' ; la Y \CYCLAMATE SWEETENERS ; HEARING. a BEFORE A SUBCOMMITTEE OF THE US. oropese, trove COMMITTEE ON | «GOVERNMENT OPERATIONS, HOUSE OF REPRESENTATIVES NINETY-FIRST CONGRESS SECOND SESSION JUNE 10, 1970 Printed for the use of the Committee on Government Operations as U.S. GOVERNMENT PRINTING OFFICE 48-798 WASHINGTON : 1970 ''al COMMITTEE ON GOVERNMENT OPERATIONS WILLIAM L. DAWSON, Illinois, Chairman CHET HOLIFIELD, California JACK BROOKS, Texas L. H. FOUNTAIN, North Carolina JOHN A. BLATNIK, Minnesota ROBERT E. JONES, Alabama EDWARD A. GARMATZ, Maryland JOHN E. MOSS, California DANTE B. FASCELL, Florida HENRY S. REUSS, Wisconsin f JOHN 8S. MONAGAN, Connecticut TORBERT H. MACDONALD, Massachusetts ‘ WILLIAM S. MOORHEAD, Pennsylvania CORNELIUS E. GALLAGHER, New Jersey WILLIAM J. RANDALL, Missouri BENJAMIN S. ROSENTHAL, New York TK JIM WRIGHT, Texas a FERNAND J. ST GERMAIN, Rhode Island - JOHN C. CULVER, Iowa FLOYD V. HICKS, Washington FLORENCE P. DWYER, New Jersey OGDEN R. REID, New York FRANK HORTON, New York \ JOHN N. ERLENBORN, Illinois JOHN W. WYDLER, New York CLARENCE J. BROWN, Ohio GUY VANDER JAGT, Michigan JOHN T. MYERS, Indiana WILLIAM O. COWGER, Kentucky GILBERT GUDE, Maryland PAUL N. McCLOSKEY, Jr., California PAUL FINDLEY, Illinois JOHN H. BUCHANAN, JR., Alabama LOWELL P. WEICKER, Jx.,¥Connecticut. SAM STEIGER, Arizona CHRISTINE Ray Davis, Staff Director Jamzs A. LANIGAN, General Counsel MiLEs Q. RoMNEY, Associate General Cownsel J. P. CARLSON, Minority Cownsel WitiiaM H. CopENHAVER, Minority Professional Staff INTERGOVERNMENTAL RELATIONS SUBCOMMITTEE L. H. FOUNTAIN, North Carolina, Chairman BENJAMIN S. ROSENTHAL, New York JOHN C. CULVER, Iowa JOHN A. BLATNIK, Minnesota FLORENCE P. DWYER, New Jersey CLARENCE J. BROWN, Ohio GUY VANDER JAGT, Michigan DELPHIS C. GOLDBERG, Professional Staff Member JaMEs R. NAUGHTON, Counsel GILBERT S. GOLDHAMMER, Consultant (11) '' Pyare Nears f CONTENTS Letters, statements, etce., submitted for the record by— Fountain, Hon. L. H., a Representative in Congress from the State of North Carolina: _/ Article entitled ‘Artificial Sweeteners,” by Dr. John J. Schrogie, Food and Drug Administration Papers, October 1969_..._.___ / Article from Nature magazine, January 4, 1969, entitled ‘‘Effects of Sodium Cyclamate on the Growth of Rats Compared With OthertVanations:in the Dies.) Gi os: (or oe ./ Article from Washington Post, June 10, 1970, entitled “HEW Is " _ Trying To Erase Law That Outlawed Cyclamates? 2 Excerpt from the Medical Letter on Drugs and Therapeutics, vol. ee i gence Ae <7 Finch, Robert H., Secretary of Health, Education, and Welfare: Premrermenbe S228 yids ee rans a a oes eae Letter from M. J. Ryan, director, Office of Legislative Services, He Wo dated Augush:o,970. 2 502 Se Letter from R. W. Kasperson, vice president, corporate regulatory affairs, Abbott Laboratories, dated July 193;.19070 52. ia \~ ./ Memorandum dated January 4, 1966, subject: General Counsel’s views as to effect of difference of opinion regarding safety of GyOraIaebog x2 Shieh Nanda ve 8 iy Vee ee aN cae oe ae Memorandum dated September 8, 1967, subject: Cyclamates__ Memorandum dated October 30, 1967, subject: Meeting on the Bumieeu of oy olamstes it! lk Si TAN Wh CON ae Memorandum dated August 19, 1968, subject: Briefing report on NOMMNoEVG sweetening agents, (oe ea Memorandum dated December 4, 1968, subject: Report of the National Academy of Sciences, National Research ouncil, on Nounwiritive Sweeteners. 20608) Sis So Pe Oa ee /Memorandum dated December 5, 1968, subject: Salient factors ~’ for consideration in the evaluation of the safety or nonsafety of nonnutritive sweeteners.) ot a ee Memorandum dated December 8, 1968, subject: Artificial sweet- eners, November 1968 report of NRC ad hoc committee_____ Memorandum dated December 13, 1968, subject: Minutes of meeting on cyclamates, December 12; POG8R SU eee ee rae /Memorandum dated October 2, 1969, subject: American scientists who have reservations about safety of cyclamates 2.0), ip aime /Memorandum dated October 6, 1969, subject: Benefits of cycla- PRR ee cases 1 Ns As Maney on oe ew OW Ny es ei Memorandum dated October 15, 1969, subject: Association of congenital defects with diabetes during pregnancy.) evan Memorandum dated December 17, 1969, subject: Conference regarding cyclamate-containing nonnutritive sweetener prod- GUE M ayn Oe) Fa NM a oe Nad TA Sia ee Memorandum dated December 19, 1969, subject: Congenital defects, diabetes, and cyclamates___....._.__....... Memorandum dated January 28, 1970, subject: Conference on labeling of foods containing cyclamates___._.__.__......____ Memorandum dated January 30, 1970, subject: Cyclamates. The problem—Handling foods containing cyclamates as drugs____ Memorandum dated February 5, 1970, subject: Cyclamate foods_ Memorandum dated March 31, 1970, subject: Attitude of Canadian officials regarding cyclamates-containing products__ Paper from files of FDA entitled ‘“Medical Effects of Cyclamintes ane. Cy ciolterylamine sya hy oP Se ae On LIBRARY Page 64 35 66 27 102 98 15 22 22 83 2k 18 17 17 16 63 84 6k 68 61 54 82 ''IV Letters, statements, etc., submitted for the record by—Continued Fountain, Hon. L. H.—Continued Report to the Secretary of HEW from the Medical Advisory Page Groupion. Gyclamates i770 * Ua ha Se ee 86 Section 121.7 of the Food, Drug, and Cosmetic Act_...-------- 48 Sundry notices from the Federal Register dated October 21, 1969; December 31, 1969; February 10, 1970; March 24, eR ROW yO no nea ee 25, 28, 29, 30 Goodrich, William W., Assistant General Counsel for Food and Drugs, HEW: Medical specialties of the members composing the Secre- tary’s Medical Advisory Group on Cyclamates______.----------- ~ 40 Minish, Hon. Joseph G., a Representative in Congress from the State atiNew Jersey: patement - <0 ei 5) ote oo ee 97 ''i CYCLAMATE SWEETENERS WEDNESDAY, JUNE 10, 1970 Houss or RepresENTATIVES, INTERGOVERNMENTAL RELATIONS SUBCOMMITTEE OF THE COMMITTEE ON GOVERNMENT OPERATIONS, Washington, D.C. The subcommittee met at 10 a.m., in room 2154, Rayburn House Office Building, the Honorable L. H. Fountain presiding. Present: Representatives L. H. Fountain, Benjamin S. Rosenthal, Florence P. Dwyer, and Clarence J. Brown. Staff members present: Dr. D. C. Goldberg and Gilbert S. Gold- hammer. Mr. Fountain. Let the committee come to order and the record show a quorum is present for the purpose of taking testimony. I might say some of the members, as is usual, are trying to be several places at one time and will be here a little later. At the close of yesterday’s hearings there was brief testimony about the role of the Food and Drug Administration as a regulatory agency versus a scientific agency—or a combination, any way you want to describe it. There was also brief testimony regarding some of the prosecution actions that had been brought. Having been a Member of Congress for a number of years and having considered and cast my vote on legislation now entrusted to the Food and Drug Administration, I believe I can to some extent address myself to the question of con- gressional intent as to FDA’s role. In my opinion Congress passed the Food, Drug, and Cosmetic Act and amended it over the years because of the need for the public pro- tection which this legislation was intended to provide. I don’t think this protection can be given unless the law is vigorously enforced. _The public it seems to me is losing confidence in some of our regula- tory agencies. A report to the Commission on Product Safety only a week or 10 days ago said much the same thing and deplored the breakdown in public protection which has occurred. I believe that this subcom- mittee can, within the limitations of time and staff, render a public service in reminding you, Dr. Edwards, and your associates, that the role of FDA is to enforce the act fully and effectively. All of the sec- tions of the law are important, and Congress did not, and I believe’ does not now, want any of them to be put in limbo, as I am sure some people would like. It is my recollection that some years ago the Food and Drug Administration was widely regarded as a vigorous, active regulatory agency. It had the reputation of giving the American public a real bargain in protection for the money which Congress ap- propriated for the agency. CED ''2 _ For its accomplishments it commanded the admiration and gratitude of the public, the Congress, and the courts. The FDA’s image today is quite different, and the question is why? And I don’t think this is your responsibility. Dr. Edwards, inasmuch as you have been a part of the agency for a limited period of time. Necessarily most of your plans are probably in the making. The subcommittee staff has provided me with some startling en- forcement statistics which may help to answer that question. A com- parison of the data from hearings before the Senate and House Com- mittees on Appropriations and the HEW annual reports reveals the following for the fiscal years 1945 and 1968. Let me say here that there are always some limitations in such comparisons and statistics. They are not always as meaningful as we would like them to be. But money appropriated for Food and Drug Administration in 1945 amounted to approximately $3 million; in 1968, $66 million. Num- ber of employees in 1945, approximately 850; in 1968, 5,100 persons. Population of the country in 1945, approximately 150 million; in 1968, over 200 million. Seizures of foods in 1945, 2,504; in 1968, 384. Seizures of drugs in 1945, 594; in 1968, 235. Injunctions for violative foods in 1945, 26; in 1968, three. Injunctions for violative drugs, 1945, nine; in 1968, four. Prosecutions for violative foods, in 1945, 278; in 1968, 70. It seems to me these are interesting figures. I am not one of those who believes in the philosophy of the chief of the highway patrol that the only way to get a good record is for patrolmen to go out and exert an extra effort to catch a lot of people, because that becomes abusive- But I think these figures are meaningful. AndI think the reason for FDA’s decline may be attributed in part to something we were talking about yesterday, Doctor, the morale of FDA personnel. The subcommittee has been aware for some time.that morale at FDA has been critically low. And there are a number of . causes for this condition, some of which I think we mentioned yester- day: frequent changes in leadership is one, frequent reorganization, physical moves from one building to another, programs begun and not completed, fear of displacement because of frequent changes, and un- certainty as to FDA enforcement programs and policies, - You gentlemen as management specialists know better than anyone else that no organization can function economically, efficiently, and effectively when the morale of employees is low. The subcommittee has received reports from members of the staff, and I have had other people discuss it with me also, of frustration, uncertainty, and the feeling of many FDA employees that their work is purposeless and aimless. This feeling appears to be widespread. Pro- ductivity and dedication to FDA’s role has suffered greatly. I don’t think it is just the press talking about it; these are employees express- ing themselves, in the wrong places, maybe, but this situation ought to be known by the leadership. You and your associates represent the new leadership and the new hope of FDA, Dr. Edwards. I think it is proper for this subcommittee to emphasize that FDA is, and I think the Congress intends it to be, a regulatory agency whose role is to enforce the laws entrusted to it— not to be abusive or unfair and always to give appropriate hearings. Your aim should be to achieve the highest compliance on the part of those regulated, whoever they may be. The scientific work in which the ''4 3 Food and Drug Administration is engaged has one principal purpose, namely to develop the necessary tools and facts to help you achieve your goal of consumer protection and maximum compliance on the part of the regulated industries. : : rey I hope and feel that you and your associates will give a high priority to the need for improving morale and institute the necessary meas- ures for the achievement of this. I wanted to make that comment, Doc- tor, before going into the subject of cyclamates. If you care to make any comments now, or submit any later, to add to, or differ in any way with my observation, we would like to have them for the record. Dr. Epwarps. I would only say, Mr. Chairman, that we appreciate everything you have said. There is no question that the morale of the agency has been low and still, for that matter, is low. We share with you this concern and we are all dedicated to making this agency a top- flight agency. I won’t bother at this time to go into the procedures, or the enforce- ment statistics, but they do show an alarming decrease. I think there are some reasons for that, but I don’t think this is the appropriate time to discuss them. But I can assure you we are dedicated to trying’ to make this the kind of agency that you and your committee would like to have it. Mr. Founrarn. With respect to cyclamate sweeteners and cyclamate- containing drugs, I want to say on behalf of the committee we ap- preciate the comments in your prepared statement. This is an area of great national interest and of tremendous con- troversy, and confusion, not only in the minds of the consuming pub- lic, but among competent scientists. Many questions have been raised concerning FDA’s decision in its © regulatory control over the use of cyclamate sweeteners and products containing this sweetener. The decisions being questioned are those of your predecessors, primarily, but also those made since you became . Commissioner. Serious charges that the Food and Drug Administration and the Department of Health, Education, and Welfare failed to enforce the law—and all of this should be in quotes, because I’m quoting— “ * * * failed to appreciate the purpose of the law in the decisions they made with respect to the cyclamates,” are contained in the recently released book, “The Chemical Feast,” by James S. Turner, based upon investi- _ gations by a Nader summer study group. - This study has been brought to my attention. I have no opinion ‘on it at this time. It is appropriate, however, for this subcommittee to inquire into the background of those decisions; the philosophy of enforcement that dictated the decisions; the requirements of the law and regulations which are controlling as to cyclamates; and whether or not the best interests of the public have been served by the manner in which cyc- Jamates have been and are being controlled by FDA and the Depart- ment of Health, Education, and Welfare. The subcommittee hopes that by analyzing the cyclamate matter in these hearings we will all get an insight into the problems, and the reasoning that went into the decisions and orders. ''Z (ifwr ong procedures, as well as errors in interpretation and applica- tion of the law and regulations, have actually