evident in the spleen and bone marrow tissues
of the rats upon examination (Ambrose et al. 1970). No histopathological changes in the spleen or
bone marrow or changes in absolute or relative spleen weights were noted in rats or Beagle dogs of
both sexes given dietary chlorfenvinphos doses of 21 mg/kg/day (males) or 24 mg/kg/day (females), or
10 mg/kg/day (males) or 50 mg/kg/day (females), respectively, for 104 week (Ambrose et a1. 1970).
C57BL/6 mice and (C57BL/6xDBA/2)F1 (BDFl/Iiw) hybrid mice (6—8 weeks old) orally exposed to
chlorfenvinphos for 90 days exhibited a reversible reduction in the number of E rosette-forming cells
as well as a dose—related decrease in the number of hemolysin-producing cells, reduction in the number
of plaque-forming cells, increases in 11-1 activity and DTH reaction, stimulation of spleen colonies,
and disturbance in humoral immune factors (immunoglobulins) at a LOAEL of 1.5 mg/kg (Kowalczyk—
Bronisz et al. 1992). The LOAEL of 1.5 mg/kg/day, based on adverse immunological/lymphoreticular
effects in this study, was used to derive an intermediate oral MRL of 0.002 mg/kg/day for
chlorfenvinphos. While the existing human inhalation study and the animal oral studies provide some

indication that chlorfenvinphos exposure is associated with immunological changes, these changes

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CHLORFENVINPHOS 86

2. HEALTH EFFECTS

were not consistent with depressive effects on immune reactions. Thus, the changes reported in these
studies may simply be immunological mobilizations of the organisms to xenobiotics in
contradistinction from damage to the major histocompatibility complex. Consequently, it is not certain

that human inhalation or oral exposure to Chlorfenvinphos can result in immune dysfunction.

Neurological Effects. No studies were located regarding neurological effects in humans after
acute— or intermediate—duration inhalation exposure to Chlorfenvinphos, or after intermediate- or
chronic-duration dermal exposure. Chlorfenvinphos inhibits cholinesterase activity in the central and
peripheral nervous system of humans and animals (Ambrose et al. 1970; Barna and Simon 1973; Cupp
et al. 1975; Gralewicz et al. I989a, 198%, I990; Hunter 1969; Maxwell and LeQuesne I982; Osicka-
Koprowska et al. I984; Pach et al. I987; Takahashi et al. I991; Vestweber and Kruckenberg I972). It
also inhibits noradrenaline activity in the central adrenergic mechanisms in animals (Brzezinski I978;
Osumi et al. I975). Inhibition of cholinesterase activity results in accumulation of choline at
muscarinic and nicotinic receptors leading to peripheral and central nervous system effects. These
effects usually appear within a few minutes to a few hours after exposure, depending on the extent of
exposure. In a human case report, a 16-year-old white male mistakenly ingested a formulation
(identified as Dermatonm’), was hospitalized 90 minutes afterward with symptoms of abdominal cramps,
nausea, vomiting, generalized weakness, cold dry skin, hypothermia, listlessness, constricted pupils,
hypertension, respiratory distress, fine generalized muscular twitching, and apprehension. Plasma and
erythrocyte activity levels were significantly inhibited. All vital signs returned to normal after gastric
lavage and treatment with atropine and pralidoxime (Cupp et al. I975).

The available information indicates that Chlorfenvinphos has similar neurological effects in animals.
The information indicates that the substance causes disruptions in the central and peripheral nervous
system in rats and dogs following acute-, intermediate-, or chronic—duration exposures via the oral
route at doses as low as 0.8 mg/kg/day (Ambrose et al. I970; Barna and Simon I973; Maxwell and
LeQuesne I982; Osumi et al. I975; Puzynska I984; Takahashi et al. I994). These disruptions are
mediated by the inhibition of cholinesterase activity in the peripheral and central nervous tissue and
are manifested as abnormal muscle reflex, muscle fasciculations, Straub tail reflex, twitches,
convulsions, chromodacryorrhea, exophthalmos, gasping, Iacrimation, prostration, salivation, sleep
disturbances, diarrhea, emesis, and urination (Ambrose et al. I970; Maxwell and LeQuesne I982;
Osumi et al, I975; Puzynska I984; Takahashi et al. I991). Cholinesterase activity in the brain of male
Wistar rats was unaffected 3 hours after oral administration of I mg/kg of Chlorfenvinphos. However,

at doses of 22 mg/kg, oral Chlorfenvinphos produced a marked decrease in the brain cholinesterase

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CHLORFENVINPHOS

2. HEALTH EFFECTS

activity to 18—38% of the control (p<0.001) value. The maximum inhibition occurred three hours after
the administration, after which the cholinesterase activity elevated gradually. Erythrocyte
cholinesterase activity also decreased after 4 mg/kg of chlorfenvinphos: the lowest level (20%,
p<0.001) was attained 3 hours after treatment (Osumi et al. 1975). This study was not used to
calculate an acute oral MRL because it was deemed less appropriate due to the gavage (oral) route of
administration. An oral feeding study is preferred for this purpose by the ATSDR MRL Workgroup.
In a chronic-duration study, chlorfenvinphos significantly inhibited both plasma and erythrocyte
cholinesterase activities in a dose-dependent manner in weanling albino (Wistar) rats (30 rats per sex
per group) fed daily chlorfenvinphos doses of 0, 0.7, 2.1, 7, or 21 mg/kg/day (males) or 0, 0.8, 2.4, 8,
or 24 mg/kg/day (females) mg/kg/day in the diet for 104 weeks. Plasma and erythrocyte
cholinesterase activities were inhibited by 48% in females and 45% in males in the first week of
treatment and by 20% in females and 33% in males in the fourth week of treatment, respectively, at
the lowest dose tested (0.7 mg/kg/day for males and 0.8 mg/kg/day for females). Essentially, no gross
or microscopic histopathology was evident in the brain tissue examined (Ambrose et al. 1970). The
LOAEL of 0.7 mg/kg/day, based on adverse neurological effects in rats in this study, was used to
derive a chronic oral MRL of 0.0007 mg/kg/day for chlorfenvinphos. In another study, all

36 Sprague-Dawley rats exposed to chlorfenvinphos doses of 10.5 mg/kg/day in the diet for

3—6 months exhibited repetitive muscle activity when given two electrical stimuli simultaneously. This
is indicative of hyper stimulation due to depletion or inactivation of neuromuscular junction
cholinesterase. The abnormality became more marked with time, even on constant dosing (Maxwell
and LeQuesne 1982). The indications from this study may be useful in explaining electrophysiological

abnormalities described in some workers chronically exposed to some organophosphorus compounds.

Besides its cholinergic action, there is limited evidence that chlorfenvinphos acts on the central
noradrenergic mechanism in rats by accelerating the noradrenaline turnover in the brain in viva by the

release of noradrenaline from brain tissue stores (Brzezinski 1978). Although all doses of

chlorfenvinphos elicited cholinergic responses (leg weakness, salivation, and retching) from hens given

100, 150, 200, or 300 mg/kg by intraperitoneal injection, the hens showed no signs of delayed

neurotoxicity after 20 days of observation (Ambrose et al. 1970).
On the basis of the existing evidence, human exposure to chlorfenvinphos is likely to result in

neurological effects stemming from interference with both the central cholinergic and adrenergic

mechanisms.

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CHLORFENVINPHOS 88

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Reproductive Effects. No studies were located regarding the reproductive effects in humans
following acute-, intermediate—, or chronic-duration inhalation, oral, or dermal exposure to
chlorfenvinphos. Reports from single—generation, intermediate- or chronic-duration rat and dog studies
are largely negative for reproductive effects (Ambrose et al. 1970). However, these studies did not
evaluate reproductive function. A 3—generation reproductive study in albino (Wistar) rats reported
significant (50%) reduction in fertility in the F/2 generation at a LOAEL of 3 mg/kg/day (Ambrose et
a1. 1970). Although human data is lacking. the indications provided by the animal data suggest that
adverse reproductive effects may result from prolonged human exposure to chlorfenvinphos at levels

found at hazardous wastes sites.

Developmental Effects. No studies were located regarding the developmental effects in humans
or animals following acute—, intermediate, or chronic—duration inhalation, oral, or dermal exposure to
chlorfenvinphos. A statistical system for hazard identification concluded that chlorfenvinphos is likely
to interfere with development in rabbits and hamsters but not in rats. This system did not evaluate the
adverse reproductive effects potential of chlorfenvinphos in primates, mice, and dogs. This method
correctly classified the study compounds 63—91 (7( of the time. The model had a sensitivity of
62—75%, a positive predictive value of 7,5400%, However, the model had a negative predictive value
of 64—91%, indicating the model is not optimal for hazard identification (Jelovsek et a1. 1989). In
acute exposures, chlorfenvinphos inhibited the respiratory efficiency of juvenile rats in a dose-
dependent manner at a LOAEL of 29 mg/kg/day. At 300 mg/kg/day, chlorfenvinphos completely
arrested respiration in these rats (Skonieczna et al. 1981). In a 3-generation rat study, chlorfenvinphos
induced significant but slightly reversible body weight gains in female rats at a LOAEL of

28 mg/kg/day as well as increased pup mortality and reduced lactational index at a LOAEL of

2.7 mg/kg/day. However, no teratogenic effects were reported in offspring rats (Ambrose et a1. 1970).
In single-generation intermediate- and chronic—duration studies with juvenile rats in which the rats
were given dietary chlorfenvinphos doses of 90 mg/kg/day (males) or 100 mg/kg/day (females) for

12 weeks, or 21 mg/kg/day (males) or 24 mg/kg/day (females) in the diet for 104 weeks, no
significant effects on development were reported (Ambrose et al. 1970). Although human data are
lacking, the indications provided by the animal data suggest that adverse developmental effects may

result from prolonged human exposure to chlorfenvinphos at levels found at hazardous wastes sites.

Genotoxic Effects. No studies were located regarding the genotoxic effects of chlorfenvinphos in

humans following oral exposure. Chlorfenvinphos was negative for rnutagenicity in both base—change-

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CHLORFENVINPHOS 89

2, HEALTH EFFECTS

type strains microorganisms (WP2 her of Esclwrichia coli; TAIS35, TA1537, TAI538, TA98 of S.
ryphimurium). However, the mutagenic potency of chlorfenvinphos for strain TAI()0 was

0.038 revertants/nmol indicative of a positive response (Dean 1972; Moriya et al. I983; Vishwanath
and Kaiser 1986). A mixture of 15 pesticides (containing 0.3% chlorfenvinphos) tested negative for
mutagenicity in the Salmonella microsome assay, with or without metabolic activation with
PCB-induced rat liver S9, at concentrations up to 500 ug/plate in the Salmonella—microsome assay.
The mixture also failed to induce SCEs in human lymphocytes in virro as well as in vivo mutagenicity
in the micronucleus bone marrow assay in male Wistar rats at concentrations proportional to the ratio
determined in foods ranging from 0.1 to 20 ug/mL (Dolara et al. I993). In other large—scale screening
programs, which revealed microbial mutagenic activity in four new compounds (all fungicides),
chlorfenvinphos (without metabolic activation) exhibited no mutation induction capacity in a rec-assay
procedure (prescreening of DNA-damaging chemicals) utilizing strains of Bacillus subtilis. HI7 Rec+
and M45 Rec—. Also. no mutation potential was evident in a reversion—assay (determination of
mutation specificities) in which two tryptophan—requiring strains (auxotrophic) of E. (‘()ll (B/r try WPZ
and WP2 try hcr) and four strains of S. Iyphimurium (TAI535, TAIS36, TAI537, TA1538) were used.
The E. ('oli auxotrophic strains and Salmonella TAI535 are reversible by base—pair change-type
mutagens and the three Salmonella strains (TA1536, TA1537, and TAI538) are reversible by

frameshift mutagens (Shirasu I973; Shirasu et al. 1976).

There are no unequivocal data to indicate that chlorfenvinphos reacts directly with DNA in VlW) or in
virro to produce mutations in either germ or somatic cells. In a study to determine the ability of vinyl
phosphate esters like chlorfenvinphos to form methylated bases in DNA of calf thymus failed to detect
6-methyl guanine, a known mutagen. In both the reaction with dsDNA and ssDNA, 7-methyl guanine
was the main methylation product. However, all methyl derivatives of adenine constituted about 40%
and 50% of all methylation products in the case of dsDNA and ssDNA, respectively. 3-Methyl-
cytosine was the only methyl derivative of a pyrimidine identified (Wiaderkiewicz et al. I986). In
another study, tetrachlorvinphos (GardonaW) was evaluated for its potential to induce chromosomal
aberrations and SCEs in vitro in a primary culture of Swiss mice spleen cells at concentrations of 0.25,
0.50, I.0, or 20 pg/mL. Tetrachlorvinphos induced a high percentage of metaphases with
chromosomal aberrations in the mouse spleen cells after four hours of treatment in a dose—dependent
manner. According to the authors, the results indicate that tetrachlorvinphos in the tested
concentrations is mutagenic in mouse spleen cell cultures (Amer and Aly I992). In both of these

studies, structural analogs of chlorfenvinphos (methylbromophenvinphos and tetrachlorvinphos,

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CHLORFENVINPHOS

2. HEALTH EFFECTS

respectively) were used; therefore, the data are difficult to relate to chlorfenvinphos without extensive

structure-activity relationship analysis. Data from these studies are shown on Table 2—3.

Cancer. There are no epidemiological or laboratory animal data to evaluate the carcinogenicity of
chlorfenvinphos in humans. However, a study to determine the ability of vinyl phosphate esters, like
chlorfenvinphos, to form methylated bases in DNA of calf thymus failed to detect 6-methyl guanine, a
known mutagen. In both the reaction with dsDNA and ssDNA, 7—methyl guanine was the main
methylation product. However, all methyl derivatives of adenine constituted about 40% and 50% of
all methylation products in the case of dsDNA and ssDNA, respectively. 3-Methylcytosine was the
only methyl derivative of pyrimidine identified (Wiaderkiewicz et al. I986). It is noteworthy that the
production of electrophilic metabolic intermediates or epoxides in the metabolism of chlorfenvinphos,
which could react with nucleophilic cellular components (DNA, RNA, and proteins) leading to

carcinogenesis, was considered unlikely by a theoretical analysis (Akintonwa I985).

In another study, tetrachlorvinphos (Gardona°°) was evaluated for potential to induce chromosomal

aberrations and SCEs in vitro in a primary culture of Swiss mice spleen cells at concentrations of 0.25,

0.50, 1.0, or 2.0 ug/mL. Tetrachlorvinphos induced a high percentage of metaphases with
chromosomal aberrations in the mouse spleen cells after four hours of treatment in a dose-dependent
manner. According to the authors, the results indicate that tetrachlorvinphos in the tested
concentrations is mutagenic in mouse spleen cell cultures (Amer and Aly I992). In both of these
studies, structural analogs of chlorfenvinphos (methylbromophenvinphos and tetrachlorvinphos,
respectively) were used, therefore, the data are difficult to relate to chlorfenvinphos without extensive
structure-activity relationship analysis. In a mutagenicity study, the dose-response curve, at doses of 0,
50, 500, and 5,000 ug/plate, for the mutagenic activity of chlorfenvinphos for the S. typhimurium
strain TAIOO was reduced by the S9 mix (metabolic activation). At present, no mutagenic pesticide,
the activity of which decreases in the presence of the S9 mix, is carcinogenic except captan (F—28)
(Moriya et al. I983). A theoretical analysis that predicted the mammalian biotransformation products
based on the recognition of the structure of chlorfenvinphos, understanding of Types I and II
metabolism of foreign compounds, and mechanistic biochemistry, also acknowledged that cytochrome
P—450 monooxygenase (an inducible enzyme) is the relevant enzyme which mediates the
biotransformation of chlorfenvinphos. The author of this study postulated that the 2,4—dichlorobenzoyl
glycine (2,4-dichlorohippuric acid) was produced in the rat by this mechanism. The production of

electrophilic metabolic intermediates or epoxides in the metabolism of chlorfenvinphos, which could

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91

2. HEALTH EFFECTS

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CHLORFENVINPHOS 92

2. HEALTH EFFECTS

react with nucleophilic cellular components (DNA, RNA, and proteins) leading to carcinogenesis, was
considered unlikely by this theoretical approach (Akintonwa 1984). Although neither human
epidemiological evidence or evidence from rodent cancer bioassays is available, the current theoretical

evidence indicates that human exposure to chlorfenvinphos is not likely to present cancer risk.

2.6 BIOMARKERS OF EXPOSURE AND EFFECT

Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They
have been classified as markers of exposure, markers of effect, and markers of susceptibility

(NAS/NRC 1989).

Due to a nascent understanding of the use and interpretation of biomarkers, implementation of
biomarkers as tools of exposure in the general population is very limited. A biomarker of exposure is
a xenobiotic substance or its metabolite(s), or the product of an interaction between a xenobiotic agent
and some target molecule(s) or cell(s) that is measured within a compartment of an organism
(NAS/NRC I989). The preferred biomarkers of exposure are generally the substance itself or
substance—specific metabolites in readily obtainable body fluid(s) or excreta. However, several factors
can confound the use and interpretation of biomarkers of exposure. The body burden of a substance
may be the result of exposures from more than one source. The substance being measured may be a
metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from
exposure to several different aromatic compounds). Depending on the properties of the substance
(e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the
substance and all of its metabolites may have left the body by the time samples can be taken. It may
be difficult to identify individuals exposed to hazardous substances that are commonly found in body
tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of

exposure to chlorfenvinphos are discussed in Section 2.6.1.

Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within
an organism that, depending on magnitude, can be recognized as an established or potential health
impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals
of tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital
epithelial cells), as well as physiologic signs of dysfunction such as increased blood pressure or

decreased lung capacity. Note that these markers are not often substance-specific. They also may not

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CHLORFENVINPHOS 93

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be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of

effects caused by chlorfenvinphos are discussed in Section 2.6.2.

A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism‘s
ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an
intrinsic genetic or other characteristic, or a preexisting disease that results in an increase in absorbed
dose, a decrease in the biologically effective dose, or a target tissue response. If biomarkers of

susceptibility exist, they are discussed in Section 2.8, Populations That Are Unusually Susceptible.

2.6.1 Biomarkers Used to Identify or Quantify Exposure to Chlorfenvinphos

Chlorfenvinphos is rapidly absorbed from the gastrointestinal tract and widely distributed throughout
the body in humans (Pach et al. 1987; Wagner et al. 1990). Traces of unchanged chlorfenvinphos
have been detected in animal urine following exposure (Hunter et al. 1972; Szczepaniak and
Sienkiewitcz 1980). Chlorfenvinphos undergoes biotransformation to a variety of polar metabolites,
including 2-chloro-l—(2,4-dichlorophenyl) vinylethylhydrogen phosphate; l-(2,4—dichlorophenyl)
ethanol; l-(2,4—dichlorophenyl) ethanediol; 2,4-dichloromandelic acid; and 2,4—dichlorobenzoyl glycine
(Hutson and Wright 1980), which have been detected in animals. Analysis of urine samples for the
presence of these metabolites represents a potentially preferable means of assessing exposure since this
method is non—invasive. However, as an organophosphate, chlorfenvinphos is rapidly metabolized and
excreted from the body; therefore, urinary metabolite analysis is useful only in the evaluation of recent

CXpOSUI‘SS.

The major action resulting from human exposure to chlorfenvinphos is the inhibition of cholinesterase
activity (see Section 2.4). Two pools of cholinesterases are present in human blood: cholinesterase in
erythrocytes and pseudocholinesterase in plasma. Cholinesterase, present in human erythrocytes, is

identical to the enzyme present in neuromuscular tissue (the target of chlorfenvinphos action), while

 

plasma pseudocholinesterase has no known physiological function. Inhibition of both forms of
cholinesterase activities has been associated with exposure to chlorfenvinphos in humans and animals
(Cupp et al. 1975', Gralewicz et al. 1989a, 198%, 1990; Hunter 1969; Maxwell and LeQuesne 1982;
Osicka—Koprowska et al. 1984', Pach et al. 1987; Takahashi et al. 1991; Vestweber and Kruckenberg
1972). Inhibition of erythrocyte, plasma, or whole blood cholinesterase activities may be used as a

marker of exposure to chlorfenvinphos. However. inhibition of cholinesterase activity is a common

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2. HEALTH EFFECTS

action of anticholinesterase compounds, which include organophosphates, like chlorfenvinphos, and
some carbamate compounds. In addition, a wide variation in normal cholinesterase values exists in the
general population, and there are no studies which report a quantitative association between
cholinesterase activity levels and exposure to chlorfenvinphos in humans. Thus, the inhibition of
cholinesterase activity is not a specific biomarker of effect for chlorfenvinphos exposure; it is
indicative only of effect and is not useful for dosimetric analysis. It should be noted that
pseudocholinesterase activity has been reported to be a more sensitive marker for organophosphate
exposure than erythrocyte cholinesterase (Endo et al. I988; Hayes et al. I980). It has been suggested
that in the absence of baseline values for cholinesterase activity, sequential post-exposure
cholinesterase analyses be used to confirm a diagnosis of organophosphate (like chlorfenvinphos)

poisoning (Coye et al. 1987).

This method of using the inhibition of cholinesterase activity as an indicator for exposure to
organophosphate exposure lacks even greater specificity when used to assess exposure to compounds
like chlorfenvinphos which are weak cholinesterase inhibitors. As a vinyl phosphate, chlorfenvinphos
is metabolized to desethyl chlorfenvinphos which could be detected in urine as a specific biomarker of
exposure to chlorfenvinphos or other vinyl phosphates. The method of detection involves conversion
of urinary desethyl chlorfenvinphos to the more easily measurable methyl desethyl chlorfenvinphos
with diazomethane. The analyses of 24—hour samples of urine from 14 male volunteers were made at
14-day intervals on 4 occasions (days 10, 24, 38, and 52) during exposure, and on one occasion,
15—16 days after cessation of exposure, using this novel detection method. The average daily
excretion of beta-methyl desethyl chlorfenvinphos during exposure was 120 ug, which was 4.7% of
the dose. In post—exposure urine, the concentrations of beta—methyl desethyl chlorfenvinphos were 0 in
most cases, and no greater than S—IO ug/day in the remainder. The excretion rate of ulp/m~methyl
desethyl chlorfenvinphos was 15 :5 ug/day during exposure, but fell to O or <5 ug/day post-exposure.

Thus, the higher level of excretion of desethyl chlorfenvinphos in the urine found in an acute dosing

 

experiment was not maintained when the dose was diminished 4—fold and administered daily.
However, since desethyl chlorfenvinphos accounts for only about 5% of the dose at this low exposure
level, its concentration in urine would lack sensitivity when used as an index of exposure to
chlorfenvinphos (Hunter et al. 1972). Although this method of assessing chlorfenvinphos exposure
may not be useful in low exposure conditions, the method could be used to evaluate exposure to high

doses of chlorfenvinphos such as occurs in human acute poisoning cases. It has been suggested that

 
   
 

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the concentration of Chlorfenvinphos (or its unique metabolites) in the blood may be a better index of

exposure than inhibition of cholinesterase activity (Hunter 1968, 1969).

2.6.2 Biomarkers Used to Characterize Effects Caused by Chlorfenvinphos

For more information on biomarkers for renal and hepatic effects of chemicals see ATSDR/CDC
Subcommittee Report on Biological Indicators of Organ Damage (I990) and for information on

biomarkers for neurological effects see OTA (1990).

Inhibition of erythrocyte, plasma, or whole blood cholinesterase activities in humans and animals that
results from Chlorfenvinphos exposure (Bama and Simon 1973; Brzezinski I978; Cupp et al. I975;
Pach et al. 1987; Kolmodin-Hedman and Eriksson 1987; Osicka-Koprowska et al. 1984; Osumi et al.
I975; Takahashi et al. 1991) may be used as a marker of effect for Chlorfenvinphos exposure.
However, inhibition of cholinesterase activity is a common action of anticholinesterase compounds,
which include organophosphates like Chlorfenvinphos and some carbamate compounds. In addition, a
wide variation in normal cholinesterase values exists in the general population, and there are no studies
which report a quantitative association between cholinesterase activity levels and exposure to
Chlorfenvinphos in humans. Thus, inhibition of cholinesterase activity is not a specific biomarker of
effect for Chlorfenvinphos exposure; it is indicative only of effect and not useful for Chlorfenvinphos—

specific dosimetric analysis.

It should be noted that pseudocholinesterase activity has been reported to be a more sensitive marker
for organophosphate exposure than erythrocyte cholinesterase (Endo et al. 1988; Hayes et al. 1980). It
has been suggested that in the absence of baseline values for cholinesterase activity, sequential post-
exposure cholinesterase analyses be used to confirm a diagnosis of organophosphate poisoning (Coye

et al. 1987).

