“gig: N-NITROSODI—n-PROPYLAMINE Agency for Toxic Substances and Disease Registry US. Public Health Service TOXICOLOGICAL PROFILE FOR N-NITROSODI-n-PROPYLAMINE Prepared by: Syracuse Research Corporation Under Subcontract to: Clement Associates, Inc. Under Contract No. 205-88—0608 Prepared for: Agency for Toxic Substances and Disease Registry (ATSDR) U.S. Public Health Service In collaboration with U.S. Environmental Protection Agency (EPA) December 1989 PUEJL/ ii DISCLAIMER Mention of company name or product does not constitute endorsement by the Agency for Toxic Substances and Disease Registry. iii R314 I 2‘? 2. ~52 FOREWORD 7662’ ( NE? The Superfund Amendments and Reauthorization Act of 1986 (Public YZL4[3(—-— Law 99—499) extended and amended the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law (also known as SARA) directed the Agency for Toxic Substances and Disease Registry (ATSDR) to prepare toxicological profiles for hazardous substances which are most commonly found at facilities on the CERCLA National Priorities List and which pose the most significant potential threat to human health, as determined by ATSDR and the Environmental Protection Agency (EPA). The lists of the most significant hazardous substances were published in the Federal Register on April 17, 1987, and on October 20, 1988. Section 110 (3) of SARA directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the list. Each profile must include the following content: (A) An examination, summary and interpretation of available toxicological information and epidemiological evaluations on the 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 which present a significant risk to human health of acute, subacute, or chronic health effects, and (C) Where appropriate, an identification of toxicological testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans. 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, but no less often than every 3 years, as required by SARA. The ATSDR toxicological profile is intended to characterize succinctly the toxicological and health effects information for the hazardous substance being described. Each profile identifies and reviews the key literature that iv describes a hazardous substance's toxicological properties. Other literature is 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, which describes in nontechnical language a substance's relevant toxicological properties. Following the statement is material that presents 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 protection of public health will be identified by ATSDR, the National Toxicology Program of the Public Health Service, and EPA. The focus of the profiles is on health and toxicological information; therefore, we have included this information in the front of the document. 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 as additional data become available. ‘ This profile reflects our assessment of all relevant toxicological testing and information that has been peer reviewed. It has been reviewed by scientists from ATSDR, EPA, the Centers for Disease Control, and the National Toxicology Program. It has also been reviewed by a panel of nongovernment peer reviewers and was made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. Walter R. Dowdl , Ph.D. Acting Administrator Agency for Toxic Substances and Disease Registry FOREWORD . CONTENTS LIST OF FIGURES. LIST OF TABLES 1. PUBLIC HEALTH STATEMENT. l. l. H‘H H2—I U‘IJ—‘UJNH O" 8 WHAT IS N- NITROSODI- -n- PROPYLAMINE? HOW MIGHT I BE EXPOSED TO N- NITROSODI— -n- PROPYLAMINE? HOW CAN N- NITROSODI- -n- PROPYLAMINE ENTER AND LEAVE MY BODY? HOW CAN N-NITROSODI-n-PROPYLAMINE AFFECT MY HEALTH?. IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO N- NITROSODI- -n- PROPYLAMINE?. WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTS? WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH?. . WHERE CAN I GET MORE INFORMATION?. 2. HEALTH EFFECTS 2. 1 INTRODUCTION . 2. 2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE. 2.2.1 Inhalation Exposure . .1. Death. . Systemic Effects Neurological Effects Immunological Effects. Developmental Effects. Reproductive Effects Genotoxic Effects. Cancer . 1 Exposure Death. . Systemic Effects. Immunological Effects. Neurological Effects Developmental Effects. Reproductive Effects Genotoxic Effects. Cancer . 1 Exposure Death. . Systemic Effects Neurological Effects Immunological Effects. Developmental Effects. Reproductive Effects mro N N m va m N H‘H‘H‘H H HIA m-u o m b¢w NIH H . 2.2.2 mVONU'I-PWNH B. . wwwwwmeMNNNNNN . (p. . . MNNNNNHNNNNNNNN 2.2.3 NNNNNNUNNNNNNNNONNNNNNNN Q‘th'IJ-\£»J|\)b--I iii ix xi N H H H H 2. NM bu NNN 6 \ooow vi 2.2.3.7 Genotoxic Effects. 2. 2. 3. 8 Cancer . . RELEVANCE TO PUBLIC HEALTH . . LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH HEALTH EFFECTS. LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS IN HUMAN TISSUES AND/OR HEALTH EFFECTS. TOXICOKINETICS . . . 2.6.1 Absorption. . . 2.6.1.1 Inhalation Exposure. 2.6.1.2 Oral Exposure. 2.6.1.3 Dermal Exposure. 2. 6. 2 Distribution. 2. 6. 3 Metabolism. 2. 6. 4 Excretion . 2.6.4.1 Inhalation Exposure. 2.6.4.2 Oral Exposure. 2. 6. 4. 3 Dermal Exposure. INTERACTIONS WITH OTHER CHEMICALS. . POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE . ADEQUACY OF THE DATABASE . 2.9.1 Existing Information on Health Effects of N- Nitrosodi- n- propylamine . 2. 9. 2 Data Needs. . 2. 9. 3 On-going Studies. 3. CHEMICAL AND PHYSICAL INFORMATION. 3.1 CHEMICAL IDENTITY. 3. 2 PHYSICAL AND CHEMICAL PROPERTIES ODUCTION, IMPORT, USE, AND DISPOSAL. PRODUCTION . IMPORT . USE. DISPOSAL . . ADEQUACY OF THE DATA BASE. 4.5.1 Data Needs. 5. POTENTIAL FOR HUMAN EXPOSURE . 5.1 OVERVIEW . . 5.2 RELEASES TO THE ENVIRONMENT. 5. 3 5.2.1 Air . 5.2.2 Water . 5.2.3 Soil. . ENVIRONMENTAL FATE . . 5.3.1 Transport and Partitioning. 5. 3. 2 Transformation and Degradation. 5.3.2.1 Air. 5.3.2.2 Water. l7 17 17 23 23 23 23 23 23 24 24 25 27 27 27 27 27 28 28 28 28 33 35 35 35 39 39 39 39 39 39 40 41 41 42 42 42 42 42 42 43 43 43 5.4 mwuu \lO‘U‘I vii 5.3.2.3 Soil . . . . . . . . . . . . LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT . 5.4.1 Air . 5.4.2 Water . 5.4.3 Soil. 5.4.4 Other Media . . . . . . . . . . . . GENERAL POPULATION AND OCCUPATIONAL EXPOSURE . POPULATIONS WITH POTENTIALLY HIGH EXPOSURE . ADEQUACY OF THE DATA BASE. 5.7.1 Data Needs. . 5.7.2 On-going Studies. 6. ANALYTICAL METHODS . 6.1 6.2 6.3 BIOLOGICAL MATERIALS . ENVIRONMENTAL SAMPLES. ADEQUACY OF THE DATA BASE. 6.3.1 Data Needs. . 6.3.2 On-going Studies. 7. REGULATIONS AND ADVISORIES 8. REFERENCES 9. GLOSSARY . APPENDIX . 44 44 44 44 45 45 46 46 47 47 48 49 49 49 49 54 55 57 59 75 79 2-1. 2-2. 2-3. ix LIST OF FIGURES Levels of Significant Exposure to N-Nitrosodi-n-propy1amine - Oral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . l4 ‘ Metabolism of N-Nitrosodi-n-propy1amine. . . . . . . . . . . . . . 26 Existing Information on Health Effects of N-Nitrosodi-n- propylamine. . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 1-1. 1-2. 1—3. 1-4. 2—1. 2-2. 2-3. 3-1. 3-2. 6-1. 6-2. 7-1. xi LIST OF TABLES Human Health Effects from Breathing N-Nitrosodi—n-propylamine. Animal Health Effects from Breathing N-Nitrosodi-n-propylamine Human Health Effects from Eating or Drinking N-Nitrosodi-n-propylamine. Animal Health Effects from Eating or Drinking N-Nitrosodi-n-propylamine. Levels of Significant Exposure to N-Nitrosodi-n-propylamine - Oral . Genotoxicity of N-Nitrosodi-n-propy1amine In Vitro . Genotoxicity of N-Nitrosodi-n-propylamine In Vivo. Chemical Identity of N-Nitrosodi-n-propylamine Chemical and Physical Properties of N-Nitrosodi-n-propylamine. Analytical Methods for N-Nitrosodi-n-propylamine in Biological Samples. Analytical Methods for N-Nitrosodi-n-propylamine in Environmental Samples. Regulations and Guidelines Applicable to N-Nitrosodi-n- propylamine. 12 20 22 36 37 50 51 58 1. PUBLIC HEALTH STATEMENT 1.1 WHAT IS N-NITROSODI—n-PROPYLAMINE? N-Nitrosodi-n-propylamine is a yellow liquid at room temperature that does not disssolve in water and evaporates slowly. It is a man-made chemical made in small amounts for use in research. There is no evidence that N-nitrosodi-n—propylamine exists naturally in soil, air, food, or water. Small amounts of N-nitrosodi-n-propylamine are produced as a side reaction during some manufacturing processes, as a contaminant in some commonly available weed killers (dinitroaniline-based), and during the manufacture of some rubber products. When exposed to sunlight, N-nitrosodi- n-propylamine usually does not last for more than a day. Without sunlight (e.g, in water deeper than sunlight reaches or in subsurface soil) N-nitrosodi-n-propylamine breaks down slowly. It takes between 14 and 80 days for one-half of any certain amount of N-nitrosodi-n-propylamine to break down when it is released to the subsurface soil. More information can be found in Chapters 3, 4, and 5. 1.2 HOW MIGHT I BE EXPOSED T0 N-NITROSODI-n-PROPYLAMINE? Persons may be exposed to N-nitrosodi-n-propylamine by eating foods treated with nitrite preservatives (e.g., cheeses, cured meats) and drinking certain alcoholic beverages. N-Nitrosodi-n-propylamine forms in the stomach during digestion of nitrite-treated foods and foods that contain certain amines, particularly di-n—propylamine. Amines occur in some medicines and in a variety of foods. Levels of N-nitrosodi-n-propylamine found in food and alcoholic beverages range between 0.03 parts per billion (ppb) in fried, salt-preserved fish to 30 ppb in cheese. The general population may be exposed to N-nitrosodi-n-propylamine in cigarette smoke. Workers making molded rubber products have been exposed to levels of N-nitrosodi-n- propylamine in workroom air that were measured in parts of compound per trillion parts (ppt) of air. Workers applying contaminated weed killers may also be exposed to extremely low (ppt) levels of N—nitrosodi-n-propylamine. At this time, N-nitrosodi-n-propylamine has been found in at least 1 of 1177 hazardous waste sites on the National Priorities List (NFL) in the United States. Workers and the general population at these sites could possibly be exposed to this compound by skin contact, breathing, and eating contaminated items. For more information, refer to Chapter 5. 