been made as charged hy some FDA critics} we hope to focus on them and bring them to light. In this way we may learn from past experience. “At this point I would like to place in the record a copy of an article entitled, “Artificial Sweeteners,” by Dr. John J. Schrogie, of FDA’s » Bureau ‘of Drugs, which appeared in FDA papers of October 1969. (The article referred to follows :) [From FDA Papers, October 1969] ARTIFICIAL SWEETENERS (By John J. Schrogie, M.D.) In the 1940’s, studies of possible new antipyretic drugs at the University of Illinois yielded an unexpected result: certain derivatives of cyclohexylsulfamic acid (cyclamate) geing tested were remarkably sweet. Further studies showed that these chemicals were at least 30 times sweeter than an equivalent quantity of sugar but were nonnutritive ; that is, they were not metabolized by the body to _energy-producing compounds as is ordinary table sugar. Although a more potent nonnutritive sweetener, saccharin, had been in general use for several decades, its consumption was somewhat limited because of a bitter aftertaste that followed ingestion of larger quantities. It soom became evident that when cyclamate was added to saccharin, reduced quantities of the latter could be used to produce sufficient sweetness without an unpleasant taste. The advent of cyclamates stimulated the development of a number of food products containing cyclamate-saccharin combinations or cyclamate alone and many new industrial producers were influenced to enter the field. Thus, during the early 1950’s, a variety of food products were developed pri- marily for use in the special diets needed, for example, in the treatment of diabetes mellitus. The purpose of such foods was to reduce the quantity of calorie- producing components in a controlled dietary regimen. It was also found that the addition of cyclamates yielded certain technologic advantages in food processing, | and so the list of cyclamate-containing foods grew longer. Yearly production of cyclamates increased nearly fivefold during the early 1960's. Laboratory and clinical studies of the pharmacology and toxicology of these compounds were carried out, of course, before and during the earliest marketing phases. Normal human volunteers, patients with a variety of diseases, and sev- eral animal species were tested at various dose levels. Except for the production of softening of stool at the higher doses tested, the cyclamates appeared to be virtually inert physiologically. Taking such observations and the relatively limited initial use of artificially sweetened foods into consideration, the Food and Drug Administration in 1958 placed the cyclamates on the Generally Recognized As Safe (GRAS) list, thus defining no specific limitation on use in food products. However, labeling of such products was required to indicate that such foods should be used by those who should restrict their intake of calories. As indicated earlier, however, a remarkable rise in consumption of artificially sweetened products has occurred during the past 7 or 8 years. The introduction of such a wide variety of products generally coincided with a trend to encourage | the desirability of bodily leanness for both esthetic and medical reasons. Hx- tensive popular acceptance of the available products stimulated further product development. (Advertising campaigns implied that simple substitution of “low calorie” products in the regular diet would be sufficient to produce weight control or loss without reference to total calorie intake versus requirement. Reacting to this suddenly increased and diversified utilization of artificial sweeteners, the Food and Drug Nutrition Board of the National Academy of Sciences-National “Research Council reevaluated the status of the cyclamates in 1962. Its report questioned ‘the use of artificial sweeteners by the general public as a weight-reducing procedure, emphasized that these compounds have no direct effect on body ‘weight, and suggested that they are useful only in closely controlled and supervised feeding regimens) The Board also questioned whether sufficient information was available to assure the safety of these substances under such widespread and indiscriminate use. This report, however, seemed to have little practical impact on the public. ''5 Research on safety by industrial, university, and FDA groups nevertheless was proceeding because of ‘the questions raised. New approaches and methodologies were being evaluated in parallel with scientific advances in other fields. Because of the sharp interest by scientific investigators in possible effects of chemicals on growth and reproduction that was stimulated by the thalidomide disaster, and assuming a considerable use of artificial sweeteners in women of childbearing years, studies were performed ina variety of animal species. Unfortunately, results in animals to date have failed to yield a consistent pat- tern. Although retardation in number and growth of offspring has been observed in small animals, consistent results between species of investigative groups have ~ not been achieved. Other studies on the possible direct effects of cyclamate and a metabolite, cyclohexylamine (CHA), on chromosomes from animal and human cells have been more consistently positive. Although such studies are provocative and stimulating, the relevance of these observations to the human under ordinary conditions of use is, at present, simply unknown. Valid questions for further investigation have been raised by the application of these new and imaginative techniques. Other improvements in investigative technique have unearthed information that calls for more direct action. Through the development of certain chemical assay procedures, the presence of appreciable quantities of CHA have been ob- “served both in finished food products and as a metabolic product in humans and animals following cyclamate ingestion. Commercially, CHA is used as the pre- cursor substance from which cyclamate is synthesized ; physiologically, CHA is produced. by many humans fed cyclamates, probably originating as a breakdown product in the gastrointestinal tract. Although CHA is known to have several potent and toxic effects, the direct significance of ingestion or production of the small quantities noted so far is uncertain, especially in view of the known rapid clearance of CHA from the body. However, because of these potentially adverse ‘effects, the FDA has proposed specific limitations on CHA content of cyclamates in food products. The possible effects of CHA formed metabolically are now under study. In addition, recent comprehensive Government supported studies at ithe Albany Medical College of the possible effects of cyclamates on a variety of physiological systems in the human have yielded essentially negative results. Because of the new scientific information being gathered, the Commissioner of Food and Drugs requested that the Food and Nutrition Board again evaluate the available data. In an interim report delivered in November 1968, the Board recog- nized no new information that would substantially alter its previous position. It did emphasize more strongly, however, the data supporting a stool softening’ effect in humans and specifically recommended that an adult not exceed a daily intake of approximately 5 grams per day of cyclamates. Similarly, the Food and Agricultural Organization of the World ‘Health Organization, in its earlier review of ‘the situation, had recommended that daily adult intake not exceed 3.5 grams per day. Taking these general recommendations and the general background of data into consideration, the Commissioner of Food and Drugs then proposed that a prudent daily intake for an adult not exceed 3.5 grams for a 154-pound adult and 1.2 grams for a 54-pound child. Appropriate statements were published in the Federal Register in April 1969 to cover the necessary labeling changes ‘as well as CHA tolerances. Comments are now being reviewed and a final order being pre- pared by FDA. , Although many questions about the safety of artificial sweeteners have been ~ raised, few have been resolved. Largely left out of the public controversy has been the issue of their effectiveness in weight reduction; none of the few con- trolled studies reported to date have established a useful role for nonnutritive sweeteners as weight-reducing aids except under the most carefully controlled conditions. Mr. Fountrary. Dr. Edwards, as I understand it, the cvclamates were used as an artificial sweetener of foods in the early fifties, and this was before the Food Additives Amendment of 1958. Ts it correct to state that after the passage of the Food Additives amendment cyclamate sweeteners were placed on what is known as the GRAS list in 1959 ? Dr. Epwarps. That is correct. ''Mr, Fountarn. As I understand it the GRAS list is the list of chemical substances which have been declared to be generally recog- nized as safe. Is that right ? : Dr. Epwarps. That is correct. Mr. Founrain. “Generally recognized as safe”—in quotes—is the language of the statute. Dr. Epwarps. Right. Mr. Fountain. Thereafter, Doctor, it is also my understanding that the use of cyclamates in foods soared dramatically, cyclamates were used both in the home and in industry in greatly increasing amounts, and in an increasing variety of foods. Would you say that is correct ? Dr. Epwarps. That is absolutely correct. Mr. Founrarn. Members of the staff of this subcommittee report that in a briefing report with recommendations on nonnutritive sweet- ening agents in the files of the Food and Drug Administration, there is a statement that—and I quote-“Artificial sweeteners are substan- tially cheaper than sugar. Sixty-four cents worth of cyclamates equals $6 worth of sugar.”) _ Dr. Edwards,dn view of this price differential, in your opinion is there a strong incentive on the part of food producers to substitute the artificial sweetener, cyclamate, for sugar in food products?) Dr. Epwarps. I would think so, yes. Mr. Founrarn. At the time the cyclamates were placed on the GRAS list, were the experimental data from a 2-year rat study re- ported in 1951 by Dr. Fitzhugh, Arthur Nelson, and John P. Fraw- ley, taken into account ? Dr. a eaene. I’m not certain, Mr. Chairman. Mr. Goodrich, do you know? Mr. Goopricu. I’m not sure whether Frawley was involved or not. But I’m sure Dr. Fitzhugh was involved in going over the so-called GRAS list and in reviewing all of the comments that came in about it. Dr. Fitzhugh was one of Dr. Lehman’s principal assistants at that time. And those two gentlemen were the scientific people who re- viewed the GRAS list. So, while I am not personally sure that they went back and re- viewed the paper, I am sure that they had their experience in the investigation of the saftey of the ¢yclamates in mind when it was placed on the GRAS list. Mr. Fountain. Would you or any of your associates care to add anything further as to whether or not that particular study was taken into account? Dr. Epwarns. No. Mr. Fine? Mr. Founrarn. I realize this was before you came to FDA. Mr. Fine. I was not in Washington at the time, so I can’t answer. I think Mr. Goodrich is in the best position. Mr. Gooprtcx. All I can say on it, Mr. Chairman, is that I was a participant in drawing up the GRAS list. I was a participant in re- viewing the comments that came in. I do know they were reviewed by the Division of Pharmacology, headed by Dr. Lehman, and Dr. Fitzhugh was his expert in toxicology on this particular operation. ''7 Now, I cannot say that he went back and personally read that paper. I do know that he was thoroughly familiar with what had been done by that Division of Pharmacology in a research way, and I feel con- - fident that that paper was taken into account. Mr. Fountarn. I am referring to the report—I think we are talk- ing about the same report—that was placed in the record earlier, in connection with the Richardson allegation, which appeared in the - Journal of the American Pharmaceutical Association in November 1951. Mr. Goopricu. Yes. Mr. Founratn. After the cyclamates were placed on the GRAS list, an increasing number of products appeared on the market with cycla- mates in them, as I understand it. i Was it the policy of the Food and Drug Administration in 1959, to limit the use of artificial sweeteners, including cyclamates, to prod- ucts which were to be used as special dietary foods? Dr. Epwarps. Again, Mr. Chairman, I would like to turn these ques- tions over to Mr. Goodrich. Mr. Goopricu. Yes, Mr. Chairman. The original use of cyclamates came in products that were strictly dietary. Along in the late fifties or the early sixties—I forget exactly when—the diet beverage craze struck the American people, and the artificially sweetened beverages soon accounted for about half of the total beverage business. This was a part of America’s desire to be a little trimmer and a little better looking. So the sale of these products did increase tremendously. And the cyclamate-sweetened articles changed from what had been originally ~ a food for diabetics and for people who must restrict their diet in car- bohydrates, to a general purpose food, used by people to cut off a few pounds by reducing a few calories. Now, the effectiveness of those measures I’m sure we will be going into in more detail as we move along. But to directly answer your ques- tion, we do have a regulation for the labeling of foods for special dietary uses—it has been in effect since 1941—which requires that these artificially sweetened products be labeled, “For use by persons who must restrict their diet in carbohydrates.” That policy was up for change in the revision of the dietary food regulations which were announced in 1966, and which have just com- — pleted a 2-year hearing, to change the labeling statement a little bit to recognize the use of these products by the general population for calorie reduction. Mr. Founratn. Was it also the policy of FDA to oppose the use of artificial sweeteners as a substitute for sugar in general purpose foods? That is, in 1959. Mr. Goopricn. In general, yes. The agency for a long time took the view that the substitution of an artificial sweetener for sugar in a gen- eral purpose food was substituting a different article. Now, our experi- ence in the courts are carrying out the provisions on adulteration in this particular area—that is, substituting one article for another, or making a product appear better or of greater value than it was, I am sorry to say, has been one of our failure points. We lost a case in the court of appeals in the third circuit and the Supreme Court denied certiorari, involving the substitution of cheaper products for another. This case ''8 involved an orange drink in which color and pulp, things of that kind, had been substituted, we thought, for orange juice, and the court held you couldn’t really apply that provision of law except where you had a comparison article. Now, in order to prove an article is adulterated, we were required