In combination with analysis of reductions in the level of cholinesterase activity, the manifestations of
severe organophosphate (Chlorfenvinphos) poisoning. clinically characterized by a collection of
cholinergic signs and symptoms (including dizziness, fatigue, tachycardia or bradycardia, miosis,
diarrhea, and vomiting) (Williams and Burson I985; Chambers and Levi I992; Cupp et al. 1975;
Klaassen et al. 1986; Takahashi et al. 1991) are useful biomarkers of effect for identifying poisoned

victims of organophosphates (Chlorfenvinphos). Also, these manifestations are not specific to

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chlorfenvinphos but to anticholinesterase compounds (such as organophosphates and some carbamate
compounds), in general. A positive response to atropine treatment is considered a confirmation of

organophosphate poisoning.

For more information on biomarkers for renal and hepatic effects of chemicals see ATSDR/CDC‘
Subcommittee Report on Biological Indicators of Organ Damage (1990) and for information on

biomarkers for neurological effects see OTA (1990).

2.7 INTERACTIONS WITH OTHER CHEMICALS

The toxicity of chlorfenvinphos may be affected by other substances. Some chemicals may increase
the toxicity of chlorfenvinphos in an additive manner. Chemical substances such as other
anticholinesterase organophosphates, carbamates, or some pyrethroid insecticides that cause
neurotoxicity are expected to act in an additive manner with chlorfenvinphos with respect to its

potential to induce cholinergic toxicity.

As direct—acting cholinesterase activity inhibitor (P=O type in contradistinction from P=S types), other
chemicals may interfere with the toxicity of chlorfenvinphos indirectly by accelerating its metabolism
to less toxic metabolites through their actions on drug-metabolizing enzymes, specifically, glutathione—
S-transferase and P-450 or mixed function monooxygenases (Akintonwa 1984, 1985; Akintonwa and
[turn I988; Donninger 197]; Hansen 1983; Hutson and Logan 1986; Hutson and Millburn I991;
Hutson and Wright 1980). The duration and intensity of action of chlorfenvinphos are largely
determined by the speed at which it is metabolized via oxidative 0-dealkylation in the body by liver
microsomal cytochrome P-450 or mixed function monooxygenases (MFO). More than 200 drugs,
insecticides, carcinogens, and other chemicals are known to induce the activity of liver microsomal
drug-metabolizing enzymes. The characteristic biological actions of these chemicals are highly varied.
Although there is no relationship between their actions or structures and their ability to induce
enzymes‘ most of the inducers are lipid-soluble at physiological pH. These inducers of the MFO
system include the following classes of drugs: hypnotic and sedatives (barbiturates, ethanol);
anesthetic gases (methoxyflurane, halothane); central nervous system stimulators (amphetamine);
anticonvulsants (diphenylhydantoin); tranquilizers (meprobamate); antipsychotics (triflupromazine);
hypoglycemic agents (carbutamide); anti-inflammatory agents (phenylbutazone); muscle relaxants

(orphenadrine); analgesics (aspirin, morphine); antihistaminics (diphenhydramine); alkaloids (nicotine);

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insecticides (chlordane, DDT, BHC, aldrin, dieldrin. heptachlorepoxide, pyrethrins); steroid hormones
(testosterone, progesterone, cortisone); and carcinogenic polycyclic aromatic hydrocarbons (3—methyl—
cholanthrene, 3,4-benzpyrene) (Akintonwa I984; Hutson and Logan I986; Hutson and Millburn I991;
Hutson and Wright I980; lkeda et al. I99]; Klaassen et al. I986; Williams and Burson I985). Thus.
exposure to any of these enzyme inducers prior to, or concurrent with, exposure to chlorfenvinphos
may result in accelerated biodeactivation of chlorfenvinphos to its less toxic metabolites. The extent
of toxicity mediated by this phenomenon is dependent on how fast chlorfenvinphos is hydrolyzed to
much less toxic metabolites, a process that is also accelerated by the enzyme induction. Similarly,
concurrent exposure to chlorfenvinphos and MFO enzyme-inhibiting substances (e.g., carbon
monoxide; ethylisocyanide; SKF 525A, halogenated alkanes, such as CCI4; alkenes. such as vinyl
chloride; and allylic and acetylenic derivatives) may increase the toxicity of chlorfenvinphos by
decreasing the rate of the oxidative dealkylation of chlorfenvinphos (Akintonwa I984; Akintonwa and
Itam 1988; Donninger I97]; Hansen I983; Hutson and Logan 1986; Hutson and Millburn I991;
Hutson and Wright 1980; Williams and Burson I985). The balance between inhibition and induction
of these enzymes determines the biological significance of these chemical interactions with

chlorfenvinphos.

Chlorfenvinphos exposure may interfere with the short-acting muscle relaxant succinylcholine used
concurrently with anesthetics. The action of succinylcholine is terminated by means of its hydrolysis
by plasma cholinesterase (Klaassen et al. I986). Since plasma cholinesterase activity is strongly
inhibited by chlorfenvinphos in humans (Cupp et al. I975; Kolmodin-Hedman and Eriksson I987;
Pach et al. I987; Takahashi et al. I99]; Vestweber and Kruckenberg I972) and animals (Gralewicz et
al. 198921, 198%, I990; Kolmodin-Hedman and Eriksson I987; Maxwell and LeQuesne I982; Osicka-
Koprowska et al. I984; Pach et al. I987; Takahashi et al. I991; Vestweber and Kruckenberg I972), it
is expected that concurrent exposure to chlorfenvinphos may result in the prolongation of the action of

succinylcholine leading to prolonged muscular paralysis.

 

2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE

A susceptible population will exhibit a different or enhanced response to chlorfenvinphos than will
most persons exposed to the same level of chlorfenvinphos in the environment. Reasons may include
genetic makeup, age, health and nutritional status. and exposure to other toxic substances (e.g.,

cigarette smoke). These parameters may result in reduced detoxification or excretion of

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chlorfenvinphos, or compromised function of target organs affected by chlorfenvinphos. Populations
who are at greater risk due to their unusually high exposure to chlorfenvinphos are discussed in

Section 5.6, Populations With Potentially High Exposure.

The magnitude of chlorfenvinphos toxicity, like the toxicity of any xenobiotic, is affected by the rate
of its metabolic biotransformation to less toxic substances (Klaassen et al. I986). Therefore, low
xenobiotic metabolizing activity would result in greater toxicity. The newborn of several animal
species, including humans, have an almost complete lack of ability to metabolize xenobiotics and may
be more sensitive to chlorfenvinphos toxicity. Studies on experimental animals showed that starvation
depressed P-450 activity due to actual loss of the enzyme protein (Boyd and Carsky I969; Puzynska
1984). Thus, it is expected that dietary deficiency in protein would increase chlorfenvinphos toxicity
by diminishing its metabolism in the liver. Hereditary factors may also contribute to population
sensitivity to chlorfenvinphos. Atypical plasma cholinesterase with low activity is present in a small
percentage of the human population. This altered enzyme is the result of an hereditary factor with
0.04% occurrence in the population. Since plasma cholinesterase activity is strongly inhibited by
chlorfenvinphos (Cupp et al. 1975; Gralewicz et al. I989a, 198%, I990; Kolmodin—Hedman and
Eriksson 1987; Maxwell and LeQuesne I982; Osicka—Koprowska et al. I984; Pach et al. I987;
Takahashi et al. I991; Vestweber and Kruckenberg I972), it is expected that individuals who have
atypical ChE (or low plasma cholinesterase activity) will be unusually sensitive to the muscle relaxant
succinylcholine (Klaassen et al. I986) and may suffer prolonged muscle paralysis if administered
succinylcholine while exposed to chlorfenvinphos. Congenital low plasma cholinesterase activity may
also increase subpopulation sensitivity to chlorfenvinphos exposure. After exposure, plasma
cholinesterase acts as a depot for chlorfenvinphos due to its strong affinity for the substance (Davies
and Holub I980; Edson and Noakes I960; Klemmer et al. I978; Williams et al. I959), thus decreasing
the availability of the chlorfenvinphos dose to neuromuscular tissue, the target of chlorfenvinphos
.toxicity in the population with normal plasma cholinesterase levels. In individuals with congenital low
plasma cholinesterase activity, less chlorfenvinphos is bound in the blood and more unbound

chlorfenvinphos is in circulation to reach neuromuscular tissue, the target of chlorfenvinphos toxicity.

Individuals who have abnormally low tissue cholinesterase due to prior exposure to cholinesterase
activity inhibitors are also exceptionally susceptible to the cholinesterase activity—inhibiting toxicity of
chlorfenvinphos. These individuals may include those who are occupationally exposed to

anticholinesterases, such as other cholinesterase activity inhibiting organophosphate or carbamate

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2. HEALTH EFFECTS

pesticides. In this regard, patients on medication that inhibits cholinesterase activity may also be

unusually susceptible to the cholinesterase activity inhibiting toxicity of chlorfenvinphos.
2.9 METHODS FOR REDUCING TOXIC EFFECTS

This section will describe clinical practice and research concerning methods for reducing toxic effects
of exposure to chlorfenvinphos. However, because some of the treatments discussed may be
experimental and unproven, this section should not be used as a guide for treatment of exposures to
chlorfenvinphos. When specific exposures have occurred, poison control centers and medical
toxicologists should be consulted for medical advice. The following text provides specific information

about treatment following exposures to chlorfenvinphos.

2.9.1 Reducing Peak Absorption Following Exposure

Organophosphate insecticides like chlorfenvinphos are rapidly absorbed after inhalation, ingestion, or
dermal contact (Hutson and Wright 1980; Ikeda et al. 1991; Wagner et al. 1990). In oral exposures,
emesis is not indicated because of the danger of aspiration of stomach contents by an obtunded patient.
Gastric lavage, with a solution of 5% sodium bicarbonate or 2% potassium permanganate, may be
indicated within the first 60 minutes after ingestion to get rid of unabsorbed chlorfenvinphos in the
stomach (Cupp et al. 1975; Pach et al. 1987; Shankar 1967, 1978). Activated charcoal can also be
used, but cathartics are not necessary due to the diarrhea induced by muscarinic activity.
Decontamination is the first step in reducing dermal- or eye—contact absorption. This decontamination
should begin immediately after the exposure is recognized. Contaminated clothing should be removed
and skin (including hair and nails) should be washed copiously with soap and water. Health care
workers and emergency responders should be protected from secondary contamination, and clothes and
other contaminated material should be treated as contaminated waste. Eyes should be irrigated with
copious amounts of room-temperature water or saline, if available, for at least 15 minutes. If irritation,
lacrimation, or especially pain, swelling, and photophobia persist after 15 minutes of irrigation, expert

ophthalmologic care should be sought.

If exposure is via inhalation, the exposed individual should be moved to fresh air and efforts should be
directed toward the maintenance of an open airway, airway suctioning, endotracheal intubation.

Artificial ventilation with supplemental oxygen may be helpful.

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2.9.2 Reducing Body Burden

Chlorfenvinphos is rapidly metabolized, with an estimated mammalian biological half—life of
12—15.I3 hours (Akintonwa I984; Akintonwa and Itam I988; Donninger I971; Hutson and Millburn
I991; Hutson and Wright 1980). Consequently, efforts at reducing body burdens of poisoned persons
may not be critical to the outcome. Although hemoperfusion has been successfully used in one
chlorfenvinphos poisoning treatment report (Pach et al. I987), dialysis and hemoperfusion are not
recommended in organophosphate poisonings because of the extensive tissue distribution of the
absorbed doses (Mticke et al. 1970; Poklis et al. 1980). The use of P—450-inducing substances such as
some antipsychotics (triflupromazine) and analgesics (aspirin, morphine) would tend to accelerate the
metabolism of chlorfenvinphos, thereby decreasing its toxicity (Akintonwa I984; Akintonwa and Itam
I988; Donninger I971; Hutson and Millburn I99]; Hutson and Wright I980; Klaassen et al. 1986;
Williams and Burson 1985).

2.9.3 Interfering with the Mechanism of Action for Toxic Effects

As an anticholinesterase organophosphate, the principal toxic effects of chlorfenvinphos in humans and
laboratory animals derive from inhibition of cholinesterase activity (Cupp et al. I975; Gralewicz et al.
l989a, l989b, 1990; Hunter I969; Kolmodin-Hedman and Eriksson 1987; Maxwell and LeQuesne
I982; Osicka—Koprowska et al. 1984; Pach et al. I987; Takahashi et al. I99]; Vestweber and
Kruckenberg 1972). Severe inhibition of the activities of these enzymes results in accumulation of
choline at its sites of action, and excessive or interminable stimulation of both sympathetic and
parasympathetic cholinergic receptors leading to muscarinic and nicotinic effects (Klaassen et al. I986;

Williams and Burson I985).

Timely treatment of chlorfenvinphos poisoning cases with atropine and cholinesterase regeneration
with pralidoxime and other oximes, significantly reduces the cholinergic effects (Cupp et al. 1975;
Pach et al. I987). Atropine is an anti-muscarinic agent which, in large doses, alleviates broncho—
constriction and reduces secretion in the oral cavity and the airway. Atropine also counters some of
the central nervous system effects (Cupp et al. I975; Pach et al. 1987). Atropine should be given
immediately by intravenous injection at a dose of 2 mg and every 10—20 minutes thereafter at an
intramuscular dose of 0.67 mg until evidence of "atropinization" or muscarinic blockade, such as
flushing, dry mouth, dilated pupils, and tachycardia is seen (Shankar I978). The most clinically

important indication for continued atropine treatment is persistent wheezing (pulmonary rales) or

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CHLORFENVINPHOS 101

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bronchorrhea (Woo I990). Pralidoxime acts to regenerate inhibited cholinesterase cholinesterase)
enzyme activity at all affected sites (Shankar 1967, 1978; Schenker et al. 1992; Taitelman 1992). It
should also be given immediately after chlorfenvinphos poisoning is diagnosed and can be repeated to
counter the nicotinic manifestations such as muscular weakness and fasciculations. Pralidoxime is
most effective if started within the first 24 hours, preferably within 6—8 hours of exposure, prior to the

irreversible phosphorylation of the enzyme (Shankar 1967, 1978; Schenker et a]. 1992).
2.10 ADEQUACY OF THE DATABASE

Section l04(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with
the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether
adequate information on the health effects of chlorfenvinphos is available. Where adequate

information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is
required to assure the initiation of a program of research designed to determine the health effects (and

techniques for developing methods to determine such health effects) of chlorfenvinphos.

The following categories of possible data needs have been identified by a joint team of scientists from
ATSDR. NTP, and EPA. They are defined as substance—specific informational needs that if met would
reduce the uncertainties of human health assessment. This definition should not be interpreted to mean
that all data needs discussed in this section must be filled. In the future, the identified data needs will

be evaluated and prioritized, and a substance-specific research agenda will be proposed.

2.10.1 Existing Information on Health Effects of Chlorfenvinphos

The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to
chlorfenvinphos are summarized in Figure 2—5. The purpose of this figure is to illustrate the existing
information concerning the health effects of chlorfenvinphos. Each dot in the figure indicates that one
or more studies provide information associated with that particular effect. The dot does not
necessarily imply anything about the quality of the study or studies, or should missing information in
this figure be interpreted as a "data need." A data need, as defined in ATSDR’s Decision Guide for
Identifying S1(ln‘lall(‘(’-Sp(’('lfi(f Data Needs Related to Toxicological Prdfiles (ATSDR 1989), is
substance-specific information necessary to conduct comprehensive public health assessments.

Generally, ATSDR defines a data gap more broadly as any substance—specific information missing

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CHLORFENVINPHOS

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l02

FIGURE 2-5. Existing Information on Health Effects of Chlorfenvinphos

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

"G
. 6%“
Systemic ~00
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Human
‘0
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Dermal

 

 

 

 

 

 

 

 

 

 

 

 

Animal

0 Existing Studies

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CHLORFENVINPHOS 103

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from the scientific literature.

The available information indicates that chlorfenvinphos is a toxic substance to most species of
experimental animals, deriving its toxicity principally from the inhibition of cholinesterase activity.

All three reports concerning the health effects of chlorfenvinphos in humans described case reports of
individuals or group of individuals exposed either occupationally or in the home by accident. The
route of the occupational exposure reports is believed to be dermal, although an occupational exposure
was reported as inhalation. The route for the accidental exposure case was oral. Thus, Figure 2-5
reflects that information exists for oral and inhalation exposures in humans. However. all of the
human reports on inhalation exposures are limited because of probable concurrent or sequential
exposures to other substances of similar qualitative toxicity present in the environment (workplace or
home), such as other organophosphate pesticides present as components of organophosphate—containing
household products. In all cases, the doses at which these effects occurred in the human studies are
not known and the purity of the of material to which these subjects were exposed is questionable
because of the accidental nature of the exposures. thus rendering evaluation of substance—relatedness to
these reported toxicities uncertain. The available human data, therefore, fail to fully characterize the
human health effects from acute—, intermediate—, or chronic-duration inhalation exposures to

chlorfenvinphos.

Information regarding the health effects of chlorfenvinphos following ingestion in laboratory animals is
also limited due to a dearth of definitive studies. Only limited information is available on the health
effects resulting from dermal exposures. In all health effects categories, acute-, intermediate—, and
chronic-duration exposure data for dermal exposure are limited for both humans and laboratory
animals. Consequently, it was not possible to develop acute—, intermediate, or chronic—duration
inhalation MRLs for chlorfenvinphos. Furthermore, no information on the cancer effects of

chlorfenvinphos exposure is available for humans or laboratory animals by any route of exposure.

An acute oral MRL of 0.002 mg/kg/day has been derived for chlorfenvinphos from a LOAEL of

2.4 mg/kg/day, based on adverse neurological effects in rats (Barna and Simon 1973). An
intermediate oral MRL of 0.002 mg/kg/day for chlorfenvinphos has been developed from a LOAEL of
2 mg/kg/day, based on adverse immunological/lymphoreticular effects in mice (Kowalczyk-Bronisz et
al. 1992). A chronic oral MRL of 0.0007 mg/kg/day for chlorfenvinphos has been developed from a
LOAEL of 0.7 mg/kg/day, based on adverse neurological effects in rats (Ambrose et al. 1970).

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2.10.2 Identification of Data Needs

Acute-Duration Exposure. No data is available on the acute—duration effects of human inhalation
exposure to chlorfenvinphos. The available inhalation animal studies reported only serious effects
(mortality, apnea, salivation, urination, exophthalmos, twitches, and tremors) (Takahashi et al. 1994;
Tsuda et al. 1986) following exposure to chlorfenvinphos. Therefore, the data from these studies are

not appropriate for use in the derivation of an acute-duration inhalation MRL.

The information available on acute oral human exposures consists primarily of studies that reported
interference with central cholinergic and adrenergic mechanisms (disturbances in cholinesterase and
noradrenaline levels) and secondary effects resulting from these disturbances manifested as
neurological symptoms and death in some cases. The adverse effects reported included death
(Felthous 1978); systemic (respiratory) (Pach et al. 1987); and neurological effects (Cupp et al. 1975,
Kolmodin—Hedman and Eriksson 1987; Pach et al. 1987). In animals, effects noted from acute oral
exposure to chlorfenvinphos included death (Gralewicz et al. 1989b; Hutson and Logan 1986; Hutson
and Wright 1980; Ikeda et a1. 1992; Kowalczyk—Bronisz et al. 1992; Puzynska 1984; Takahashi et al.
1991; Wysocka-Paruszewska et al. 1980), metabolic (Puzynska 1984), neurological (Barna and Simon
1973; Brzezinski 1978; Osumi et al. 1975; Takahashi et al. 1991, 1994) immunological/
lymphoreticular (Kowalczyk-Bronisz et al. 1992; Roszkowski 1978), and developmental effects
(Skonieezna et al. 1981). Thus, the acute effects of oral chlorfenvinphos are relatively well-

characterized, stemming principally from the inhibition of cholinesterase activity.

Effects noted from human dermal exposures include systemic (renal) (Hunter 1968) and neurological
(Hunter 1968, 1969). In animals, neurological effects (Vestwebcr and Kruckenberg 1972) and death
(Ambrose et al. 1970) have resulted from dermal exposures to chlorfenvinphos. Additional studies via
the inhalation and dermal routes of exposure would be helpful for establishing a dose—response
relationships and for identifying thresholds for adverse effects for chlorfenvinphos exposure. This
information is necessary for determining levels of significant exposure to chlorfenvinphos that are
associated with adverse health effects for the protection of potentially exposed populations living near

hazardous waste sites that contain chlorfenvinphos.

Intermediate-Duration Exposure. No information is available on the effects of human

intermediate-duration exposure, by any route (inhalation, oral, dermal), to chlorfenvinphos. No

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information on the effects of intermediate-duration dermal exposures to chlorfenvinphos is currently

available.

No animal studies were available on intermediate-duration inhalation exposures to chlorfenvinphos.
Therefore, no intermediate—duration inhalation MRL was derived for chlorfenvinphos. Additional
studies via the inhalation and dermal routes of exposure would be helpful for establishing a dose-
response relationships and for identifying thresholds for adverse effects for chlorfenvinphos exposure.
This information is necessary for determining levels of significant exposure to chlorfenvinphos that are
associated with adverse health effects for the protection of potentially exposed populations living near

hazardous waste sites that contain chlorfenvinphos.

Information on the adverse effects resulting from oral exposures of animals to chlorfenvinphos
included systemic (cardiovascular, hepatic, renal, endocrine, body weight) (Ambrose et al. 1970;
Roszkowski 1978), immunological/lymphoreticular (Ambrose et al. 1970; Kowalczyk-Bronisz et al.
I992; Roszkowski I978), neurological (Ambrose et al. 1970; Bama and Simon 1973; Maxwell and
LeQuesne 1982), reproductive (Ambrose et al. 1970), and developmental (Ambrose et al. 1970)
effects. An intermediate oral MRL of 0.002 mg/kg/day for chlorfenvinphos has been developed from
a LOAEL of 2 mg/kg/day, based on adverse immunological/lymphoreticular effects in mice

(Kowalczyk-Bronisz et al. I992).

Chronic-Duration Exposure and Cancer. No controlled epidemiological studies regarding the
systemic toxicities of chlorfenvinphos resulting from chronic-duration inhalation exposure are
available. However, two retrospective epidemiological studies regarding the systemic toxicities of
chlorfenvinphos resulting from chronic-duration inhalation exposures are available. Although the
existing human studies reported immunological (Wysocki et al. 1987) and neurological effects
(Kolmodin—Hedman and Eriksson 1987), the subjects in the Wysocki et al. (1987) study were also
concurrently exposed to greater concentrations of other potentially immunotoxic substances such as
formothion, sumithion, and malathion while the subjects in the Kolmodin—Hedman and Eriksson (1987)
study were exposed to unknown concentrations of a mixture of potentially neurotoxic pesticides which
included dimethoate, formothion, and isofenphos. Therefore, data from these studies were not useful
for developing inhalation a chronic inhalation MRL for chlorfenvinphos. Additional studies via the
inhalation and dermal routes of exposure would be helpful for establishing a dose—response

relationships and for identifying thresholds for adverse effects for prolonged exposure to

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chlorfenvinphos. This information is necessary for determining levels of significant exposure to
chlorfenvinphos that are associated with adverse health effects for the protection of potentially exposed

populations living near hazardous waste sites that contain chlorfenvinphos.

Information is available on the effects of chronic-duration oral exposures in humans and experimental
animals (rat and dog). The type of information available includes studies on systemic (cardiovascular,
hepatic, renal, endocrine, body weight) (Ambrose et al. 1970), reproductive, immunological/
lymphoreticular, neurological (Ambrose et al. I970; Maxwell and LeQuesne 1982), and reproductive
effects (Ambrose et al. I970). Data from these studies sufficiently demonstrate that chlorfenvinphos is
an anticholinesterase organophosphate. A chronic oral MRL of 0.0007 mg/kg/day for chlorfenvinphos
has been developed from a LOAEL of 0.7 mg/kg/day, based on adverse neurological effects in rats
(Ambrose et al. 1970).

No information on the effects of chronic-duration dermal exposures to chlorfenvinphos is currently

available.

No epidemiological studies or chronic rodent cancer bioassays are available for assessing the
carcinogenic potential of chlorfenvinphos. However, a study to determine the ability of vinyl
phosphate esters (like chlorfenvinphos) to form methylated bases in DNA of calf thymus failed to
detect 6—methyl guanine, a known mutagen. In both the reaction with dsDNA and ssDNA, 7—methyl
guanine was the main methylation product. However, all methyl derivatives of adenine constituted
about 40% and 50% of all methylation products in the case of dsDNA and ssDNA, respectively.
3-Methylcytosine was the only methyl derivative of pyrimidine identified. An analog of
chlorfenvinphos, methylbromophenvinphos, was used in this study (Wiaderkiewicz et al. 1986);
therefore, the data are difficult to relate to chlorfenvinphos without extensive structure—activity
relationship analysis. In a mutagenicity study, the dose-response curve, at doses of 0, 50, 500, or
5,000 ug/plate for the mutagenic activity of chlorfenvinphos for the S. typhimurium strain TAIOO was
reduced by the S9 mix (metabolic activation). At present, no mutagenic pesticide for which activity

decreases in the presence of the S9 mix is carcinogenic except captan (F—28) (Moriya et al. 1983).