1.3 HOW CAN N-NITROSODI-n-PROPYLAMINE ENTER AND LEAVE MY BODY? N-Nitrosodi-n-propylamine can enter the body when a person breathes air that contains N-nitrosodi-n-propylamine, or eats food or drinks water contaminated with N—nitrosodi-n-propylamine. N-nitrosodi-n-propylamine is not likely to get into your body unless you eat certain foods, drink ' alcoholic beverages, or are exposed to it at a waste disposal site by breathing N-nitrosodi-n-propylamine vapors. It is likely that N-nitrosodi- n-propylamine can enter the body by direct skin contact with wastes, 1. PUBLIC HEALTH STATEMENT pesticides, or soil that contains it. Experiments with animals suggest that if N-nitrosodi—n-propylamine enters the body, it will be broken down into other compounds and will leave the body in the urine. More information on how N-nitrosodi-n-propylamine can enter and leave your body is given in Chapter 2. 1.4 HOW CAN N-NITROSODI-n—PROPYLAMINE AFFECT MY HEALTH? The effects of short- or long—term exposures to N-nitrosodi-n- propylamine on human health have not been studied. Little is known about the health effects of short exposures to N-nitrosodi-n-propylamine in experimental animals except that eating or drinking certain amounts of this chemical can cause liver disease and death. Long-term exposure of experimental animals to N-nitrosodi-n-propylamine in food or drinking water causes cancer of the liver, esophagus, and nasal cavities. Although human studies are not available, the animal evidence indicates that it is reasonable to expect that exposure to N-nitrosodi-n-propylamine by eating or drinking could cause liver disease and cancer in humans. It is not known whether other effects, such as birth defects, occur in animals or could occur in humans exposed to N-nitrosodi-n-propylamine by eating or drinking. It is also not known whether exposure to N-nitrosodi-n-propylamine by breathing contaminated air or contact with the skin can affect the health of animals or humans. Liver disease and cancer due to exposure to N-nitrosodi- n-propylamine by breathing or skin contact are, however, a possibility and a health concern. More information on the health effects of N-nitrosodi-n— propylamine is given in Chapter 2. 1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO N-NITROSODI-n-PROPYLAMINE? The presence of N-nitrosodi-n—propylamine in blood and urine can be measured by chemical analysis, but this analysis is not usually available at your doctor's office and has not been used to test for human exposure or to predict possible health effects. These considerations are discussed in more detail in Chapter 2. 1.6 WHAT LEVELS OF EXPOSURE HAVE RESUIEED IN HARMFUL HEALTH EFFECTS? Tables 1-1 through 1—4 show the relationship between exposure to N-nitrosodi-n-propylamine and known health effects. As indicated in Tables l-l and 1-2, nothing is known about the health effects on humans or animals of breathing N-nitrosodi~n-propy1amine. Also, nothing is known about the health effects in humans of eating food or drinking water containing N-nitrosodi-n-propylamine (Table 1-3). A Minimal Risk Level (MRL) is also included in Table l-3. This MRL was derived from animal data for short-term exposure as described in Chapter 2 and in Table 2-1. The MRL provides a basis for comparison with levels that people might encounter in drinking water. If a person is exposed to N-nitrosodi-n-propylamine at an amount 3 1. PUBLIC HEALTH STATEMENT TABLE l-l. Human Health Effects from Breathing N-Nitrosodi-n-propylamine* Short-term Exposure (less than or equal to 14 days) Levels in Air Length of Exposure Description of Effects The health effects resulting from short-term exposure of humans to air containing N-nitrosodi-n-propy1amine are not known. Long-term Exposure (greater than 14 days) Levels in Air Length of Exposure Description of Effects The health effects resulting from long-term exposure of humans to air containing N-nitrosodi-n-propylamine are not known. *See Section 1.2 for a discussion of exposures encountered in daily life. 4 1. PUBLIC HEALTH STATEMENT TABLE 1-2. Animal Health Effects from Breathing N-Nitrosodi-n-propylamine Short-term Exposure (less than or equal to 14 days) Levels in Air Length of Exposure Description of Effects The health effects resulting from short-term exposure of animals to air containing N-nitrosodi-n-propylamine are not known. Long-term Exposure (greater than 14 days) Levels in Air Length of Exposure Description of Effects The health effects resulting from long-term exposure of animals to air containing N-nitrosodi-n-propylamine are not known. 5 1. PUBLIC HEALTH STATEMENT TABLE 1-3. Human Health Effects from Eating or Drinking N-Nitrosodi-n-propylamine* Short-term Exposure (less than or equal to 14 days) Levels in Food Length of Exposure Description of Effects The health effects resulting from short- term exposure of humans to food containing N-nitroso-di-n-propyl- amine are not known. Levels in Water (ppm) 3.3 Minimal risk level (based on animal data; see Section 1.6 for discussion). Long-term Exposure (greater than 14 days) Levels in Food Length of Exposure Description of Effects The health effects resulting from long-term exposure of humans to food containing N-nitroso-di—n-propyl- amine are not known. Levels in Water The health effects resulting from long-term exposure of humans to food containing N-nitrosodi-n-propylamine are not known. *See Section 1.2 for a discussion of exposures encountered in daily life. 6 1. PUBLIC HEALTH STATEMENT TABLE 1-4. Animal Health Effects from Eating or Drinking N-Nitrosodi-n-propylamine 1 Short-term Exposure (less than or equal to 14 days) Levels in Food (ppm) 308 4 days Liver injury in mice. Levels in Water (ppm) Length of Exposure Description of Effects* 3429 once Liver injury and death in rats. Long-term Exposure (greater than 14 days) Levels in Food Length of Exposure Description of Effects The health effects resulting from long-term animal exposure to food containing specific levels of N-nitrosodi-n- propylamine are not known. Levels 13 Water The health effects resulting from long-term animal exposure to water containing specific levels of N-nitrosodi-n- propylamine are not known. *These effects are listed at the lowest level at which they were first observed. They may also be seen at higher levels. 7 1. PUBLIC HEALTH STATEMENT below the MRL, it is not expected that harmful (noncancer) health effects will occur. Because this level is based on information that is currently available, some uncertainty is always associated with it. Also, because the method for deriving MRLs does not use any information about cancer, an MRL does not imply anything about the presence, absence, or level of risk of cancer. The levels of N—nitrosodi-n-propylamine in food and drinking water linked with known health effects in animals are given in Table 1-4. It is not known whether skin contact with N-nitrosodi-n-propylamine can affect the health of humans or animals. More information on levels of exposure linked with adverse health effects can be found in Chapter 2. 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? The EPA controls the release of N-nitrosodi-n-propylamine. It is proposed that releases or spills of 10 pounds or more of N-nitrosodi-n- propylamine must be reported to the National Response Center. 1.8 WHERE CAN I GET MORE INFORMATION? If you have more questions or concerns, please contact your State Health or Environmental Department or: Agency for Toxic Substances and Disease Registry Division of Toxicology 1600 Clifton Road, E-29 Atlanta, Georgia 30333 2. HEALTH EFFECTS 2.1 INTRODUCTION This chapter contains descriptions and evaluations of studies and interpretation of data on the health effects associated with exposure to N-nitrosodi-n-propylamine. Its purpose is to present levels of significant exposure for N-nitrosodi-n-propylamine based on toxicological studies, epidemiological investigations, and environmental exposure data. This information is presented to provide public health officials, physicians, toxicologists, and other interested individuals and groups with (1) an overall perspective of the toxicology of N-nitrosodi-n-propylamine and (2) a depiction of significant exposure levels associated with various adverse health effects. 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE To help public health professionals address the needs of persons living or working near hazardous waste sites, the data in this section are organized first by route of exposure -- inhalation, oral, and dermal -- and then by health effect -- death, systemic, immunological, neurological, developmental, reproductive, genotoxic, and carcinogenic effects. These data are discussed in terms of three exposure periods -- acute, intermediate, and chronic. Levels of significant exposure for each exposure route and duration (for which data exist) 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. These distinctions are intended to help the users of the document identify the levels of exposure at which adverse health effects start to appear, determine whether or not the intensity of the effects varies 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 on the tables and graphs may differ depending on the user’s perspective. For example, physicians concerned with the interpretation of clinical findings in exposed persons or with the identification of persons with the potential to develop such disease may be interested in levels of exposure associated with "serious" effects. Public health officials and project managers concerned with response actions at Superfund 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 (NOAEL) have been observed. Estimates of levels posing minimal risk to humans (minimal risk levels, MRLs) are of interest to health professionals and citizens alike. lO 2. HEALTH EFFECTS For certain chemicals, levels of exposure associated with carcinogenic effects may be indicated in the figures. These levels reflect the actual doses associated with the tumor incidences reported in the studies cited. Because cancer effects could occur at lower exposure levels, the figures also show estimated excess risks, ranging from a risk of one in 10,000 to one in 10,000,000 (10'4 to 10'7), as developed by EPA. Estimates of exposure levels posing minimal risk to humans (MRLs) have been made, where data were believed reliable, for the most sensitive noncancer end point for each exposure duration. MRLs include adjustments to reflect human variability and, where appropriate, the uncertainty of extrapolating from laboratory animal data to humans. Although methods have been established to derive these levels (Barnes et a1. 