to prove that the mablic would expect it to contain sugar and would be deceived by its containing cyclamates. The facts were the cyclamates were boldly labeled as means of reduc- ing calories, and so no one really was deceived by this kind of a substi- tution, It was taken—instead of a cheapening—as an advantage in the food. This is what led to the great increase in the use of cyclamates. Mr. Founrary. Mr. Goldhammer? Mr. Gotpuamner. Mr. Goodrich, if standards had been promulgated for the food in question that went up to the court of appeals, would you have had any problem in excluding the artificial sweenteners from such products? Mr. Goopricu. As of 1959, probably not. Later the artificially sweet- ened drinks did obtain a place in the market. There was a general con- sumers’ desire for them. They gained acceptance on an unprecedented scale by weight-conscious Americans. So, later we would probably have had to provide a standard for an artificially sweetened orange juice drink. We have been in the process of trying to establish standards for that class of product for some time and there are difficulties in distinguishing between 100-percent orange juice, orange juice drink, an orange drink, and orange soda pop that has no orange in it. These are the economic issues involved in the hear- ings that take so long to resolve. But you know as well as anyone, hav- ing been in cases of this kind, what the difficulties were of proof of this ‘kind of adulteration, absence a standard. Mr. Founrarn. During the period of burgeoning sales of cyclamate- containing food in the years 1962 to 1969, probably due to heavy pro- motional advertising campaigns on television and in publications, is it true that cyclamate-containing foods were being consumed in in- creasing quantities by all segments of the population ? Dr. Epwarps. That is correct. Mr. Founratn. Could the Food and Drug Administration have taken steps to control the sale and intended use of such products by limiting the products strictly to dietary use? Mr. Goopricn. I don’t think so; no, sir. The desire of Americans to cut these calories down made those products acceptable and under- standably, and desired by the American people as long as they were safe. Now, when an issue of safety, doubt of safety, was raised by the October events, I believe Americans generally accepted the idea that they would rather have safety than saving a few calories. Mr. Founrarn. Didn’t the Food and Drug Administration during these years make any attempt to assure the proper representation and sale and use of these products? Mr. Goopricu. Yes; by requiring they be labeled as artificially sweetened, that they be labeled as containing cyclamates, that they be differentiated by name from the other drinks or other foods. A num- _ber of standards were adopted, Mr. Chairman, for artificially sweet- -ened products. ''9 Mr. Rosenruar. Mr. Goodrich, what were the October events? Mr. Goopricu. This was when Secretary Finch announced the find- ings that cyclamates had been shown to produce cancer and therefore they were being withdrawn from general use in foods. : Mr. GorpnamMer. Mr. Goodrich, these beverages which contained artificial sweeteners, limited for dietary purposes, were used in the’ general household ? ee Mr. Goopricu. Yes; both for the diabetic and the weight conscious. They were really no longer strictly diabetic foods. This is the change that occurred from the first introduction of cyclamates into drinks, into their use in Diet Rite Cola and the other things that were so pop- ular—Tab, et cetera—with the household. Mr. GorpHamner. Mr. Goodrich, you aren’t taking the position that these carbonated beverages with artificial sweeteners were being con- sumed solely by persons who had to limit their caloric intake, are you? Mr. Goopricu. Not at all. Just the contrary, I am saying the reason they obtained such great use—and I said to you about half of the total bottle drink business was in this—was for people like myself who are not willing to diet, but would like to lose a few pounds. Mr. GotpHammnen. I recall seeing some of the television promotional programs for some of these drinks which showed adolescents and children drinking them with considerable pleasure. Would you call such use by normal, healthy, active children in keeping with the restricted use for special dietary purposes? Mr. Goopricu. I wouldn’t call it a dietetic drink under any such cir- cumstances. But I would think a product represented as a means of | reducing calories in any kind of a diet is a food for special dietary use and this is a part of the regulatory scheme we have. Mr. GotpHamer. Does the product become misbranded by reason of the fact that its use, at least in part, is not for special dietetic pur- poses, as, for instance, children drinking it or young adolescents. Mr. Goopricu. I know of no provision of that kind that would make a product misbranded simply because it was shown being taken by young children. If the product was limited to sale for diabetics, let us say, as the original purpose of this product was, and then it was offered for general use with that kind of labeling, of course it would be misbranded. But, the point I tried to make was that after the original introduction of the artificially sweetened drinks as dietetic products, they changed in character to general purpose foods for the purpose of reducing calo- ries and they were labeled this way, promoted this way and there was nothing illegal about them from the misbranding standpoint after that change. Mr. GotpHammer. But if the promotion represented that this had general food purpose use, for instance, showing children drinking it, would that act of promotion result in the article being misbranded by reason of the fact that it is represented on its label as being a special: dietary food and it isn’t? Mr. Goopricu. No, I don’t think so. The special dietary food regula- tions are concerned with some general purpose foods that have a special dietary use, which is this, artificially sweetened. I wouldn’t want the idea left that a special dietary food has to be something that is essentially a drug. It is something different. ''10 Mr. Founratn. Doctor, and Mr. Goodrich also, the Food, Drug, and Cosmetic Act defines a food additive as meaning any substance the in- ‘tended use of which results in or may be reasonably expected to result directly or indirectly in its becoming a component or otherwise affect- ing the characteristics of any food, if such substance is not generally recognized among experts qualified by scientific training and experi- ence to evaluate its safety as having been adequately shown to be safe. Now with particular attention to the words in that definition “generally recognized as safe,” what is your understanding, Doctor, of the mean- ing and the application of that term in the enforcement of the Food, Drug, and Cosmetic Act? Mr. Goopricu. May I address myself to that? We are still involved, ‘Mr. Chairman, in a good deal of litigation over the exact meaning of that term, both from the standpoint of the new drug law and food additives. But the cases we have so far—and I think they are mostly good, because we won most of them—are that where there is a genuine difference of opinion among responsible experts, the product cannot be generally recognized as safe. A product can only be generally recognized as safe, say some of the courts, if there is in the open literature a source of data to which ex- perts could turn to determine whether or not the product had been tested adequately and shown to be safe. Now the cyclamates are under another provision of that definition that you ‘end which is also relevant to a degree, that additives in use prior to January 1, 1958, had to be generally recognized as safe, either on the basis of scientific data or common use in food, I would put Serene myself as being one of those that required data to support the GRAS idea. But the products with cyclamates were considered repeatedly by the NAS-NRC advisory panels and by ourselves from the standpoint of data to support their use. Mr. Fountatn. In your opinion is “generally” to be construed or should it be construed to mean unanimously and universally ? Mr. Goopricu. No. I have written an article on this that I am sure your staff is familiar with. The answer is that to be generally recog- nized as safe would not require unanimous opinion but a product would be generally recognized as safe unless there were some very significant or substantial opinion to the contrary. Mr. Founrarn. I am not saying I disagree with you, but am simply asking these questions to find out what you do think. If “general” is not to be construed as universally or unanimously, what are the criteria which apply in making the finding that a chemical is generally recog- nized as safe or not generally recognized as safe? Mr. Goopricu. The criteria I would apply from a legal standpoint is that if there were a responsible scientific opinion contrary to the belief in safety that that could not be generally recognized as safe, even though the vast majority may believe the product safe. If there was a responsible dissenting opinion, then I would think the product is not generally recognized as safe. This is the kind of thing that was involved in some of our litigation, in which the substance was believed by most people to be generally recognized as safe, and then some new development comes along, or some new scientific paper appears, which raises a substantial doubt, then the product could no longer be generally recognized as safe. ''11 In connection with the cyclamates, these events from time to time — came up in publications and the issues were reexamined each time to determine whether or not there had been a substantial issue of doubt raised. Mr. Fountain. Section 201 (s) of the Federal Food, Drug, and Cosmetic Act also refers to experts qualified by scientific training and experience to evaluate the safety of food additives. Would you regard your scientists in the Bureau of Foods, Pesticides, and Product Safety who review and evaluate petitions for food additive regulations as experts within the meaning of 201 (s) ? Before you answer I would like to read into the record part of this regulation 121.3. Under the food additive section of the law it states “the training and experience necessary to qualify experts to evaluate the safety of food additives for the purposes of section 201 (s) of the act are sufficient training and experience in virology, medicine, phar- macology, physiology, toxicology, veterinary medicine or other appro- priate science to recognize and evaluate the behavior and effects of chemical substances in the diet of man and animals.” Let me repeat my question, Dr. Edwards: In the light of this defini- tion in the regulations, do your scientific employees in the Bureau of Foods, Pesticides, and Product Safety, qualify as experts within the meaning of 201 (s) ? Dr. Epwarps. Mr. Chairman, I think so. Obviously we have varying degrees of competency within the agency. But as a general answer I would have tomake a very positive yes. Mr. Founvarn. And within that definition ? Dr. Epwarps. Yes. - Mr. Fountatn. Doctor, at least for new drugs, I believe the courts haye consistently held—you can correct me if I am wrong, Mr. Good- rich—that a drug is not generally recognized as safe if there is genuine difference of opinion among the experts qualified by experience and training to evaluate the drug’ssafety. Would you say that the same criteria is to be applied for food — additives? Mr. Goopricu. Yes. . : Mr. Fountain. How much ofa difference of opinion do you have to - have before FDA decides that there is a genuine difference of opinion | among its experts as to a food additive’s safety in order to say the additive is not generally recognized as safe ? Mr. Goopricu. Well, in the broadest terms in the way you are expressing the question, this is one of our major problems now in deal- ing with the GRAS list as Mr. Grant said yesterday. We are in the process of an overall review of the so-called GRAS list and we are seeking both to establish protocols for evaluation and the assistance of the NAS-NRC in coming to grips with some of these issues, But to be more specific, the kind of difference of opinion, which. in my judgment, raises the issue is a documented scientific report that is evaluated as having such significance to the scientific evaluators as to create a reasonable doubt about the judgment on safety. Dr. Epwarps. Mr. Chairman, could [ also refer your question to Dr. Wodicka, who is Director of our Bureau of Foods and Nutrition, who has a direct involvement in this? Mr. Fountatn. Yes. ''12 Dr. Wopicxa. Mr. Chairman, it would be difficult or perhaps impos- sible in the present state of our knowledge to give any kind of quanti- tative criterion on the extent of difference of opinion that must exist to raise doubts of safety. I think I would make the point in this way, that any scientific evaluation involves two steps. First, the observation of the facts, and the second, the inference from a highly controlled situation to some more general situation that is of true interest, because the controlled situation is only representative. And there is frequently a wide difference of opinion on the extent to which the test situation is truly representative of the situation that is of interest. And here is where the difference of opinion often comes in. In other words, are the data presented in a particular study relevant to the question that is really at issue. And at some point in time anyone with regulatory responsibility is going to have to stand up and be counted on a matter of scientific and personal judgment because there is seldom unanimous agreement on any of these inferential situations. Mr. Fountain. You would regard your own scientists and medical officers such as Dr. Fitzhugh, Dr. Frawley, Dr. Jennings of your agency as experts within the meaning of this act? Dr. Epwarps. Yes, sir. Mr. Fountatn. Now if the experts on your own staff had a genuine difference of opinion among themselves as to the safety of a chemical to be added to food, would you conclude that the chemical substance was generally recognized as safe ? Mr. Goopricu. On the basis of just the internal opinions about safety, that is one thing and the general recognition of safety is another. But if those scientific people come to the decisionmakers with a scientific memorandum recommending that in their judgment, having reviewed all that was known about this substance, that there was a sub- ‘stantial difference of opinion about it, the decisionmakers would accept that, I think. Now it may be that they would refer it to NAS-NRC, which was done here. It may be that this was an issue that was under study by the expert group of the World Health Organization in which we were participating. And all of those factors might be relevant to accepting the opinion at a particular point in time. But as a direct answer, yes, we would