Inhalation, oral, and dermal bioassays would be helpful to determine whether populations with long-

term inhalation, oral, or dermal exposures, especially those living near hazardous waste sites or

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establishments where wastes containing chlorfenvinphos are released into the air or water are at risk of

developing cancers.

Genotoxicity. No studies were located regarding the genotoxic effects of chlorfenvinphos in
humans following inhalation, oral. or dermal exposure. Chlorfenvinphos was negative for
mutagenicity in both base—changc—typc strains microorganisms (WPZ her of E. coli; TA1535, TA1537,
TA1538, and TA98 of S. typhimmium). However, the mutagenic potency of chlorfenvinphos for strain
TA100 was 0.038 revertants/nmol, indicative of a positive response (Dean 1972; Moriya et al. 1983;
Vishwanath and Kaiser 1986). A mixture of 15 pesticides (containing 0.3% chlorfenvinphos) tested
negative for mutagenicity in the Salmonella microsome assay, with or without metabolic activation
with PCB-induced rat liver 59, at concentrations up to 500 pg/plate in the Salmonella—microsome
assay. The mixture also failed to induce SCEs in human lymphocytes in vitro as well as in viva
mutagenicity in the micronucleus bone marrow assay in male Wistar rats at concentrations proportional
to the ratio determined in foods (i.e.. ranging from 0.1 to 20 pg/mL) (Dolara et al. 1993). In other
large-scale screening programs, which revealed microbial mutagenic activity in four new compounds
(all fungicides), chlorfenvinphos (without metabolic activation) exhibited no mutation induction
capacity in a rec-assay procedure (prescreening of DNA—damaging chemicals) utilizing strains of B.
subtilis, H17 Rec+ and M45 Rec-. Also. no mutation potential was evident in a reversion—assay
(determination of mutation specil‘icities) in which two tryptophane—requiring strains (auxotrophic) of E.
coli (B/r try WP2 and WPZ try hcr) and four strains of S. Atypliimurlum (TAI535, TA1536, TA1537,
and TA1538) were used. The E. coll auxotrophic strains and Salmonella TA1535 are reversible by
base—pair change type mutagens and the three .S'almmze/la strains (TA1536, TA1537, and TA1538) are
reversible by frameshift mutagens (Shirasu I973: Shirasu et al. 1976). There are no unequivocal data
to indicate that chlorfenvinphos reacts directly with DNA in vivo or in virra to produce mutations in
either germ or somatic cells. In a study to determine the ability of vinyl phosphate esters (like
chlorfenvinphos) to form methylated bases in DNA of calf thymus, DNA failed to detect 6—methyl
guanine. a known mutagcn. In the reaction with both dsDNA and ssDNA. 7-methyl guanine was the
main methylation product. However. all methyl derivatives of adenine constituted about 40% and 50%
of all methylation products in the case of dsDNA and ssDNA, respectively. 3-Methylcytosine was the
only methyl derivative 01‘ pyrimidine identified (Wiaderkiewicz et a1. 1986). In another study, tetra-
chlorvinphos (Gardonalw) was evaluated for potential to induce chromosomal aberrations and SCEs in
vitm in a primary culture of Swiss mice spleen cells at concentrations of 0.25, 0.50, 1.0, or 2.0 ug/mL.

Tetrachlorvinphos induced a high percentage of metaphases with chromosomal aberrations in the

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mouse spleen cells after 4 hours of treatment in a dose-dependent manner. According to the authors,
the results indicate that tetrachlorvinphos, in the tested concentrations, is mutagenic in mouse spleen
cell cultures (Amer and Aly I992). In both of these studies, structural analogs of chlorfenvinphos
(methylbromophenvinphos and tetrachlorvinphos, respectively) were used; therefore, the data are
difficult to relate to chlorfenvinphos without extensive structure-activity relationship analysis. These
limited data suggest that chlorfenvinphos might not be genotoxic. Thus, the existing information on
the mutagenic potential of chlorfenvinphos is equivocal. Additional genotoxicity assays in
microorganisms and mammalian cells (in viva and in vitro) will be helpful in determining if the
substance is clastogenic or can cause mutation in somatic OLgerm cells. This information is necessary
to determine whether potentially exposed populations, especially those living near hazardous waste

sites, are at risk of developing genetic diseases.

Reproductive Toxicity. No studies were located regarding the reproductive effects in humans
following acute-, intermediate-, or chronic—duration inhalation, oral, or dermal exposure to
chlorfenvinphos. Animal studies regarding reproductive effects after acute-, intermediate-, or chronic-
inhalation or dermal exposure to chlorfenvinphos, or acute—duration oral exposure to chlorfenvinphos
are also lacking. A 3—generation reproductive study in albino (Wistar) rats orally exposed to
chlorfenvinphos reported significant (14%) reduction in fertility and decrease in maternal body weight
gains at a LOAEL of 2.7 mg/kg/day (Ambrose et al. l970). Single—generation studies, in which rats
and dogs were exposed to chlorfenvinphos for intermediate— or chronic-duration found no
histopathology or changes in relative weights of the testes and ovaries of the tested animals (Ambrose
et al. 1970). However, these studies did not evaluate reproductive function. Consequently, additional
reproductive toxicity studies in animals exposed to chlorfenvinphos via inhalation, oral, or dermal
route would be helpful in evaluating the potential for chlorfenvinphos to cause adverse reproductive
effects in humans. This information is necessary to determine whether potentially exposed
populations, especially those living near hazardous waste sites, are at risk of developing reproductive

diseases.

Developmental Toxicity. No studies were located regarding the developmental effects in humans
or animals following acute-, intermediate—, or chronic—duration inhalation or dermal exposure to
chlorfenvinphos. Animal studies regarding developmental effects after acute-, intermediate-, or
chronic—duration inhalation or dermal exposure to chlorfenvinphos are also lacking. The limited

information on the developmental toxicity of oral chlorfenvinphos exposure indicates that the

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CHLORFENVINPHOS 109

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substance may interfere with the normal development of rats by inhibiting cellular respiration
(Skonieczna et al. 1981) and interfering with maternal body weight gains, and reducing lactational
index and offspring survivability in the developing rodents (Ambrose et al. 1970). A statistical system
for hazard identification developed for use in predicting the developmental toxicity of 175 chemicals,
including chlorfenvinphos, produced equivocal results concerning the developmental toxicity of
chlorfenvinphos to the rat, rabbit, and hamster. However, the model had a sensitivity of 62~75%, a
positive predictive value of 75—100%, and a negative predictive value of 64—91%, indicating that it is
not optimal for hazard identification (Jelovsek et al. 1989). Additional information on the
developmental effects in animals exposed to chlorfenvinphos via the inhalation, oral, or dermal route
would be helpful in evaluating the potential for chlorfenvinphos to cause developmental toxicity in
humans. This information is necessary to determine whether offspring of potentially exposed
populations, especially those living near hazardous waste sites, are at risk of developmental adverse

effects.

lmmunotoxicity. No studies were located regarding the immunological and lymphoreticular effects
in humans following acute— or intermediate-duration inhalation exposure to chlorfenvinphos, or
regarding the immunological and lymphoreticular effects in humans following acute-, intermediate-, or
chronic-duration oral exposure to chlorfenvinphos. No studies were available regarding immunological
and lymphoreticular effects in animals following acute—, intermediate-, or chronic-duration inhalation

or dermal exposure to chlorfenvinphos.

Only one study was located that reported immunological effects in humans. In this report,
occupational exposure to inhaled chlorfenvinphos for an average of 15 years was associated with
damage to humoral mechanisms in humans. This study is not suitable for assessing the immunological
and lymphoreticular effects of human exposure to chlorfenvinphos because the subjects of this study
were also concurrently exposed to greater concentrations of other potentially immunotoxic substances
such as formothion, sumithion, and malathion (Wysocki et al. 1987). In animal studies, intermediate—
duration dietary exposure of rats resulted in a significant and irreversible reduction in relative spleen
weight of female rats given 23 mg/kg/day chlorfenvinphos for 12 weeks. However, no gross or
microscopic histopathology was evident in the spleen and bone marrow tissues of the rats upon
examination (Ambrose et al. 1970). A chronic study in dogs and rats did not note any
histopathological changes in the spleen or bone marrow or changes in absolute or relative spleen

weights in Wistar rats or Beagle dogs of both sexes given dietary chlorfenvinphos doses of

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CHLORFENVINPHOS 110

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2| mg/kg/day (males) or 24 mg/kg/day (females). or I0 mg/kg/day (males) or 50 mg/kg/day (females),
respectively, for 104 week (Ambrose et al. I970). In other animal studies, C57BL/6 mice and
(C57BL/6xDBA/2)FI (BDFl/Iiw) hybrid mice (6—8 weeks old) orally exposed to chlorfenvinphos for
90 days exhibited a reversible reduction in the number of E rosettes-forming cells as well as a dose—
related decrease in number of hemolysin-producing cells, reduction in the number of plaque-forming
cells, increases in 11—] activity and DTH reaction, stimulation of spleen colonies, and disturbance in
humoral immune factors (immunoglobulins) at a LOAEL of 1.5 mg/kg (Kowalezyk-Bronisz et al.
I992). Rabbits orally exposed to chlorfenvinphos for 90 days also exhibited significantly elevated
serum hemagglutinin level (I6%) and hemolysin activity (66%, p<().05) as well as increased number
of nucleated lymphoid cells producing hemolytic antibody to sheep erythrocytes. Spleen
cytomorphology changes, manifested mainly as transformation of primary follicles into secondary ones
with well—developed germinal centers, were also observed (Roszkowski 1978). While the existing
human inhalation study and the animal oral studies provide some indication that chlorfenvinphos
exposure is associated with immunological changes, these changes were not consistent with depressive
effect on immune reactions. Thus, the changes reported in these studies may simply be immunological
mobilizations of the organisms to xenobiotics in contradistinction from immune system damage.
Consequently, additional TIER II animal immunotoxicity testing (cell-mediated immunity, cell surface
marker profile immunopathology, humoral immunity, cytolytic macrophage function, and bone marrow
tests) via inhalation, oral, or dermal route for chlorfenvinphos would be helpful to more fully assess
the potential of chlorfenvinphos to cause immunotoxicity in humans. This information is necessary to
determine whether potentially exposed populations, especially those living near hazardous waste sites,

are at risk of developing immunological diseases.

Neurotoxicity. No studies were located regarding neurological effects in humans after acute— or
intermediate-duration inhalation exposure to chlorfenvinphos; or following acute-, intermediate—, or
chronic-duration oral exposure; or after intermediate— or chronic-duration dermal exposure. In humans,
chlorfenvinphos inhibits cholinesterase activity in the central and peripheral nervous system when
administered by the oral (Cupp et al. 1975; Pach et al. I987) or inhalation route in acute-duration
exposures (Kolmodin—Hedman and Eriksson I987). Inhibition of cholinesterase activity results in
accumulation of choline at muscarinic and nicotinic receptors leading to peripheral and central nervous
system effects. These effects usually appear within a few minutes to a few hours after exposure
depending on the extent of exposure. In a human case report, a I6—year-old white male mistakenly

ingested a formulation (identified as Dermatonw), was hospitalized 90 minutes afterward with

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symptoms of abdominal cramps, nausea, vomiting, generalized weakness, cold dry skin, hypothermia,
listlessness, constricted pupils, hypertension, respiratory distress, fine generalized muscular twitching,
and apprehension. Plasma and erythrocyte activity levels were significantly inhibited. All vital signs

returned to normal after gastric lavage and treatment with atropine and pralidoxime (Cupp et al. 1975).

No studies were located regarding neurological effects in animals after acute- or intermediate-duration
inhalation or dermal exposure to chlorfenvinphos. The available information indicates that
chlorfenvinphos has similar neurological effects in animals. In animals, chlorfenvinphos inhibits
cholinesterase activity in the central and peripheral nervous system when administered by the oral
route in acute—duration exposures (Bama and Simon 1973; Osicka—Koprowska et al. 1984; Takahashi et
al. 1991). In addition, chlorfenvinphos inhibits noradrenaline activity in the central adrenergic
mechanism in acute oral exposures in animals (Brzezinski 1978; Osumi et a1. 1975). The information
indicates that the substance causes disruptions in the central and peripheral nervous system in rats and
dogs following acute-, intermediate-, or chronic-duration exposures via the oral route at doses as low
as 0.2 mg/kg/day (Ambrose et al. 1970; Bama and Simon 1973; Maxwell and LeQuesne 1982; Osumi
et a1. 1975; Puzynska 1984; Takahashi et a1. 1994). These disruptions are mediated by the inhibition
of cholinesterase activity in the peripheral and central nervous tissue and are manifested as abnormal
muscle reflex, muscle fasciculations, Straub tail reflex, twitches, convulsions, chromodacryorrhea,
exophthalmos, gasping, lacrimation, prostration, salivation, sleep disturbances, diarrhea, emesis, and
urination (Ambrose et al. 1970; Maxwell and LeQuesne 1982; Osumi et al. 1975; Puzynska 1984;
Takahashi et a1. 1991). In one of these studies, all 36 Sprague—Dawley rats exposed to
chlorfenvinphos doses of 10.5 mg/kg/day in the diet for 3—6 months exhibited repetitive muscle
activity when given two stimuli simultaneously. This abnormality became more marked with time,
even on constant dosing (Maxwell and LeQuesne 1982). The findings from this study may be useful
in explaining electrophysiological abnormalities described in some workers chronically exposed to
some organophosphorus compounds. Besides its cholinergic action, chlorfenvinphos also acts on the
central noradrenergic mechanism in rats by accelerating the noradrenaline turnover in the brain in vivo
by the release of noradrenaline from brain tissue stores (Brzezinski 1978). Although all doses of
chlorfenvinphos elicited cholinergic responses (leg weakness, salivation, and retching) from hens given
100, 150, 200, or 300 mg/kg by intraperitoneal injection, the hens showed no signs of delayed
neurotoxicity after 20 days of observation (Ambrose et al. 1970). Although the available toxicity
information in humans and animals is sufficient to establish that short— and long—term exposure to

chlorfenvinphos result in adverse neurological effects, additional animal studies by the inhalation, oral,

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and dermal routes will be helpful in the more accurate assessment of the exposure levels at hazardous

waste sites at which these effects are likely to occur.

Epidemiological and Human Dosimetry Studies. Although the available epidemiological
studies sufficiently identify inhibition of cholinesterase activity as the characteristic and most critical
effect of human exposure to chlorfenvinphos, these studies inadequately identify the dose at which this
effect occurs (Cupp et al. 1975; Kolmodin-Hedman and Eriksson 1987; Pach et al. 1987: Wysocki et
al. 1987). Well-conducted acute-, intermediate-. and chronic—duration (for effects other than inhibition
of cholinesterase activity) human dosimetry studies are not available. Therefore, well-conducted
epidemiological and acute-, intermediate-, and chronic-duration human dosimetry studies would be
helpful in determining and quantifying the effect of inhalation, oral, or dermal chlorfenvinphos
exposure on human health including neurologic. immunologic. and reproductive effects; they would
also provide useful data regarding the carcinogenic potential of chlorfenvinphos in humans, especially
those living around hazardous waste sites or establishments where wastes containing chlorfenvinphos
are released into the air or water, and people who are occupationally exposed to chlorfenvinphos for

long periods of time.

Biomarkers of Exposure and Effect.

Exposure. The major action resulting from human exposure to chlorfenvinphos is the inhibition of
cholinesterase activity (see Section 2.4). Two pools of cholinesterases are present in human blood:
cholinesterase in erythrocytes and pseudocholinesterase in plasma. Cholinesterase. present in human
erythrocytes. is identical to the enzyme present in neuromuscular tissue (the target of chlorfenvinphos
action) while plasma pseudocholinesterase has no known physiological function. inhibition of the
activity of both forms of cholinesterase has been associated with exposure to chlorfenvinphos in
humans and animals (Cupp et al. 1975; Gralewicz et al. 1989a, 1989b, 1990; Hunter 1969; Kolmodin—
Hedman and Eriksson 1987; Maxwell and LeQuesne I982: Osicka—Koprowska et al. 1984; Pach et al.
1987; Takahashi et al. 1991; Vestweber and Kruckenberg 1972). Inhibition of erythrocyte, plasma. or
whole blood cholinesterase may be used as a marker of exposure to chlorfenvinphos. However.
inhibition of cholinesterase activity is a common action of anticholinesterase compounds, which
include organophosphates like chlorfenvinphos, and some carbamate compounds. in addition, a wide

variation in normal cholinesterase values exists in the general population. and there are no studies

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CHLORFENVINPHOS 113

2. HEALTH EFFECTS

which report a quantitative association between cholinesterase activity levels and exposure to

chlorfenvinphos in humans.

Chlorfenvinphos undergoes biotransformation to a variety of polar metabolites, including 2-chloro-
l-(2,4-dichlorophenyl) vinylethylhydrogen phosphate; l-(2,4-dichlorophenyl) ethanol; l-(2,4-dichloro—
phenyl) ethanediol; 2,4-dichloromandelic acid; and 2,4-dichlorobenzoyl glycine (Hutson and Wright
1980), which have been detected in animals. Analysis of blood samples for the presence of these
metabolites represents a potential means of assessing exposure. Analysis of urine samples for
metabolic products provides a non-invasive method for detecting exposure. As an organophosphate,
chlorfenvinphos is rapidly metabolized and excreted from the body; therefore, urinary metabolite
analysis is useful only in the evaluation of recent exposures (Hutson and Wright I980). There are no
studies which report a quantitative association between metabolite levels and exposure to
chlorfenvinphos in humans. Therefore, these biomarkers are only indicative of exposure and are also
not useful for dosimetric analysis. The inhibition of cholinesterase activity method as a measure of
organophosphate exposure lacks even greater specificity when used to assess exposure to compounds
which are weak inhibitors of cholinesterase activity, like chlorfenvinphos (Hunter et al. 1972). As a
vinyl phosphate, chlorfenvinphos is metabolized to desethyl chlorfenvinphos, which could be detected
in urine as a specific biomarker of exposure to chlorfenvinphos, or other vinyl phosphates (Akintonwa
1984, 1985; Akintonwa and Itam 1988; Donninger l97l; Hansen 1983; Hutson and Logan 1986;
Hutson and Millburn 1991; Hutson and Wright 1980). The method of detection involves conversion
of urinary desethyl chlorfenvinphos to the more easily measurable methyl desethyl chlorfenvinphos
with diazomethane. This method is a more specific biomarker for chlorfenvinphos exposure and has
been successfully used as such in a case of [4 male volunteers exposed to chlorfenvinphos for

53 days. However, since desethyl chlorfenvinphos accounts for only about 5% of the dose at this low
exposure level, its concentration in urine would lack sensitivity when used as an index of exposure to
chlorfenvinphos (Hunter et al. I972). Although this method of assessing chlorfenvinphos exposure
may not be useful in low exposure conditions, the method could be used to evaluate exposure to high
doses such as occur in human acute poisoning cases. Further research in the adaptation of this method

for low-dose exposure would be useful.

Effect. Inhibition of the activities of erythrocyte, plasma, or whole blood cholinesterase in humans
and animals that results from chlorfenvinphos exposure (Cupp et al. 1975; Gralewicz et al. 198921,

l989b, 1990; Hunter I969; Kolmodin—Hedman and Eriksson 1987; Maxwell and LeQuesne 1982;

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CHLORFENVINPHOS 114

2. HEALTH EFFECTS

Osicka-Koprowska et al. 1984; Pach et al. 1987; Takahashi et al. 1991; Vestweber and Kruckenberg
I972) may be used as a marker of effect for chlorfenvinphos exposure. However, the inhibition of
cholinesterase activity is a common action of anticholinesterase compounds, which include
organophosphates, like chlorfenvinphos, and some carbamate compounds. In addition, a wide
variation in normal cholinesterase values exists in the general population, and there are no studies
which report a quantitative association between cholinesterase activity levels and exposure to
chlorfenvinphos in humans. Thus, the inhibition of cholinesterase activity is not a specific biomarker
of effect for chlorfenvinphos exposure; it is indicative only of effect and is not useful for
chlorfenvinphos—specific dosimetric analysis. In combination with analysis of reductions in the level
of cholinestcrase activity, the manifestations of severe organophosphate (chlorfenvinphos) poisoning,
clinically characterized by a collection of cholinergic signs and symptoms (which may include
dizziness, fatigue, tachycardia or bradycardia, miosis, and vomiting) (Williams and Burson I985;
Chambers and Levi I992; Cupp et al. 1975; Klaassen et al. 1986; Pach et al. 1987; Takahashi et al.
l99l ). are useful biomarkers of effect for identifying victims of organophosphates (chlorfenvinphos)
poisoning. These manifestations, however, are also not specific to chlorfenvinphos, but to
anticholinesterase compounds, such as organophosphates and some carbamate compounds, in general.
A study conducted in rats reported that 1—6 hours after administration, chlorfenvinphos (13 mg/kg)
decreased the noradrenaline level in rat brain by 20% as compared to controls (Brzezinski 1978). A
similar study in Wistar rats found a 16% transient reduction in brain noradrenaline 3 hours following
oral dosing with 4 mg/kg chlorfenvinphos (Osumi et al. I975). Further research on the adrenergic
effects of chlorfenvinphos exposure might provide a more specific biomarker for chlorfenvinphos
when used in combination with inhibition of cholinesterase activity and clinical signs of interference

with the central cholinergic mechanism.

Absorption, Distribution, Metabolism, and Excretion. No studies were located regarding the
absorption of chlorfenvinphos after inhalation exposure; or regarding the distribution or metabolism of
chlorfenvinphos after inhalation or dermal exposure; or regarding excretion of chlorfenvinphos after
inhalation or dermal exposure in humans. In humans, dermally applied chlorfenvinphos was absorbed
in a concentration-dependent manner with rates of 0.06 to 1.43 cmZ/hour. Concentrations of intact
chlorfenvinphos of <0.7 to 22 pg/L were found in the blood of volunteers 8 hours later (Hunter 1969).
The rates of chlorfenvinphos de-ethylation by liver microsomal fractions are 0.36 nmol/minute per mg
protein (range 0.] 1—082) without induction and 1.03 nmol/minute per nmol of cytochrome P-450

(range 0.42—1.78) with induction (Hutson and Logan 1986). Chlorfenvinphos levels of l3.66, 1.69,

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CHLORFENVINPHOS 115

2. HEALTH EFFECTS

2.02, and 1.89 jig/kg were detected in 4 of the 11 samples of cervical mucus in environmentally
exposed persons. Chlorfenvinphos levels of 0.42 jig/kg were detected in l of the 10 sperm fluid
samples and l of the 10 human milk samples, respectively (Wagner et al. 1990). A serum
concentration of 300 ng/mL Chlorfenvinphos was reported for a 29-year-old patient who had ingested
about 50 mL of the preparation Enolofos®, which contains 50% Chlorfenvinphos, in a suicide attempt.
The authors of this study surmised that orally absorbed Chlorfenvinphos is widely and rapidly
distributed (Pach et al. 1987).

No studies were located regarding the absorption of Chlorfenvinphos after inhalation or dermal
exposure; or regarding the distribution or metabolism of Chlorfenvinphos after inhalation, oral, or
dermal exposure; or regarding excretion of Chlorfenvinphos after inhalation or dermal exposure in
animals. The available animal studies indicate that orally administered Chlorfenvinphos is minimally
absorbed and metabolized in rats (Hutson and Wright 1980). The metabolism of oral doses of the
substance is mediated by hepatic microsomal monooxygenase (cytochrome P-450) via oxidative
dealkylation (Donninger 1971; Hutson and Millbum 199]; Ikeda et al. 1991). Thirteen metabolites of
Chlorfenvinphos have been identified in animal studies or predicted from theoretical biotransformation
as justified by known structure of Chlorfenvinphos and understanding of biochemical reactions of
monooxygenation, reduction, hydrolysis, glucuronidation, glutathione-S-transferase conjugation, and
amino acid conjugation. The 13 metabolites identified or predicted are: 2—chloro-l—(2',4'-dichloro-
phenyl) vinyldiethyl phosphate; acetaldehyde; 2—chloro—l—(2',4'—dichlorophenyl) vinylethylhydrogen
phosphate; 2,4—dichlorophenacylchloride; 2-chloro-l-(2',4'—dichlorophenyl) ethanol; 2,4—dichloro-
mandelic acid; 2,4-dichloromandelic acid ester glucuronide; 2,4-dichloroacetophenone;
l-(2',4'—dichlorophenyl) ethanol; l—(2',4'-dichlorophenyl) ethanediol; l-(2',4'-dichlorophenyl) ethanediol-
2—glucuronide; l-hydroxy-l—(2',4'—dichlorophenyl) acetyl glycine; and l-(2',4'-dichlorophenyl)
ethanediol. 2-Chloro-1-(2‘,4'—dichlorophenyl) vinylethylhydrogen phosphate, 2,4-dichloromandelic acid,
l-(2',4'-dichlorophenyl) ethanediol-2-glucuronide, and l-(2',4'-dichlorophenyl) ethanediol (Akintonwa
1984; Akintonwa 1985; Akintonwa and Itam 1988; Hunter et al. 1972; Hutson and Millbum 1991;
Hutson and Wright 1980). Orally absorbed Chlorfenvinphos is eliminated mainly in the urine in rats in
0—32 hours (Hutson and Wright 1980). Additional studies in animals, designed to measure the rate of
inhalation, gastrointestinal, and dermal absorption, distribution, and excretion of Chlorfenvinphos would
be useful in extrapolating the toxicokinetics of Chlorfenvinphos in humans, especially those living

around hazardous waste sites.