1987; EPA 1980a), uncertainties are associated with the techniques. 2.2.1 Inhalation Exposure No studies were located regarding the following effects in humans or animals following inhalation exposure to N-nitrosodi-n-propylamine: 2.2.1.1 Death 2.2.1.2 Systemic Effects 2.2.1.3 Neurological Effects 2.2.1.4 Immunological Effects 2.2.1.5 Developmental Effects 2.2.1.6 Reproductive Effects 2.2.1.7 Genotoxic Effects 2.2.1.8 Cancer 2.2.2 Oral Exposure 2.2.2.1 Death No studies were located regarding lethality in humans following oral exposure to N-nitrosodi-n-propylamine. Druckrey et al. (1967) determined a single dose gavage LD50 of 480 mg/kg for N-nitrosodi-n-propylamine in rats. The value was determined using an unspecified graphic technique but specific mortality data were not reported. Deaths occurred after 3-7 days and appear to have been due primarily to hepatotoxicity. Other acute oral lethality data were not located in the reviewed literature. The 480 mg/kg LD50 is indicated in ll 2. HEALTH EFFECTS Table 2-1 and Figure 2-1. No short-term studies of N-nitrosodi-n-propylamine administered in drinking water were located; therefore, the dose level of 480 mg/kg, which was administered by gavage in water (Druckrey et al. 1967), was converted to an equivalent concentration of 3400 ppm in water for presentation in Table 1-4. Decreased longevity occurred in rats that were treated with N-nitrosodi-n-propylamine at doses of 6.3 mg/kg/day (females) or 12.6 mg/kg/day (males) by gavage for 2 days/week for 30 weeks (Lijinsky and Reuber 1983), or 5.1 mg/kg/day (males) via drinking water for 5 days/week for 30 weeks (Lijinsky and Taylor 1978, 1979). Mortality in the Lijinsky and Reuber (1983) study was 92-100% after 40—60 weeks compared to 5-10% after 100 weeks in controls; comparable data were reported by Lijinsky and Taylor (1978, 1979) for the treated rats but a control group was not used. The mortality in these studies was due to tumor development (see Section 2.2.2.8, Oral exposure, Cancer). The 5.1, 6.3 and 12.6 mg/kg/day doses are serious LOAEL values for lethality in rats due to intermediate duration oral exposure and are recorded in Table 2-1 and plotted in Figure 2-1. No studies were located regarding survival in animals following chronic oral exposure to N-nitrosodi-n-propylamine. 2.2.2.2 Systemic Effects No studies were located regarding systemic effects in humans following oral exposure to N-nitrosodi-n-propylamine. Hepatic Effects. Pathologic examinations of rats that received single lethal doses of various nitrosamines, including N-nitrosodi-n-propylamine, showed centrilobular necrosis and fatty degeneration of the liver (Druckrey et al. 1967). Specific doses of N-nitrosodi-n—propylamine that produced these effects were not reported, but the LD50 was determined to be 480 mg/kg; this dose is indicated in Table 2-1 and Figure 2-1 as a serious LOAEL for hepatic effects in rats due to acute oral exposure. No short-term studies of N-nitrosodi-n-propylamine administered in drinking water were located; therefore, the dose level of 480 mg/kg, which was administered by gavage in water (Druckrey et al. 1967), was converted to an equivalent concentration of 3400 ppm in water for presentation in Table 1-4. Nishie et a1. (1972) determined pentobarbital sleeping time (PST) in mice that were treated by gavage with single doses or with four consecutive daily doses of various nitrosamines, including N-nitrosodi-n-propylamine. Doses of N-nitrosodi-n-propylamine were 160 mg/kg/day in the single dose study and 40 mg/kg/day in the four-day study. N-nitrosodi-n-propylamine treatment resulted in significantly prolonged PST in both studies. Liver histology was evaluated in the four-day study, but results of the histologic examinations were not reported specifically for any of the nitrosamines. Hepatic histological alterations attributed to unspecified nitrosamines included hepatocyte swelling and necrosis in the centrilobular areas; due to the inadequately reported data, it cannot be determined whether N-nitrosodi- TABLE 2-1. Levels of Significant Exposure to N-Nitrosodi-n-propylamim - Oral Duration/ LOAELc (Effect) Graph Frequency b Key Speciesa Route Exposure Effect NOAEL Less Serious Serious Reference (mg/kglday) (mg/kglday) (mg/kglday) ACUTE EXPOSURE Death 1 rat (G) one dose 480 (L050) Druckrey et al. 1967 Systemic 2 mouse (u) 1 uk, Hepatic 9.5d Tyndall et al. 1978 daily 3 mouse (G) l. d, Hepatic 40 (increased PST) Nishie et al. 1972 once/day 4 rat (G) one dose Hepatic 480 (necrosis) Druckrey et al. 1967 INTERMEDIATE EXPOSURE Death 5 rat (W) 30 wk, 5.1 (decreased longevity) Lijinsky and Taylor 1978, 5 d/wk 1979 6 rat (G) 30 wk, 12.6 (decreased longevity) Lijinsky and Reuber 1983 (male) 2 d/wk 7 rat (G) 30 wk, 6.3 (decreased longevity) Lijinsky and Reuber 1983 (female) 2 d/wk Cancer 8 rat (U) 30 wk, 2.6 (CELe-esophagus, Lijinsky and Reuber 1981 5 d/uk forestonach tumors) 9 rat (a) 30 wk, 6.3 (CELe-liver, nasal, Lijinsky and Reuber 1983 2 d/uk esophagus tunors) 'Z SlOHflfiH HL'IVHH ZI TABLE 2-1 (continued) Duration/ LOAELC (Effect) Graph Frequency b Key Speciesa Route Exposure Effect NOAEL Less Serious Serious Reference (mg/kg/day) (mg/kg/dav) (mg/kglday) 10 rat (F) life, 1. (CELe-liver carcinoma) Druckrey et al. 1967 daily 11 mouse (G) 50 wk, 1 (CELe-forestomach, Griciute et al. 1982 2 d/wk pulmonary tunors) aG - gavage, u — water, F - feed bNOAEL - No Observed Adverse Effect Level cLOAEL - Lowest Observed Adverse Effect Level dUsed to derive acute oral MRL; dose divided by an uncertainty factor of 100 (10 for extrapolation from animals to hunans and 10 for hunan variability), resulting in a MRL of 0.095 mg/kg/day. This MRL has been converted to an equivalent concentration in water (3.3 ppm) for presentation in Table 1-3. eCEL - Cancer Effect Level '3 $1033.13 HJTIVHH SI (m QM- cm— OJIIIIM .— um .— IMIIMI L ACUTE INTERMEDIATE CHRONIC (5 14 Days) (15-364 Days) (:365 Days) 4: as dIf +4? 0“ of 0" . It .4: 0 3m 0" 9' 02" . 71, : ID i 5' 0" : . Hm I I \12 10“ 10-5 Estimded Upper-Balm K" 10 , Hyman Cancer v M I L050 3 Wrist Inna R's“ L an noun 0 IOAELUqu-Miwun : Mon-"Mum o lOAEL in In: salons m “my . 10" O W NOAEL (awn-Is) O CEI. - Cam cm W mmmummmnmuiummm. FIGURE 2-1. Levels of Significant Exposure to N-Niirosodi-n-propylamlne - OraI 'Z 8103:1313 Hl'IVEH '7'! 15 2. HEALTH EFFECTS n-propylamine was among the nitrosamines that produced these effects. However, considering the aforementioned findings for nitrosamines in general as well as evidence for hepatotoxicity of N-nitrosodi-n-propylamine and other nitrosamines from other studies, the increase in PST provides an indirect indication of adverse liver effects. Therefore, since N-nitrosodi- n-propylamine markedly increased PST in the four-day study, 40 mg/kg/day can be regarded as a LOAEL for less serious hepatic effects due to acute oral exposure (Table 2-1 and Figure 2-1). No short—term studies of N-nitrosodi-n- propylamine administered in food were located; therefore, the dose level of 40 mg/kg/day, which was administered by gavage in olive oil (Nishie et al. 1972), was converted to an equivalent concentration of 308 ppm in food for presentation in Table 1-4. Liver histology and activities of liver-associated serum enzymes (SGOT, alkaline phosphatase, lactate dehydrogenase, gamma-glutamyl-transferase) were unaltered in mice exposed to 9.5 mg/kg/day via drinking water for one week (Tyndall et al. 1978). This dose represents a NOAEL for hepatic effects due to acute duration exposure (Table 2-1 and Figure 2-1). Because this NOAEL is lower than the 40 mg/kg/day LOAEL for hepatic effects (Nishie et a1. 1972), it can be used as the basis for an acute MRL (Figure 2-1). Based on this value, an acute oral MRL of 0.095 mg/kg/day was calculated, as described in the footnote in Table 2-1. This MRL has been converted to an equivalent concentration in drinking water (3.3 ppm) for presentation in Table 1-3. Other Effects. Plasma esterase profiles were examined in mice exposed to various carcinogenic, weakly carcinogenic and noncarcinogenic chemicals in the drinking water for one week (Tyndall et a1. 1978). N-nitrosodi-n- propylamine, administered at a dose 9.5 mg/kg/day, produced esterase alterations that were similar to those produced by other N- nitrosodialkylamines. The alterations were not accompanied by weight loss, altered liver-associated serum enzymes or histologic effects. This study was conducted to determine whether altered esterase patterns in plasma would provide a more sensitive indicator of exposure to a carcinogenic chemical than standard clinical chemistry tests. It was concluded that it is not known if the altered esterase profiles that were observed for N-nitrosodi-n- propylamine and the other carcinogens are related to carcinogenicity, toxicity or metabolism. Since the biological significance of the altered esterase profiles is unknown, it cannot be determined if 9.5 mg/kg/day represents a NOAEL or LOAEL for serum chemistry alterations due to acute oral exposure. No studies were located regarding the following effects in humans or animals following oral exposure to N-nitrosodi-n-propylamine: 2.2.2.3 Immunological Effects 2.2.2.4 Neurological Effects 16 2. HEALTH EFFECTS 2.2.2.5 Developmental Effects 2.2.2.6 Reproductive Effects 2.2.2.7 Genotoxic Effects Single doses of N—nitrosodi-n—propylamine, administered by gavage, produced fragmentation of liver DNA in rats (Brambilla et a1. 