accept their judgment on how to proceed. Dr. Epwarps. Dr. Wodicka, would you like to add to that? Dr. Woprcka. Only that in at least a part of the disagreement that was relevant here, this question of inference that I mentiondd earlier is uite pertinent in that some of the evidence that raised questions about the safety of cyclamates was obtained on the basis of test procedures which had not been established, generally accepted. ge pier words, the only thing they could do was raise suspicion, not proof. Dr. Epwarps. I think in recent months we have certainly tended, in all cases where there is any reasonable difference of opinion between the scientific talents within our Agency, to either bring in expert groups to help us in our decision, refer the problem to the National Academy, or thing like that. I think over the years this is the course we have to pursue. Mr. Founrarn. In other words, if you had a difference of opinion among your experts within the Agency, inasmuch as your are a regu- ''13 latory agency and have to make decisions, you would want some cor- robative expressions from at least other qualified experts from outside of the Agency ? Dr. Epwarps. Yes, sir. Mr. Founrarn. Dr. Edwards, there are many documents in the files of FDA which suggest that cyclamates had been shown to have tox- icity in various ways to test animals, and often these data were not persuasive to certain food and drug scientists who contended that the results of the animal studies could not be transferred to human beings. And for this reason, no action against cyclamates was taken. Will you tell us whether or not it is your belief that once a sub- stance is placed on the GRAS list it may not be removed from the list until it is found to be harmful to human beings ? Dr. Epwarps. Well, Mr. Chairman, we at Food and Drug Admin- istration in 1970 have a responsibility to maintain a constant review of the GRAS list, regardless of whether a substance is considered safe, or obviously if it is harmful, to be removed. One of our major goals is an attempt to carry out an ongoing re- view of the GRAS list, so if there is any reasonable doubt as to the safety of a particular additive, it can be appropriately handled. Mr. Fountarn. Are you saying that it wouldn’t have to be found to be harmful before it could be removed ? Dr. Epwarps. There would certainly have to be some reasonable doubt or some question as to its safety before we would remove it from the GRAS list. I think a case in point, or the case I could bring up, would be saccharin. There are those who have questioned it. As you know, we have pulled together all of the information that is available. We do not believe at this point that saccharin need be removed from the GRAS list, but we have referred it to the NAS— NRC. We have no reason to question its safety at this point, but we have referred it to the Academy for outside consultation, and will act accordingly when we receive their recommendations. Mr. Founrarn. I have saccharin which I now carry around. I don’t know what I will have next. I used to have cyclamates. Mr. Goldhammer ? Mr. GorpHammer. The question that I would like to raise is this: If you have evidence in animal studies of certain toxic effects in the animals, but you have no evidence as to the significance of that with respect to the transferability of those observations to human beings, is it your position that before you can take the product off the GRAS list, you would have to show in some way or other that the same toxic effects are transferable to humans? Dr. Epwarps. No. I think after the Delaney amendment. we have to - move in that general direction. : Mr. GorpHamo™enr. Aside from the Delaney amendment. Dr. Epwarps. I would say in general—on all toxicity matters—we have to move in that direction. Mr. GotpHammer. Don’t you think if you took any view other than that you would be subjecting the population to a sort of laboratory test ? Dr. Epwarps. Absolutely. Until we know more about how to extrap- olate animal findings to man, we have this as our basic philosophy. 48-798—70——2 ''14 Mr. Fountarn. Let me ask you this, Dr. Edwards, as to the purpose of the food and drug additives amendment. What is your opinion as to whether or not it 1s to prevent the use of food additives until they are proven safe for use as intended ? Dr. Epwarps. It is my understanding that was the basic intent of it, yes. eae Mr. Fountatn. Well, suppose there is a serious question among the experts as to the safety of a food additive. Should that additive be permitted to be used while such questions about its safety exist ? Dr. Epwarps. I think if this question is based upon reasonable scien- © tific evidence, then this substance has to be removed from the GRAS list. Mr. Fountarn. At this time I would like to put into the rec- ord a series of memorandums from the files of the Food and Drug Administration : : (1) A memorandum of a meeting dated October 30, 1967, on the _ subject of cyclamates. Present were Dr. Philip Derse, director of lab- _ oratories, Wisconsin Alumni Research Foundation, Madison, Wis.; Dr. Nees, Wisconsin Alumni Research Foundation; Dr. James L. Goddard, Commissioner of Food and Drugs; Mr. J. K. Kirk, Asso- ciate Commissioner for Compliance. I quote the following from the memorandum: They felt the cyclamates should clearly be removed from the GRAS list. Their first proposal was to limit the product to use in truly special dietary areas where nutritive sweetners are contraindicated, but after further discussion of the possible harmful effects they believe have been shown they changed their position to the point where the cyclamates should be ruled out of our food supply completely. (2) A memorandum dated September 8, 1967, from O. G. Fitzhugh, Ph. D., Division of Toxicological Evaluation, SCI, to Mr. L. L. Ram- sey, Assistant Director for Regulatory Program, Bureau of Science, from which I am quoting: We cannot say today that the cyclamates are generally recognized as safe; however, removing them from the GRAS list and establishing ‘tolerances in soft ‘drinks, et cetera, will produce difficult problems. (3) A memorandum of December 4, 1968, from Dr. O. G. Fitzhugh, "Toxicological Adviser, Bureau of Science, to Dr. H. F. Kraybill, Assistant Director for Biological Sciences Research, on the subject of “Report of the National Academy of Sciences—National Research Council on Nonnutritive Sweeteners” from which I quote: The cyclamates should be removed from the GRAS status. They should be considered to be food additives and tolerances could be established to limit the amount according to the usage of the product. ; : (4) A memorandum dated December 5, 1968, from H. F. Kraybill, Ph. D., Assistant Director for Biological Sciences Research, to W. H. Summerson, Ph. D., Director, Bureau of Science, on the subject of “Salient factors for consideration in the evaluation of the safety or nonsafety of nonnutritive sweeteners,” from which I quote: Consequently, it may be appropriate to present, in capsule form, some salient points from this report as guidelines which certainly would recommend that these nonnutritive sweeteners be removed from the GRAS list. Under “General Coriments,” Dz, Kvaybill says, and I quote further : ''15 From the foregoing discussion it is obvious that our prior position regarding tthe safety of nonnutritive sweeteners should be altered. Current recognition of the relevance of subliminal pharmacology as a factor in chronic microinsult | by environmental factors dictates more than a passive attitude concerning these dietary adjuncts, especially the cyclamates which are now under closer serutiny than the saccharins. The NAS-NRS Committee report appears to be a fair coverage of the literature, excluding the recent findings on cytogenetic effects as reported in our laboratories and at Worcester Foundation. It is dis- appointing that the committee did not assume a stronger position in their rec- ommendations. To allow this problem to remain in limbo until the results of long-term research are available, as laudable as those objectives may be, may not be an acceptable solution to the American consumer at this point in time. Memorandum No. 5, from Bert J. Vos, M.D., to A. J. Lehman, M.D., dated December 8, 1968, on the subject of “Artificial Sweeteners, November 1968 Report of NRC Ad Hoe Committee,” from which I quote : ; As a minimum, cyclamates should be taken off the GRAS list and the limit of 70 mg/kg/day proposed by the committee established. (6) A memorandum from Alfred Weissler, Office of the Associate Commissioner for Science, to Mr. Winton B. Rankin, Deputy Com- missioner, dated December 18, 1968, on the subject, “Minutes of Meeting on Cyclamates, December 12, 1968,” from which I also quote : The following conclusions were reached: * * * Cyclamates will be removed from the GRAS list. (7) A memorandum from Leo Friedman, Director of the Division of Pharmacology and Toxicology, to W. B. Rankin, Deputy Commis- sioner of Food and Drugs, dated October 2, 1969, listing American scientists who have reservations about the safety of cyclamates. (8) A memorandum from William W. Goodrich to Mr. Kirk, dated January 4, 1966, which sheds some light on the General Counsel’s views as to the effect of a difference of opinion regarding the safety of cyclamates. I quote from the memorandum: The second paragraph of your letter, to the effect that there is a sharp dif- ference of opinion as to the significance of the Wisconsin Alumni Research Foundation findings, would lead to the conclusion that this product should be classified as a food additive. It could not be generally recognized as safe, if there were indeed a sharp difference of opinion about its safety. I recommend answering the letter with the points made in Dr. Kline’s memo of December 20. (The memorandums follow :) U.S. GOVERNMENT MEMORANDUM, JANUARY 4, 1966 To: Mr. Kirk, FDA/ACO. From: William W. Goodrich, Assistant General Counsel. Subject : Mr. Rowe’s letter of November 29 about cyclamates. The second paragraph of your letter, to the effect that there isa sharp difference of opinion as to the significance of the Wisconsin Alumni Research Foundation © findings, would lead to the conclusion that this product should be classified as a food additive. It could not be generally recognized as safe, if there were indeed a sharp difference of opinion about its safety. I recommend answering the letter with the points made in Dr. Kline’s memo of December 20. We could tell Mr. Rowe that the data submitted are not convincing to show that cyclamates in the current uses exert a positive influence upon metabolism, and thus do not provide a basis for a change in the policy regarding the use of cyclamates we have previously announced. We should add that further studies may be valuable in showing some possible physiological effects of cyclamates, and that such studies are to be encouraged. Finally, we should tell him that the whole problem of a correct labeling for artificial sweeteners will be given consideration in connection with our revision of the 403(j) regulations. ''16 OcToBER 2, 1969. To: Mr. W. B. Rankin, Deputy Commissioner of Food and Drugs (DC-2). From: Leo Friedman, Director, Division of Pharmacology and Toxicology (SC-900). Through: Dr. K. H. Lewis, SC-1. CYCLAMATES In accordance with your request at a meeting yesterday, I am submitting the following information : American scientisis who have reservations about the safety of cyclamates Friedman, Vos, Legator, Ver- rett, and McLaughlin________ FDA. Me austell ot ecg eg Boston. Pep pcCnubenben Fs ee Pittsburgh. ee lett esti SS a Be, Wisconsin Alumni Res. Found. INS r ek rai s Do. nt Che yest te 2 aes Albany Medical College (probably) De eeLOnMN ee y 2 Se Ss Bio-Research, Cambridge, Mass. (probably) ©. Kenslere isso 2 _ A. D. Little, Cambridge, Mass. (probably) George T. Bryan____ University of Wisconsin. Ow ald -DuImer University of Pittsburgh. Bras ee ee SS ee Worcester Foundation. eninge Pra zere 2 oe Published letter to the editor of Pediatrica, August 1969, suggesting a possible relation- ship of limb malformation and cleft palate in two human infants to cyclamate ingestion by mother. In the paper by McLaughlin et al. attached, reference is made on page 765 to the fact that at the time prior to 1963, more than 100 chemicals had been tested by the chick embryo method. The following list is the best recollection that Dr. McLaughlin has of those compounds which show teratogenic effects both in the chick embryo and in at least one mammalian species. There is a long list of com- pounds which did not show much effects in the chick embryo. We plan, as soon as possible, to compile a complete list of all compounds studied in our laboratory by the chick method and the results obtained. This will take some time. TERATOGENIC EFFECTS OBSERVED At least 1 : Chick mammalian Chemical embryo species RTI eS a apa ee oco 5 585 Folpet___- Carbaryl__ Tetracycline_____ Streptomycin_--__- on idomide___-__- Mercury__ Selenium_ Cyclamate Rusidon (d Actinomycin D_ Streptomycin+-penicillin Styrene___ a 4 Acetic acid. -_--_- - ee zs 5 ‘ewes NOe BHA (antioxidant)__ y = Soa BHT (antioxidant)___.-.__.-- er - No. cD NO; Carboxymethyl-cellulose_____ ‘ 4 cat aNOu sacs Np ERIS Se Paap aed eae el a lh Sp MU pe ea ge VS ori ac Noses ce SONGS 1 Not directly tested. ~t ''17 Styrene (monomer) allowed by regulation* up to 50 parts per million from food packaging. Styrene has never had a long-term feeding study or reproduction test. The chick embryo helped provide the basis for not requiring long-term and/or reproduction and/or teratology studies. Foop AND DruG ADMINISTRATION MEMORANDUM, DECEMBER 13, 1968 — To: Mz. Winton B. Rankin, Deputy Commissioner OC-2. From: Alfred Weissler, Office of the Associate 'Commissioner for Science CS—50. Subject : Minutes of meeting on cyclamates, December 12, 1968. : A meeting to consider “review and recommendations of the NAS-NRC Food Protection Committee Report on the nonnutritive sweeteners’ by Dr. J. J. Schrogie (ND-430) and Dr. H. F. Kraybill (SC-4) was held in Mr. Rankin’s office on December 12, 1968. Besides Mr. Rankin, those present were Drs. W. H. Sum- merson, K. Lewis, and H. F. Kraybill of the Bureau of Science; Drs. J. J. Schrogie and J. J. Jennings of the Bureau of Medicine; Mr. P. A. Schuette, Dep- uty ACEI; and Dr. A. Weissler, Office of ACS. The following conclusions were reached, numbered to correspond with Recom- mendations 1 through 6 in the Schrogie-Kraybill document : ‘ 1. FDA will undertake a public education program ‘to inform consumers that unrestricted use of cyclamates is not warranted. Mr. Schuette will work up a draft of the proposed program. 2. Cyclamates will be removed from the GRAS list, taking into account certain procedural complications pointed ou by Dr. Summerson. The Bureau of Science will, after further study, recommend the type of restriction which should be imposed (somewhere in between complete banning and simple labeling of cyclamate content in foods) in order to limit daily ingestion to 4 or 5 grams per person. 