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CHLORFENVINPHOS 116

2. HEALTH EFFECTS

Comparative Toxicokinetics. Chlorfenvinphos inhibits cholinesterase activity in the central and
peripheral nervous system, resulting in cholinergic symptoms as reported in several human poisoning
incidents (Cupp et al. I975; Hunter I969; Pach et al. I987; Kolmodin—Hedman and Eriksson 1987).
However, the purity of the material to which these subjects were exposed is questionable because of
the accidental nature of the exposures. For the same reason, the doses at which these effects occurred
are unknown. Therefore, it is difficult to determination whether the adverse effects reported in these
human studies are attributable to exposure to technical ehlorfenvinphos. Although information is
available that indicate that dermally applied ehlorfenvinphos was absorbed in a concentration-
dependent manner (with rates of 0.06—I .43 cmZ/hour), inhibiting cholinesterase in a dose-dependent
manner in the human subjects (Hunter 1969), information on the toxicokinetics of ehlorfenvinphos in

humans is limited to serum levels following ingestion (Pach et al. 1987).

Similarly, chlorfenvinphos inhibits cholinesterase activity in the central and peripheral nervous system
in animals (Gralewicz et al. I989a, 198%, I990; Kolmodin-Hedman and Eriksson I987; Maxwell and
LeQuesne I982; Osicka—Koprowska et al. I984; Pach et al. I987; Takahashi et al. I99]; Vestweber
and Kruckenberg I972).

The level of activity of cholinesterases in the livers of mammalian species livers and the distribution of
these enzymes has been suggested to be an important factor in accounting for species specificity of
some phosphate triester anticholinesterase agents, including ehlorfenvinphos. It may account for the
great variation in the conversion of ehlorfenvinphos to less toxic metabolites and, consequently, the
toxicity of ehlorfenvinphos among different animal species. The relative rates of conversion of
ehlorfenvinphos (by 0-dealkylation) to the diester by liver slices from the rat, mouse, rabbit, and dog
are I, 8, 24, and 80 hours, respectively; evidently correlating with the published acute oral LD50 values
for the species. A quantitative study of the species distribution of phosphate esterases and glutathione
S-alkyl transferase found that these enzymes are significantly less in the pig than all the other species
studied (Donninger l97l; Hansen I983; lkeda et al. 1991). The ease of absorption, bioavailability in
blood, and rates of uptake by the brain and sensitivity of brain cholinesterase to the phosphorylating
action of the compound may be additional factors in species sensitivity to the toxicity of

ehlorfenvinphos as demonstrated in the dog and rabbit (Hutson and Millburn I991).

Additional comparative studies regarding the absorption, distribution, and excretion of ehlorfenvinphos

after inhalation, oral, or dermal exposure in animals would be useful in species or route—route

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CHLORFENVINPHOS 117

2. HEALTH EFFECTS

extrapolation. This information could be used to determine an appropriate animal model for the

evaluation of the toxicokinetics of chlorfenvinphos.

Methods for Reducing Toxic Effects. Although dialysis and hemoperfusion are currently not
recommended in organophosphate poisonings because of the extensive tissue distribution of the

absorbed doses (Miicke et al. l970; Poklis et al. 1980), hemoperfusion has been successfully used in
one chlorfenvinphos poisoning treatment (Pach et al. 1987). Further studies are necessary in view of
the relatively few clinical observations concerning the use of hemoperfusion in the treatment of acute

poisoning caused by vinyl phosphate compounds like chlorfenvinphos.

2.10.3 Ongoing Studies

No information on ongoing studies in humans or laboratory animals for chlorfenvinphos was located.

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CHLORFENVINPHOS 119

3. CHEMICAL AND PHYSICAL INFORMATION

3.1 CHEMICAL IDENTITY

Information regarding the chemical identity of chlorfenvinphos is located in Table 3—l.

3.2 PHYSICAL AND CHEMICAL PROPERTIES

Chlorfenvinphos is a vinyl organophosphate insecticide. The technical material is an amber liquid
with a mild odor containing about 80—90% chlorfenvinphos (trans and cis isomers with a typical ratio
of 8.521). It is sparingly soluble in water, but miscible with most organic solvents. It hydrolyses
slowly in water, but is unstable in alkali (Worthing 1987). Information regarding the physical and

chemical properties of chlorfenvinphos is located in Table 3-2.

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CHLORFENVINPHOS

3. CHEMICAL AND PHYSICAL INFORMATION

120

Table 3-1. Chemical Identity of Chlorfenvinphos

 

Characteristic

Information

Reference

 

Chemical name

Synonym(s)

Registered trade name(s)

Chemical formula

Chemical structure

Identification numbers:
CAS Registry
NIOSH RTECS
EPA Hazardous Waste
OHMfr ADS
DOT/UN/NA/IMCO
HSDB
NCI

2-chloro-1-(2,4-dichlorophenyl)
vinyl diethyl phosphate

Phosphoric acid 2-chloro-1-(2,4-
dichlorophenyl)ethenyl diethyl ester;
0,0-diethyl O-[2-chloro-1-
(2,4-dichlorophenyl)vinyl] phosphate;

2,4—dichloro-a-(chloromethylene)benzy|

alcohol diethyl phosphate

CVP; SD 7859; Compound 4072;
Birlane; Dermaton; Sapecron;
Steladone; Supona

C12H14CI304P

CH CH o O CHCI
3 2 \IL' CC] C
— I
CH3CH20/

Cl

470—90—6
TB 8750000
No data
810041

UN 2783 Organophosphorus pesticide

1 540
No data

Worthing 1987

Merck 1989

Merck 1989

Worthing 1987

Worthing 1987

Merck 1989
HSDB 1994

HSDB 1994
HSDB 1994
HSDB 1994

 

CAS = Chemical Abstracts Services; DOT/UN/N

A/IMCO = Department of Transportation/United

Nations/North America/International Maritime Dangerous Goods Code; EPA = Environmental Protection

Agency; HSDB = Hazardous Substance Data Bank; NCI =
Institute for Occupational Safety and Health; OHM/TADS 2
Assistance Data System; RTECS = Registry of Toxic Effect

"'DRAFT FOR PUBLIC COMMENT'"

National Cancer Institute; NIOSH = National
Oil and Hazardous Materials/rechnical
s of Chemical Substances

 

 

CHLORFENVINPHOS

3. CHEMICAL AND PHYSICAL INFORMATION

Table 3-2. Physical and Chemical Properties of Chlorfenvinphos

121

 

 

Property Information Reference
Molecular weight 359.56 Merck 1989
Color Amber liquid (Technical) Merck 1989
Colorless liquid Hartley 1987
Physical state Liquid Merck 1989
Melting point —19 to —23 °C (Technical) Worthing 1987
~16 to —22 °C Ouellette and King 1977

Boiling point at 0.01 mm
Boiling point at 0.5 mm

Density at 25 °C
Odor

Odor threshold:
Water
Air

Solubility:
Water at 23 “’0

Organic solvent(s)

Partition coefficients:
Log KOW
Log K0C

Vapor pressure at 25 °C
Henry’s law constant at 25 °C

Autoignition temperature
Flashpoint
Flammability limits at 25 °C

Conversion factors (25 °C)

Explosive limits

120 °C (Technical)
167—170 °C (Technical)

1.5272 g/mL
Mild odor

No data
No data

145 ppm

Miscible with acetone. ethanol,
propylene glycol, dichloro-
methane, hexane, xylene

3.806
2.45

4x10‘6 mm Hg
7.5x10'6 mm Hg
1.7x10‘7 mm Hg

1.53x10‘8 atm-m3/mol
2.76x10'9 arm-m3/moi

No data
No data
No data

1 ppm = 14.7 mg/m3
1 mg/m3 = 0.068 ppm
No data

"'DRAF—I' FOR PUBLIC COMMENT'"

Merck 1989
Merck 1989

Merck 1989
Merck 1989

Merck 1989

Merck 1989; Worthing 1987

Bowman and Sans 1983
Kenaga 1980

Worthing 1987
Merck 1989
Verschueren 1983

HSDB 1994
Domine et al. 1992

CHLORFENVINPHOS

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

4.1 PRODUCTION

Chlorlenvinphos was introduced into the United States in l963 (Hayes 1982). by the Shell
lntemational Chemical Compzuiy Ltd, Ciba AG (now Ciba-Geigy AG). and by Allied Chemical
Corporation (Worthing 1987). The Burroughs Wellcome Company produced several chlorfenvinphos-
containing l‘onnulated products including Dennaton‘” dust. Demiatonl'” dip. Dermaton'” II and
Dermaton'“ flea and tick collars (EPA 1978a, 1978b. l979. l982a. 1982b. 1983). lnl‘onnation on
current production of chlorl‘envinphos is conflicting. One source lists current base producers of the
compound as American Cyzuiamid Compzmy (under the trade names Birlanem and Supona‘") and Ciba
Ltd. (under the trade names Sapecron‘“ and Steladone‘”) (Fann Chemicals Handbook 1993). However.
no producers of chlorfenvinphos were identified in a recent Directory of Chemical Producers for the

United States of America (SRl 1993).

Chlorlenvinphos is produced by reaction of triethyl phosphite with 2,2,2‘.4’-tetrachli)roacetophenone
(Wonhing 1987). The technical grade material contains greater than 92% chloifenvinphos as both the

Z (trams) and E (cis) isomers in a ratio (ZzE) of 8.511 (Spencer 1982; Worthing 1987).

No int‘onnation on historic production volumes was found; however. there are currently no registered

uses for chlorl'envinphos in the United States (REFS 1995).

No information is available in the Toxics Release Inventory (TRI) database on total environmental
releases of chlorl‘envinphos from production facilities because chlorfenvinphos is not included under
SARA. Title III (40 CFR 372.65). and. therefore, is not one of the toxic chemicals that facilities are

required to report to the Toxics Release lnventory database (EPA 1993).
4.2 IMPORT/EXPORT
Chlorlenvinphos is not likely to be imported as there are currently no registered uses for this

compound as a pesticide in the United States (REFS 1995). No infonnation on historical import

volumes was found.

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CHLORFENVINPHOS 124

4, PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

Current production of chlorfenvinphos in the United States could not be verified (SRI 1993), but is
unlikely as all registered uses in the United States were canceled in 1991 (REFS l995). Because there
are currently no registered uses for this pesticide, export is unlikely. No information on current or

historic export volumes was found.

4.3 USE

In the United States, chlorfenvinphos was registered for a variety of uses from 1963 until 199] when
all products containing chlorfenvinphos as an active ingredient were canceled (REFS 1995).
Chlorfenvinphos was first registered in l963 under the trade name Dermaton® as an insecticide/
acaricide dip for veterinary use in controlling fleas and ticks on domestic pets and other animals.
During the mid-l960s and early l970s, chlorfenvinphos was registered for additional uses as a residual
fly spray, surface spray and larvicide. As part of these registrations, chlorfenvinphos was used to
control adult flies in dairy barns, milk rooms, poultry houses and yards, other animal buildings,
feedlots, and animal holding pens; and to control larval flies in manure storage pits and piles, and in
other refuse accumulation areas around dairies and feedlots (REFS 1995). Beginning in the early
1980s, it was registered for additional uses under the trade name Dermaton®, in a dust formulation for
use in dog kennels and in dog collars for the control of fleas and ticks (Farm Chemicals Handbook

I984, I993; Hayes 1982; REFS 1995).

Available formulations of chlorfenvinphos included a 0.5% dust, l0% pelletized granules, 21%
emulsifiable concentrate, 24.5% emulsifiable concentrate, 25% WP, and 40% seed dressing (with 2%
mercury compounds); however, some of these formulations were not registered for use in the United
States (Hayes 1982; REFS l995; Spencer 1982). A summary of the registered uses of chlorfenvinphos

in the United States prior to the cancellation of its registration is given in Table 4-l (REFS 1995).

Chlorfenvinphos was subject to re—registration by the Office of Pesticide Programs of EPA in the
mid-l980s. At that time, the sole manufacturer, Shell International Chemical Company decided not to
support reregistration and allowed its registration of both the technical compound 4072 and of a
variety of formulated products to laps and be canceled (EPA l994a). A summary of chlorfenvinphos

product registrations and their effective dates of cancellation are given in Table 4-2.

"'DRAFT FOR PUBLIC COMMENT'"

 

CHLORFENVINPHOS

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"'DRAFT FOR PUBLIC COMMENT'"

 

126

CHLORFENVINPHOS

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

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"'DRAFT FOR PUBLIC COMMENT'"

CHLORFENVINPHOS

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

Table 4-2. Cancelled Chlorfenvinphos Registrations in the United States

127

 

 

Effective
Percent Cancellation
Chlorfenvinphos ID Number Product Name Date
21.10 218-608 Arcadian Residual Fly Spray 02-21-86
21.10 59-144 Residual Surface Spray and Larvicide 02-21-86
21.10 59-173 Coopona Poultry Premise Larvicide 02-21-86
24.50 59-136 Dermaton® Dip 07-01-87
92.00 201-209 Shell Technical Compound 4072, Insecticide for 10-10-89

Manufacturing Purposes Only
92.00 31629-1 Technical Compound 4072 Insecticide (for 10-10-89

Manufacturing Purposes Only)
00.50 59-189 Dermaton Dust 01-22-91
15.00 59-197 Dermaton Dog Collar 01-22-91
12.25 59-203 Dermaton l|| 01-22-91

 

Source: EPA 1994

"'DRAFT FOR PUBLIC COMMENT'"

 

CHLORFENVINPHOS

4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL

Outside the United States, Chlorfenvinphos is registered for use under the trade names Birlanew.
C8949, CGA 26351, Sapecron®, Steladone® and Suponaw (Farm Chemicals Handbook 1993).
Chlorfenvinphos (under the trade name Birlanew) is used as a soil insecticide for controlling root
maggots, root worms, and cutworms (Farm Chemicals Handbook 1984; Spencer I982; Worthing
1987). As a foliar insecticide, it controls Colorado beetles, Leptinomrsa decemlinmta on potatoes, and
scale insects on citrus, where it also exhibits ovicidal activity against mite eggs. It also controls stem
borers on maize, rice and sugarcane, and whiteflies (Benusia spp.) on cotton (Farm Chemicals
Handbook 1984; Worthing I987). Birlane® 24 controls root flies, phorid and sciarid fly larvae, fruit
flies on maize and sweet corn, and wheat bulb flies in winter wheat. Birlanew 10% granules are used
to control root flies and Birlanew Liquid Seed Treatment is used to control wheat bulb flies in winter
wheat. Supona‘") is used to control ticks, flies, lice and mites on cattle; blowflies. lice ked, and
itchmites on sheep; and fleas and ticks on dogs. Steladone‘” and Sapecronw are used as cattle dips or
sprays to control ectoparasites on cattle (Farm Chemicals Handbook I984; REFS I995; Spencer I982).
Chlorfenvinphos is also used in public health applications for control of mosquito larvae (The

Agrochemicals Handbook I991).

No quantitative information on the volume of Chlorfenvinphos usage in the United States or on historic
trends in usage was found. It is known however, that Chlorfenvinphos was first introduced for use in
the United States on October 3, 1963 and that the last EPA approved label date for a Chlorfenvinphos-
containing product was September I986. Use is likely to have declined from I986 until January 22,

199], when all uses of the chemical were canceled in the United States (REFS I995).

4.4 DISPOSAL

Chlorfenvinphos is considered to be an extremely hazardous substance (EPA I988). The
recommended disposal method for Chlorfenvinphos consists of hydrolysis and subsequent transport to a
landfill (IRPTC I985). Chlorfenvinphos and Chlorfenvinphos-containing wastes should be treated by
alkali and then mixed with a portion of soil which is rich in organic matter before burial (at least to a
depth of 0.5 meters) in a pit or in clay soil. For disposal of large quantities of Chlorfenvinphos,
incineration at high temperatures in a unit equipped with an effluent gas scrubbing device is

recommended (IRPTC 1985). See Chapter 7 for further information on regulations.

"'DRAFT FOR PUBLIC COMMENT"*

 

 

 

CHLORFENVINPHOS

5. POTENTIAL FOR HUMAN EXPOSURE

5.1 OVERVIEW

Chlorfenvinphos is currently released to the environment only from runoff and leaching from
hazardous waste disposal sites. Soil is the environmental medium most likely to be contaminated with
chlorfenvinphos. The processes that may transport chlorfenvinphos from soil to other media include
volatilization to the air, leaching to groundwater, runoff to surface water, and absorption by plants.
Biodegradation appears to be the dominant process responsible for chlorfenvinphos loss from soil
(Miles et al. 1979, 1983). Biodegradation, hydrolysis and adsorption of organic matter are likely to be
responsible for the loss of chlorfenvinphos from water (Beynon et al. 197], I973; Rouchaud et al.

1988).

Chlorfenvinphos does not appear to partition extensively from water into aquatic organisms. Estimated
whole-body concentration factors for chlorfenvinphos were significant, but relatively low, ranging from
37 to 460 (Mackay 1982', Veith et al. 1979; Veith et all 1980 in Bysshe 1990). No measured
bioconcentration factor (BCF) values were located in the literature for any aquatic invertebrate or fish
species. Chlorfenvinphos is absorbed by plants primarily from the soil, but residues generally decline
fairly rapidly in the tissues through the course of the growing season (Beynon et al. 1968; Suett 1971,
1975a).

The estimated half-life of chlorfenvinphos in soil ranges from 9 to 210 days (30 weeks). The rate of
degradation is influenced by the soil type, amount of organic matter in the soil, soil temperature, soil
moisture content, and the history of chlorfenvinphos use. Repeated exposure to chlorfenvinphos

enhanced microbial degradation of the pesticide (Rouchaud et al. 1989a, 1991).

No information was found on concentrations of chlorfenvinphos in ambient air samples or in drinking
water in the United States. Chlorfenvinphos was detected in surface and groundwater samples
(concentrations not specified) at a hazardous waste site where chlorfenvinphos was detected (HazDat
I995). Chlorfenvinphos was also detected in topsoil and subsurface soil samples (concentrations not
specified) at a hazardous waste site where chlorfenvinphos was detected (HazDat 1995). It should be
noted that the amount of chlorfenvinphos found by chemical analysis is not necessarily the amount

that is bioavailable.

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CHLORFENVINPHOS 130

5. POTENTIAL FOR HUMAN EXPOSURE

Currently, both domestic and imported foods (fresh fruits and vegetables) and lanolin-containing
pharmaceutical products appear to be sources of exposure for the general population. In the past,
occupational exposure to chlorfenvinphos may have occurred through dermal contact and inhalation of
dusts and sprays especially to workers applying the compound as a pesticide. Occupational exposure
to chlorfenvinphos was reported in California in workers who handled flea control products (Ames et

al. 1989).

Workers involved in disposal of chlorfenvinphos or chlorfenvinphos-contaminated wastes are at a
higher risk of exposure than the general population. People living in the vicinity of plants where
chlorfenvinphos was manufactured or formulated, or living near dairy farms, cattle or sheep holding
areas, or poultry producing facilities where chlorfenvinphos was used, and people living near

hazardous waste sites containing chlorfenvinphos also are potentially at higher risk of exposure.

Chlorfenvinphos has been identified in at least 1 of 1,416 hazardous wastes sites that have been
proposed for inclusion on the EPA National Priorities List (NPL) (HazDat 1995). However, the
number of sites evaluated for chlorfenvinphos is not known. The frequency of these sites within the

United States can be seen in Figure 5-1.

5.2 RELEASES TO THE ENVIRONMENT

Information on historic production of chlorfenvinphos (including producers, production sites,
production volumes and years of production) in the United States was not found. Releases of
chlorfenvinphos are not required to be reported under SARA Section 313; consequently there are no

data for this compound in the 1992 Toxic Release Inventory (EPA 1993).

There is one NPL hazardous waste site where chlorfenvinphos has been identified (HazDat 1995).
Hazardous waste disposal sites appear to be the major source for release 01' this compound into the
environment since there are currently no registered uses for chlorfenvinphos in the United States

(REFS 1995).

"*DRAFT FOR PUBLIC COMMENT'“

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"'DRAFT FOR PUBLIC COMMENT'"

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CHLORFENVINPHOS 132

5. POTENTIAL FOR HUMAN EXPOSURE

5.2.1 Air

No information was found on detection of chlorfenvinphos in the air at NPL hazardous waste sites
(HazDat 1995). No other information on releases of chlorfenvinphos to air was located; however,
there is no current production or registered uses of this compound in the United States (REFS I995;

SRI I993).

If chlorfenvinphos was produced in the United States, it may have been released into the air during its
production. Historically, chlorfenvinphos may have volatilized into the air during its use in sprays
applied to dairy, poultry, and cattle facilities to control flies and fly larvae, or from the skin of animals
exposed to chlorfenvinphos in cattle dips or sprays. Because of the relatively low volatility of the
compound and lack of registration for crop use in the United States (REFS I995), releases to the air

from registered uses would be expected to be negligible.

5.2.2 Water

Chlorfenvinphos has been detected in surface water and groundwater samples collected at a NPL
hazardous waste site where chlorfenvinphos has been detected in some environmental medium (HazDat
I995). No other information on releases of chlorfenvinphos to water was located; however, there is no

current production or use of this compound in the United States (REFS I995; SRI I993).

If chlorfenvinphos was produced in the United States, it may have been released to surface water
during its production. Chlorfenvinphos also may have been released to water via runoff after its
application to dairy, poultry, and cattle facilities to control flies and fly larvae, or when residues from
sheep or cattle dip tanks were discharged onto soil (Inch et al. 1972). Because chlorfenvinphos was
not registered for crop use in the United States (REFS I995), its releases to water from its registered
uses would be expected to be minimal. Adsorption to particulate matter will eventually transport

chlorfenvinphos from water to suspended solids and sediment in water.

5.2.3 Soil

Chlorfenvinphos has been detected in surface top soil samples and subsurface soil samples (>3 inches
deep) collected at a NPL hazardous waste site where chlorfenvinphos has been detected in some

environmental medium (HazDat I995). No other information on releases of chlorfenvinphos to soil or

m‘DRAFT FOR PUBLIC COMMENT'"

 

 

CHLORFENVINPHOS 133

5. POTENTIAL FOR HUMAN EXPOSURE

sediments was located; however. there is no current production or use of this compound in the United

States (REFS 1995; SR1 1993).

if chlorfenvinphos were produced in the United States, it may have been released directly to soil
during its production and is likely to have been released during its disposal as the recommended
disposal practice for small quantities was burial in a disposal pit or in clay soil (IRPTC 1985). The
compound may also have been released to soil and sediment indirectly from runoff from treated
manure storage areas. and areas around poultry or cattle holding areas. or when residues from sheep or
cattle dip tanks were discharged onto soil (Inch et al. 1972). Adsorption to particulate matter will
eventually transport chlorfenvinphos from water to suspended solids and sediment. Because
chlorfenvinphos was not registered for crop use in the United States, its releases to soil from its

registered uses would be expected to be minimal.

5.3 ENVIRONMENTAL FATE

5.3.1 Transport and Partitioning

There is a paucity of experimental data regarding the transport and partitioning of chlorfenvinphos in
the air. Given a vapor pressure ranging from 4.0x10'“ mm Hg (Worthing 1987) to 7.5x10'6 mm Hg
(Merck 1989), chlorfenvinphos should exist in the atmosphere in the vapor phase, but will also
partition to available airborne particulates (Eisenreich et a1. 1981). The solubility of 145 mg/L (Merck
1989) ensures that at least partial removal of atmospheric chlorfenvinphos will occur by wet

deposition.