1981, 1987a). Doses ranged from 0.31 to 25 mg/kg and the effect was dose-related. 2.2.2.8 Cancer No studies were located regarding carcinogenic effects in humans following oral exposure to N-nitrosodi-n-propylamine. The carcinogenicity of N-nitrosodi-n-propylamine has been demonstrated unequivocally in oral studies. High incidences of liver carcinomas, nasal cavity carcinomas, esophageal carcinomas and papillomas, forestomach tumors or tongue tumors occurred in rats that were exposed to N—nitrosodi-n- propylamine by gavage at doses of 6.3 or 12.6 mg/kg/day for 2 days/week for 30 weeks (Lijinsky and Reuber 1983), via drinking water at a dose of 2.6 mg/kg/day for 5 days/week for 30 weeks (Lijinsky and Reuber 1981), via drinking water at a dose of 5.1 mg/kg/day for 5 days/week for 30 weeks (Lijinsky and Reuber 1981; Lijinsky and Taylor 1978, 1979), and via diet daily at reported doses of 4-30 mg/kg/day for life (survival duration not specified) (Druckrey et al. 1967). Tumor incidences in the liver, nasal cavity, esophagus and forestomach were generally in the range of 60-100Z, and tongue tumor incidences ranged from 30-40%. The Lijinsky and Reuber (1983) study was the only study that used control groups; no tumors occurred in the control rats at any of the sites in which tumors developed in the treated rats. The lack of controls in the other studies is not considered to be a serious deficiency due to the high tumor incidences. As indicated in Section 2.2.2.1 (Oral exposure, Death), tumor development in all of the rat studies was life-shortening. The lowest drinking water and gavage doses of N—nitrosodi-n- propylamine that were carcinogenic to rats are 2.6 mg/kg/day (Lijinsky and Reuber 1981) and 6.3 mg/kg/day (Lijinsky and Reuber 1983), respectively; these are intermediate duration effect levels for carcinogenicity (cancer effects levels, CELs) because exposure durations were 30 weeks (Table 2-1 and Figure 2-1). The lowest dose tested in the study of Druckrey et a1. (1967) (4 mg/kg/day) is also presented in Table 2-1 and Figure 2-1 in the intermediate duration category as this study is used as the basis for a carcinogenic potency factor for N-nitrosodi-n—propy1amine (EPA 1988). The 4 mg/kg/day dose from the Druckrey et a1. (1967) study is considered to be the lowest CEL due to intermediate duration exposure because (1) time to tumor data suggest that survival was generally less than one year, and (2) survival was less than one year in the other cancer studies which used l7 2. HEALTH EFFECTS similar or lower doses. Although a carcinogenic potency factor is based on this study, it should be recognized that the study is limited by small numbers of treated rats, no controls and unreported specific tumor incidences. Using hepatocellular carcinoma response data from this study, EPA (1988) derived and verified an oral slope factor (BH) of 7.0 (mg/kg/day)‘1 for N-nitrosodi-n-propylamine. Using this slope factor the doses associated with upper bound lifetime cancer risk levels of 10'4 to 10'7 are calculated to be 1.4 X 10'5 to 1.4 x 10'8 mg/kg/day, respectively. The cancer risk levels are plotted in Figure 2-1 in the chronic duration category because they represent lifetime risks for humans. In an oral carcinogenicity study conducted with mice, the animals received an estimated N-nitrosodi-n-propylamine dose of 1 mg/kg by gavage, twice a week for 50 weeks (Griciute et a1. 1982). Incidences of forestomach papillomas, forestomach carcinomas and pulmonary adenomas were significantly higher than in mice that were similarly treated with 40% ethanol; a vehicle (water) control was not used. The 1 mg/kg/day dose from the Griciute et al. (1982) study represents an intermediate duration CEL in mice (Table 2-1 and Figure 2-1). 2.2.3 Dermal Exposure No studies were located regarding the following effects in humans or animals following dermal exposure to N-nitrosodi-n-propylamine: 2.2.3.1 Death 2.2.3.2 Systemic Effects 2.2.3.3 Neurological Effects 2.2.3.4 Immunological Effects 2.2.3.5 Developmental Effects 2.2.3.6 Reproductive Effects 2.2.3.7 Genotoxic Effects 2.2.3.8 Cancer 2.3 RELEVANCE TO PUBLIC HEALTH Death. Information regarding death of humans following exposure to N-nitrosodi-n—propylamine by any route was not found. Case reports indicate that intentional oral and accidental inhalation exposures to unknown levels of N-nitrosodimethylamine, however, have resulted in deaths in humans (Barnes and Magee 1954, Cooper.and Kimbrough 1980, Freund 1937, Fussgaenger and Ditschuneit 1980, Pedal et al. 1982); these deaths apparently were due 18 2. HEALTH EFFECTS to hepatotoxicity. Limited data are available for acute lethality in N‘nitrosodi—n-propylamine-exposed animals. In the only acute study that used a natural route of exposure, an oral LD50 value of 480 mg/kg was determined for rats (Druckrey et al. 1967). Subcutaneous injection LD50 values have been determined for N-nitrosodi-n-propy1amine in various species; these are consistent with the oral LD50 and include 487.2 mg/kg for rats (Reznik et al. 1975), 689 mg/kg for mice (Dickhaus et al. 1977) and 600 mg/kg for hamsters (Pour et a1. 1973). Pathologic examinations revealed centrilobular liver necrosis and hemorrhages in the lungs, stomach, kidneys and/or heart. Oral administration of N—nitrosodi-n-propylamine at doses ranging from 5.1-12.6 mg/kg/day, on 2 or 5 days a week for 30 weeks, produced high mortality in rats (Lijinsky and Reuber 1983; Lijinsky and Taylor 1978, 1979). Once-weekly subcutaneous injections of similar doses of N—nitrosodi- n-propylamine to rats ($24.4 mg/kg) (Reznik et al. 1975), mice (234.5 mg/kg) (Dickhaus et al. 1977) and hamsters (23.75 mg/kg) (Pour et al. 1973, Althoff et al. 1973a,b) also were life-shortening (average survival times of 27-54 weeks). Weekly intraperitoneal injection of 40 mg/kg N-nitrosodi-n- propylamine produced deaths in monkeys after an average period of 28 months (Adamson and Sieber 1979, 1983). Mortality in the above studies is dose- related and due to tumor development. The available lethality data indicate that deaths resulting from acute exposure to N—nitrosodi-n-propylamine are due primarily to hepatotoxicity, that deaths resulting from repeated exposure to N-nitrosodi—n-propylamine are due to tumors occurring primarily in the liver, and that causes of death and lethal doses are similar in different species. The causes of death produced by N-nitrosodi-n-propylamine also are consistent with those produced by other dialkylnitrosamines (Magee et a1. 1976). Systemic Effects. Information regarding systemic effects in humans following exposure to N—nitrosodi-n-propylamine was not found. Very limited information is available for systemic effects of N-nitrosodi-n-propylamine in animals because interest in this compound has focused overwhelmingly on carcinogenicity. As indicated in the previous subsection (see Death above), lethal single oral or subcutaneous doses of N-nitrosodi-n—propylamine produced hepatic necrosis and hemorrhagic lesions in the liver and other internal tissues in rats and hamsters (Druckrey et al. 1967, Pour et a1. 1973, Reznik et al. 1975). Similar effects were reported by Nishie et a1. (1972), who observed that gavage doses of 40 mg/kg/day for 4 consecutive days produced swelling of hepatocytes and possibly necrosis in the centrilobular area of the liver in mice. Hepatotoxicity and hemorrhagic lesions in the liver and other internal tissues are also the primary acute effects of other dialkylnitrosamine compounds (Magee et al. 1976). Based on data for other dialkylnitrosamines, it can be inferred that systemic effects of intermediate or chronic duration exposure to N-nitrosodi-n-propylamine are likely to include acute-type responses and preneoplastic alterations. 19 2. HEALTH EFFECTS Although it is apparent that N-nitrosodi-n-propy1amine produces hepatotoxicity and hemorrhages in the lungs, stomach, kidney and heart at acute lethal doses in animals, there is only limited information regarding the threshold for these effects following acute exposure and documentation of these effects following intermediate or chronic duration exposure is not available. Although human data are not available, human fatalities due to intentional oral and accidental inhalation exposures to unknown levels of N-nitrosodimethylamine have been described in case reports in which hemorrhagic, necrotic and cirrhotic alterations in the liver and diffuse internal bleeding were observed (Barnes and Magee 1954; Cooper and Kimbrough 1980; Freund 1937; Fussgaenger and Ditschuneits 1980; Pedal et al. 1982). The available information for N-nitrosodi-n-propylamine and related nitrosamines therefore indicates that N-nitrosodi-n-propylamine is likely to produce characteristic hepatic and/or hemorrhagic effects in humans exposed orally or by inhalation. Systemic effects of N-nitrosodi-n-propylamine may result from dermal exposure, since evidence indicates that dermal absorption of N—nitrosodi-n—propylamine is likely (Section 2.6.1.3, Absorption, Dermal exposure). Developmental Effects. Limited information regarding developmental effects of N-nitrosodi-n-propy1amine in humans or in animals is available from subcutaneous injection transplacental carcinogenesis studies with hamsters (Althoff et al. 1977a; Althoff and Grandjean 1979). Injection of a single dose of 100 mg N-nitrosodi-n-propylamine/kg on day 8, 10, 12, or 14 of gestation did not produce gross malformations in the offspring but the scope of the examination was not specified. However, transplacental carcinogenicity was observed in the offspring of dams treated with N-nitrosodi-n-propylamine. There were no treatment-related effects on litter size but postnatal mortality in the first four weeks was increased (Althoff et al. 