3. The question of strengthening the proposed new labeling of cyclamate- containing foods will be considered by Mr. Kirk's office, ‘with consultations with the food standards group. 4. Specifications for an exact limit on the cyclohexylamine content in food- grade cyclamate, and the absence of dicyclohexylamine as shown by analysis with a method of specified sensitivity, will be proposed in a statement to be prepared by the Bureau of Science. ; 5. With regard to ‘the cyclamate-containing oral drug preparations (mainly antibiotics) in which the cyclamate may interfere with the absorp- tion and therapeutic efficacy of the drug, as well as provide a substantial contribution to the daily ingestion level of the cyclamates, the Bureau of Medicine will prepare a statement on exactly what additional information on safety and efficacy is needed and how it is to be obtained. 6. Ten areas in which further research is needed 'were identified in the Schrogie-Kraybill briefing report. A priority listing and timetable will be prepared jointly by the Bureau of Medicine and the Bureau of Science for ‘these ten areas, with assignment of ‘the responsibility to either FDA or industry in each case. One important area which should be pursued imme- diately is further studies of human converters of cyclamates into cyclohex- ylamine, who have been identified previously under the Albany Medical Col- lege Contract with Dr. Coulston; Dr. Kraybill will take care of this. Mr. Rankin expects to have another meeting on the same subject early next week, which will provide Dr. Ley with a picture of the situation at that time. Foop AND Drug ADMINISTRATION MEMORANDUM, DECEMBER 8, 1968 To: A. J. Lehman, M.D., SC-900. From: Bert J. Vos, M.D., SC-901. Subject: Artificial sweeteners, November 1968 report of NRC ad hoe committee. I agree with the conclusion (p. 8) that “unrestricted use of the cyclamates is not warranted at this time.” On the other hand, there is no clear indication. of how the committee arrived at a safe level of 70 milligram/kilogram or less per day (p. 9), other than that it is a refinement of the 5 grams or less per day of 1 FAP 602; FAP 662. ''18 the earlier Food Protection Committee report. On page 87 it is concluded that the “breakpoint” for a significant reduction in weight gain in animals is prob- ably somewhat above 1.0 gram/kilogram of body weight per day for extended periods. Other effects were inconstant and appeared only at higher doses. Since: control of weight is the principal reason for the use of cyclamates, it is possible that the committee did not attach much importance to this finding. Otherwise the 14-fold factor between the “breakpoint” in animals and the safe level pro- posed in man is on the skimpy side. , The picture is further complicated by the cyclohexylamine problem. Aithough the conversion of cyclamate to cyclohexylamine is generally well below 10 per- cent of the ingested dose in most humans, in some cases it may run as high as. 30 or 40 percent (p. 65). No experimental animals have been reported to achieve conversion of this magnitude. Accordingly a toxicological evaluation of cyclo- hexylamine itself will be necessary for the evaluation of the safety of cycla- mates. Long term studies are in progress (pp. 74-76) but the top dose is only 15 milligram/kilogram in both rats and dogs. Even if this comes out essentially negative (so far the only reported effect is a slight weight depression in the male rats), it does not provide much basis for confidence for the man who con- verts 40 percent of the proposed 70 milligram of cyclamate per kilogram body weight per day to cyclohexylamine. (40 percent of 70 milligram = 28 milligram). Direct experiments on man give some reassurance, but apparently have not continued long enough in enough subjects, particularly in “high converters,’” to give any final answers. As a minimum, cyclamates should be taken off the “GRAS” list and the limit of 70 milligram/kilogram/day proposed by the committee established. If the 40 percent converter stands up after careful scrutiny by DFCT chemists, an even lower figure will be possible only after a meticulous review of the original re- _ ports. This I have not done. Foop AND Drua ADMINISTRATION, PUBLIC HEALTH SERVICE, MEMORANDUM, DECEMBER 5, 1968 To: W. H. Summerson, Ph. D., Director, Bureau of Science, SC-1. From: H. F. Kraybill, Ph. D., Assistant Director for Biological Sciences Research, SCH. ‘ Subject: Salient factors for consideration in the evaluation of the safety or nonsafety of nonnutritive sweeteners. The recent NAS-NRC report on “Nonnutritive Sweeteners” attempts to make a general evaluation as to the safety of cyclamates and. saccharin which are being consumed in increasing amounts by the American public. The assignment by Commissioner Ley to Dr. Schrogie and the writer to carefully review this report and provide him with a briefing report (comparable to the one in August) does not justify a perfunctory or hurried analysis but rather one in which each section of that report is considered and commented upon as a scientific back- ground to support what future official action FDA may deem advisable to take with reference to nonnutritive sweeteners. A coalescence of viewpoints such as those from Drs. Fitzhugh and Lehman, which have been requested to be sent to us and which will probably be available early next week, will be made. Dr. Schrogie, who has a good grasp of the literature and who is knowledgeable in this field, will probably have his commentaries and views on the report by that time. Presumably another task, the presentation of a so-called “talking paper” requires some urgency in preparation and may not permit the careful analysis of this 101 page report. Consequently, it may be appropriate to present, in cap- sule form, some salient points from this report as guidelines which certainly would recommend that these nonnutritive sweeteners be removed from the GRAS list. Hence this is an interim report only and a more comprehensive, joint report by me and Dr. Schrogie will follow. A, GENERALLY REGARDED AS SAFE (GRAS LIST) Nonnutritive sweeteners have been placed in this category along with other traditional and common food additives (condiments, flavoring materials, etc.) ostensibly in the absence of any toxicological or epidemiological data that would challenge the safety of these dietary components. There is now fragmentary evidence which raises doubts as to the innocuousness of these nonnutritive ''19 sweeteners. It is inappropriate, if not heresy, to an epidemiologist to indicate that cyclamates, for example, are absolutely safe (for consumption) in an unre- stricted sense in the absence of extensive followup studies of a population group at risk for a significant number of years of observation (retrospective and prospective studies). In this connection it is of interest to note in the NAS-NRO report that conclusions made on the general state of health of humans admin- istered cyclamates, based on laboratory or physical examinations, are predicted on relatively short periods of observation (days in some cases and 10 weeks to 18 months in other situations). B. LIMITATIONS ON LEVELS CONSUMED One of the major conclusions (page 8 of the report) is that “totally unre- stricted use of the cyclamates is not warranted at this time.” There is an un- certainty on this point in the committee deliberations based primarily on the uncertainty about the toxicological significance of cyclohexylamine, a metabolic derivative of cyclamate, in some consumers. Further comments will be made relevant to increasing concern for safety of these chemicals in 1968 which did not prevail at time of last report in 1955. A conclusion that 5 grams per day for ingestion of cyclamates by healthy adults is not hazardous was implied because of limited experience with cyclamates. Surprisingly enough that im- pression on the part of the present committee in 1968 has not been altered and no obvious attention is drawn to this fact in the recommendations (p. 10). In contrast to this omission the FAO recommendations and British Ministry of Agriculture, Fisheries, and Food Regulations recommend a provisional accept- able daily intake (ADI) value for sodium and calcium cyclamate of 0 — 50: milligrams/kilograms be adopted (3.5 grams for 70 kilograms man—top limit). For sodium and calcium saccharin a conditional ADI of 5 — 15 milligrams/kilo- grams of body weight for dietetic foods and for other uses 0 — 5 milligrams/ kilograms of body weight be likewise established. In my opinion such a declaration on the part of the FAO and the British Goy- ernment has important implications to public concern for health and safety. Whether it is enforceable from a regulatory standpoint is not the sole point at issue in the fact of current and widespread concern on the part of the public, industry and impending congressional interest and activity. Admittedly, the declaration on cigarette packages as to the nicotine or tar content may not discourage youths or adults from smoking, but at least along with other edu- cational media it draws attention to the health hazard in terms of bronchiogenic: carcinoma and cardiovascular problems. Similarly the restrictive limitation on cyclamates (saccharin is in and of itself self-limiting) has a virtue in terms of recognition of concern by a health agency and has some peripheral benefits in terms of public relations, which a government agency cannot ignore. In like manner the establishment of limits of cyclohexylamine in cyclamates (sodium and calcium) by the British Ministry of Agriculture, Fisheries and Food—Food Additives and Contaminants Committee (Second Report on Cycla- mates, 1967—page 8) recommends that the cyclohexylamine content of cycla- mates should not exceed 100 ppm. This recommendation was arrived at on the basis of recent findings that indicated that five out of 40 persons ingesting’ cyclamates for 2 to 3 days excreted on average about 0.8 percent of the dose as cyclohexylamine, while after administration for 17 days the percentage of ingested cyclamates converted to cyclohexylamine rose in one person to 7.5 per- cent. Concern was also indicated on the basis of recent studies by an Austriam Physiological Institute on toxicity of cyclamates administered to guinea pigs. In further support of this position the National Formulary in this eountry in the new edition (appearing in 1969) considers the establishment of a limitation on CHA in sodium and calcium cyclamate at 50 ppm. The NF Committee in their deliberations viewed this limitation as quite attainable in industry on the basis of good manufacturing practices and the ability to remove or reduce impurities in the basic compound cyclamate (see my memo of December 4, 1968). Certainly the level of cyclohexylamine in the starting material (cyclamate) can be regulated and through surveillance the CHA levels in foods and beverages can probably be controlled. The need for controls is based on the mounting evidence on the toxicity of CHA (two studies on cytogenicity and the pressor response in cats an intravenously administered doses as low as 1 mg./kg.). In addition, according to the NAS-NRC report (p. 85) there is a question from reproduction studies of greater susceptibility to CHA in prenatal and neonatal life. ''20 Whether storage of purified cyclamate and processing of foods and beverages will increase CHA levels in the finished product can be checked by continuous surveillance programs and remedial measures taken to reduce or eliminate the CHA which might occur. C. SOME ABERRANT RESPONSES WHICH MAY CHALLENGE ASSESSMENT OF SAFETY OF NONNUTRITIVE SWEETENERS 1. Bowel function and stool softening This is the most common observation reported in man and experimental ani- mals. Cyclamate and sulfate increases gastrointestinal motility, liquidity of the stool and the bulk of fluid in the gastrointestinal lumen. The effect is apparently due to the activity of the unabsorbed portion of the salt. It has been postulated and observed in some instances that diarrhea and stool softening is readily attained and a significant deviation from normal was observed when human test subjects received 5 grams/day of cyclamate. In a Pillsbury Co. sponsored National Family Opinion, Inc, survey of 1966 concerned with normal consumption by chil- dren of cyclamate “sweetened” foods and beverages there was a higher inci- dence of diarrhea among the 1- to 3-year-old group. No conclusions or speculations are made in any of the reported material relevant to the potential adverse effect of diarrhea or adaptation of the individual to this effect after chronic insult from cyclamates. At high doses of sodium cyclamate given to monkeys there was an occasional rectal prolapse. 2. Liwer pathology Although challenged by some investigators as to relevance of cyclamate admin- istration on liver changes reported in the guinea pig, mouse, and monkey, more recent studies by the Austrians suggest that the effect on this target organ may be of some consequence. Administration of 2 percent cyclamate doses to guinea pigs evoked a positive sign of liver damage and at lower doses (.5 percent cyclamate) histological changes associated with changes in blood levels of SGP—transaminase and lactic dehydrogenase suggest serious consideration be given toward potential liver damage and eventual liver disease in man, especially under conditions of continuous ingestion. It is of interest that although plasma retains 46 percent of cyclamate bound to plasma protein and 54 percent in plasma water, at equilibrium liver was the only tissue with a concentration higher (1.6 times) than plasma (NAS-NRGC rep. p. 60). This would be a profitable area for epidemiological studies. - 3. Drug interaction The NAS-NRG report discusses this aspect of the problem but not as critically as our briefing report of August 1968 (pp. 30-31). As previously indicated, the effect of cyclamate on binding of drug to plasma protein is likely to increase the therapeutic effect of this class of drugs, however, in the susceptible individual it also might enhance toxic reactions by making more free drug available. Potentiation of effects on blood pressure has been observed in combination of CHA with monoamine oxidase inhibitors. Since different individuals have vari- able amounts of CHA released by biotransformation there is the possibility of adverse effects under specific conditions. Cyclamates may interfere with vitamin K absorption, direct antagonism to the effects of vitamin K, or a change in plasma protein binding. In any event, regular use of cyclamates might make control of anticoagulation unstable in humans. 