The transport of chlorfenvinphos from water to air can occur due to volatilization. Henry’s law
constant provides a qualitative indicator of the importance of volatilization. Compounds with a
Henry‘s law constant (H) of <10" atm-mx/mol volatilize slowly from water (Thomas 1990).
Chlorfenvinphos with an H value of 2.76x10") atm-m‘lmol (Domine et al. 1992), therefore, will
volatilize slowly from water. Since H <10“ atm—mx/mol, chlorfenvinphos is less volatile than water
and its concentration in water may increase as water evaporates. Because humidity in the air reduces
the volatilization rate of water somewhat so the lower limit can be set at 107, chlorfenvinphos could

be considered essentially nonvolatile (Thomas 1990).

"'DRAFT FOR PUBLIC COMMENT'"

CHLORFENVINPHOS

5. POTENTIAL FOR HUMAN EXPOSURE

Adsorption to particulate matter will transport Chlorfenvinphos from water and partition it to suspended

solids and sediment in water. The estimated organic carbon-adjusted soil sorption coefficient (Km) for
Chlorfenvinphos is 280 (Kenaga 1980). This Km. value suggests that Chlorfenvinphos in the water
column adsorbs moderately to suspended solids and sediments based on criteria established by Swann
et al. (1983), and this process may transport considerable amounts of Chlorfenvinphos from water to
particulate matter. Partitioning of Chlorfenvinphos from water to solid suspended matter was studied
in a field experiment. Chlorfenvinphos was sprayed at a rate of 74 kg/ha on to the surface of a pond
so the water contained an average concentration of 6.] ppm (Beynon et al. l97l). The concentration
decreased to 2.0 ppm after 5 hours, and to 0.12 ppm after one month. The sediment concentrations
increased and persisted for at least 34 days after treatment. Chlorfenvinphos disappears from water in
two distinct phases, a rapid initial phase and a much slower second phase. It is suggested that the first
phase represents the initial precipitation of the heavier particles and plankton containing the adsorbed
pesticide. Later, Chlorfenvinphos is gradually adsorbed to other suspended matter, which then
precipitates much more slowly, or the second phase represents the slower removal of the residues by

biotic processes.

Based on structure and activity relationships, certain regression equations have been developed to
estimate the bioconcentration factor (BCF) for Chlorfenvinphos from its water solubility and K0,.
values. Using these regression equations, the BCF value for Chlorfenvinphos in aquatic organisms is
estimated to be 37 (Kenaga 1980). A log K0w value of 3.806 was reported by Bowman and Sans
(I983). Using regression equations involving log Kow, the following BCF values were estimated;
306 (Mackay I982), 343 (Veith et al. 1979), and 460 (Veith et al. 1980 in Bysshe 1990). No
measured BCF values were located in the literature for any aquatic invertebrate or fish species.
However, bioconcentration of Chlorfenvinphos in aquatic organisms, although relatively low, ranging
from 37 to 460, may have some environmental significance. No information was found on the

biomagnification of chlorfenvinphos through aquatic or terrestrial food chains.

The transport processes that may move chlorfenvinphos from soil to other media are volatilization,
leaching, runoff, and absorption by plants. Based on the estimated Henry’s law constant, volatilization
is not expected to be an important transport process for moving Chlorfenvinphos from soil to other
media. Like other pesticides, Chlorfenvinphos in soil partitions between soil—sorbed and soil-water
phases (Racke I992). This latter phase may be responsible for the volatilization of Chlorfenvinphos

from soil; however, due to the low Henry’s law constant value, the rate of Chlorfenvinphos

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CHLORFENVINPHOS 135

5. POTENTIAL FOR HUMAN EXPOSURE

volatilization from the soil-water phase to the atmosphere would be low. In a laboratory study of
volatilization from soil, chlorfenvinphos was incorporated into sterilized sand and into a sterilized
sandy loam at a concentration of 50 ppm. The media contained 25% moisture and were maintained at
20 0C in an open beaker. Forty-five days after incorporation more than 95% of the chlorfenvinphos '
was still present in the beaker (Rouchaud et al. 1988). However, in a field study conducted by
Williams (1975a), the author suggests that rapid loss (42% in 2 days) of surface—applied
chlorfenvinphos (granular) was probably due to volatilization and/or photodecomposition. Subsurface
application of the granular formulation at the same concentration showed only a 6% loss in 2 days
post-application. In another field study, Suett (1977) reported that the combination of sunlight and
warm wet soil for 48 hours immediately after application of chlorfenvinphos marginally increased

isomerization on both the coarse and fine soil tilthes, but did not enhance volatilization.

The reported K0C value of 280 (Kenaga 1980) suggests that the adsorption of chlorfenvinphos to soil is
moderately strong; therefore, the rates of leaching and runoff will be relatively minor processes in
most soils. Very little leaching of chlorfenvinphos and no leaching of its degradation products was
observed in several field studies. The leaching characteristics of chlorfenvinphos were studied by
applying it to sloping arable land at 22 kg active ingredient/hectare (al./ha) and following its
movement down a slope (Edwards et al. 1971). Only 0.18% of the chlorfenvinphos applied was
leached through the soil, but this was nine times more than was observed with dieldrin in a similar
experiment. Only very small amounts of chlorfenvinphos moved down the slope and were present in
runoff. In one of the experiments there was a pond located at the bottom of the slope and residues
could not be detected in the mud or water from this pond. Residues of the main soil degradation
products were not detected in the pond water at 23 or 36 weeks post—application. More
chlorfenvinphos leached vertically into drainage water than laterally over the soil surface.
Chlorfenvinphos residues in soil following broadcast applications on the surface showed that even after
150 days, only 1—1.5% of the applied chlorfenvinphos leached to a depth of 7.5—15 cm despite 12 cm
of rainfall that occurred during the first 60 days post—application (Williams 1975a). Furthermore,
when the granular formulation was applied at a depth of 7.5 cm, there was little movement of
chlorfenvinphos below a depth of 10 cm. In a similar study by Agnihotri et al. (1981), when
chlorfenvinphos granules were applied to the 0—15 cm soil layer, no leaching of the compound

occurred below the 15 cm depth over a period of 120 days.

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CHLORFENVINPHOS 136

5. POTENTIAL FOR HUMAN EXPOSURE

Chlorfenvinphos is also transported from the soil of one area to soil of another area or from soil to
surface water (rivers, lakes, and streams) via runoff. Pesticides with a water solubility >l() mg/L
move mainly in solution phase in runoff water (Raeke I992). Chlorfenvinplios with a water solubility
of I45 mg/L (Merck 1989) is expected to be found mainly in runoff water. This does not seem to be
completely substantiated, however, by results of several field studies conducted in agricultural
watersheds. In one field study, only (IS—0.6% of the applied chlorfenvinphos was found in runoff
water after a rainfall event (Racke I992). Braun and Frank (I980) analyzed pesticide residues in
surface water samples over a 3—year period (l975~77) collected in l l agricultural watersheds in
Southern Ontario, Canada. Although chlorfenvinphos was known to have been used as a soil pesticide
in at least one of the watersheds, it was not detected in any surface water samples (detection limit

I pg/L [1 ppb]). In a more recent study. Frank et al. (l99l) analyzed pesticide residues in surface
water samples over a 5-year period “986—90) collected from the mouths of the 3 major agricultural
watersheds, the Grand, the Saugeen, and the Thames Rivers in Ontario. Canada. All three rivers flow
into Lake Erie. Although it was known to have been used as a soil pesticide in the Thames River
basin in l988, no chlorfenvinphos residues were detected in any surface water samples during the
study period (detection limit <l.0 pg/L [<1 ppbl). Most recently. Wan et al. (1994) studied residues
of several organophosphate pesticides including chlorfenvinphos in farm ditch water. and sediments
and farm soils in the lower Fraser Valley of British Columbia, Canada from July through December
l99l. The farm ditches drained into three rivers; the Fraser, the Niicomekl, and the Sumas Rivers.
During the study period, no sales of chlorfenvinphos were reported. Chlorfenvinphos was used as a
soil insecticide in 1990, but was not recommended for this use in Canada in l99l. Although
chlorfenvinphos was not detected in any of the farm ditch water or sediment samples analyzed at the
7 sampling sites, it was detected in 7% of the soil samples. Adsorption of chlorfenvinphos to
particulate matter will transport the pesticide from the water column and partition it to suspended
solids and sediment. From these results, it seems clear that surface water runoff and leaching of
chlorfenvinphos into drainage water from treated agricultural fields is not likely to be a serious

problem.

Adsorption of chlorfenvinphos from water solutions of hydrogen, calcium, sodium, and potassium ions
were studied (Barba et al. l99l). In all cases. the saturating cations influenced the Freundlich—type
adsorption, with adsorption decreasing in the following sequence: H*> Ca“> N113 K+ for adsorption
on two clays, kaolinite and bentonite. The extent of adsorption of chlorfenvinphos was generally

slower in kaolinite than in bentonite.

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CHLORFENVINPHOS 137

5. POTENTIAL FOR HUMAN EXPOSURE

When it was first introduced, chlorfenvinphos was generally considered to be a non-systemic pesticide
(i.e., when it is applied to soil it should not move into plants and when sprayed on plant foliage, it
should not move from the treated leaves into other untreated parts of the plant) (Rouchaud et al.
198%). This view was based on the fact that at plant maturity or at harvest very low residues

(<0.02 mg/kg [ 0.02 ppm]) were found in turnips, carrots, cabbages, white radishes and potatoes
planted or sown in chlorfenvinphos-treated soil (Beynon and Wright 1968; Beynon et al. 1968). In
addition, no translocation of chlorfenvinphos from treated leaves to other parts of plants was observed
(Beynon et al. I973). Earlier work with potato tubers under recommended field conditions also
confirmed this finding (Beynon et al. I968). Rouchaud et al. (1989b), however, found that in the
foliage of the spring cauliflower, the concentration of chlorfenvinphos increased, reaching a peak
concentration 15 days after soil treatment, then progressively decreased until harvest. The presence of
chlorfenvinphos and two metabolites, trichloroacetophenone and 2,4-dichlorobenzoic acid, was the
result of their absorption by the plant from the soil and of their biodegradation by the plant. Two
crops were studied for their chlorfenvinphos uptake (Rouchaud et al. 1991). The periods of time
required for chlorfenvinphos foliage concentrations to attain residues 1 mg/kg (1 ppm) fresh weight
were: cauliflower, 24—37 days; and Brussels sprouts, 41—45 days. Suett (1974, 1975a) also reported
that carrots accumulated high residue concentrations of chlorfenvinphos applied to the soil and
continued to accumulate the pesticide during the entire period of active plant growth. Thirty weeks
after sowing carrots, the carrot peel contained 88% of the total chlorfenvinphos residues of carrots
grown in soil treated with chlorfenvinphos at a depth of 10 cm. The upper 6 cm of carrot root always
contained most of the chlorfenvinphos residue irrespective of the application mode. Significant
residues of chlorfenvinphos were detected in immature onion bulbs (64—76 days after seeding) with the
level of chlorfenvinphos residue being much higher in the roots and outer skin (Ritcey et al. 1991).
The chlorfenvinphos concentrations in the bulbs dropped below the detection limit (unspecified) by

96 days after seeding (2 months before harvesting).

In recent experiments, plant cuticle was investigated as the first and rate-limiting barrier in foliar
uptake of chlorfenvinphos. Mobility studies of chlorfenvinphos across the cuticular membranes of
bitter orange (Cirrus aurantium) leaves and green pepper (Capsicum annuum) fruits gave first order
rate constants of 6.7 (:3.3)xle/sec and 10.2 ($3.4)x107/sec, respectively (Bauer and Schonherr 1992).
These correspond to penetration half-lives of 120 days (2,874 hours) and 7.8 days (189 hours),

respectively.

"'DRAFT FOR PUBLIC COMMENT‘"

CHLORFENVINPHOS 138

5. POTENTIAL FOR HUMAN EXPOSURE

5.3.2 Transformation and Degradation

5.3.2.1 Air

One of the important reactions for most organic pollutants in the atmosphere is with hydroxyl radicals.
No rate constant for the reaction of hydroxyl radicals with chlorfenvinphos in air has been
experimentally determined. Using an estimation method, the estimated rate constant value for the
vapor—phase reaction of chlorfenvinphos with hydroxyl radicals is 5.3lx10‘ll ch/radical—sec at 25 0C
(Atkinson 1988; HSDB 1994; Meylan and Howard 1993). Based on this value, and assuming an
average annual atmospheric concentration of hydroxyl radicals in the northern hemisphere of 4.8xl05
radicals/cmJ (Lyman et al. 1990), the estimated half-life of chlorfenvinphos in the atmosphere due to
this reaction is 7 hours. Therefore, chlorfenvinphos is short—lived in the atmosphere. Chlorfenvinphos
can also be degraded by ozonation in the atmosphere. However, no rate constant for the reaction of
ozone with chlorfenvinphos in air has been experimentally determined. An estimated value of the rate
constant is 3x10’18cm3/molecule-sec at 25 0C (Atkinson and Carter 1984; HSDB 1994; Meylan and
Howard I993). Based on this value and assuming an average atmospheric ozone concentration of
9.6x10lI molecules/cm3 (Lyman et al. 1990). the estimated half-life of chlorfenvinphos in the
atmosphere due to this reaction is 92 hours (3.4 days). Photolysis is probably the least significant of
the atmospheric degradation processes. Chlorfenvinphos is not susceptible to direct photolysis in
sunlight because its absorption maximum for ultra violet light is 228 nm (Schlett l99l ), which is less

than the 290 nm wavelength limit for sunlight absorption to occur.

5.3.2.2 Water

The processes that can result in the transformation and degradation of chlorfenvinphos in water are
hydrolysis, photosensitized oxidation, and biodegradation. Hydrolysis pathways for chlorfenvinphos in
water are shown in Figure 52. Chlorfenvinphos is most stable in water at ambient temperatures and
neutral pH. Chlorfenvinphos hydrolyzed slowly in water resulting in a half—life of 170 days at pH

6 and 80 days at pH 8 at 20—30 C’C (Beynon et al. 1971). In laboratory studies, hydrolysis was
observed under conditions of high temperature and extreme pH (highly alkaline or highly acidic),
resulting in a half-life of >400 hours (>33 days) at pH 9.1, and >700 hours (58 days) at pH 1.] at

38 OC (The Agrochemicals Handbook 1991; Beynon et al. 1973; Hayes 1982). Hydrolysis probably

does not contribute much to the initial disappearance of chlorfenvinphos from natural waters (Beynon

*"DRAFT FOR PUBLIC COMMENT‘“

CHLORFENVINPHOS 139

5. POTENTIAL FOR HUMAN EXPOSURE

FIGURE 5-2. Hydrolysis Pathways for Chlorfenvinphos in Water

  
 
 

Cl H
o \C/ Cl
cause i ll
\
/PO—C CI
C2H50
Acidic. Chlorfenvinphos Baosic, .
100'C iO/o NaOH, 100 C
CI CI
Neutral
CICHZC(O) CI C'CH2C(O) '
Trichloroacetophenone Trichloroacetophenone
Stable
+ +
0 Cl
C H O
2 5 ll
>P—‘OH HO\C_C Cl
cszo || |
O OH
Diethyl phosphoric acid 2,4-Dichioropheny|glycolic acid
+
O
CszO\|| - +
/P——O Na
‘3sz0

Diethyl phosphoric acid, sodium

Adapted from Beynon et ai‘ 1973

"'DRAFT FOR PUBLIC COMMENT'"

CHLORFENVINPHOS 140

5. POTENTIAL FOR HUMAN EXPOSURE

et al. 197]). Based on hydrolysis studies (Ruzicka et al. 1967) conducted at 70 oC and correcting for
temperature differences assuming an environmental temperature of 20 °C, the aqueous hydrolysis half—
life of chlorfenvinphos is approximately 1—1.3 years (Harris 1990). Direct photolysis of
chlorfenvinphos is negligible, since the compound does not significantly absorb ultra-violet wavelength
light >290 nm. No information was found in the literature regarding the photosensitized reaction of
chlorfenvinphos in water with ozone, hydroxyl radicals or singlet oxygen. Therefore, biodegradation
appears to be the dominant degradation process in natural waters. This is likely, as microbial
degradation is the dominant degradation process in soils (Miles et at. 1979, I983; Rouchaud et al.

1988).

The catalytic degradation of chlorfenvinphos on Hi Ca2+, Na”, and K+ mono-ionic kaolinite and
bentonite was found to be influenced by the nature of the exchange cations and their degree of
hydration in the order K+> Na+> Ca3"> HVAll+ (Camara et al. l992). In both types of clays, the
process of hydrolysis occurred in two stages involving first-order kinetics giving different hydrolysis
rates. The first stage consists of a rapid hydrolysis rate of short duration, while the second phase

consists of a slow but continuous hydrolysis rate.

5.3.2.3 Sediment and Soil

Chlorfenvinphos in soil and sediment may undergo degradation and transformation by hydrolysis, and
biotic processes. Various screening studies have demonstrated that microbial degradation is the
dominant degradation process in soil (Miles et al. 1979, I983; Rouchaud et al.1988, 1989a, l989b).
The hydrolysis of chlorfenvinphos may occur in the soil/sediment-water phase, as opposed to the soil/
sediment-sorbed phase. As a result, the rate of hydrolysis is expected to be comparable to that in
water. Based on the slow hydrolysis rates observed in water (see Section 5.3.2.2.), hydrolysis of
chlorfenvinphos in soil is not expected to be significant. In the laboratory, chlorfenvinphos was
incubated in sterilized and unsterilized soil for more than 2 months at 20 OC. The rate of
disappearance of chlorfenvinphos from the sterilized soil was more than IS times slower than that
observed in unsterilized soil. The persistence of chlorfenvinphos was examined in sterile and natural
mineral (sandy loam/organic matter 2 2.7%, pH = 7.2) and organic (muck, organic matter = 48%,

pH = 6.5) soils at a range of temperatures (3—28 DC) for 24 weeks (Miles et al. 1979, I983). In
general. chlorfenvinphos is less stable in sandy loam than in muck, less stable at higher temperatures

(the exception was the stability of chlorfenvinphos in sterile sandy loam at all temperatures studied),

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5. POTENTIAL FOR HUMAN EXPOSURE

and considerably less stable in natural soils (half-lives 311 weeks at 15 and 28 °C) compared to sterile
soils (half-lives >24 weeks at all temperatures), indicating the major role microbes play in degrading
chlorfenvinphos in soil. A summary of degradation pathways of chlorfenvinphos in soil is presented

in Figure 5—3.

Chlorfenvinphos is degraded in soil to trichloroacetophenone, 2,4-dichlor0acet0phenone, oc-(chloro—
methyl)—2,4-dichlorobenzyl alcohol, and 1-(2’,4’—dichloropheny|)—ethan-1-01 (Rouchaud et al. 1988,
1991). Other degradation products identified are 2,4-dichlorobenzoic acid, 2-hydroxy-4—chlorobenzoic
acid, and 2,4—dihydroxybenzoic acid. None of the degradation products retain any pesticide
characteristics. Trichloroacetophenone is the main transformation product, which when hydrolyzed,
oxidized and decarboxylated, becomes 2,4—dichlorobenzoic acid. Reduction of trichloroacetophenone
to (x-(chloromethyl)-2,4-dichlorobenzyl alcohol is a slow process, and replacement of a chlorine atom
by a hydrogen atom to become 2,4—dichloroacetophenone and 1(-2’,4’—dichlorophenyl)-ethan-l-ol is
also slow. The degradation products 2-hydroxy-4-chlorobenzoic acid and 2,4-dihydroxybenzoic acid

are produced from 2,4—dichlorobenzoic acid by replacement of chlorine atoms by hydroxyl groups.

Biodegradation of chlorfenvinphos was influenced by several factors: soil type, presence of organic
matter, moisture content, soil temperature, and a history of chlorfenvinphos use. Chlorfenvinphos
degrades fastest in sandy soils and slowest in peat, probably because of its degree of adsorption to
organic matter (Beynon et a1. 1973; Williams 1975a). Because the rate of degradation by hydrolysis is
greater than expected, breakdown is assumed to be mainly biotic. Initial half-lives of 4—30 weeks
have been determined for sandy soils. In peat, chlorfenvinphos persists longer. Chlorfenvinphos was
found to be very slowly degraded in a peat soil (47.8% organic matter), but was much less persistent
on several sandy soils (lb—2.2% organic matter) (Williams 1975a). In the peat (soil water pH = 6.0),
70% of the applied chlorfenvinphos remained after 21 weeks and 30% remained after nearly

12 months. In sandy soil (soil water pH = 6.9—7.5) only 3—15% of the applied chlorfenvinphos
remained after a period of 15 weeks. The persistence in peat was attributed to strong adsorption
rendering the pesticide unavailable to microorganisms and to plant roots. In sandy soil, rainfall was

also correlated to increased loss of chlorfenvinphos.

Chlorfenvinphos was more stable and had increased persistence in soils that had been treated with
organic fertilizer such as pig slurry, cow manure, city refuse, or mushroom cultivation composts

relative to its persistence in untreated control plots (Rouchaud et al. 1992a, 1992b). For example, the

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5. POTENTIAL FOR HUMAN EXPOSURE

FIGURE 5-3. Environmental Degradation Pathways for Chlorfenvinphos in Soil

    

CI H
O \C/ Cl
CZHSO ICI: Cl
/
CszO
/ Chlorfenvinphos
Cl
Cl
0 CHCI
cszod u
/POC Cl CICHZCH Cl
—————>
HO
Desethyl chlorfenvinphos Trichloroacetophenone
C
O CHCI CI
H0\T H
/POC C' CICHQCH CI
HO |
OH
(HO)3P(O) a-(Chloromethyl)-2,4-dichlorobenzyl alcohol

Phosphoric acid

Cl CI Cl
HO\
C C] HOCH2CH ClwfiCHgf/CH Cl
g l o
OH
2,4-Dichlorobenzoic acid 1-(2,4-Dichlorophenyl)- 2,4-Dichlorophenyl
ethan-1,2-diol oxirane
Cl Cl
2-Hydroxy-4-chlorobenzoic acid
HOCHZfH Cl + CHa—(IJH Cl
OH OH
2,4-Dihydroxybenzoic acid 2,4-Dichloroacetophenone 1-(2,4-Dichlorophenyl)-
ethan—1-ol

Adapted from Edwards et al. 1968; Beynon et al. 1973; Rouchaud et al. 1991, 1988

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CHLORFENVINPHOS

5. POTENTIAL FOR HUMAN EXPOSURE

half-life of chlorfenvinphos at the Gembloux site was 18, 36, 35, and 43 days for the control, city

refuse compost, cow manure, and mushroom compost plots respectively. At another site

(St. Katelijne-Waver), both a spring and summer application study were conducted. In the spring

study, the half—life of chlorfenvinphos was 9, l3, l4, and 21 days and in the summer study, the half-
life was 23, 42, 46, and 53 days for the control, city refuse compost, cow manure, and mushroom
compost plots respectively. The humic acid concentrations and the total soil organic matter content

were always higher in the organic fertilizer treated plots.

Rates of chlorfenvinphos loss from soil also appear to be related to soil moisture conditions. In dry
seasons, although the initial rate of loss was high, the subsequent rate of degradation was slower than
in wetter seasons of higher soil moisture content (Williams 19753). Under conditions of average
summer rainfall and relatively moist soils, the residues were less than 5% of applied dose, but when
the soils were much drier than normal, residues were higher at 15% of applied dose after the same

period of time (Miles et al. 1984).

Degradation of chlorfenvinphos ceases in soil at low temperatures (below 6—7 OC) (Suett 1975b). A
granular formulation of chlorfenvinphos was broadcast at 2 kg active ingredient/ hectare and
incorporated to 10 cm into sandy—loam soil in May and in September 1971. When applied in
September, the chlorfenvinphos persisted for a longer period than when applied in May. Degradation
was slower during the winter while the mean soil temperature remained below 6—7 °C. Rising soil
temperature during the following spring rapidly increased the rate of degradation. The late summer/
early fall applications to control carrot flies would leave appreciable residues of chlorfenvinphos in the
soil at the beginning of the next growing season which might contribute to the terminal crop residues.
Residues of chlorfenvinphos applied in May declined to less than 20% of the initially applied dose,
and there was little loss subsequent to the December sampling. In the September application, more
than 60% of the chlorfenvinphos applied still remained when the loss rates decreased in October. The
relatively high concentration of chlorfenvinphos remaining then continued to decline only slowly
throughout the winter until March when the rate of loss of chlorfenvinphos residues increased to rates

similar to those of the previous September.
An inverse relationship between the history of chlorfenvinphos use in the soil and foliage

concentrations was found that suggested enhanced biodegradation (Rouchaud et al. l99l ). The longer

the history of chlorfenvinphos use in a field, the lower the chlorfenvinphos residues and residues of its

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CHLORFENVINPHOS 144

5. POTENTIAL FOR HUMAN EXPOSURE

metabolites that were found, suggesting that specific soil microbial fauna adaptation was due to
previous soil treatments. In soil from cauliflower, Brussels sprouts, and Chinese cabbage fields, the
half-life of chlorfenvinphos was found to vary from 9 to 35 days, and for chlorfenvinphos plus
degradation products, the half-life ranged from 50 to 80 days (Rouehaud et al. I989a). The fields in
which chlorfenvinphos exhibited the shorter half—lives were those with the longer histories of

chlorfenvinphos use in the soil, suggesting enhanced biodegradation was occurring.