1977a). Transplacental transport of N-nitrosodi—n-propylamine by the hamsters was demonstrated by detection of the chemical in the placenta, fetus and amniotic fluid. No studies were located demonstrating that N-nitrosodi-n-propylamine crosses the placenta in humans and it is not known whether N-nitrosodi-n-propylamine can cause developmental effects in humans. It is relevant to note, however, that limited evidence indicates that N-nitrosodimethylamine is fetotoxic but not teratogenic. Also, it has been estimated from studies with rodents that drugs with a molecular weight of less than 1,000 can readily cross the placenta (Mirkin 1973); the molecular weight of N-nitrosodi~n-propylamine is 130.2. Genotoxic Effects. No studies were located regarding the genotoxicity of N-nitrosodi-n-propylamine in humans by the inhalation, oral or dermal routes. Fragmentation of DNA was observed, however, in human hepatocytes cultured in the presence of N-nitrosodi-n-propylamine (Brambilla et al. 1987b). Genotoxicity of N-nitrosodi-n-propy1amine has been demonstrated consistently in numerous in vitro studies. As indicated in Table 2-2, TABLE 2-2. Genotoxicity of N-Nitrosodi-n-Propylamine In Vitro Result Species Hith Without Endpoint (Test System) Activation Activation References Gene mutation Salmonella tmimuriun + - Yahagi et al. 1977, Bartsch et al. 1976, 1980, McMahon et al. 1979, Rao et al. 1979, Araki et al. 1984, Phillipson and loamides 1985, Guttenplan and flu 1984, Guttenplan 1987, Moore et al. N 1985, Dahl 1985, Rao et al. 1982, . Probst et al. 1981 :1: Escherichia coli + - McMahon et al. 1979, g Araki et al. 1984, l" Nakajima et al. 1974, g Rao et al. 1981, 1982 F1 Mouse lynphoma L5178Y + - Amacher et al. 1979, :11 cells Amacher and Paillet 1982, 1983, g 0-1 Chinese hamster V79 + - Kuroki et al. 1977, w cells Bartsch et al. 1980, Jones and Muberman 1980, Langenbach 1986 DNA fragmentation Rat hepatocytes + N1 Bradley and Dysart 1981a,b, Bradley et al. 1982, Parodi et al. 1982 Hunan hepatocytes + NR Bran'billa et al. 1987b Unscheduled DNA synthesis Rat hepatocytes + NT Probst et al. 1981 HeLa cells + - Martin et al. 1978 DNA repair Rat hepatocytes + NT Yamazaki et al. 1985 Chromosome aberrations Chinese hamster + - Kaneko et al. 1978 fibroblasts Chinese hamster lung (+) - Matsuoka et al. 1979 cells NT = not tested; NR = not reported OZ 21 2. HEALTH EFFECTS N-nitrosodi-n-propylamine was mutagenic in bacteria (Salmonella typhimurium,Escherichia coli) and mammalian cells (mouse lymphoma L5178Y, Chinese hamster V79), caused DNA effects (fragmentation, unscheduled synthesis, repair) in rat hepatocytes, and chromosome aberrations in Chinese hamster cells. The in vitro assays generally required addition of an exogenous metabolic activation system for expression of effects; this is consistent with the apparent indirect carcinogenicity of N-nitrosodi-n- propylamine. Single doses of N-nitrosodi-n-propylamine produced DNA fragmentation in rats treated orally and sister chromatid exchange and DNA synthesis suppression in mice treated by intraperitoneal injection (Table 2- 3). In addition, intraperitoneal injection (133 mg/kg) of N-nitrosodi—n- propylamine to rats results in propylation of DNA and RNA, an event regarded as critical in the initiation of carcinogenesis by this and related alkylating agents (Park et al. 1980). The weight of evidence indicates that N-nitrosodi-n-propylamine is genotoxic in mammalian cells. The effect observed in the study with human hepatocytes (DNA fragmentation) (Brambilla et al. 1987b) is consistent with the results of other assays, particularly the in vitro and in vivo rat hepatocyte DNA fragmentation assays (Table 2-2 and 2—3). Given the type and weight of genotoxicity evidence, one can predict that N-nitrosodi-n- propylamine poses a genotoxic threat to humans. Cancer. Information regarding the carcinogenicity of N-nitrosodi-n- propylamine in humans was not located. In animals, carcinogenicity of N-nitrosodi-n-propylamine has been demonstrated in several species in all studies that have been conducted. In rats observed for life, daily or partial weekly (2 days/week or 5 days/week) oral exposure produced tumors primarily in the liver, nasal cavity and esophagus (Druckrey et al. 1967; Lijinsky and Reuber 1981, 1983; Lijinsky and Taylor 1978, 1979). In mice, increased incidences of forestomach tumors occurred as a result of twice weekly orally treatment for 50 weeks (Griciute et al. 1982). Weekly subcutaneous injections of N-nitrosodi-n-propylamine to rats (Althoff et al. 1973b, Reznik et al. 1975), mice (Dickhaus et al. 1977) and hamsters (Althoff et al. 1973a, 1977b; Pour et al. 1973, 1974) for life produced high incidences of tumors primarily in the nasal cavity and other parts of the respiratory system, but also in the liver and esophagus. Subcutaneous injection of single 100 mg/kg doses of N-nitrosodi-n-propylamine into hamsters during gestation induced tumors, primarily in the respiratory and digestive tracts, in the dams and offspring (Althoff et al. 1977a; Althoff and Grandjean 1979). Weekly intraperitoneal injections of 40 mg N-nitrosodi- n-propylamine produced death due to hepatocellular carcinomas in monkeys after an average duration of 28 months (Adamson and Sieber 1979, 1983). Overall, there is conclusive evidence that N-nitrosodi-n-propylamine is carcinogenic in animals. The carcinogenicity of N-nitrosodi-n-propylamine may be related to alkylation of DNA. It is important to recognize that cancer was observed in the oral and injection studies after durations as short as 20—30 weeks, and that once weekly oral exposures and single TABLE 2-3. 22 2. HEALTH EFFECTS Genotoxicity of N-Nitrosodi-n-propylamine In Vivo Species Endpoint (Test System) Result References DNA alkylation Rat liver + Park et al. 1980 DNA fragmentation Rat hepatocytes + Brambilla et al. 1981, 1987a Suppressed DNA synthesis Mouse liver and renal + Amlacher and Rudolph 1981 epithelial cells Sister chromatid exchange Mouse bone marrow cells + Parodi et al. 1983 23 2. HEALTH EFFECTS exposure by injection were sufficient to induce cancer. Based on the evidence of carcinogenicityin animals, it is reasonable to anticipate that N-nitrosodi-n-propy1amine will be carcinogenic in humans. 2.4 LEVELS IN HUMAN TISSUES AND FLUIDS ASSOCIATED WITH HEALTH EFFECTS There is no known association between levels of N-nitrosodi-n- propylamine or its metabolites in human tissues and fluids and health effects of N-nitrosodi-n-propylamine. N-nitrosodi—n-propylamine was detected in the liver of 1 of 4 deceased subjects (Cooper et a1. 1987). As indicated in Section 2.6.2 (Distribution), the cause of death is not attributable to N-nitrosodi-n-propylamine. 2.5 LEVELS IN THE ENVIRONMENT ASSOCIATED WITH LEVELS IN HUMAN TISSUES AND/OR HEALTH EFFECTS There is no known association between levels of N-nitrosodi-n- propylamine in the environment and levels of N-nitrosodi-n-propy1amine or its metabolites in human tissues and fluids or health effects of N-nitrosodi—n-propylamine. 2.6 TOXICOKINETICS 2.6.1 Absorption 2.6.1.1 Inhalation Exposure No studies were located regarding absorption in humans or animals following inhalation exposure to N-nitrosodi-n-propylamine. However, structurally similar compounds, such as, N-nitrosodimethylamine and N-nitrosodiethanolamine, are readily absorbed (70-90% of the dose) following inhalation exposure in experimental animals (Klein and Schmezer 1984; Preussmann et a1. 1981). Absorption was inferred by monitoring urinary excretion of the unchanged compounds. 2.6.1.2 Oral Exposure No studies were located regarding absorption in humans following oral exposure to N—nitrosodi-n-propylamine. Specific information regarding absorption in animals following oral exposure to N-nitrosodi-n-propylamine was not located. Gastrointestinal absorption of N-nitrosodi-n-propylamine by rodents is indicated by the occurrence of metabolites in the urine following oral treatment (Section 2.3.1.3) and systemic effects in oral carcinogenicity and toxicity studies (Section 2.2). Other nitrosamines are rapidly absorbed from the gastrointestinal tract after oral exposure. Diaz Gomez et a1. (1977) found that less than 2% of radiolabelled dimethylnitrosamine could be recovered from the stomach and intestine of rats 15 minutes after administration. Also 24 2. HEALTH EFFECTS in rats, Lijinsky et al. (1981) and Preussmann et a1. (1978) estimated absorption rates of 25% and 70% of the dose for N-nitrosodiethanolamine, respectively (estimates are from urinary excretion). 2.6.1.3 Dermal Exposure No studies were located regarding absorption in humans following dermal exposure to N—nitrosodi-n-propylamine. However, absorption of N- nitrosodiethanolamine through human skin in vivo (Edwards et a1. 1979) and in vitro (Bronaugh et a1. 1979, 1981) has been demonstrated. Diffusion of N-nitroso-di-n-propy1amine through rat skin in vitro has been demonstrated (Wishnok et a1. 1982). Information regarding dermal absorption of N-nitroso-di-n-propylamine by animals in vivo was not located in the reviewed literature. Dermal absorption of N-nitrosodiethanolamine has been determined in pigs (Marzulli et a1. 1981), monkeys (Marzulli et a1. 1981), and rats (Airoldi et al. 1984; Lijinsky et a1. 1981). The degree of absorption varied greatly (4-78%) depending on the site of the application and the vehicle used. Based on the data for N-nitrosodi-n-propylamine and N—nitrosodiethanolamine, it is likely that N-nitrosodi-n-propylamine will be absorbed following dermal exposure. 