4. Cyclohexylamine excretion The NAS-NRC Committee draws attention at several points in the report to the potential hazard of CHA. They have indicated that it “should be necessary to evaluate the safety of this material in the same way as would be done for any new food chemical.” The fact that there is a variation in conversion of cyclamates to cyclohexylamine among some species of experimental animals and man, especially information on ability of infants and children to effect conversion, raises some doubts whether there are components of the population at higher risk because of continuous and excessive insult from CHA. Further- more the fact that CHA can occur as an impurity in cyclamates, can be found through storage or processing, or appears in the body through biotransformation, suggests that the continuous and unrestricted use of cyclamates on the basis of CHA appearance alone would not offer strong support for the safety and uncontrolled use of this food additive in our dietary. Reproduction studies in animals suggest the greater susceptibility to eyclo- hexylamine in prenatal and neonatal life. If these findings hold for man and ''21 realizing that there is a localization of cyclamate in the placenta and fetus, this poses a problem as to the advisability of unrestricted use of cyclamates during pregnancy. D. GENERAL COMMENTS From the foregoing discussion it is obvious that our prior position regarding the safety of nonnutritive sweeteners should be altered. Current recognition of the relevance of subliminal pharmacology as a factor in chronic microinsult by en- vironmental factors dictates more than a passive attitude concerning these dietary adjuncts, especially the cyclamates which are now under closer scrutiny than the saccharins. The NAS-NRC Committee report appears to be a fair cov- erage of the literature, excluding the recent findings on cytogenetic effects as reported in our laboratories and at Worcester Foundation. It is disappointing that the committee did not assume a stronger position in their recommendations. To allow this problem to remain in limbo until the results of long term research are available, as laudable as those objectives may be, may not be an acceptable solution to the American consumer at this point in time. DECEMBER 4, 1968 Dr. H. F. Kraybill, Assistant Director for Biological Science Research, Bureau of Science (SC-4). Dr. O. G. Fitzhugh, Toxicological Adviser, Bureau of Science (SC-3). Report of the National Academy of Sciences, National Research Council on Nonnutritive Sweeteners. ‘The safety data at hand support the conclusion of the Ad Hoe Committee on Nonnutritive Sweeteners that 70 mg/kg or less per day of cyclamates and 15 mg/kg per day of saccharin are safe for the adult. Although, the acceptable daily intake of 70 mg/kg per day of cyclamates for the adult is slightly more than the 50 mg/kg/day figure of the United Kingdom and the World Health, my review of the data confirms the conclusion of the ad hoc committee that 5 grams per day for the adult presents no hazard. Our problems at the present time concerns the ever increasing consumption of nonnutritive sweeteners, particularly cyclamates, and the cyclohexylamine. The latter substance occurs as a contaminant of the cyclamates and as a biotransformation product from the cyclamates. Accepting the conclusion of the ad hoe committee that 70 mg/kg/day or less of cyclamates are safe and that the safe amount of 15 mg/kg of saccharin per day will not be exceeded my recommendations would be as follows: 1. The cyclamates should be removed from the GRAS status. They should be considered to be food additives and tolerances could be established to limit the amount according to the usage of the product. 2. Labeling of cyclamates-containing products should contain a statement to the effect that maximum daily intake should not exceed 70 mg/kg/day because of possible diarrhea. A suggestion as to how this might be done is: (a) State total weight of cyclamate in the item ; (b) State total weight of cyclamate ina serving ;and (c) Include a table of acceptable total intake in relation to ages in years or weights in pounds. Such an approach would allow consumers te add intake from all sources and assure themselves that the total will not exceed the value suggested on the table. 3. The amount of cyclohexylamine in food grade cyclamate should be limited to the lowest possible figure according to gocd manufacturing practice. From my discussion with Mr. Ericson of the Abbott Laboratories, I believe this could be below 50 ppm; however, if a lower figure does not meet the requirement of good manufacturing procedure, I would want te limit it to 50 ppm of cyclohexyla- mine. The Food Chemicals Codex should add a specification for cyclohexylamine to their present specifications on the cyclamates. 4. Further studies should be continued on cyclohexylamine, both those recom- mended by the ad hoe committee and those in progress in FDA, to elucidate fur- ther the safety of this substance. 5. Altho the studies on cyclohexylamine are the more important, all the studies recommended by the ad hoc committee have some importance and should be continued or recommended. 6. Both the ad hoe committee and FDA should review the safety of cyclamates again as soon as sufficient data are available on cyclohexylamine or other metabolites of cyclamate. ''22. SEPTEMBER 8, 1967 Mr. L. L. Ramsey, Assistant Director for Regulatory Program, Bureau of Science. O. G. Fitzhugh, Ph. D. Division of Toxicological Evaluation, SCI. Cyclamates. I have gone through the mass of information included in this package. It is a good compilation of the published data. There is nothing new in it and it lacks some unpublished data from the Abbott Laboratories. I recently reviewed these data and all other available data for the Joint WHO/FAO Expert Committee on Food Additives. The Expert Committee arrived at the conclusion in Geneva that there was no apparent hazard from an amount of 50 mg/kg ef body weight per day (3 grams). This amount follows the British regulations and was agreed upon to be a con- ditional acceptable daily intake until further information was obtained, espe- cially on cyclohexylamine. From all present information, we have no data to indicate a hazard from the five grams per day which we previously said were safe. We cannot say today that the cyclamates are generally recognized as safe; however, removing them from the GRAS list and establishing tolerances in soft drinks, et cetera, will produce difficult problems. Therefore, we ask ourselves what are the scientific reasons for concern. The following have arisen since our statement that 5 grams per day were safe. 1. The continued increase in the consumption of cyclamates.—Individuals, ‘especially children, may consume more than 5 grams per day. We do not know that this amount is safe or unsafe. It does produce a laxative effect which has not been explained satisfactorily. The laxative effect could be a self-limiting factor. 2. The teratogenic studies in mice by Japanese workers and the rat studies at the Wisconsin Alumni Research Foundation.—Both of these were discussed in detail in Dr. Kraybill’s Memorandum to Dr. Summerson. Neither of these has added substantial information to an evaluation of safety. : 3. The subcellular alterations in monkeys and other observations of the Couls- ton Group at Albany. These have been reports of uncompleted studies and may ‘or may not prove to be alarming. 4. The discovery that cycloherylamine is a metabolite of cyclamate in some men and in some animals. Since cyclohexylamine is a metabolite of cyclamate in rats and dogs, we do have some information on the safety of this substance from the feeding of cyclamate to these animals. Certainly much more information is needed ‘on the safety of cyclohexylamine. There is no indication that this substance is a carcinogen, and several biochemists told me that they did not believe that di- ‘eyclohexylamine could be formed in vivo. CONCLUSIONS Toxicology data to date indicates that 5 grams per day is safe for humans. Before we can say that larger amounts are safe, more information is needed on the mechanism of action of the laxative effect. Also for complete evaluation of | the cyclamates, we need additional information on the safety of cyclohexylamine, the teratogenic potential of the cyclamates, evaluation of changes observed in primates treated with cyclamates and further observations in humans. RECOMMENDATION On the basis that the present toxicity data do not indicates that five grams per day is unsafe, I would delay a change in our GRAS regulation for cyclamates until the Coulston Study has progressed further and/or more information is developed elsewhere. MEMORANDUM OF MEETING, OCTOBER 30, 1967 Present: Dr. Philip H. Derse, Director of Laboratories, Wisconsin Alumni . Research Foundation, Madison, Wis.; Dr. Nees, Wisconsin Alumni Research Foundation; James L. Goddard, M.D., Commissioner of Food and Drugs; and J. K. Kirk, Associate Commissioner for Compliance. ''23 The visitors called to discuss artificial sweeteners. They pointed out that they have been doing a great deal of work for the Sugar Research Foundation, and normally their results are reported directly to their clients without any pub- licity. They stated, however, that they felt they had now in their own labora- tories and had seen sufficient other scientific results to lead them to the point where they should speak out in the public interest. They felt the cyclamates should clearly be removed from the GRAS list. ‘ Their first proposal was to limit the product to use in truly special dietary areas where nutritive sweeteners are contraindicated, but after further discus- sion of the possible harmful effects they believe have been shown they changed their position to the point where the cyclamates should be ruled out of our food supply completely. j } The visitors left with the Commission a paper not yet published, “The Effect of Feeding Calcium Cyclamate on the Growth and Reproduction of Swine” and referred to a paper which Arthur D, Little is about to publish on some work done with 25 individuals. They did not have a copy of the paper, however. They referred repeatedly to a cyclohexylamine excretion and its passing of the placental barrier. They expressed the view that when pregnant women ingest cyclamates, their offspring may be born normal, but by the time of weaning they are somewhat stunted in growth and never catch up. They also expressed the view that there is mental disturbance in the child, as evidenced by some of their maze studies with animals. They expressed the view that Dr. Coulston and Dr. Stare are generally in agreement with their view about this product. They left with us a copy of “Perinatal and Infant Mortality in the United States and Six West European countries” referring specifically to the table on page 1741 on neonatal mortality for “all other diseases.” They regard as signifi- cant the upward curve starting about 12 years ago when the cyclamates began to be very popular. They also left us three other papers which are attached. Dr. Goddard expressed the view that much of their conclusion was based on theory and even though the cyclamates may be metabolized, there was no real showing that these cause harm. The visitors agreed, but felt that the questions raised were serious. They mentioned incidentally that their studies show that the excretion of cyclamates decreases materially as the intake increases, going — from 100 percent to about 25 percent. They also mentioned that present day uses of cyclamates can well result in intake of more than 1% of the diet on the dry basis. Dr. Goddard assured the visitors that review of these products is a continuing one with FDA, and while he did not tell them so, contemplates taking the matter up again with the National Academy of Sciences-National Research Council. J. K. Kirk. Mr. Fountarn. Now, in light of the statements I just read, and the documents themselves, which you are probably familiar with in detail, what would you say as to whether or not there is a firm feeling among a body of qualified experts, going back several years, who had definite reservations about the safety of cyclamates and felt that it should not be on the GRAS list but made a food additive? Dr. Epwarps. Mr. Chairman, I am aware of the memorandums that you referred to and read from. And there is no question that from reading or from looking at these memorandums, you would certainly question whether or not a decision on the safety of cyclamates couldn’t have been made more rapidly than it was. However, one thing I have found is that it is far easier to look at a problem in retrospect than it is being on the spot. So I think it would be only fair to ask Mr. Goodrich if he would like to comment on that. Mr. Goopricu. I hope my memorandum that you just read from was consistent with what I have said here, and I believe it was. What happened, Mr. Chairman, was that the sugar foundation supported some research at the Wisconsin Alumni Research Foun- dation. ‘They had an understandable interest in getting cyclamates out ''24 of the soft drinks, because it was a competitive situation with them. As you know from the files, their lawyers bombarded me with memo- randa and scientific arguments of every sort that the product cyclamate could not be generally recognized as safe. In accordance with our procedure, I submitted all of those papers to the scientific people. Now, there were a series of events occurring about the time these memos you read from appeared. First, in 1967 the World Health Organization took up the problem of cyclamates, artificial sweeteners. They concluded that the product — we almost ready for approval, but that a little more work needed to be done. And meanwhile, as I remember the facts, they would limit the daily intake to 50 milligrams per kilo of body weight. That is my recollection of the thing. This was in 1967, and our scientific people participated in it. The doubts about cyclamates were based upon observations of animal feed- ing at high levels of dosage—well above what was involved. e referred the whole problem to NAS-NRC in 1968, and they came back with a report about in November or December. The report was disappointing to us, because they said on one hand that there is no real reason to question the safety of cyclamates, but that the product should not be allowed for general use in foods. What we were focusing on was excessive amounts. They were concerned about a child, for example, taking a half case of soda and in that way reaching a thresh- oe level at which there would be some diarrhea, as the observable effect. The committee that reported in December did certainly, in my view—and I reflected this view—create enough doubt about it to lead to its removal from the GRAS list. We took the steps to do that. But the reason for removing it from the GRAS list was not any serious problem of safety at the levels of ordinary use, but to guard against excessive use. This is what we proposed in, I believe, the April announcement. That had not been acted on when we received the later evidence from Abbott Laboratories that the cyclamates had been shown to be cancer- producers in test animals. When we got the second bit of information, instead of removing