Environmental transformation pathways for chlorfenvinphos in plants are summarized in Figure 5-4.

A trans to cis rearrangement of chlorfenvinphos sprayed on plant foliage has been observed (Beynon et
al. I973). This conversion has been attributed to photochemical processes. The same conversion has
not been observed for chlorfenvinphos applied directly to soil. The initial half—life of chlorfenvinphos
on foliage is 2~3 days, and the rate of degradation decreases thereafter. Over 50% of the radioactivity
from I4C-(vinyI)-trans-chlorfenvinphos disappeared from foliage in 4—7 days. It is not known whether
it is released as chlorfenvinphos or as a degradation product. The major breakdown product of

chlorfenvinphos on plant foliage is a conjugate of the ethan-I—ol [8], probably with a sugar.

5.4 LEVELS MONITORED 0R ESTIMATED IN THE ENVIRONMENT

5.4.1 Air

No information was located on the ambient concentrations of chlorfenvinphos in the atmosphere or on

concentrations associated with occupational exposures in the United States.

5.4.2 Water

No information was located on the ambient concentrations of chlorfenvinphos in drinking water,
surface water, or ground water in the United States. Chlorfenvinphos was detected (concentration
unspecified) in surface water and ground water samples collected at a hazardous waste site where it

has been identified in some environmental media (HazDat I995).

Environmental monitoring data are available for surface waters from Canadian studies in the Great
Lakes region and from British Columbia. Braun and Frank (1980) analyzed pesticide residues in
surface water samples over a 3—year period (1975—77) collected in l l agricultural watersheds in

Southern Ontario, Canada. Although chlorfenvinphos was known to have been used as a pesticide in

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5. POTENTIAL FOR HUMAN EXPOSURE

FIGURE 5-4. Environmental Transformation Pathways for Chlorfenvinphos In Plants

 

Cl
0 \C/HCI
C H O . .
2 5 \g—fl Cl Mam, cis-Chlorienvinphos
CZHSO / on foliage
trans-Chlortenvinphos
CI
0 CHCl 0'
CZHSO \4 I
POC CI _______> CICHZC(O) CI
HO
Desethyl chlorotenvinphos Trichloroacetophenone
Foliage, in crops in treated soil
CI
HO\ -—
0 CI
|| \ /
O
2,4-Dichlorobenzoic acid
crops in treated soil
OH l
HO\ — Cl V
C OH
H \ /
2-Hydroxy-4-chlorobenzoic acid 0
crops in treated soil +
l CI
OH CHa-CIDH Cl
0
HO\ H
C CH .
II 1-(2',4-dlchlorophenyl)-ethan-1-o|
O

2,4-Dihydroxybenzoic acid
crops in treated soil
Conjugates
foliage
Adapted from Beynon et al. 1973 and
Rouchaud et al. 1989, 1991

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5. POTENTIAL FOR HUMAN EXPOSURE

at least one of the watersheds, it was not detected in any surface water samples (detection limit 1 pg/L
[1 ppb]). Frank et a1. (1991) analyzed pesticide residues in water samples over a 5-year period
(1986—90) collected from the mouths of the three major agricultural watersheds, the Grand, the
Saugeen, and the Thames rivers in Ontario, Canada. All three rivers flow into Lake Erie. Although it
was known to have been used as a soil pesticide in the Thames River basin in 1988, no
Chlorfenvinphos residues were detected in any water samples during the study period (detection limit
<1.0 pg/L [<1 ppb]). Most recently, Wan et a1. (1994) studied residues of several organophosphate
pesticides including Chlorfenvinphos in farm ditch water and farm soils in the lower Fraser Valley of
British Columbia, Canada from July through December 1991. The farm ditches drained into three
rivers; the Fraser, the Niicomekl, and the Sumas Rivers. During the study period, no sales of
Chlorfenvinphos were reported. Chlorfenvinphos was used as a soil insecticide in 1990, but was not
recommended for this use in Canada in 1991. Although Chlorfenvinphos was not detected in any of
the farm ditch water or sediment samples analyzed at the 7 sampling sites, it was detected in 7% of
the soil samples. Residue results obtained in these Canadian studies may be inappropriate for
estimating water residues in the United States, as Chlorfenvinphos was never registered for use as a

soil insecticide in the United States (REFS 1995).

5.4.3 Sediment and Soil

Chlorfenvinphos was detected (concentration not specified) in topsoil and subsoil samples (>3 inches
deep) collected at a hazardous waste site where it has been identified in some environmental media
(HazDat 1995). No other information was located on the concentrations of Chlorfenvinphos in soil or

sediment samples collected in the United States.

Environmental monitoring data are available for agricultural soils from Canadian studies in the Great
Lakes region and from British Columbia. Chlorfenvinphos residues in organic farm soils of the
Holland Marsh, Ontario, Canada were analyzed in the fall from 1972 to 1975 and residue levels
generally exceeded 0.1 ppm (Miles et a1. 1978). The annual mean residues of Chlorfenvinphos
sampled in 13 farm soils were as follows: 1972, 0.12 ppm; 1973, 0.05 ppm; 1974, 0.36 ppm; and
1975, 0.13 ppm, given on a dry weight basis. Wan et a1. (1994) studied residues of several
organophosphate pesticides including Chlorfenvinphos in farm soils from seven different sites in the
lower Fraser Valley of British Columbia, Canada from July through December 1991. Chlorfenvinphos

was used as a soil insecticide in 1990, but was not recommended for this use in Canada in 1991

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CHLORFENVINPHOS 147

5. POTENTIAL FOR HUMAN EXPOSURE

(during the study period). Despite the fact that chlorfenvinphos was not used during the study period,
it was detected in 7% of the soil samples analyzed. The mean chlorfenvinphos concentration found in
soil at the Cloverdale site was 31 ug/kg (ppb) and ranged from 12 to 60 ug/kg (ppb). The authors
believed that these residues were a carryover from the previous years. Residue results obtained in
these Canadian studies may be inappropriate for estimating soil residues in the United States, as

chlorfenvinphos was never registered for use as a soil insecticide in the United States (REFS 1995).

5.4.4 Other Environmental Media

Chlorfenvinphos was not monitored in many of the federal, regional, and state food studies conducted
from the late 19605 through the mid-19803 (Comeliussen 1970; Duggan and Corneliussen 1972;
Duggan et al. 1983; Gartell et al. 1986; Gunderson 1988; Hundley et al. 1988). The FDA’s
monitoring program for domestic and imported food commodities detected chlorfenvinphos in
unspecified foods at unspecified concentrations during fiscal years 1978—82 (Yess et al. 1991a) and
during fiscal years 1983—86 (Yess et al. 1991b). During 1982—86, the FDA Los Angeles District
Laboratory analyzed 19,851 samples of domestic and imported food and feed commodities (Luke et al.
1988). Chlorfenvinphos was not detected in any samples of the 6,391 domestic agricultural
commodities or in any of the 12,044 imported agricultural commodities analyzed. Chlorfenvinphos
was detected in unspecified foods at unspecified concentrations in 14,492 domestic and imported food
samples analyzed as part of the FDA pesticide monitoring program for 1986—87 (FDA 1988). In a
pesticide residue screening program conducted in 1989—91 in San Antonio, Texas, on 6,970 produce
samples, chlorfenvinphos was detected (0.75 ppm detection limit) in one produce sample of tomatoes
(frequency of <0.5%) (Schattenburg and Hsu 1992). In a similar study conducted by Agriculture
Canada of 13,230 domestic and imported food items analyzed during the same period (1989—91),
chlorfenvinphos was not detected in any domestic foods but was detected in 13 imported food samples
(frequency < 0.1%) (Neidert et al. 1994). Detectable residues were found in fresh oranges, peppers,
pineapples, and spinach. As part of the FDA’s Pesticide Monitoring Program for domestic and
imported foods, chlorfenvinphos residues have been detected in unspecified foods at unspecified

concentrations during 1988—89, 1989—90, 1990—91, and 1991—92 (FDA 1990, 1991, 1992, 1993).
The effect of cooking on chlorfenvinphos concentrations in raw foods was examined by Askew et al.

(1968). These authors spiked samples of raw potato and cabbage mash with 2 ppm of chlorfenvinphos

and boiled the samples for 30 minutes to simulate the effect of cooking raw vegetables contaminated

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5. POTENTIAL FOR HUMAN EXPOSURE

with chlorfenvinphos. Total residues were reduced by 37—53% for potato and 56—86% for cabbage
mash. A cooking process such as boiling leads to a partial reduction of chlorfenvinphos residues, but
does not completely eliminate the pesticide. A similar study examined the effects of milk processing
procedures on organophosphate residues in milk (Skibniewska and Smoczynski I985). These authors
reported that boiling in an enamel vessel to simulate home cooking, and 3 pasteurization procedures
involving heating for 30 minutes at ()2 0C, for 2 minutes at 72 OC, and for 5 seconds at 85 oC, resulted
in about a 20% decrease in the residues of organophosphates including chlorfenvinphos. Reduction of
the pesticide residues was more affected by the duration of heating rather than the temperature to

which the milk was heated.

Nagayama et al. (1989) studied the residue levels of chlorfenvinphos on commercial tea leaves grown
in Japan and the leaching of the pesticide into tea. Chlorfenvinphos was detected at concentrations
ranging from trace to 3.4 ppm on tea leaves and more that 12% of the chlorfenvinphos was found to

leach from the leaves into the tea.

Heikes and Craun (1992) analyzed the residues of several pesticides including chlorfenvinphos in
anhydrous lanolin and lanolin—containing pharmaceutical preparation sampled from 1988 through 1992.
Concentrations of chlorfeiwinphos in anhydrous lanolin samples collected in I989 ranged from 0.60 to
5.9 mg/kg; those collected in I99] ranged from 0.81 to IO mg/kg. In I988, chlorfenvinphos was
detected in a wide range of pharmaceutical preparations including A & D ointment, analgesic balm,
nitroglycerin cream, atropine sulfate ointment, and dibucaine ointment at concentrations ranging from
0.08 to 1.] mg/kg (ppm). In I992, chlorfenvinphos was detected in antibiotic, cold sore, and

ophthalmic ointments at concentrations ranging from trace to 0.32 mg/kg (ppm).

5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE

Currently, the general population is primarily exposed to chlorfenvinphos by ingesting food containing
chlorfenvinphos, particularly fresh fruits and vegetables imported from countries where this pesticide is
used. In addition, the general population may be dermally exposed to chlorfenvinphos concentrations

in lanolin and lanolin—containing pharmaceutical products.

No information is available on the concentrations of chlorfenvinphos in ambient air. However,

because this pesticide currently has no registered uses in the United States, the extent of exposure of

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CHLORFENVINPHOS 149

5. POTENTIAL FOR HUMAN EXPOSURE

the general population to chlorfenvinphos from inhalation is probably insignificant. No information is
available on the concentrations of chlorfenvinphos in drinking water. Because chlorfenvinphos was
not used as an agricultural pesticide on crops in the United States. it was not monitored extensively in
ground water. As a result of its relatively limited use, current exposure of the general population to

chlorfenvinphos from consumption of drinking water is probably negligible.

Chlorfenvinphos has been detected in both domestic and imported foods, but especially in imported
fresh fruits and vegetables (see Section 5.4.4). Thus, consumers can be exposed to chlorfenvinphos by
ingesting contaminated food. No information was available on the FDA—estimated daily food intakes
of chlorfenvinphos for different age/sex groups in the United States for fiscal years 1982—84

(Gunderson I988) or 1986—91 (FDA 1993).

Workers who were involved in the manufacture, formulation, handling. or application of
chlorfenvinphos are likely to have been exposed to higher concentrations by dermal exposure and
inhalation of chlorfenvinphos particles than the general population. Workers who are currently
involved in the disposal of chlorfenvinphos—contamimited wastes are likely to be exposed to higher
concentrations by dermal contact and inhalation of chlorfenvinphos particles or chlorfenvinphos-
contaminated soil particles than the general population. Occupational exposure to chlorfenvinphos was
reported to have occurred in workers in California who handled flea control products. However,

chlorfenvinphos was not associated with statistically elevated symptom frequency (Ames et al. I989).

No information was found in the National Occupational Exposure Survey (NOES) conducted by
NIOSH from I98] to I983 on the number of workers and the number of facilities where workers
could be potentially exposed to chlorfenvinphos in the United States (NOES I990). NIOSH (I992)
did not provide recommendations for occupational exposure levels to chlorfenvinphos for a 10-hour

time weighted average workday.
5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES
In the past, individuals who were occupationally exposed to chlorfenvinphos during its production,

formulation, packaging, distribution, use, or disposal. were exposed to higher—than—background

concentrations of chlorfenvinphos.

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CHLORFENVINPHOS

 

5. POTENTIAL FOR HUMAN EXPOSURE

At the present time, several groups within the general population may receive potentially high
exposures to chlorfenvinphos. These groups include individuals living near chemical manufacturing or
processing sites or those currently involved in the disposal of chlorfenvinphos or chlorfenvinphos—
contaminated materials, those living on dairy, beef, sheep, or poultry farms where chlorfenvinphos was
extensively used, and those living near hazardous waste sites. Individuals living near these sites may
be exposed to potentially higher concentrations of chlorfenvinphos or its metabolites in their drinking
water if they obtain tap water from wells near these sources. Children playing in chlorfenvinphos-
contaminated soils may consume this pesticide or its degradation products from their contaminated

hands.

5.7 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with
the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether
adequate information on the health effects of chlorfenvinphos is available. Where adequate
information is not available, ATSDR, in conjunction with the NTP. is required to assure the initiation
of a program of research designed to determine the health effects (and techniques for developing

methods to determine such health effects) of chlorfenvinphos.

The following categories of possible data needs have been identified by a joint team of scientists from
ATSDR, NTP, and EPA. They are defined as substance—specific informational needs that if met would
reduce the uncertainties of human health assessment. This definition should not be interpreted to mean
that all data needs discussed in this section must be filled. In the future, the identified data needs will

be evaluated and prioritized, and a substance-specific research agenda will be proposed.

5.7.1 identification of Data Needs

Physical and Chemical Properties. As seen in Table 3-2, the relevant physical and chemical

 

properties of chlorfenvinphos are known (Bowman and Sans 1983; Domine et al. 1992; HSDB 1994;
Kenaga l980; Merck 1989; Worthing 1987) and predicting the environmental fate and transport of this
compound based on the KM, KM, and Henry’s law constant is possible. No further information is

required.

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Production, Import/Export, Use, Release, and Disposal. It has not been definitely
determined whether chlorfenvinphos was ever produced in the United States or whether it was only
imported into the United States either as the technical grade compound or in formulations registered
for use in the United States (Farm Chemicals Handbook 1984, 1993; REFS 1995; SRI 1993). No
historic import/export information was available for this chemical. In the United States,
chlorfenvinphos use appears to have been limited to dairies, feedlots, or poultry yards to reduce adult
fly populations, in manure containment areas to reduce adult and larval fly populations, as a cattle and
sheep dip to reduce ectoparasites, and as a wettable powder (WP), granular form, or contained in a
collar for killing fleas and ticks in dogs (REFS 1995). While chlorfenvinphos has been extensively
used in agricultural applications in foreign countries, especially for root and cole crops, this pesticide
was not used for crop applications in the United States (Farm Chemicals Handbook 1984, 1993;
Spencer 1982; The Agrochemicals Handbook 199]; Worthing 1987). More complete information on
the production and import/export of chlorfenvinphos would be useful to assess the possible routes of
exposure, potential for environmental contamination and human exposure. Information on the number
of producers and production sites, locations of production facilities, years of production, and the
volume of production would be helpful. Information on import/export volumes and estimates of
yearly usage during those years prior to the cancellation of its pesticide registration would also be
useful. While adequate information on disposal procedures exists (IRPTC 1985), more recent

information would be helpful.

According to the Emergency Planning and Community Right-to—Know Act of 1986, 42 U.S.C. Section
1 1023, industries are required to submit chemical release and off—site transfer information to the EPA.
The Toxics Release Inventory (TRI). which contains this information for 1992, became available in
May of 1994. This database will be updated yearly and should provide a list of industrial production

facilities and emissions.

No information is available from TRI 92 because chlorfenvinphos is not one of the toxic chemicals

that producers currently are required to report (EPA 1993).

Environmental Fate. Information regarding the fate of chlorfenvinphos in the air was not located
in the literature. Given a vapor pressure ranging from 4x10“ to 7.5xl("‘ mm Hg ( Merck 1989;
Worthing 1987), chlorfenvinphos should exist in the atmosphere in the vapor phase, but will also

partition to available airborne particulates (Eisenreich et a1. 1981). The solubility of 145 mg/L (Merck

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CHLORFENVINPHOS

5. POTENTIAL FOR HUMAN EXPOSURE

I989) ensures that at least partial removal of atmospheric chlorfenvinphos will occur by wet
deposition. Based on these chemical and physical properties, the atmospheric concentrations of
chlorfenvinphos are expected to be low because chlorfenvinphos is not highly volatile. Additional
information would help predict the residence time and distance of its aerial transport. The fate of
chlorfenvinphos in water has been more extensively studied (see Section 5.3.I.) (Barba et al. I991;
Beynon et al. I97I‘ I973: Braun and Frank I980; Frank et al. I99I; Wan et al. I994), including
information on its degradation under various environmental conditions. The fate of chlorfenvinphos in
soil, including information on its mobility and biodegradation. has also been well documented (see
Section 5.3.1.) (Beynon et al. I973; Edwards et al. I971; Miles et al. 1979, 1983; Racke I992;
Rouchaud et al. 1988, I989a. I989b, I989c. l99l. l992a, I992b; Williams 1975a). Additional
information on the degradation of chlorfenvinphos in air and ground water would be helpful in
estimating exposure to chlorfenvinphos under various conditions of environmental release for purposes

of planning and conducting meaningful follow—up exposure and health studies.

Bioavailability from Environmental Media. Available information regarding the rate of
chlorfenvinphos absorption following inhalation. oral, and dermal contact has been discussed in the
Toxicokinetics section (see Section 2.3) (Hunter I969; Hutson and Wright I980; Pach et al. I987).
Although no data on chlorfenvinphos’ bioavailability from contaminated air are available, the
bioavailability from inhalation exposure is expected to be relatively low because the compound is
likely to partition to available particulates. No data are available on the bioavailability of
chlorfenvinphos from water. soil. or plant material. Chlorfenvinphos is adsorbed moderately to soil
(Beynon et al. I973; Edwards et al. l97l; Racke I992). Since the part that remains adsorbed to soil
or sediment may be only partially bioavailable, chlorfenvinphos is expected to have reduced
bioavailability from soil and water. Additional data on the bioavailability of chlorfenvinphos from
environmental media and the difference in bioavailability from different media would be helpful in
assessing the potential body burdens that may occur as a result of exposure to environmental

concentrations.

Food Chain Bioaccumulation. The only information on bioconcentration factors for
chlorfenvinphos was derived from equations based on information on physical and chemical properties
(see Section 5.3.1.) Estimated whole-body concentration factors calculated for chlorfenvinphos were
significant, but relatively low. ranging from 37 to 460 (Mackay I982; Veith et al. 1979; Veith et al.

I980 in Bysshe I990). No measured BCI‘s for any aquatic organisms were found in the literature.

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CHLORFENVINPHOS 153

5. POTENTIAL FOR HUMAN EXPOSURE

Available data indicate that chlorfenvinphos applied to plant foliage is transported across the cuticular
membrane (Bauer and Schonherr 1992). Chlorfenvinphos applied to the soil is accumulated in the
roots, stem and leaves of plants (Ritcey et al. 1991; Rouchaud et al. l989b; Suett 1974, 1975b). No
information was found on the biomagnification of chlorfenvinphos in aquatic or terrestrial food chains.
These data would be helpful in assessing the potential for human exposure as a result of consuming

contaminated food.

Exposure Levels in Environmental Media. No data were located on the concentrations of
chlorfenvinphos in ambient air or in occupational settings; therefore, no estimate of inhalation
exposure to chlorfenvinphos can be obtained for the general population or for any occupationally
exposed groups. No data on the concentration of chlorfenvinphos in drinking water. surface water, or
ground water in the United States were located in the literature. Monitoring data for surface waters
are available from several Canadian studies conducted in the Great Lakes region and British Columbia;
however, monitoring results from these Canadian studies may be inappropriate for estimating water
residues in the United States, as chlorfenvinphos was never registered for agricultural use as a soil
insecticide. Current monitoring data on the concentrations of chlorfenvinphos in ambient air, in
drinking water, surface water, groundwater, and in soil from the United States would be helpful.

Many of the federal, regional, and state food studies conducted from the late l9()()s through the
mid—1980s did not monitor chlorfenvinphos concentrations in foods (Corneliussen 1970; Duggan and
Corneliussen 1972; Duggan et al. 1983; Gartell et al. 1986; Gunderson I988; Hundley et al. 1988),
despite the fact that chlorfenvinphos was most extensively used in the United States during this period
(see Section 4.3). Recent FDA monitoring studies on imported and domestic foods have detected
chlorfenvinphos residues; however the foods in which chlorfenvinphos was detected and the residue
concentrations were not specified) (FDA I990, I991, I992, 1993). Additional quantitative information
on chlorfenvinphos concentrations in food and the daily human intake of chlorfenvinphos from foods

would be helpful in assessing current exposure levels to this pesticide.

Reliable monitoring data for the concentrations of chlorfenvinphos in contaminated media at hazardous
waste sites are needed so that the information obtained on levels of chlorfenvinphos in the
environment can be used in combination with the resulting body burden of chlorfenvinphos to assess
the potential risk of adverse health effects in populations living in the vicinity of hazardous waste

sites.

*“DRAFT FOR PUBLIC COMMENT‘"

CH LOR FENVINPHOS

5. POTENTIAL FOR HUMAN EXPOSURE

 

Exposure Levels in Humans. No data on chlorfenvinphos levels in various human tissues and
body fluids of unexposed populations, populations near hazardous waste sites, or occupationally
exposed groups in the United States are available. Although chlorfenvinphos is a hydrophilic
substance, it has not been widely found in human tissues because of its relatively short half-life.
However, in a recent study conducted in the Federal Republic of Germany, chlorfenvinphos was found
in some of the 41 specimens of cervical mucus, follicular and sperm fluids, and human milk that were
examined. Chlorfenvinphos concentrations of 13.66, 1.69, 2.02, and 1.89 ug/kg were detected in 4 of
the l l samples of cervical mucus. Chlorfenvinphos was also detected at concentrations of 0.42 ug/kg
in l of the 10 sperm fluid samples and l of the 10 human milk samples, respectively (Wagner et al.
1990). Additional data on the concentrations of chlorfenvinphos and its metabolites in body tissues
and fluids are needed to estimate the extent of exposure to chlorfenvinphos. This information is

necessary for assessing the need to conduct health studies on these populations.

Exposure Registries. No exposure registries for chlorfenvinphos were located. This substance is
not currently one of the compounds for which a subregistry has been established in the National
Exposure Registry. The substance will be considered in the future when chemical selection is made
for subregistries to be established. The information that is amassed in the National Exposure Registry
facilitates the epidemiological research needed to assess adverse health outcomes that may be related

to exposure to this substance.

5.7.2 Ongoing Studies

No information was located on ongoing studies on chlorfenvinphos.

““DRAFT FOR PUBLIC COMMENT'“

 

 

CHLORFENVINPHOS 155

6. ANALYTICAL METHODS

The purpose of this chapter is to describe the analytical methods that are available for detecting, and/or
measuring, and/or monitoring chlorfenvinphos, its metabolites, and other biomarkers of exposure and
effect to chlorfenvinphos. The intent is not to provide an exhaustive list of analytical methods.

Rather, the intention is to identify well-established methods that are used as the standard methods of
analysis. Many of the analytical methods used for environmental samples are the methods approved
by federal agencies and organizations such as EPA and the National Institute for Occupational Safety
and Health (NIOSH). Other methods presented in this chapter are those that are approved by groups
such as the Association of Official Analytical Chemists (AOAC) and the American Public Health
Association (APHA). Additionally, analytical methods are included that modify previously used

methods to obtain lower detection limits, and/or to improve accuracy and precision.