2.6.2 Distribution Route-specific distribution data for N-nitrosodi-n-propylamine in humans were not located in the reviewed literature. Quantitative analyses of six volatile nitrosamines in postmortem organs (brain, liver, kidneys, pancreas) from four human subjects were conducted (Cooper et al. 1987). N-nitrosodi-n—propylamine was detected only in the liver of one of the subjects (female, age 84 years) at a concentration of 19.30 ng/SO g of tissue. The ages of the other subjects (two males, one female) ranged from 47-80 years. Unusual sources of nitrosamine exposure or causes of death were not indicated. Transplacental transport of N-nitrosodi-n-propy1amine was shown in pregnant hamsters (Althoff et al. 1977a, Althoff and Grandjean 1979). After a single 100 mg/kg subcutaneous injection, N-nitrosodi—n-propylamine was detected in the maternal blood, placenta, fetus, and amniotic fluid. The concentration of the chemical in maternal blood reached a maximum at 45 and 90 minutes after the injection, whereas a single peak at 90 minutes was observed in the fetus. Analysis for metabolites was not conducted, but 1.6% of the unchanged compound was found in the placenta and 1.3% in the fetus at day 14 of gestation. Detection of 06-methylguanine in human placental DNA by immunoassay indicates that nitrosamines, as a group, can reach the placenta in humans (Foiles et a1. 1988). Limited data are available regarding the distribution of related nitrosamines. Daugherty and Klapp (1976) reported that after oral administration of 14C—N-nitrosodimethylamine to mice radioactivity could be 25 2. HEALTH EFFECTS detected in the homogenates of heart, forestomach, esophagus, liver and lungs. Radioactivity was detected in all organs and tissues of rats after oral doses of 14C-N-nitrosodiethanolamine (Lethco et al. 1982). After intravenous injection of 1[“C-N—nitrosodi-n-buty1amine to rats the highest concentrations of radiolabel occurred in the nasal mucosa, liver and preputial gland (Brittebo and Tjalve 1982). 2.6.3 Metabolism No studies were located regarding metabolism in humans following exposure to N-nitrosodi-n-propylamine. In vitro and in vivo studies with rodents have been conducted that provide evidence that N-nitrosodi-n-propy1amine can be metabolized Via oxidation at the alpha, beta and gamma carbon positions (Figure 2-2). Alpha carbon oxidation (hydroxylation) is regarded as the primary pathway, resulting in formation of propionaldehyde and 1-propanol and 2-propanol as metabolites (Farrelly et a1. 1984; Park and Archer 1978; Park et a1. 1977). l-Propanol and 2-propanol are formed via propyldiazohydroxide and a propyl cation (carbonium ion). It is generally believed that the carbonium ions can also react with nucleic acids to form propylated adducts, but Park et a1. (1980) have suggested that propylation takes place via a bimolecular reaction. However, reaction of DNA with propylnitrosourea (a direct acting equivalent of N—nitrosodi-n-propy1amine) results in formation of n-propyl and isopropyl DNA adducts, suggesting carbonium ions are involved. Alkylation of nucleic acids and proteins by metabolites of nitrosamines has been suggested as the mechanism responsible for the toxic and carcinogenic properties of these substances. Beta-carbon hydroxylation yields N-nitroso-2-hydroxy-propylpropylamine which is excreted as the glucuronide or further oxidized to a small extent to N-nitroso-2-oxopropylpropylamine (Bauman et a1. 1985; Leung and Archer 1981; Park and Archer 1978; Suzuki and Okada 1981). Methylated hepatic nucleic acids have been recovered from rats and hamsters treated with N-nitrosodi-n-propy1amine (Althoff et al. 1977b; Kruger 1971, 1973; Kruger and Bertram 1973; Leung and Archer 1984). Putative methylating intermediates, formed from N-nitroso-2-oxo-n-propy1amine, are N-nitrosomethylpropylamine and diazomethane. Gamma-carbon hydroxylation yields N-nitroso-3-hydroxy-propylpropylamine and its oxidation product, N-propyl-N—(2-carboxyethy1)nitrosamine (Baumann et al. 1985; Blattmann and Preussman 1973, Suzuki and Okada 1981). Urinary N—propyl-N-(2-carboxyethyl)nitrosamine amounted to approximately 5% of a 300 mg/kg oral dose of N-nitrosodi-n—propylamine in rats (Suzuki and Okada 1981). Documented and postulated metabolites of N-nitrosodi-n-propy1amine have been shown to be carcinogenic in hamsters and rats (IARC 1978). These include N-nitroso-bis-(2-hydroxy-n-propy1)amine, N-nitroso-Z-oxo-n- c-hydroxylcilon OH NO cu,-cH,-cn-N-cH,-cH,-cn, l "-0" cn,-cu,-cuo + N-cn,-cfl,-cu, proploncldohylo propyldlcxohydrOIldo l + cu,-cu,-cu, + cu,—cH-cu,"" outta-I'm lo- 1 l cn,—cu-cn, cH,-cu,-cu,ou 0H 1-propclnl l-proplnol FIGURE 2-2. cH,-cn,—cH,—N-cn,-cn,—cn, OH NO cH,-cu—cH,—u—cH,—cu,—cu, I-nl0roIo-I-hydruxypvupylpropylcmlno \ Glucuronldc o no H I cM,-c-cn,-N-cH,-cH,-cn, I-nlDrone-Z-IlcpropyIpropylcmlno 7-hydroxyluilon l-NlIvor-ll-n-pvopyllmlno ~\\\\\\\\\\\\\\‘t l-hydronyluflon OH NO cH,-cn,-cu,-N-cu,-cH,-cu, l-nlironu-l-hydrOIyprcpylpropylumlno 0H c—cu,-cu,—u-cu,-cH,—cu3 o l-prnpyl-I—(l-IchOIy-thl)nlironcml Metabolism of N-Nitrosodi-n—propylamine 'Z SlOHJdH HLTVBH 9Z 27 2. HEALTH EFFECTS propylpropylamine, N-nitroso-bis(2-oxo-n-propyl)amine and N-nitroso-bis(2- acetoxy-n-propy1)amine. Main tumor sites of many of these metabolites include those associated with N-nitrosodi-n-propy1amine treatment (Section 2.2.2.8, Oral exposure, Cancer). 2.6.4 Excretion 2.6.4.1 Inhalation Exposure No studies were located regarding excretion in humans or animals following inhalation exposure to N-nitrosodi-n-propylamine. 2.6.4.2 Oral Exposure No studies were located regarding excretion in humans following oral exposure to N-nitrosodi-n-propylamine. Rats excreted metabolites but not unchanged N-nitrosodi—n-propy1amine in the urine following oral dosing with N—nitrosodi-n-propy1amine (Blattmann and Preussmann 1973, Suzuki and Okada 1981). The principal metabolite in the Suzuki and Okada (1981) study, N-propyl—N-(2-carboxyethy1)nitrosamine, amounted to approximately 5% of the administered dose. Additional information regarding the extent or rate of excretion in either of the studies was not reported. 2.6.4.3 Dermal Exposure No studies were located regarding excretion in humans following dermal exposure to N—nitrosodi-n-propy1amine. Excretion of unchanged N-nitrosodiethanolamine in the urine of rats has been reported in several studies after cutaneous application of N-nitrosodiethylamine (Airoldi et a1. 1984; Lijinsky et al. 1981; Preussmann et a1. 1981). 2.7 INTERACTIONS WITH OTHER CHEMICALS Ethanol was found to enhance the carcinogenicity of N-nitrosodi-n- propylamine. Mice that were treated with estimated 1 mg/kg doses of N-nitrosodi-n-propylamine dissolved in 40% ethanol by gavage, twice a week for 50 weeks, developed higher incidences of tumors than mice that were similarly treated with the same dose of compound given in water (Griciute et a1. 1982). The most pronounced tumor enhancement was in the forestomach (51% carcinomas vs. 10% in N-nitrosodi-n-propylamine/water group), but increases in pulmonary adenomas and lymphomas also occurred. 28 2. HEALTH EFFECTS 2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE No populations with unusual susceptibility to health effects of N-nitrosodi-n-propy1amine have been identified. However, heavy consumers of alcoholic beverages might be considered to be a susceptible population based on a single report in which ethanol was shown to potentiate the carcinogenicity of N-nitrosodi-n-propylamine in mice (Griciute et al. 1982). 2.9 ADEQUACY OF THE DATABASE Section 104 (i) (5) of CERCLA, 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 N-nitrosodi-n-propylamine is available. Where adequate information is not available, ATSDR, in cooperation with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine these health effects (and techniques for developing methods to determine such health effects). The following discussion highlights the availability, or absence, of exposure and toxicity information applicable to human health assessment. A statement of the relevance of identified data needs is also included. In a separate effort, ATSDR, in collaboration with NTP and EPA, will prioritize data needs across chemicals that have been profiled. 2.9.1 Existing Information on Health Effects of N-Nitrosodi-n—propy1amine Information regarding health effects of N-nitrosodi-n-propylamine in humans is not available. Health effects of N-nitrosodi—n-propylamine in animals have been investigated only in oral exposure studies. As indicated in Figure 2-3, animal oral data are available for lethality, acute systemic effects, genotoxicity and cancer. These data indicate that the acute toxicity of N-nitrosodi-n-propylamine is attributable to hepatic effects and that intermediate duration exposure is life-shortening due to cancer. 2.9.2 Data Needs Single Dose Exposure. Information on lethality (LD50) and severe systemic effects in rats are available from one single dose oral study. Similar information is available from single dose subcutaneous injection studies with rats, mice and hamsters. Another oral study reported a non- lethal effect (increased pentobarbital sleeping time) but none of the other studies reported non—lethal doses or attempted to identify dose-response data for other subtle systemic effects. Additional single dose oral studies would provide better information on thresholds for lethality and systemic toxicity as well as interspecies differences. Inhalation and dermal studies with N-nitrosodi-n-propylamine have not been conducted; single dose studies involving exposure by these routes would provide information on lethality, systemic effects and skin and eye irritation. 29 HEALTH EFFECTS 2. Inhalation Denna! Oral HUMAN f o Inhalation Oral Dermal ANIMAL . Existing Studies Existing Information on Health Effects of N-Nitrosodi-n-propylamine FIGURE 2-3. 