it from the GRAS list and placing labeling limitations on it, we removed it from the GRAS list completely. Mr. Fountain. We all know hindsight is better than foresight, but some mistakes of lack of foresight are not always as dangerous in some matters as in others. I would like to ask you, on the basis of these records, would you or would you not say now, in retrospect, that there was more than sufficient basis for FDA taking cyclamates off the GRAS list at least a year or two before the time it was taken off ? Dr. Epwarps. I think without any question the cyclamates could have been removed from the GRAS list earlier than they were. I am not prepared, Mr. Chairman, to say specifically when, but I think it could have been done considerably sooner than it was. Mr. Founrarn. Mr. Goodrich ? Mr. Goopricu. Yes; and what would have occurred, Mr. Chairman, would have been, J think, based on the data as we look at it, even today, a limitation on use rather than phasing it completely out of food. ''ho 5 This is the point I’m trying to make, is that the new development, in October, was one that showed an effect that required its removal from food, not only from the GRAS list. ; Mr. Fountarn. I don’t guess you are in a position to explain the. failure of FDA to take the advice of its own experts to remove cycla- mates from the GRAS list sooner; or are you? Dr. Epwarps. No, I certainly wouldn’t want to attempt to explain this procrastination, or whatever the reason was for their failure to act when they should, or as promptly as they should have. Mr. Fountatn. I would like to ask you, Mr. Goodrich—or any others who were there before Dr. Edwards’ arrival—was there, to your knowledge, any feeling among the decisionmakers, both in the Food and Drug Administration in HEW, that the evidence did not yet show cyclamates could harm humans? Mr. Goopricu. There was the feeling among the top of Food and Drug that the issue had not been one that showed any reason for alarm on cyclamates. As I indicated awhile ago, I did refer all those papers that I received from the sugar industry to the Food and Drug Administration peo- ple, and as you will note from the files, they did examine them and came to the conclusion that the best course of action was to resubmit the matter to the NAS-NRC. The evidence of doubt of safety was weak, the evidence of safety to the contrary was pretty strong, in the view of the decisionmakers at that time. Mr. Fountain. I believe you have already testified that this was not a prerequisite before action against the cyclamates, to remove them from the GRAS list, could be undertaken. 5 Mr. Goopricu. Yes, sir. Mr. Fountain. In light of the wording of section 201(s) of the Food, Drug, and Cosmetic Act, which defines a food additive in terms of being generally recognized as safe, did not FDA have the legal obligation to remove cyclamates from the GRAS list as soon as it was evidenced that a genuine difference of opinion existed among the qualified experts as to the safety of cyclamates? Mr. Goopricu. I thought so and said so in that 1966 memorandum. Mr. Fountar. Do you agree with that, Dr. Edwards? Dr. Epwarps. I would certainly agree with that, yes. Mr. Fountain. I want to place in the record the order dated October 17, 1969, which was published in the Federal Register, volume 34 No. 202, Tuesday, October 21, 1969. (The document referred to follows :) ? [From the Federal Register, Oct. 21, 1969] TITLE 21—Foop anp Drucs—CHaptTer I—Foop anp Drug ADMINISTRATION, DrE- PARTMENT OF HEALTH, EDUCATION, AND WELFARE—SUBCH,APTER B—Foop AND Koop Propucts—Part 121—Foop AppiTIves—SuBpeart B—EXEMPTION OF CER- TAIN Foop ADDITIVES FROM THE REQUIREMENT OF TOLERANCES—CYCLAMIC ACID AND ITs SAtts On the basis of animal studies recently reported to the Food and Drug Adminis- tration by Abbott Laboratories, and the review of the studies and the underlying data by experts in the National Cancer Institute, by an outside consultant, and by an ad hoc Committee of the National Academy of Sciences-National Research Council, Food Protection Committee, the Commissioner concludes that cyclamates can no longer be regarded as generally recognized as safe for use in food. ''26 beh . Accordingly, pursuant to the provisions of the Federal Food, Drug, and Cos- metic Act (sec. 201(s), 72 Stat. 1784, 21 U.S.C. 321(s) ; see. 409, 72 Stat. 1785, 21 U.S.C. 348 and see. 701(a), 52 Stat. 1055, 21 U.S.C. 371(a)) and under au- thority delegated to the Commissioner (21 CFR 2.120), Par. 121 is amended as follows: 1. Section 121.101 Substances that are generally recognized as safe is amended by deleting from paragraph (d) (4) the items “Calcium cyclamate (calcium cy- clohexyl sulfamate),” “Magnesium cyclamate (magnesium cyclohexyl sulfa- mate),” “Potassium cyclamate (potassium cyclohexyl sulfamate), and “Sodium cyclamate (sodium cyclohexyl sulfamate).” Effective date. This order shall become effective on the date of its publication in the FEDERAL REGISTER. (Sec. 201(s), 72 Stat. 1784, 21 U.S.C, 321(s) ; sec. 400. 72 Stat. 1785, 21 U.S.C. 348; sec. 701(a), 52 Stat. 1055, 21 U.S.C. 871 (a) ) Cyclamates and artificially sweetened products intended for use in the dietary management of disease in man, including the management of such diseases as diabetes and obesity, should be relabeled promptly to comply with the drug pro- visions of the law if they are to continue on the market. Drugs containing cycla- mates for nontherapeutic use should be withdrawn by July 1, 1970. The Commissioner finds that existing stocks of artifically sweetened bever- ages and packaged mixes for the preparation of such beverages for general use © should be withdrawn from the market between the date of this order and Jan- uary 1, 1970. The Commissioner further finds that other artifically sweetened foods for general use containing substantially lower levels of cyclamates may be phased out of use by February 1, 1970. Dated : October 17, 1969. HERBERT L. Ley, Jr., Commissioner of Food and Drugs. [F.R. Doc. 69-12628; Filed, Oct. 20, 1969; 9:50 a.m.] Mr. Fountarn. Dr. Edwards, I may have asked this question, but I am not sure. What part did the Commissioner of Food and Drugs and the Secretary of HEW play in making the decision to delist cyclamates from the GRAS list ? Dr. Epwarps. Mr. Chairman, with your permission, I would like to again have Mr. Goodrich answer this question. I was not aboard then. Mr. Gooprrcu. The initial report of the Abbott findings was de- livered, as I remember, to a scientist at the National Cancer Institute, Dr. Saffietti, I believe. He communicated with the Surgeon General early during the week of October 18—October 18 was a Saturday— and the information was brought to Dr. Steinfeld, the Surgeon Gen- eral, early that week. Dr. Ley, then the Commissioner of Food and Drugs, was immediately brought in. He met with the Abbott people in the afternoon, a day or two after that, and Dr. Ley and Dr. Steinfeld, together, set in motion a review procedure of the Abbott data. They made a recommendation to the Secretary and the Secretary acted on the 18th. The details of this are set forth in Dr. Steinfeld’s statement which he made at the October 18 press conference in which he detailed, or stated in some detail what. had happened. Mr. Founrarn. At this time, I would like to put into the record a copy of a statement by HEW Secretary Robert Finch dated Octo- ber 18, 1969, in which he declared : I am today ordering that the artificial sweetener, “cyclamate,” be removed from the list of substances generally recognized as safe for use in foods. Elsewhere in the statement, Secretary Finch states: My order requires the use of cyclamates in the production of general purpose foods and beverages be discontinued forthwith. : it ''27 Still further on in the Secretary’s statement, he declared : I should emphasize also, that my order does not require the total disappearance from the marketplace of soft drinks, foods, and prescription drugs containing cyclamates. These products will continue to be available to persons whose health depends upon them such as those under medical care for such conditions as. diabetes or obesity. I expect that in the future these products will be labeled as. drugs to be consumed on the advice of a physician. The Delaney amendment is mentioned on page 2 of Secretary Finch’s statement. The Delaney amendment provides in part: See. 409(c) (8) (A) * * * That no additive shall be deemed to be safe if it is found to induce cancer when ingested by man or animal, or if it is found, after tests which are appropriate for the evaluation of the safety of food additives, to induce cancer in man or animal * * * (Secretary Finch’s statement follows :) STATEMENT BY HEW Secretary Rosert H. Fincu, Ocroser 18, 1969 I am today ordering that the artificial sweetener, cyclamate, be removed from the list of substances generally recognized as safe for use in foods. Recent experiments conducted on laboratory animals disclosed the presence of malignant bladder tumors after these animals had been subjected to strong dose levels of cyclamates for long periods. The findings of these experiments form the basis for my action. The fact that cyclamates have induced cancer in animals was confirmed by a panel of the National Academy of ‘Sciences, which unanimously reported its findings to me late yesterday. The Academy met in special session at my request to review the results of various research projects involving cyclamates. Before I go any further, let me emphasize in the strongest possible terms that we have no evidence at this point that cyclamates have indeed caused cancer in humans. Thus, my decision to remove cyclamates from the list of approved substances in no sense should be interpreted as a “lifesaving” or emergency measure. I have acted under the provisions of law because it is imperative to follow a prudent course in all matters concerning public health. fi Specifically, the so-called Delaney amendment enacted 11 years ago states that any food additive must be removed from the market if it has been shown to cause cancer when fed to humans or animals. My order requires the use of cyclamate in the production of general purpose foods and beverages be discontinued forthwith. As for general purpose foods and beverages already produced, my action will — permit orderly withdrawal of the products from the marketplace. In the case of beverages which contain a higher level of cyclamates, we are requiring a recall to be completed by January 1, 1970. All other artificially sweetened foods contain a lower level of cyclamates and pose a very minimal risk according to the advice I have from top scientists, both in and out of the Government. These products ~ will be phased out of the market by February 1, 1970. I should emphasize also that my order does not require the total disappearance from the marketplace of soft drinks, foods, and nonprescription drugs containing cyclamates. These products will continue to be available to persons whose health depends upon them, such as those under medical care for such conditions as diabetes or obesity. I expect that in the future these products will be labeled as drugs, to be con sumed on the advice of a physician. ‘ It is my intention beginning today to hold consultations with representatives of the affected industries and consumer groups to determine the most effective methods of offering these products for restricted rather than general consumption and for developing new and safe formulations without cyclamates. : Mr. Fountain. I also want to place in the record a copy of a pro- cedural and interpretative regulation, 130.40, on abbreviated new drug applications for cyclamates, signed on December 23, 1969, by then Acting Commissioner of Food and Drugs, Dr. Edwards, which was published in the Federal Register, volume 34, No. 249, Wednesday, December 31, 1969. ''28 This regulation requires the submission of an abbreviated new drug application for cyclamate sweeteners intended for drug use and labeled to state that the product is “for use only with calorie-controlled diets by diabetics or obese patients under medical supervision.” ” And it also requires a boxed statement, “Caution: Medical super- vision is essential for safe use.” (The document referred to follows :) [From the Federal Register, Dec. 31, 1969] -SuscHarrer C—Druas—Part 130—New Drues—Susparrt A—PROCEDURAL AND INTERPRETATIVE REGULATIONS—ABBREVIATED NEW-DRUG APPLICATIONS FOR CYCLAMATES On October 18, 1969, in announcing the removal of cyclamates from the list of substances generally recognized as safe for use in food, the Secretary of Health, Education, and Welfare noted that these artificial sweeteners would have to comply with the drug provisions of the Federal Food, Drug, and Cosmetic Act if they were to be available for use by diabetics and obese patients under medical supervision. (The order removing the substances from 21 CFR 121.101(d) (4) was published in the FreprraL ReeisteR of October 21, 1969 (34 F.R. 17063).) The Assistant Secretary for Health and Scientific Affairs drew together a Medical Advisory Group on cyclamates to consider the benefit-to-risk ratio for the cyclamates in drug use. The Medical Advisory Group reviewed all available data, including that sub- mitted by the Food and Drug Administration to the ad hoc Committee of the Food Protection Committee, National Academy of Sciences-National Research Council, and: 1. Endorsed the prohibition of cyclamates in beverages for general use and in the future processing of general purpose foods. 2. Expressed the unanimous opinion that under appropriate medical manage- ment of individuals with diabetes (particularly in the case of juvenile diabetes) and of patients in whom weight reduction and control are essential for health, cyclamates provide medical benefits which outweigh their hazards. 