6.1 BIOLOGICAL SAMPLES

Few methods are available for the determination of chlorfenvinphos in biological samples. Some
methods which may be applicable to biological media are summarized in Table 63-]. Most methods
involve an extraction step followed by one or more purification and fractionation procedures, then
analysis, usually by gas chromatography (GC). Two detection methods are commonly used, nitrogen-
phosphorus detection (NPD) (Thier and Zeumer 1987; Wagner et al. 1990) and flame photometric
detection (FPD) (Ivey et al. 1973). Both of these methods are specific for phosphorus—containing
compounds and are very sensitive (low- to sub-ppb levels). Recovery, where reported, is very good

(>80%).

Several cautions should be noted. First, the stability of chlorfenvinphos in biological media is
unknown. The cold-storage stability (5 to —20 0C) of chlorfenvinphos in crops and soil has been
reported (Kawar et al. I973). However, enzymes present in biological media may reduce levels of
organophosphate pesticides (Singh et al. 1986). Second, it is difficult to eliminate or reduce

interfering compounds and maintain acceptable recovery of chlorfenvinphos. Quality control

 

procedures are recommended to assure that the method performance is acceptable. Third, other
organophosphorus pesticides may co-elute with chlorfenvinphos (Sasaki et al. 1987), so a confirmatory

method is recommended.

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;__—_____—

156

CHLORFENVINPHOS

6. ANALYTICAL METHODS

 

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"'DRAFT FOR PUBLIC COMMENT'“

 

 

CHLORFENVINPHOS

6. ANALYTICAL METHODS

A few methods are available for measuring metabolites of chlorfenvinphos. Chlorfenvinphos
undergoes biotransformation to a variety of polar metabolites including diethyl phosphate. Methods
for measurement of dialkyl phosphates involve extraction from urine using an ion exchange resin and
derivatization prior to GC analysis (Bradway et al. 198l; Lores and Bradway I977). The performance
of the methods is variable; extraction is not always complete, and GC interferences often present

problems.

6.2 ENVIRONMENTAL SAMPLES

Representative analytical methods for determining chlorfenvinphos in environmental samples are
summarized in Table 6-2. Methods involve solvent extraction, purification and fractionation, and gas
chromatographic analysis. Although most methods for measuring chlorfenvinphos in environmental
samples involve GC coupled with specific detectors (including MS), other methods are available,
including high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection (Bagon and
Warwick 1982; Schlett 1991), and thin layer chromatography (TLC) (Roberts and Stoydin 1976).

Methods for determining chlorfenvinphos in aqueous samples include solvent extraction (EPA l992b‘.
Wan et al. 1994) or isolation using solid phase extraction (SPE) (Schlett 199]). Further clean-up of
the extract may not be required prior to analysis by HPLC (Schlett 1991) or GC (EPA 1992b; Wan et
al. l994). For GC analysis, confirmation using a second column is recommended (EPA 1992b; Wan

et al. 1994). Detection limits are in the sub—ppb range; recovery was not reported.

Similarly, methods for determining chlorfenvinphos in sediments, solid wastes, and soils utilize a
solvent extraction procedure. A variety of clean—up procedures are used, including Florisil column
purification (Beynon et al. 1966), solvent partition (Miles et al. 1979; Williams 1975b), and gel
permeation chromatography (Wan et al. 1994). Extracts are analyzed by GC with electron capture
detection (ECD) (Beynon et al. 1966; Edwards et al. I968) or phosphorus-specific detectors (Wan et
al. 1994; Williams l975b). Detection limits are in the low—ppb range (1—20); recovery is excellent

(295%).
Methods for determining chlorfenvinphos on a variety of foods and crops have been reported. Most

involve solvent extraction followed by clean—up using adsorption column techniques (FDA 1979;

Kadenczki et al. 1992; Leoni et al. I992) or solvent partitioning (Frank et al. 1990; Stijve 1984).

"'DRAFT FOR PUBLIC COMMENT'"

 

 

CHLORFENVINPHOS

6. ANALYTICAL METHODS

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"'DRAFT FOR PUBLIC COMMENT'"

 

CHLORFENVINPHOS 160

6. ANALYTICAL METHODS

Chlorfenvinphos is determined by GC with phosphorus—specific detectors (flame photometric, FPD;
and nitrogen—phosphorus. NPD) (Agtiera et al. l993; Leoni et al. I992; Kadenczki et al. 1992: Stijvc
1984). Chlorfenvinphos in sample extracts is confirmed using GC with MS (Agtiera et al. I993; Leoni
et al. 1992) or TLC (Stijve l984). Detection limits are in the low-ppb range; recovery is acceptable

(>80%).

A summary of methods for determination of chlorfenvinphos environmental degradation products is
shown in Table 6—3. The breakdown products 2.4-dichloroacetophenone, |-(2‘4—dichlorophenyl)-
l-ethan-l-ol, and 2,4—dichlorophenacyl chloride can be determined in soil and earthworms using
solvent extraction and GC/ECD (Edwards et al. 1968). Detection limits are approximately 0.05 ppm
and recovery is excellent (95—1 l5%). The hydrolysis product 2.2”,4”-trichloroacetophenone has been
determined in corn extracts using GC/ECD and GC/FPD). Detection limits are 0.02 ppm (ECD) and
0.002 (FPD) and recovery is excellent (Beroza and Bowman 1966). Free and conjugated degradation
products have been determined in soils and crops by GC/ECD (Beynon et al. l968). Free products are
extracted with solvent; conjugated products are hydrolyzed with sulfuric acid. Recovery is acceptable
(80—l00% for soils, 50~90% for crops); detection limits range from 0.0l to 0.2 ppm for soils (varies
with compound) and from 0.005 to 0.05 ppm for crops. Degradation products. including soil—bound
(polar) compounds, were determined by GC/ECD of soil extracts. The polar compounds were
methylated prior to CC analysis. Recovery is acceptable (65—105%); detection limits are

approximately 0.02 ppm.

6.3 ADEQUACY OF THE DATABASE

Section 104(i)(5) of CERCLA, as amended‘ directs the Administrator of ATSDR (in consultation with
the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether
adequate information on the health effects of chlorfenvinphos is available. Where adequate
information is not available, ATSDR, in conjunction with the NTP. is required to assure the initiation
of a program of research designed to determine the health effects (and techniques for developing

methods to determine such health effects) of chlorfenvinphos.
The following categories of possible data needs have been identified by a joint team of scientists from

ATSDR, NTP, and EPA. They are defined as substance—specific informational needs that if met would

reduce the uncertainties of human health assessment. This definition should not be interpreted to mean

m'DFlAFT FOR PUBLIC COMMENT'"

 

161

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"‘DRAFT FOR PUBLIC COMMENT'"

 

CHLORFENVINPHOS 162

6. ANALYTICAL METHODS

that all data needs discussed in this section must be filled. In the future, the identified data needs will

be evaluated and prioritized, and a substance—specific research agenda will be proposed.

6.3.1 Identification of Data Needs

Methods for Determining Biomarkers of Exposure and Effect. Few methods are available
for measuring exposure to chlorfenvinphos. These are summarized in Table 6—4. Blood levels of
chlorfenvinphos were determined in a case of human poisoning (Klys 1985); however, sensitivity and
reliability were not reported. Chlorfenvinphos is metabolized in the body to esters of phosphoric acid,
and methods are available for determining urine levels of these metabolites (Bradway et al. 1981;
Lores and Bradway 1977). However, these phosphate compounds are not specific for chlorfenvinphos,
but are common to all organophosphate pesticides. Decreased levels of acetyleholinesterase in plasma
or erythrocytes have been reported to be indicative of chlorfeiwinphos poisoning (Zwiener and
Ginsberg 1988). Again, this assay is not specific for chlorfenvinphos. An increase in the level of
tryptophan after exposure to chlorfenvinphos has been reported in rats (Dudka and Szczepaniak 1993).
Good precision and accuracy were reported for the method; however. specific values were not given.
It is not known if the available analytical methods will be sensitive enough to measure
chlorfenvinphos levels in body tissues and fluids of the background population. Since chlorfenvinphos
is apparently not produced or imported into this country, it should not be necessary to determine these
background levels. It would be helpful to have methods which would permit assessment of the

severity of exposure of a highly exposed population.

Methods for Determining Parent Compounds and Degradation Products in
Environmental Media. Methods are available for determining chlorfenvinphos in water, soils and
sediments, and foods (Table 6—2). A summary of available methods for determining the environmental
degradation products of chlorfenvinphos in soils (Beynon et al. 1908; Rouchaud et al. 1988), crops
(Beynon et al. 1968; Beroza and Bowman 1966). and worms (Edwards et al. 1968) is shown in Table
6-3. Sensitive methods (sub-ppb levels) are available for determining chlorfenvinphos in water;
however, better information is needed regarding the recovery and precision of the methods (EPA
1992b; Schlett 1991; Wan et a1. 1994). Methods for determining chlorfenvinphos in soils and
sediments are sensitive (10w ppb levels) and good recovery (295%) has been reported (Beynon et al.

1966; Edwards et a1. 1968; Wan et al. 1994). Methods for measuring chlorfenvinphos in some foods

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163

CHLORFENVINPHOS

6. ANALYTICAL METHODS

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"'DRAFT FOR PUBLIC COMMENT'"

CHLORFENVINPHOS 164

6. ANALYTICAL METHODS

are sensitive (low ppb levels) with acceptable recovery (72—105%) (Aguera et al. I993; FDA I979;
Frank et al. 1990; Kadenczki et al. 1992; Leoni et al. 1992; Stijve 1984). Available methods have
sufficient sensitivity for measuring chlorfenvinphos in water, soils and sediments, and foods at
background levels. Information on the precision of these methods would be helpful. No methods are
available for measuring chlorfenvinphos in ambient air. Given its low volatility, chlorfenvinphos is
not likely to be detected in ambient air. Methods are available for monitoring occupational exposure
to chlorfenvinphos (Bagon and Warwick 1982). Research investigating the relationship between levels
of chlorfenvinphos measured in water, soils and sediments, and food and health effects would be

helpful.

6.3.2 Ongoing Studies

No ongoing studies involving chlorfenvinphos were located.

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CHLORFENVINPHOS 165

7. REGULATIONS AND ADVISORIES

The national regulations and guidelines regarding chlorfenvinphos in air, food, and other media are
summarized in Table 7—1. No international or state regulations were identified for chlorfenvinphos,

nor were regulations and guidelines identified for chlorfenvinphos in air or water.

ATSDR has not derived MRLs for inhalation exposure for any duration of exposure.

An acute oral MRL of 0.002 mg/kg/day for chlorfenvinphos has been developed from a LOAEL of

2.4 mg/kg/day, based on adverse neurological effects in rats (Barna and Simon 1973).

An intermediate oral MRL of 0.002 mg/kg/day for chlorfenvinphos has been developed from a
LOAEL of 1.5 mg/kg/day, based on adverse immunological/lymphoreticular effects in mice

(Kmvalczyk-Bronisz et al. 1992).

A chronic oral MRL of 0.0007 mg/kg/day for chlorfenvinphos has been developed from a LOAEL of

0.7 mg/kg/day. based on adverse neurological effects in rats (Ambrose et al. l970).

No reference concentration or dose exists for chlorfenvinphos.

Chlorfenvinphos is one of the chemicals regulated under ”The Emergency Planning and Community
Right-to—Know Act of 1986" (EPCRA) (EPA l987). Section 3l3 of Title III of EPCRA requires
owners and operators of certain facilities that manufacture, import, process, or otherwise use the

chemicals on this list to report annually their release of those chemicals to any environmental media.
An Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) for
chlorfenvinphos does not exist. nor is it regulated by the Clean Water Effluent Guidelines contained in

Title 40. Sections 400—475, of the Code of Federal Regulations.

Tolerances for chlorfenvinphos in agricultural products have been established (EPA l982b). It is also

listed as a restricted—use pesticide (EPA I978c).

“‘DRAFT FOR PUBLIC COMMENT'"

CHLORFENVINPHOS 166

7. REGULATIONS AND ADVISORIES

TABLE 7-1. Regulations and Guidelines Applicable to Chlortenvlnphos

 

Agency Description Information References

 

INTERNATIONAL

IARC Carcinogenic classification None
NATIONAL
Regulations:
a. Food
FDA FDA action level None
EPA OPTS Tolerances for Related Pesticide Yes 40 CFR 180.3, EPA 1976
Chemicals

0005-02 ppm 40 CFR 180.322, EPA 1982b
Tolerance Range for Agriculture

Products 500 lb. 40 CFR 355, App A. EPA 1987
Threshold Planning Quantity 1 lb. 40 CFR 355, App A, EPA 1987
Restricted Use Pesticide Yes 40 CFR 152.175, EPA 1978c
b. Other
EPA Carcinogen Classification None IRIS 1995
Reference Dose (RfD) None IRIS 1995
Reference Concentration (RfC) None IRIS 1995
EPA OERR Reportable quantity None
App. B - National Priorities List Yes 40 CFR 300, EPA 1992
EPA OW Designation of Hazardous Substances None
NPDES Form 2D None
App. D - NPDES Permit Application None
Testing Requirements
NPDES - Instructions - Form 2C None
EPA OSW App. || - Municipal Solid Waste - List of None
Hazardous Inorganic and Organic
Constituents
App. VIII - Listing as a hazardous waste None
constituent
App. IX - Groundwater monitoring None
requirement
App. Ill - LDR - List of Halogenated None
Organic Compounds Regulated Under
40 CFR 268.32
Guidelines:
a. Air:
NIOSH REL TWA None NIOSH 1992

 

EPA = Environmental Protection Agency; FDA = Food and Drug Administration; IARC = International Agency for
Research on Cancer; IRIS = Integrated Risk Information System; LDR = Land Disposal Restrictions; NIOSH :
National Institute for Occupational Safety and Health; OERR 2 Office of Emergency and Remedial Response;
OSW = Office of Solid Wastes; REL = Recommended Exposure Limit; TWA = time-weighted average

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CHLORFENVINPHOS 167

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CHLORFENVINPHOS 178

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CHLORFENVINPHOS 179

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CHLORFENVINPHOS

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*Zwiener RJ, Ginsburg CM. 1988. Organophosphate and carbamate poisoning in infants and
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CHLORFENVINPHOS 183

9. GLOSSARY

Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the
Toxicological Profiles.

Adsorption Coefficient (Knc)—The ratio of the amount of a chemical adsorbed per unit weight of
organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium.

Adsorption Ratio (Kd)—The amount of a chemical adsorbed by a sediment or soil (i.e., the solid
phase) divided by the amount of chemical in the solution phase, which is in equilibrium with the solid
phase, at a fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per
gram of soil or sediment.

Bioconcentration Factor (BCF)—The quotient of the concentration of a Chemical in aquatic
organisms at a specific time or during a discrete time period of exposure divided by the concentration
in the surrounding water at the same time or during the same period.

Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that
produces significant increases in the incidence of cancer (or tumors) between the exposed population
and its appropriate control.

Carcinogen—A chemical capable of inducing cancer.
Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously.

Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological
Profiles.

Developmental Toxicity—The occurrence of adverse effects on the developing organism that may
result from exposure to a chemical prior to conception (either parent), during prenatal development, or
postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any
point in the life span of the organism.

Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure
to a chemical; the distinguishing feature between the two terms is the stage of development during
which the insult occurred. The terms, as used here, include malformations and variations, altered
growth, and in utero death.

EPA Health Advisory—An estimate of acceptable drinking water levels for a chemical substance
based on health effects information. A health advisory is not a legally enforceable federal standard,
but serves as technical guidance to assist federal, state, and local officials.

Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a
contaminant from which one could escape within 30 min without any escape-impairing symptoms or

irreversible health effects.

Intermediate Exposure—Exposure to a chemical for a duration of 15—364 days, as specified in the
Toxicological Profiles.

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CHLORFENVINPHOS

9. GLOSSARY

Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result
from exposure to environmental agents such as chemicals.

In Vitro—Isolated from the living organism and artificially maintained, as in a test tube.
In Vivo—Occurring within the living organism.

Lethal Concentration(L0) (LCLO)—The lowest concentration of a chemical in air which has been
reported to have caused death in humans or animals.

Lethal Concentratiomso) (LC50)—A calculated concentration of a chemical in air to which exposure
for a specific length of time is expected to cause death in 50% of a defined experimental animal
population. '

Lethal Dose(L0) (LDLO)—The lowest dose of a chemical introduced by a route other than inhalation
that is expected to have caused death in humans or animals.

Lethal Dose(50) (LD50)—The dose of a chemical which has been calculated to cause death in 50% of
a defined experimental animal population.

Lethal Time(50) (LT50)—A calculated period of time within which a specific concentration of a
chemical is expected to cause death in 50% of a defined experimental animal population.

Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest dose of chemical in a study, or
group of studies, that produces statistically or biologically significant increases in frequency or severity
of adverse effects between the exposed population and its appropriate control.

Malformations—Permanent structural changes that may adversely affect survival, development, or
function.

Minimal Risk Level—An estimate of daily human exposure to a dose of a chemical that is likely to
be without an appreciable risk of adverse noncancerous effects over a specified duration of exposure.

Mutagen—A substance that causes mutations. A mutation is a change in the genetic material in a
body cell. Mutations can lead to birth defects, miscarriages, or cancer.

Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to
chemical.

No-Observed-Adverse-Effect Level (NOAEL)—The dose of chemical at which there were no
statistically 0r biologically significant increases in frequency or severity of adverse effects seen
between the exposed population and its appropriate control. Effects may be produced at this dose, but
they are not considered to be adverse.

Octanol-Water Partition Coefficient (Kow)—The equilibrium ratio of the concentrations of a
chemical in n—octanol and water, in dilute solution.

Permissible Exposure Limit (PEL)—An allowable exposure level in workplace air averaged over an
8-hour shift.

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CHLORFENVINPHOS 185

9. GLOSSARY

ql*—The upper-bound estimate of the low—dose slope of the dose-response curve as determined by the
multistage procedure. The q1* can be used to calculate an estimate of carcinogenic potency, the
incremental excess cancer risk per unit of exposure (usually ug/L for water, mg/kg/day for food, and
ug/m3 for air).

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the
daily exposure of the human population to a potential hazard that is likely to be without risk of
deleterious effects during a lifetime. The RfD is operationally derived from the NOAEL (from animal
and human studies) by a consistent application of uncertainty factors that reflect various types of data
used to estimate Rst and an additional modifying factor, which is based on a professional judgment
of the entire database on the chemical. The Rst are not applicable to nonthreshold effects such as
cancer

Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable
under CERCLA. Reportable quantities are (l) 1 pound or greater or (2) for selected substances, an
amount established by regulation either under CERCLA or under Sect. 3] l of the Clean Water Act.
Quantities are measured over a 24-hour period.

Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result
from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the
related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual
behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the
integrity of this system.

Short-Term Exposure Limit (STEL)—The maximum concentration to which workers can be exposed
for up to 15 min continually. No more than four excursions are allowed per day. and there must be at
least ()0 min between exposure periods. The daily TLV-TWA may not be exceeded.

Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or
physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited
exposure to those assumed over a lifetime of exposure to a chemical.

Teratogen—A chemical that causes structural defects that affect the development of an organism.

Threshold Limit Value (TLV)—A concentration of a substance to which most workers can be
exposed without adverse effect. The TLV may be expressed as a TWA, as a STEL, or as a CL.

Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8—
hour workday or 40-hour workweek.

Toxic Dose (TD50)—A calculated dose of a chemical, introduced by a route other than inhalation,
which is expected to cause a specific toxic effect in 50% of a defined experimental animal population.

Uncertainty Factor (UF)——A factor used in operationally deriving the RfD from experimental data.
UFs are intended to account for (l) the variation in sensitivity among the members of the human
population, (2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in
extrapolating from data obtained in a study that is of less than lifetime exposure, and (4) the
uncertainty in using LOAEL data rather than NOAEL data. Usually each of these factors is set equal
to 10.

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CHLORFENVINPHOS A-1

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical name: Chlorfenvinphos

CAS number: 470—90-6

Date: August 14, 1995

Profile status: Draft 4

Route: [ ] Inhalation [x] Oral

Duration: [x] Acute [ ]Intermediate [ ] Chronic
Key to figure: 12

Species: Rat

MRL: 0.002 [x] mg/kg/day [ ] ppm [ ] mg/m3

Reference: Bama J, Simon G. 1973. The effect of chlorphenvinphos insecticide in small often
repeated dose. Cereal Research Commun. Vol.1, No. 3: 33—44.

Experimental design (human study details or strain, number of animals per exposure/control group,
sex, dose administration details):

Two groups (SS/group) of adult female albino (Wistar) rats weighing 208 g were orally administered
Birlane® (chlorfenvinphos) at a dose of 0 or 2.4 mg/kg/day in the diet for 10 days. The study was
designed to investigate the effects of oral chlorfenvinphos on body weight increase, the gastrointestinal
absorption of glucose, Na”, and Ca2+, as well as the effects of oral chlorfenvinphos on plasma and
erythrocyte cholinesterase activity levels.

Effects noted in study and corresponding doses:

Plasma cholinesterase activity was inhibited by 52% while erythrocyte cholinesterase activity level was
inhibited by 30% at a dose of 2.4 mg/kg/day (the only dose tested). Gastrointestinal (g.i.) absorption
of glucose was increased by 30% over control values while Na+ absorption was decreased by 32%
below control values. Gastrointestinal absorption of Ca2+ and body weight increases were unaffected
by chlorfenvinphos exposure. These changes in the gastrointestinal absorption of glucose and Na+
were not considered statistically significant (P>0.05) by the investigators.

Dose endpoint used for MRL derivation:

[ ] NOAEL [x] LOAEL

2.4 mg/kg/day; 30% decrease in erythrocyte cholinesterase activity in female rats.

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CHLORFENVINPHOS A-2

APPENDIX A

Uncertainty factors used in MRL derivation:

l ] l [ J 3 [x] l() (for use ofa LOAEL)
[ ] l [ ] 3 [x] 10 (for extrapolation from animals to humans)
[ l l [ ] 3 [x] 10 (for human variability)

Was a conversion factor used from ppm in food or water to a mg/body weight dose?
If so, explain: No, the doses used are author-provided.

If an inhalation study in animals, list conversion factors used in determining human equivalent dose:
Not applicable.

Was a conversion used from intermittent to continuous exposure? Not applicable.
Other additional studies or pertinent information that lend support to this MRL:

Neurological effects, mediated by cholinesterase inhibition, are the principal and most sensitive
toxicological consequence of acute-duration exposure to chlorfenvinphos in humans (Cupp et al. 1975;
Pach et al. 1987). Chlorfenvinphos also inhibits noradrenaline in the central nervous system
(Brzezinski 1978). Human subjects, exposed to large acute doses of chlorfenvinphos, exhibited severe
cholinergic signs. These cholinergic signs were relieved by the administration of atropine and/or
pralidoxime, indicating cholinesterase inhibition etiology (Cupp et al. 1975; Pach et al. 1987). In rats,
relatively moderate to low doses (2.4—30 mg/kg) of oral chlorfenvinphos significantly inhibited
cholinesterase activities in a number of tissue including the brain, erythrocyte, and plasma (Osumi et
al. 1975; Osicka—Koprowska et al. 1984; Puzynska 1984). An acute-duration oral study also found
alterations in noradrenaline level in rat brain following exposure to chlorfenvinphos. A
chlorfenvinphos dose of 13 mg/kg decreased noradrenaline levels in rat brains by 20%, as compared to
control rats. According to the investigators, chlorfenvinphos accelerated the rate of NA disappearance
from the brain (Brzezinski 1978).

Therefore, it is appropriate to base the acute oral MRL for chlorfenvinphos on cholinesterase
inhibition.

It should be noted that a study by Osumi et al. (1975) which defined a NOAEL of 1 mg/kg/day and a
LOAEL of 2 mg/kg/day for 38% inhibition of brain cholinesterase in rats. However, this LOAEL

(2 mg/kg/day) is essentially the same as the LOAEL defined in the Bama and Simon (1973) study
(2.4 mg/kg/day). Since feeding studies more closely mimic potential human exposure than do gavage
studies, the Bama and Simon (1973) study was used to derive the MRL.

Agency Contact (Chemical Manager): Alfred Dorsey.

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CHLORFENVINPHOS A-3

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical name: Chlorfenvinphos

CAS number: 470-90-6

Date: August 14, 1995

Profile status: Draft 4

Route: [ ] Inhalation [x] Oral

Duration: [ ] Acute [x] Intermediate [ ] Chronic
Key to figure: 23

Species: Mouse

MRL: 0.002[x] mg/kg/day []ppm []mg/m3

Reference: Kowalczyk—Bronisz S, Gieldanowski J, Bubak, Kotz J. 1992. Studies on the effect of
pesticide chlorfenwinphos on mouse immune system. Arc Immunol Ther Exp (Warsz)
40(5-6):283-289.