30 2. HEALTH EFFECTS Repeated Dose Exposure. Oral studies provide limited information on the threshold for hepatotoxicity in mice. Several intermediate duration oral studies with rats, one limited oral study with mice and injection studies with rats, mice, hamsters and monkeys provide survival data but noinformation on effects other than cancer. Additional short-term repeated dose oral studies (e.g., 14-28 day studies) in various species could provide additional information on systemic effects, particularly dose-response characterization of hepatic/hemorrhagic effects. Repeated dose inhalation studies are lacking and could provide useful information regarding lethality and systemic effects. Chronic Exposure and Carcinogenicity. Chronic oral toxicity data for N-nitrosodi-n-propylamine are not available because treated animals have died of cancer within one year of treatment. Animals treated with doses lower than those used in the intermediate duration studies may survive chronic exposure and provide information on nonneoplastic effects. With the exception of a single study with mice, species other than rat have not been tested for carcinogenicity by the oral route. Genotoxicity. The genotoxicity of N-nitrosodi-n-propylamine is documented but only one in vivo study used an environmentally relevant route of exposure (oral), and only two studies (in vitro) evaluated human cells. Additional studies, particularly types providing information on the potential for heritable mutations in humans, would add to the data base on genotoxicity. Reproductive Toxicity. Information on the reproductive toxicity of N-nitrosodi-n-propylamine is not available. Histological examinations of reproductive organs of animals exposed in subchronic and chronic studies would provide relevant data. Multigenerational or continuous breeding studies would provide further information regarding reproductive effects of N-nitrosodi-n—propylamine in animals, which may be related to possible reproductive effects in humans. Developmental Toxicity. Some data on developmental toxicity are available from single-dose subcutaneous injection studies with hamsters. Developmental effects of N-nitrosodi~n-propy1amine have not been investigated in animals exposed by natural routes. Developmental studies in animals by natural routes of exposure would provide information on possible developmentally toxic effects, including transplacental carcinogenicity, that might be relevant to humans. These studies should include postnatal evaluations for neonatal mortality, as well as for tumor incidence in adult animals. Immunotoxicity. Histological examination of organs and tissues of the immunological system from animals exposed in subchronic and chronic studies would provide relevant information as immunotoxicity data for N-nitrosodi-n- propylamine are not available. Specific immunotoxicity tests or a battery of immunotoxicity tests would provide a better assessment of possible 31 2. HEALTH EFFECTS immunotoxic effects. Sensitization tests in animals might provide information on whether there is likely to be an allergic response to N-nitrosodi-n-propylamine. Although the low molecular weight of N-nitrosodi-n-propy1amine would probably preclude activity as an antigen by itself, it is possible that a higher molecular weight moiety resulting from alkylation of proteins by N-nitrosodi-n-propylamine could produce an allergic response. Neurotoxicity. Information on the neurotoxicity of N-nitrosodi-n- propylamine is not available. A battery of tests for neurotoxicity would provide further information of neurotoxicity in animals, which then might be related to possible neurotoxic effects in humans. Epidemiological and Human Dosimetry Studies. Health effects of N-nitrosodi-n-propylamine have not been described in humans. Effects in treated animals, however, include hepatotoxicity and cancer. As discussed in Chapter 5, the potential for environmental exposure to N-nitrosodi-n- propylamine is very low, and segments of the general population with potentially high or specific exposure to N-nitrosodi-n-propylamine have not been identified. N-nitrosodi-n-propy1amine has been detected in rubber manufacturing facilities but concentrations are low and exposure is complicated by the presence of other nitrosamines and additional chemicals. If N-nitrosodi—n-propylamine or its metabolites in urine can be correlated with exposure in humans, it may be possible to monitor humans for exposure. If toxic effects of N-nitrosodi-n-propylamine are identified in humans, it may then be possible to correlate urinary levels of N-nitrosodi- n-propylamine or one its metabolites with systemic effects. Biomarkers of Disease. N0 disease states in humans produced by exposure to N-nitrosodi-n-propylamine are known. If epidemiological studies are conducted that correlate exposure with diseases, it may be possible to identify subtle changes, such as altered blood chemistry indices, associated with a particular disease state. Disease Registries. Diseases in humans produced by exposure to N-nitrosodi-n-propylamine are not known. If epidemiological studies identify particular diseases produced by N-nitrosodi-n-propylamine, it may be possible to determine the number of people affected and the factors associated with identifying the disease in certain populations, such as, those with exposure to high levels near hazardous waste sites. Bioavailability from Environmental Media. No studies were located regarding the bioavailability of N-nitrosodi-n-propylamine from environmental media. The lack of data concerning levels in human tissues and fluids does not necessarily indicate a lack of bioavailability since the monitoring literature reports that N-nitrosodi-n-propylamine is present in some foods, water, beverages and workroom air. It is, therefore, important to determine if N-nitrosodi-n-propylamine can be absorbed by humans from 32 2. HEALTH EFFECTS environmental samples. An understanding of the bioavailability of N-nitrosodi-n-propylamine from environmental media may be obtained by studying the biological fluids of individuals exposed to N-nitrosodi—n- propylamine in the workplace or through the ingestion of N-nitrosodi-n— propylamine-containing foods and beverages such as cheeses, cured meats, and whiskey. Limited information is available regarding absorption parameters of N-nitrosodi-n-propylamine in experimental animals. However, one could assume, based on data obtained with other nitrosamines, that N-nitrosodi-n- propylamine would be readily absorbed from the gastrointestinal tract if ingested from contaminated soil. Food Chain Bioaccumulation. No studies were available concerning food chain bioaccumulation of N-nitrosodi-n-propylamine from environmental media. The monitoring literature indicates that N-nitrosodi-n-propylamine has been detected in samples of cooked fish and meat; however, occurrence of N-nitrosodi-n-propylamine in these samples was not the result of bioaccumulation, but was the result of formation resulting from preservation and/or cooking. Various studies have also shown that N-nitrosamines, such as N-nitrosodi-n-propylamine, form in the gastrointestinal tract during digestion of foods containing secondary amines. Estimation techniques have been used to determine that N-nitrosodi-n-propylamine would not bioaccumulate in lipids of fish (see Section 5.3.1, Transport and Partitioning). Based on this limited amount of information it is speculated that human exposure to N-nitrosodi-n-propylamine through diet is not the result of food chain bioaccumulation. Monitoring for the accumulation of N-nitrosodi-n-propylamine in organisms from several trophic levels could be used to support this conclusion. Absorption, Distribution, Metabolism, Excretion. The general metabolic pathways of N-nitroso-di—n-propylamine in animals have been identified, but the relative contribution of the pathways in vivo, particularly following exposure by natural routes, is inadequately characterized. The identity of the alkylating agent(s) associated with carcinogenesis is unclear. Information is available regarding absorption and distribution of N-nitrosodi-n-propylamine. Evidence from other nitrosamines indicates that a number of factors (e.g., species, route of exposure, dosing schedule) appear to determine the organ specificity and the severity of the effects induced by these compounds. Therefore, to fully characterize the pharmacokinetics of N-nitrosodi—n-propylamine, studies of absorption, distribution, metabolism, and excretion in animals following exposure by all three routes are needed. Comparative Toxicokinetics. The toxic and carcinogenic effects of N-nitroso-di-n-propylamine are attributable to activity of metabolites but no data are available to determine if there are quantitative differences in metabolism among species. Information from other nitrosamines suggests that there are species-characteristic tumors induced by nitrosamines. This seems to be the reflection of differences in metabolic activities (and also repair mechanisms) existing among animal species; therefore, caution must be 33 2. HEALTH EFFECTS exercised when extrapolating possible effects in humans. Although toxicity and carcinogenicity of N-nitroso-di-n-propylamine has been demonstrated in rodents and monkeys, the animal species that serves as the best model for extrapolating results to humans may be difficult to identify. 2.9.3 On—going Studies No on-going studies of N-nitrosodi-n-propy1amine were identified. 35 3. CHEMICAL AND PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY Data pertaining to the chemical identity of N-nitrosodi-n-propylamine are listed in Table 3-1. , 3.2 PHYSICAL AND CHEMICAL PROPERTIES The physical and chemical properties of N-nitrosodi-n-propy1amine are presented in Table 3-2. 3. 36 CHEMICAL AND PHYSICAL INFORMATION TABLE 3-1. Chemical Identity of N-Nitrosodi—n-Propylamine Value Reference Chemical name l-Propanamine, N-nitroso-N-propyl CAS 1988 Synonyms N-nitrosodipropylamine; SANSS 1988; N,N-dipropylnitrosamine; HSDB 1988 N-Nitroso-N-di-n-propy1amine; NDPA; DPNA; DPN Trade name(s) Not available Chemical formula C6H14N20 CAS 1988 Chemical structure CH3-CH2—CH2 \ N-N=O SANSS 1988 / CH3—CH2-CH2 Identification numbers: CAS Registry 621-64-7 CAS 1988 NIOSH RTECS JL9700000 RTECS 1988 EPA Hazardous Waste Ulll RTECS 1988 OHM-TADS 8300201 OHM-TADS 1988 DOT/UN/NA/IMCO Not available HSDB 5108 HSDB 1988 NCI Not available CAS = Chemical Abstract Service ’NIOSH — National Institute for Occupational Safety and Health RTECS = Registry of Toxic Effects of Chemical Substances EPA = Environmental Protection Agency OHM-TADS = Oil and Hazardous Materials - Technical Assistance Data Base DOT/UN/NA/IMCO = Department of Transportation/United Nations/North America/International Maritime Consultive Organization HSDB = Hazardous Substances Data Bank NCI = National Cancer Institute 37 3. CHEMICAL AND PHYSICAL INFORMATION TABLE 3-2. Chemical and Physical Properties of N-Nitrosodi-n-Propylamine Property Value Reference Molecular weight 130.19 Weast 1983 Color Yellow IARC 1978 Physical state Liquid IARC 1978 Melting point 6.6°C (estimated) Lyman 1985 -12°C (estimated) EPA 1986a Boiling point 206°C Weast 1983 Specific gravity, 20/4°C 0.9163 Weast 1983 Odor Odor threshold Not available Water Not available Air Not available Solubility Water 9,894 mg/L (23-25°C) Mirvish et a1. 1976 Organic solvents Soluble in alcohol, ether, Weast 1983; other organic solvents IARC 1978 Partition coefficient Log octanol/water L08 Koc Vapor pressure Henry’s Law constant Autoignition temperature 1.36 2.11 (estimated) 0.086 mm Hg (20°C) (estimated) l.l+7x10'6 atm-m3/mole at 20°C (estimated from vapor pressure and water solubility data) Not available Hansch and Leo 1985 Klein 1982 38 3. CHEMICAL AND PHYSICAL INFORMATION TABLE 3-2 (continued) Property Value Reference Flashpoint Not available Flammability limits in air Not availablea Conversion factors ppm (v/v) to mg/m3 in air (20°C) ppm (v/v) x 5.41 = mg/m3 mg/m3 to ppm (v/v) in air (20°C) mg/m3 x 0.185 - ppm (v/v) aVapor probably does not form an explosive mixture with air at ordinary temperatures (OHM-TADS 1988). 39 4. PRODUCTION, IMPORT, USE, AND DISPOSAL 4.1 PRODUCTION N-Nitrosodi-n-propylamine is not produced for commercial use in the United States (HSDB 1988). The public portion of the EPA TSCA Production File indicates that The Ames Laboratories in Milford, CT prepared 10'4 mm Hg should exist almost entirely in the vapor phase in the atmosphere (Eisenreich et a1. 1981). The 43 5. POTENTIAL FOR HUMAN EXPOSURE estimated vapor pressure of N-nitrosodi-n-propylamine [0.086 mm Hg at 25°C (see Table 3-2)] indicates that this compound should not partition from the vapor phase to particulates in the atmosphere. Using linear regression equations based on log Kow data [log Kow = 1.36 (see Table 3-2)], a bioconcentration factor of 6 and an adsorption coefficient (Koc) of 129 have been estimated for N-nitrosodi-n-propylamine (Bysshe 1982; Hansch and Leo 1985; Lyman 1982). These values indicate that bioaccumulation in aquatic organisms and adsorption to suspended solids and sediments in water would not be important fate processes. The low Henry's Law constant for N-nitrosodi-n-propylamine [1.47x10'6 atm-m3/mol (see Table 3-2)] suggests that volatilization would be a relatively insignificant fate process in water. If a herbicide containing N-nitrosodi-n-propylamine were applied to warm, moist soil surfaces, most of the nitrosamine would be expected to volatilize. The volatilization half-life from soil surfaces under field conditions is estimated to be on the order of 2 to 6 hours (Berard and Rainey 1979, Oliver 1979). If a herbicide containing N-nitrosodi-n- propylamine were incorporated into soil (below the soil surface), volatilization would be of minor importance (Oliver 1979). When incorporated into soil, N-nitrosodi-n—propylamine is expected to be highly mobile and it has the potential to leach into shallow groundwater supplies (Saunders et a1. 1979, Swann et a1. 1983). 5.3.2 Transformation and Degradation 5.3.2.1 Air In the atmosphere, N-nitrosodi-n-propylamine vapor would be rapidly degraded by direct photolysis and/or reaction with photochemically-generated hydroxyl radicals. Crosby et a1. (1980) determined a pseudo-first order half-life of 5 to 7 hours for photolysis of N-nitrosodi-n-propylamine vapor in air exposed to sunlight. Although experimental conditions did not closely simulate environmental conditions (the concentration of N-nitrosodi- n-propylamine was relatively high), results of this study did indicate that N-nitrosodi-n-propylamine is susceptible to rapid photolysis. The half-life for the reaction of N-nitrosodi-n-propylamine vapor with photochemically- generated hydroxyl radicals has been estimated to be about 16 hours in typical ambient air. This value is based on a reaction rate constant of 2.42x10'11 cm3/molecules-sec at 25°C which was estimated using the method of Atkinson (1987). 5.3.2.2 Water N-nitrosodi-n-propylamine is not expected to undergo abiotic degradation under the conditions found in natural waters (Callahan et al. 1979, Oliver et al. 1979, Saunders and Mosier 1980). The dominant removal process for N-nitrosodi—n-propylamine in surface water is probably 44 5. POTENTIAL FOR HUMAN EXPOSURE photolysis. A study of low levels (0.65 ppm) of N—nitrosodi-n-propylamine in lake water resulted in a photolytic half-life of about 2.5 hours. The major photoproduct was found to be n-propylamine, but the formation of di-n-propylamine was also observed (Saunders and Mosier 1980). Beyond the reach of sunlight it appears that N-nitrosodi-n-propylamine would be subject to slow microbial degradation in aerobic waters (Tabak et al. 1981, Tate and Alexander 1975). Insufficient data are available to predict the rate at which this would occur. 5.3.2.3 Soil It appears that microbial degradation would be the dominant removal process for the nitrosamine in subsurface soil under aerobic conditions. Half-lives ranging from 14 to 40 days have been observed in aerobic subsurface soil and from 47 to 80 days in anaerobic subsurface soil (Oliver et al. 1979, Saunders et al. 1979, Tate and Alexander 1975). Initial losses were due primarily to volatilization; however, biodegradation was the dominant fate process. Available data on the degradation of the nitrosamine in water and air, indicate that photolysis may be an important removal process on soil surfaces. 5.4 LEVELS MONITORED 0R ESTIMATED IN THE ENVIRONMENT 5.4.1 Air There is no indication in the available literature that N-nitrosodi-n- propylamine has been detected in ambient air in the United States. Air samples collected above agricultural fields before, during, and after application of the pesticide trifluralin contained no detectable levels of N-nitrosodi-n-propylamine (detection limit 50 ng/m3) (Day et al. 1982, West and Day 1979). 5.4.2 Water No data were available regarding the monitoring and detection of N-nitrosodi-n-propylamine in ambient surface water, groundwater, or drinking water in the United States except at EPA National Priorities List (NPL) hazardous waste sites. There were only a couple of monitoring studies available pertaining to the occurrence N-nitrosodi—n-propylamine in treated wastewater. In a survey of 32 U.S. textile plants, N-nitrosodi-n— propylamine was detected at concentrations of 2-20 pg/L in 2 out of 32 samples of secondary effluent, while no detectable levels were found in samples of raw wastewater from these same plants (Rawlings and Samfield 1979). This suggests that N—nitrosodi-n-propylamine was formed during the treatment process. N-nitrosodi-n-propylamine has also been detected at a maximum concentration of 1.2 pg/L in the final effluent from a German chemical manufacturing plant involved in the manufacture and/or use of amines (Hartmetz and Slemrova 1980). A survey of stormwater runoff samples collected from 15 cities geographically located across the U.S. revealed 45 5. POTENTIAL FOR HUMAN EXPOSURE that N-nitrosodi—n-propylamine is not a typical contaminant of stormwater runoff (Cole et al. 1984). Water samples collected from agricultural fields immediately following application of the pesticide trifluralin contained no detectable levels of N-nitrosodi-n-propylamine (detection limit 0.01-0.02 pg/L) (Ross et al. 1978, West and Day 1979). 5.4.3 Soil Soil samples collected from agricultural fields immediately following application of the pesticide trifluralin contained no detectable levels of N-nitrosodi—n-propy1amine (detection limit 0.2-1 ng/g) (Ross et a1. 1978, West and Day 1979). It has been detected in at least 1 of 1177 NPL hazardous waste sites (VIEW 1989). 5.4.4 Other Media A number of studies have focused on the monitoring of volatile N-nitrosamines in various foodstuffs, including cheese, cured meats, cooked fish, and alcoholic beverages; however, N-nitrosodi-n-propylamine has rarely been detected (Alliston et al. 1972, Gavinelli et a1. 1988, Goff and Fine 1979, Gross and Newberne 1977, Huang et al. 1981, Sen et a1. 1987). The nitrosamines appear to have formed in these foods as the result of the reaction of secondary amines with the preservative sodium nitrite (Gray and Dugan 1974). N-nitrosodi-n-propylamine has been monitored in food at the following levels: salt-preserved fish (steamed), 0.050 pg/kg; salt-preserved fish (fried), 0.030 pg/kg; salt-preserved fish (raw), not detected; cheese, 5-30 pg/kg; apple brandy, up to 3.6 pg/kg; cognac, rum and whiskey, up to 0.2 pg/kg (Cerutti et al. 1975, Gross and Newberne 1977, Huang et al. 1981, IARC 1978). A study of cigarette smoke condensate from European cigarettes showed that N-nitrosodi-n-propylamine was found at a level equivalent to 1 ng per cigarette in smoke condensate from 1 out of 11 types of cigarettes, while condensate from 10 out of 11 cigarettes had levels below the detection level of 0.5 ng per cigarette (McCormick et a1. 1973). Although a number of volatile N—nitrosamines have been identified in children's pacifiers and baby-bottle nipples, N-nitrosodi-n-propylamine was not among them (Billedeau et al. 1986, Gavinelli et al. 1988, Westin et al. 1987). Crops and plants harvested from fields treated with the pesticides trifluralin, benefin, or oryzalin contained no detectable levels of N-nitrosodi-n-propylamine (detection limit 0.2 ng/g) (Ross et al. 1978, West and Day 1979). In the mid-to-late 19705, N-nitrosodi-n—propylamine was detected in the herbicide trifluralin at levels as high as 154 mg/L, oryzalin at <1 mg/L and isopropalin at 39-87 mg/L (Cohen et al. 1978, Ross et al. 1977). Subsequent to these findings, the production process for trifluralin was modified; current levels of the nitrosamine in technical trifluralin are