Experimental design (human study details or strain, number of animals per exposure/control group,
sex, dose administration details):

The authors investigated the effect of chlorfenvinphos on mouse immune system. In the study, male
and female inbred C57BL/6 mice and (C57BL/6 x DBA/2)F1 (BDFl/Iiw) hybrids mice (6—8 weeks
old) were orally dosed with chlorfenvinphos (suspended in 1% methylcellulose solution) and evaluated
for 5 days for the effect of chlorfenvinphos exposure on the mouse immune system. The rats were
exposed to oral chlorfenvinphos doses of 0, 1.5, 3, and 6 mg/kg (0, 1 in 100, 1 in 50 and l in

25 LDSO) daily for 3 months; control group was given 1% methylcellulose. Then exposed and control
mice were immunized by intraperitoneal injections of 0.2 ml 10% SRBC. IgM—PFC (plaque-forming
or antibody-producing cells) number in spleen cell suspension was tested on day 4 after immunization
and the procedure repeated 3 weeks after the exposure to chlorfenvinphos had been ceased. Exposed
and control groups were subjected to immunological tests and hematological examinations. Lymphatic
organs were histologically examined. *

Effects noted in study and corresponding doses:

A dose-related decrease in number of hemolysin producing cells was observed: plaque—forming cells
(PFC) were 58% at the 6 mg/kg dose group and 85% at the 3 mg/kg dose level as compared to control
values. Chlorfenvinphos treatment also caused reduction in E rosettes forming cell number by 30% at
the 6 mg/kg dose level and by 25% at the 3 mg/kg dose level. Increases in Interlukin-l (ll—1) activity
and DTH reaction were observed 24 hours after challenge. Spleen colonies were stimulated as
evidenced by the increase of endogenous spleen colonies and exogenous spleen colonies (CFU-S)
increased 190% at the 1.48 mg/kg dose level and 137% at the 6 mg/kg dose level, and 162% at

1.5 mg/kg dose level and 70% at the 6 mg/kg dose level, respectively). When the IgM PFC number
was tested 3 weeks later, after the exposure to chlorfenvinphos in the small dose (1.5 mg/kg), and
increase (about 40%) in plaques number was observed. There was a 50% reduction in thymus weight
at the 1.5 mg/kg dose level as compared to controls, as well as significant involution of thymus.

""DRAFT FOR PUBLIC COMMENT'“

 

CHLORFENVINPHOS A.4

APPENDIX A

Dose endpoint used for MRL derivation:
[ ] NOAEL [x] LOAEL

1.5 mg/kg/day; 190% increase of spleen endogenous colonies; 162% increase of spleen exogenous
colonies; 50% reduction in thymus weight.

Uncertainty factors used in MRL derivation:
x] 10 (for use of a LOAEL)

[
[x] 10 (for extrapolation from animals to humans)
[x] 10 (for human variability)

3

Was a conversion factor used from ppm in food or water to a mg/body weight dose?
If so, explain: Doses were provided as 1/100, 1/50, and 1/25 of the LD50 (148 mg/kg) by the authors,
resulting in doses of 1.5, 3, and 6 mg/kg, respectively.

If an inhalation study in animals, list conversion factors used in determining human equivalent dose:
Not applicable.

Was a conversion used from intermittent to continuous exposure?
Not applicable.

Other additional studies or pertinent information that lend support to this MRL:

In other studies, adverse immunolymphoreticular effects have been associated with exposure to oral
chlorfenvinphos. In an intermediate-duration dietary study with albino (Wistar) rats, there was a
significant and irreversible reduction in relative spleen weight of female rats given 23 mg/kg/day
chlorfenvinphos for 12 weeks (Ambrose et al. 1970). A study was undertaken to evaluate selected
serological and cytoimmunological reactions in rabbits subjected to a long-term poisoning with
subtoxic oral doses (10 mg/kg in a soya oil solution with a small amount of food) of chlorfenvinphos
for 90 days. Chlorfenvinphos treatment significantly elevated serum hemagglutinin level (16%) and
hemolysin activity (66%, p<0.05) as well as increased the number of nucleated lymphoid cells
producing hemolytic antibody to sheep erythrocytes as compared to controls (treated 906, p<0.05 and
controls 618). Spleen cytomorphology changes, manifested mainly as transformation of primary
follicles into secondary ones with well developed germinal centers, were also observed (Roszkowski
1978).

Therefore, it is appropriate to base the intermediate oral MRL for chlorfenvinphos on immunological
effects.

Agency Contact (Chemical Manager): Alfred Dorsey.

""DRAFT FOR PUBLIC COMMENT'“

 

CHLORFENVINPHOS A-5

APPENDIX A

MINIMAL RISK LEVEL (MRL) WORKSHEET

Chemical name: Chlorfenvinphos

CAS number: 470-90-6

Date: August 14 I995

Profile status: Draft 4

Route: [ ] Inhalation [x] Oral

Duration: [ ] Acute [ ] Intermediate [x] Chronic
Key to figure: 35

Species: Rat

MRL: 0.0007 [x] mg/kg/day [ ] ppm [ ] mg/m3

Reference: Ambrose AM, Larson PS, Borzelleca JF, Hennigar GR. I970. Toxicologic studies on
diethyl-l-(2,4-dichlorophenyl)-2—chlorovinyl phosphate. Toxicology and Applied Pharmacology,
17:323-336.

Experimental design (human study details or strain, number of animals per exposure/control group,
sex, dose administration details):

The authors conducted toxicological studies with chlorfenvinphos in weanling albino (Wistar) rats. In
the study, four matched groups of weaning albino (Wistar) rats (30 rats per sex per group) were culled
to a narrow starting weight range and fed daily GC-4072 (technical chlorfenvinphos) doses of O, 0.7,
2.1, 7, or 21 mg/kg/day (males) or 0, 0.8, 2.4, 8, or 24 mg/kg/day (females) in the diet for 104 weeks.
An additional group of non-littermate rats (30 per sex) were administered 21 mg/kg/day (males) or

24 mg/kg/day (females) chlorfenvinphos for 104 weeks. Plasma and erythrocyte cholinesterase (ChE)
and 12 weeks. At 13 weeks, 4 rats per sex per dose group were sacrificed for histopathologic
examination. At 13 weeks, 4 rats/sex/dose group were sacrificed for histopathologic examination. The
rats in the 21 mg/kg/day (males) and 24 mg/kg/day (females) were sacrificed on the 95th week while
all other dose group animals were sacrificed on the end of the study (104 weeks). At each autopsy,
relative organ weights were determined for heart and kidneys. All animals sacrificed in moribund
condition as well as those sacrificed at week 13, 95, and 104 weeks were examined grossly and
microscopically and organs (heart, lungs, liver, kidney, urinary bladder, spleen, stomach, small and
large intestine, skeletal muscle, skin, bone marrow, pancreas, thyroid, adrenal, pituitary) from these
animals were histopathologically examined. Chlorfenvinphos significantly decreased body weight gain
of females at the 8 and 24 mg/kg/day dose groups from the 26th week till towards the end of the
study, although the decreased body weight gain became not statistically significant at the end of the
study. Increased relative liver weights were observed in males at the 7 mg/kg/day dose level but no
other signs of hepatopathology was reported. No consistent difference in body weight gains in males,
survival of the test animals, food consumption, or mortality was evident at all dose levels tested, as
compared to undosed controls. Essentially, no gross or microscopic histopathology was evident in all
the organs (heart, lungs, liver, kidney, urinary bladder, spleen, stomach, small and large intestine,
skeletal muscle, skin, bone marrow, pancreas, thyroid, adrenal, pituitary) examined. No changes in
organ-to-body weight were observed in the heart, kidney, spleen and testes (Ambrose et al. 1970).

“‘DRAFT FOR PUBLIC COMMENT‘"

CHLORFENVINPHOS A-6

APPENDIX A

Dose endpoint used for MRL derivation:
[ ] NOAEL [x] LOAEL

0.7 mg/kg/day; 45% inhibition of plasma cholinesterase activity; 33% inhibition of erythrocyte
cholinesterase activity

Uncertainty factors used in MRL derivation:
3 [x 10 (for use of a LOAEL)

l
3 [x] 10 (for extrapolation from animals to humans)
3 [x] IO (for human variability)

r--ir—ir—\
L—l|—J|—J

ll]
ll]
l[l

Was a conversion factor used from ppm in food or water to a mg/body weight dose?

If so, explain: Doses, provided as food concentrations (10, 30, 100, or 300 ppm), were converted to
doses in mg/kg/day using rat daily food intake factor for chronic Wistar rat obtained from EPA
(1988).

CALCULATIONS: 10 ppm = [0 mg/kg; Male - 10 mg/kg x 0.07 mg/kg/day (chronic male Wistar rat
food factor) = 0.7 mg/kg/day; 30 ppm = 2.] mg/kg/day; 100 ppm = 7 mg/kg/day; 300 ppm 2
2] mg/kg/day: Female - 10 mg/kg x 0.08 mg/kg/day (chronic female Wistar rat food factor) =
0.8 mg/kg/day; 30 ppm = 2.4 mg/kg/day; 100 ppm = 7 mg/kg/day; 300 ppm = 24 mg/kg/day.

If an inhalation study in animals, list conversion factors used in determining human equivalent dose:
Not applicable.

Was a conversion used from intermittent to continuous exposure? Not applicable.
Other additional studies or pertinent information that lend support to this MRL:

Although the neurological effects of human prolonged exposure to low oral doses of chlorfenvinphos
are not known due to a dearth of studies, acute-duration exposure data indicate that neurological
effects, mediated by cholinesterase inhibition, are the most sensitive toxicological consequence of
human exposure to chlorfenvinphos (Cupp et al. 1975; Pach et al. 1987; Taitelman 1992). Similarly,
chlorfenvinphos significantly inhibited both plasma and erythrocyte cholinesterase activities in Beagle
dogs (2/sex) fed daily chlorfenvinphos doses of 0, 0.3, 2, or 10 mg/kg/day (males), or 0, l.5, 10, or
50 mg/kg/day (females) in the diet (moist) for 104 weeks. Plasma cholinesterase activities were
significantly inhibited at all dietary levels through week 39 of the study; 49% inhibition at the

0.3 mg/kg/day (males) and 1.5 mg/kg/day (females) dose levels. Erythrocyte cholinesterase activity
was significantly and consistently inhibited (36%) during the first 12 weeks only in the 10 mg/kg/day
(males) and 50 mg/kg/day (females) dose levels (Ambrose et al. 1970).

Therefore, it is considered appropriate to use this endpoint for developing a chronic oral MRL for
chlorfenvinphos.

Agency Contact (Chemical Manager): Alfred Dorsey.

""DRAFT FOR PUBLIC COMMENT‘“

CHLORFENVINPHOS B-1

APPENDIX B

USER’S GUIDE

Chapter 1
Public Health Statement

This chapter of the profile is a health effects summary written in non—technical language. lts intended
audience is the general public especially people living in the vicinity of a hazardous waste site or
chemical release. If the Public Health Statement were removed from the rest of the document. it
would still communicate to the lay public essential information about the chemical.

The major headings in the Public Health Statement are useful to find specific topics of concern. The
topics are written in a question and answer format. The answer to each question includes a sentence
that will direct the reader to chapters in the profile that will provide more information on the given
topic.

Chapter 2
Tables and Figures for Levels of Significant Exposure (LSE)

Tables (2-1, 2-2, and 2—3) and figures (2-1 and 2-2) are used to summarize health effects and illustrate
graphically levels of exposure associated with those effects. These levels cover health effects observed
at increasing dose concentrations and durations, differences in response by species. minimal risk levels
(MRLs) to humans for noncancer end points, and EPA’s estimated range associated with an upper-
bound individual lifetime cancer risk of l in l0,()00 to l in 10,000,000. Use the LSE tables and
figures for a quick review of the health effects and to locate data for a specific exposure scenario. The
LSE tables and figures should always be used in conjunction with the text. All entries in these tables
and figures represent studies that provide reliable, quantitative estimates of No—Observed-Adverse-
Effect Levels (NOAELs), Lowest-Observed-Adverse—Effect Levels (LOAELs), or Cancer Effect Levels
(CELs).

The legends presented below demonstrate the application of these tables and figures. Representative
examples of LSE Table 2—1 and Figure 2—1 are shown. The numbers in the left column of the legends
correspond to the numbers in the example table and figure.

LEGEND
See LSE Table 2-1

(1) Route of Exposure One of the first considerations when reviewing the toxicity of a substance
using these tables and figures should be the relevant and appropriate route of exposure. When
sufficient data exists, three LSE tables and two LSE figures are presented in the document. The
three LSE tables present data on the three principal routes of exposure. i.e., inhalation, oral. and
dermal (LSE Table 2—l, 2-2, and 2-3, respectively). LSE figures are limited to the inhalation
(LSE Figure 2-l) and oral (LSE Figure 2—2) routes. Not all substances will have data on each
route of exposure and will not therefore have all five of the tables and figures.

"’DRAFT FOR PUBLIC COMMENT'“

CHLORFENVINPHOS B-2

(2)

(3)

(4)

(5)

(6)

(7)

(8)

(9)

APPENDIX B

Exposure Period Three exposure periods — acute (less than 15 days), intermediate (15—364 days),
and chronic (365 days or more) are presented within each relevant route of exposure. In this
example, an inhalation study of intermediate exposure duration is reported. For quick reference
to health effects occurring from a known length of exposure, locate the applicable exposure
period within the LSE table and figure.

Health Effect The major categories of health effects included in LSE tables and figures are
death, systemic, immunological, neurological, developmental, reproductive, and cancer.
NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer.
Systemic effects are further defined in the ”System" column of the LSE table (see key number
18).

Key to Figure Each key number in the LSE table links study information to one or more data
points using the same key number in the corresponding LSE figure. In this example, the study
represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL
(also see the 2 "l8r" data points in Figure 2—1).

Species The test species, whether animal or human, are identified in this column. Section 2.5,
"Relevance to Public Health," covers the relevance of animal data to human toxicity and Section
2.3, "Toxicokinetics," contains any available information on comparative toxicokinetics.
Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent
human doses to derive an MRL.

Exposure Frequency/Duration The duration of the study and the weekly and daily exposure
regimen are provided in this column. This permits comparison of NOAELs and LOAELs from
different studies. In this case (key number 18), rats were exposed to l,l,2,2-tetrachloroethane
via inhalation for 6 hours per day, 5 days per week, for 3 weeks. For a more complete review
of the dosing regimen refer to the appropriate sections of the text or the original reference paper,
i.e., Nitschke et al. 1981.

System This column further defines the systemic effects. These systems include: respiratory,
cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular.
"Other" refers to any systemic effect (e.g., a decrease in body weight) not covered in these
systems. In the example of key number 18, l systemic effect (respiratory) was investigated.

NOAEL A No-Observed—Adverse—Effect Level (NOAEL) is the highest exposure level at which
no harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of

3 ppm for the respiratory system which was used to derive an intermediate exposure, inhalation
MRL of 0.005 ppm (see footnote "b").

LOAEL A Lowest—Observed-Adverse-Effect Level (LOAEL) is the lowest dose used in the
study that caused a harmful health effect. LOAELs have been classified into "Less Serious" and
"Serious" effects. These distinctions help readers identify the levels of exposure at which
adverse health effects first appear and the gradation of effects with increasing dose. A brief
description of the specific endpoint used to quantify the adverse effect accompanies the LOAEL.
The respiratory effect reported in key number 18 (hyperplasia) is a Less serious LOAEL of 10
ppm. MRLs are not derived from Serious LOAELs.

(10) Reference The complete reference citation is given in chapter 8 of the profile.

“‘DRAFT FOR PUBLIC COMMENT‘"

 

CHLORFENVINPHOS 8-3

(11)

APPENDIX B

@ A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of
carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious
effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report
doses not causing measurable cancer increases.

Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found
in the footnotes. Footnote ”b" indicates the NOAEL of 3 ppm in key number 18 was used to
derive an MRL of 0.005 ppm.

LEGEND

See Figure 2-1

LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the
reader quickly compare health effects according to exposure concentrations for particular exposure
periods.

(13)

(14)

(15)

(l6)

(l7)

(l8)

([9)

Exposure Period The same eprsure periods appear as in the LSE table. In this example, health
effects observed within the intermediate and chronic exposure periods are illustrated.

Health Effect These are the categories of health effects for which reliable quantitative data
exists. The same health effects appear in the LSE table.

Levels of Exposure concentrations or doses for each health effect in the LSE tables are
graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log
scale "y" axis. Inhalation exposure is reported in mg/m" or ppm and oral exposure is reported in
mg/kg/day.

NOAEL In this example, 18r NOAEL is the critical endpoint for which an intermediate
inhalation exposure MRL is based. As you can see from the LSE figure key, the open—circle
symbol indicates to a NOAEL for the test species-rat. The key number 18 corresponds to the
entry in the LSE table. The dashed descending arrow indicates the extrapolation from the
exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005 ppm (see footnote "b"
in the LSE table).

CEL Key number 38r is 1 of 3 studies for which Cancer Effect Levels were derived. The
diamond symbol refers to a Cancer Effect Level for the test species-mouse. The number 38
corresponds to the entry in the LSE table.

Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the
upper-bound for lifetime cancer risk of l in 10,000 to l in 10,000,000. These risk levels are
derived from the EPA’s Human Health Assessment Group’s upper-bound estimates of the slope

of the cancer dose response curve at low dose levels (q,*).

Key to LSE Figure The Key explains the abbreviations and symbols used in the figure.

""DRAFT FOR PUBLIC COMMENT"‘

5-4

CHLOR FE NVINPHOS

 

APPENDIX B

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*"DRAFT FOR PUBLIC COMMENT"*

 

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"‘DRAFT FOR PUBLIC COMMENT'“

 

CHLORFENVINPHOS B—6

APPENDIX B

Chapter 2 (Section 2.5)
Relevance to Public Health

The Relevance to Public Health section provides a health effects summary based on evaluations of
existing toxicologic, epidemiologic, and toxicokinetic information. This summary is designed to
present interpretive, weight—of—evidence discussions for human health end points by addressing the
following questions.

1. What effects are known to occur in humans?
2. What effects observed in animals are likely to be of concern to humans?

3. What exposure conditions are likely to be of concern to humans, especially around hazardous
waste sites?

The section covers end points in the same order they appear within the Discussion of Health Effects
by Route of Exposure section, by route (inhalation, oral, dermal) and within route by effect. Human
data are presented first, then animal data. Both are organized by duration (acute, intermediate,
chronic). In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.)
are also considered in this section. If data are located in the scientific literature, a table of
genotoxicity information is included.

The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using
existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer
potency or perform cancer risk assessments. Minimal risk levels (MRLs) for noncancer end points (if
derived) and the end points from which they were derived are indicated and discussed.

Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to
public health are identified in the Data Needs section.

Interpretation of Minimal Risk Levels

Where sufficient toxicologic information is available, we have derived minimal risk levels (MRLs) for
inhalation and oral routes of entry at each duration of exposure (acute, intermediate, and chronic).
These MRLs are not meant to support regulatory action; but to acquaint health professionals with
exposure levels at which adverse health effects are not expected to occur in humans. They should
help physicians and public health officials determine the safety of a community living near a chemical
emission, given the concentration of a contaminant in air or the estimated daily dose in water. MRLs
are based largely on toxicological studies in animals and on reports of human occupational exposure.

MRL users should be familiar with the toxicologic information on which the number is based.
Chapter 2.5, "Relevance to Public Health," contains basic information known about the substance.
Other sections such as 2.7, "Interactions with Other Substances,” and 2.8, "Populations that are
Unusually Susceptible" provide important supplemental information.

MRL users should also understand the MRL derivation methodology. MRLs are derived using a
modified version of the risk assessment methodology the Environmental Protection Agency (EPA)
provides (Barnes and Dourson 1988) to determine reference doses for lifetime exposure (Rst).

"'DRAFT FOR PUBLIC COMMENT‘"

 

 

CHLORFENVINPHOS B-7

APPENDIX B

To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement,
represents the most sensitive human health effect for a given exposure route and duration. ATSDR
cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is
available for all potential systemic, neurological, and developmental effects. If this information and
reliable quantitative data on the chosen endpoint are available, ATSDR derives an MRL using the
most sensitive species (when information from multiple species is available) with the highest NOAEL
that does not exceed any adverse effect levels. When a NOAEL is not available, a lowest~observed-
adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor (UF) of 10
must be employed. Additional uncertainty factors of 10 must be used both for human variability to
protect sensitive subpopulations (people who are most susceptible to the health effects caused by the
substance) and for interspecies variability (extrapolation from animals to humans). In deriving an
MRL, these individual uncertainty factors are multiplied together. The product is then divided into the
inhalation concentration or oral dosage selected from the study. Uncertainty factors used in
developing a substance-specific MRL are provided in the footnotes of the LSE Tables.

“‘DRAFT FOR PUBLIC COMMENT'"

 

CHLORFENVINPHOS C-1

ACGIH
ADME
atm
ATSDR
BCF
BSC

C

CDC
CEL
CERCLA
CFR
CLP

cm

CNS

(1
DHEW
DHHS
DOL
ECG
EEG
EPA
EKG

F

F1
FAO

F EMA
FIFRA
fpm

ft

FR

g

GC
gen
HPLC
hr
IDLH
IARC
ILO

in

Kd

kkg

0C

0W

APPENDIX C

ACRONYMS, ABBREVIATIONS, AND SYMBOLS

American Conference of Governmental Industrial Hygienists
Absorption, Distribution, Metabolism, and Excretion
atmosphere

Agency for Toxic Substances and Disease Registry
bioconcentration factor

Board of Scientific Counselors

Centigrade .
Centers for Disease Control

Cancer Effect Level

Comprehensive Environmental Response, Compensation, and Liability Act
Code of Federal Regulations

Contract Laboratory Program

centimeter

central nervous system

day

Department of Health, Education. and Welfare
Department of Health and Human Services
Department of Labor

electrocardiogram

electroencephalogram

Environmental Protection Agency

see ECG

Fahrenheit

first filial generation

Food and Agricultural Organization of the United Nations
Federal Emergency Management Agency

Federal Insecticide, Fungicide, and Rodenticidc Act
feet per minute

foot

Federal Register

gram

gas chromatography

generation

high—performance liquid chromatography

hour

Immediately Dangerous to Life and Health
International Agency for Research on Cancer
International Labor Organization

inch

adsorption ratio

kilogram

metric ton

organic carbon partition coefficient

octanol—watcr partition coefficient

"*DRAFT FOR PUBLIC COMMENT'"

 

CHLORFENVINPHOS

LC
LCM,
LCso
LDLO
LDSO
LOAEL
LSE

m

mg

min

mL

mm

mm Hg
mmol
mo
mppcf
MRL
MS
NIEHS
N IOSH
N IOSHTIC
ng

nm
NHANES
nmol
NOAEL
NOES
NOHS
NPL
NRC
NTIS
NTP
OSHA
PEL

Pg

pmol
PHS
PMR
ppb
PPm

PPt
REL

RfD
RTECS
sec
SCE
SIC
SMR

APPENDIX C

liter

liquid chromatography

lethal concentration, low

lethal concentration, 50% kill

lethal dose, low

lethal dose, 50% kill
lowest-observed-adverse-effect level

Levels of Significant Exposure

meter

milligram

minute

milliliter

millimeter

millimeters of mercury

millimole

month

millions of particles per cubic foot

Minimal Risk Level

mass spectrometry

National Institute of Environmental Health Sciences
National Institute for Occupational Safety and Health
NIOSH’s Computerized Information Retrieval System
nanogram

nanometer

National Health and Nutrition Examination Survey
nanomole

no-observed-adverse-effect level

National Occupational Exposure Survey

National Occupational Hazard Survey

National Priorities List

National Research Council

National Technical Information Service

National Toxicology Program

Occupational Safety and Health Administration
permissible exposure limit

picogram

picomole

Public Health Service

proportionate mortality ratio

parts per billion

parts per million

parts per trillion

recommended exposure limit

Reference Dose

Registry of Toxic Effects of Chemical Substances
second

sister chromatid exchange

Standard Industrial Classification

standard mortality ratio

"'DRAFT FOR PUBLIC COMMENT'"

 

CHLORFENVINPHOS

APPENDIX C

STEL short term exposure limit
STORET STORAGE and RETRIEVAL
TLV threshold limit value

TSCA Toxic Substances Control Act
TRI Toxics Release Inventory
TWA time—weighted average

US. United States

UF uncertainty factor

yr year

WHO World Health Organization
wk week

 

greater than

greater than or equal to
equal to

less than

less than.or equal to
percent

alpha

beta

delta

gamma

um micrometer

ug microgram

<me§IAA IIIVV

if US. GOVERNMENT PRINTING OFFICEI1995-639-414

""DRAFT FOR PUBLIC COMMENT'"

 

 

Pursue HEALTH 1mm

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(0147277195