3. Recommended that cyclamates continue to be made available for such patients on medical advice and on a nonprescription, drug-labeled basis. : 4. Recommended that the Food and Drug Administration carry out an annual review of data on cyclamates and other nonnutritive sweeteners. : Therefore, the Commissioner of Food and Drugs concludes that the following policy should be adopted regarding abbreviated new-drug applications for cycla- mates. Accordingly, pursuant to provisions of the Federal Food, Drug, and Cosmetic Act (sees. 505, 701(a), 52 Stat. 1052-53, as amended, 1055; 21 U.S.C. 355, 371(a)) and under authority delegated to the Commissioner (21 CFR 2.120), the following statement of policy is added to Part 130, Subpart A: § 130.40 Abbreviated new-drug applications for cyclamates (a) The Food and Drug Administration is prepared to approve abbreviated new-drug applications in the form described in the proposed amendments to § 130.4, published in the FrpreraL Reeister of February 27, 1969 (34 F.R. 2673), for cyclamate-containing artificial sweeteners intended solely for drug use and labeled in accordance with the following: (1) Identity. List active ingredients with the statement “an artificial, non- nutritive sweetener.” (2) Indications. Include the statement “For use only with calorie-controlled diets by diabetics or obese patients under medical supervision.” Also, set forth oxida as in a box the statement “Caution: Medical supervision is essential for safe use.” (3) Dosage. The label shall bear a statement of the amount of cyclamate in a tablet, capsule, pill, or other unit form or specified serving, a statement that Bes Re ae een gt is as sweet as ______ teaspoonful(s) of sugar,” and a statement that the lowest amount to achieve sweetening should be used. (b) Recordkeeping and reporting: Reports of the data described in § 130.13 (b) (1) (ii) and (2) (i) shall be submitted as required by that section. (Sees. 505, 701(a), 52 Stat. 1052-53, as amended, 1055; 21 U.S.C. 355, 371(a)) ''29 Dated : December 23, 1969. ‘ CHARLES C. Epwarps, Acting Commissioner of Food and Drugs. Mr. Fountarn. [am also placing in the record an order dated Febru- ary 4, 1970, signed by Sam D. Fine, Associate Commissioner for Compliance, published in the Federal Register, volume 35, No, 28, Tuesday, February 10, 1970, which declares that : Abbreviated new drug applications for artificial sweeteners containing cycla- mates have been submitted and approved for such sweeteners marketed by sev- eral manufacturers. The order requires a relabeling of all stocks of cyclamate-contain- ing artificial sweeteners for which an abbreviated new drug application has been approved which were then in wholesale or retail channels. (The document referred to follows :) [From the Federal Register, Feb. 10, 1970] TirLe 21—Foop anp Drues—CHaprterR I—Foop AnD DRUG ADMINISTRATION, DE- - PARTMENT OF HEALTH, EDUCATION, AND WELFARE—SUBCHAPTER A—GENERAL— Parr 3—STATEMENTS OF GENERAL POLICY OR INTERPRETATION—DrvUG LABELING FOR CYCLAMATE-CONTAINING ARTIFICIAL SWEETENERS Pursuant to provisions of the Federal Food, Drug, and Cosmetic Act (secs. 201(s), 409, 505, 701(a), 52 Stat. 1052-53, as amended, 1055, 72 Stat. 1784-88, as amended; 21 U.S.C. 321(s), 348, 355, 371(a)}) and under authority delegated to the Commissioner of Food and Drugs (21 CFR 2.120), the following new sec- tion is added to Part 3: : § 3.75 Drug labeling for cyclamate-containing artificial sweeteners (a) In the Freprrat ReersTer of December 31, 1969 (34 F.R. 20426), the Com- misioner of Food and Drugs promulgated § 130.40 Abbreviated new-drug appli- cations for cyclamates (§ 130.40 of this chapter) prescribing conditions under which abbreviated new-drug applications for cyclamate-containing artificial sweeteners would be approved. Such applications have since been submitted and approved for such sweeteners marketed by several manufacturers. (b) Stocks of these products witheut the newly developed drug labeling are regarded by the Food and Drug Administration as misbranded and adulterated foods ; however, they can be brought into compliance with the law by use of stick- on labels offering the products for drug use as described in § 180.40 of this chapter. (ec) Accordingly, products shipped by the holders of new-drug applications shall relabeled or have applied thereto additional labeling sufficient to bring such products into compilance with § 130.40 of this chapter. (d) Holders of the new-drug applications shall furnish, down to the wholesale level, supplies of such additional labels (1) sufficient to bring into compliance all stocks on hand at that level and (2) sufficient for distribution to retail outlets served by such wholesalers to provide for the relabeling of any stocks in retail channels. If they wish, manufacturers may furnish supplies of such labels di- rectly to retail outlets. (e) In transmitting the new labeling materials, holders of the new-drug appli- cations shall notify wholesalers and/or retailers (1) that existing stocks must be relabeled to bring them into compliance with the law and (2) that failure to re- label the products may result in the products being proceeded against in seizure actions under the Federal Food, Drug, and Cosmetic Act. (Secs. 201(s), 409, 505, 701(a), 52 Stat. 1052-53, as amended, 1055, 72 Stat. 1784-88, as amended; 21 U.S.C. 321(s), 848, 855, 371(a) ) Dated: February 4, 1970. Sam D. FIne, Associate Commissioner for Compliance. [F.R. Doc. 70-1619 ; Filed, Feb. 9, 1970; 8:46 a.m.] 48-798—70——_3 ''30 Mr. Founrarn. I am also placing in the record at this time an order dated March 17, 1970, signed by Sam D. Fine, Associate Commissioner for Compliance, and published in the Federal Register, volume 35, No. 57, Tuesday, March 24, 1970, and identified as “Section 130.43. Con- ditions for marketing cyclamate-containing products as drugs.” __ This order requires the filing of an abbreviated new drug applica- tion for cyclamate-containing products and specifying certain labeling statements including, among other things, a declaration of the cycla- mate contents and the statement “An artificial nonnutritive sweet- ener” and the following two statements : For use only by diabetic or obese patients under medical supervision. And immediately thereafter in the box, the statement : Medical supervision is essential for safe use. This order also directs that the abbreviated new drug applications meeting the required conditions should be submitted to the Food and Drug Administration district office in whose jurisdiction the sub- mitting firm is located. (The document referred to follows :) [From the Federal Register, Mar. 24, 1970] TrrLE 21—Foop anp Drues—CHAPTER 1—Foop AND DruG ADMINISTRATION, DE- PARTMENT OF HEALTH, EDUCATION, AND WELFARE—SUBCHAPTER C—Drucgs— Part 130—Nrw Drucs—Suppart A—-PROCEDURAL ,AND INTERPRETATIVE REGULA- TIONS—ABBREVIATED NEWw-DruG APPLICATIONS FOR CYCLAMATE-CONTAINING PrRopucts In an order published in the Federal Register of October 21, 1969 (34 F.R. 17063), deleting cyclamates from the list of substances generally recognized as safe in food (21 CFR 121.101), the Commissioner of Food and Drugs gave notice that cyclamate-sweetened products intended for use in the dietary management of diabetes and obesity should be relabeled promptly to comply with the drug provisions of the law if they are to continue on the market. In an order published December 31, 1969 (34 F.R. 20426), promulgating 21 | CFR 130.40, notice was given that the Medical Advisory Group on Cyclamates established by the Assistant Secretary for Health and Scientific Affairs concurred that cyclamates should be made available under appropriate medical management on a nonprescription, drug-labeled basis to individuals with diabetes and to pa- tients in whom weight reduction and control are essential for health. This advisory group also recommended that the Food and Drug Administration carry out an annual review of data on cyclamates. ‘ Accordingly, the Commissioner concludes that guidelines should be established as set forth below to define the conditions under which such products may be marketed. : Therefore, pursuant to provisions of the Federal Food, Drug, and Cosmetic Act (sees. 505, 701 (a), 52 Stat. 1052-53, as amended, 1055; 21 U.S.C. 355, 371 (a) ) and under authority delegated to the Commissioner (21 CFR 2.120), the follow- ing new section is added to Part 130, Subpart A: § 130.48 Conditions for marketing cyclamate-containing products as drugs (a) Products that are useful in regulating the intake of protein, fats, carbo- hydrates, or calories for the purpose of maintaining or reducing body weight under medical supervision or that are useful in the diet of diabetics may be marketed on the basis of approved abbreviated new-drug applications that are submitted in the form described in the proposed amendments to § 130.4, published in the Federal Register of February 27, 1969 (34 F.R. 2678), and that provide for the following: (1) A label for the product that bears: (i) Immediately following the name of the product, a statement identifying the cyclamate salt present and the statement “An artificial, nonnutritive sweetener.” ''31 (ii) A declaration of the cyclamate content, carbohydrate content, and num- ber of calories in an appropriate unit of measure; for example, a 4-ounce serving or one-half measuring cup, per wafer, per can, per container, ete., by which measure the patient can readily calculate his cyclamate intake. (iii) In a prominent place on the principal display panel, a statement limiting the indications to “For use only by diabetic or obese patients under medical. supervision,’ and immediately thereafter in a box, the statement “Caution: Medical supervision is essential for safe use,” provided that where the label area is too small to accommodate these statements, they may extend beyond the border of the principal display panel. (iv) A statement comparing the calorie content of the artificially sweetened article and the same food made with an amount of added sugar or other carbo- hydrate providing equivalent sweetness. (2) A product so formulated that its caloric value is at least 50 percent less than the caloric value of the comparable product made without artificial sweeteners. (b) Recordkeeping and reporting: Reports of the kinds described in § 130.13 (b) (i) Gi) and (2) (i) shall be submitted as required of the applicant by that section. (ec) Persons desiring to market or continue marketing preparations covered by this section should submit an abbreviated new-drug application meeting the conditions specified in this section to the Food and Drug Administration District Office in whose jurisdiction such firm is located. If this information is not known, write to the Food and Drug Administration, Bureau of Drugs, 5600 Fishers Lane, Rockville, Md. 20852. (d) Distribution of any such preparation on the market may continue: Provided, That an abbreviated new-drug application has been submitted and the labeling of the preparation is in accord with this section by April 1, 1970, for dietetic jams, jellies, desserts, and ice cream, and by September 1, 1970, for canned fruits and vegetables. (e) The Food and Drug Administration will undertake an annual review of the data on cyclamates and on the basis of such review these guidelines may be revoked or amended. (Sees. 505, 701(a), 52 Stat. 1052-53, as amended, 1055; 21 U.S.C. 355, 371(a)) Dated : March 17, 1970. Sam D. FIne, Associate Commissioner for Compliance. [F.R. Doc. 70-3370 ; Filed, Mar, 23, 1970; 8:49 a.m.] Mr. Founrarn. Dr. Edwards, with respect to the order which you signed on December 23, 1969, as Acting Commissioner of Food and Drugs, the following statement is made: The medical advisory group reviewed all available data including that sub- mitted by the Food and Drug Administration to the ad hoe committee of the Food Protection Committee, National Acadenmy of Sciences, National Regional Council, and endorsed the prohibition of cyclamates in beverages for general use and in the future processing of general purpose foods. I think we are particularly interested in the significance of the use of the words “general purpose foods.” What is the meaning of that expression ? Mr. Goopricu. It means foods that were sold in the supermarket, as these cyclamate products were being sold. That is, the artificially sweetened drinks, the artificially sweetened cake mixes, the artificially sweetened canned fruits, jams, jellies, ice cream, et cetera. Those were general purpose foods containing cyclamates. Its general purpose being to distribute to all who wanted to cut out a few calories, Mr. Founrarn. Would non-general-purpose foods be excluded from this statement ? Mr. Goopricu. Yes, they would, but the distinction being made in this statement, that the cyclamate-sweetened products were being with- drawn from the grocery store type of sale as food items. ''82 Mr. Founrarn. Could you give us an example of non-general pur- pose foods? 3 Mr. Goopricu. There are some dietetic foods that appear in the special categories in some stores, but what we had to deal with here was the general use, the general sale of these products as ordinary foods eth a less calorie load. Mr. Fountarn. Regulation 1.11 promulgated under section 403 (j) of the Federal Food, Drug, and Cosmetic Act, which relates to foods for special dietary usage, defines special dietary use as follows: A. The term “special dietary use” as applied to food for man means “par- ticular” as distinguished from “general” use of food as follows * * * And I notice the regulation makes a distinction between the general use of foods and special dietary use of foods, Is this the distinction that is being made in your order of Decem- ‘ber 23, when you refer to general purpose foods? Mr. Goopricu. No, Mr. Chairman, not at all. What the regulation you have in your hand there on special dietary foods refers to as a special characteristic of food, like one that is low in sodium, that has a dietary use for people who are trying to maintain a low-sodium diet, or a food that is recommended for special use in supplying vitamins and so forth. What the order was addressing itself to on October 18, was the gen- eral purpose sale and use of cyclamate-sweetened products as substi- tutes for ordinary foods, the only difference being that they contained fewer calories. Mr. Founratn. What were the events which led up to the decision that artificial sweeteners containing cyclamates were to be regarded as drugs? Mr. Goopricu. When the announcement was first considered by the Department, the medical people inside concluded there was a place for the artificially sweetened products in the diets of diabetics and in a limited number of obese persons in whom weight control was abso- lutely essential for health. This view was expressed publicly by Dr. Egeberg himself at the Secretary’s press conference on October 18. We, of course, knew that Dr. Schrogie’s article had been written, that he had questions about the usefulness of these artificially sweetened products in this particular kind of patients. But there was also a different point of view on this. Acting on that medical advice, the Secretary made the statement in his October 18 statement that the products would remain available for drug use. But to be sure that this was proceeding in a proper man- ner, it was decided to impanel an ad hoe committee of experts, par- ticularly concerned with diabetes and this type of thing. Dr. Egeberg appointed the group at the Secretary’s direction soon after the announcement of October 18. It was requested he appoint the group in November and it was appointed by mid-November and it made a report in December. The issue there was, was there a place for these artificially sweetened products to play as drugs? Now, this was the scientific background. The legal background, of course, came to me. The decision on these products had to be that they could no longer be sold as food of any kind, special dietary or not. That is, that the Delaney clause forbid their sale as food. There was also a line of cases under the ''33. Federal Food, Drug, and Cosmetic Act that a drug depends upon its intended use. , He A case, for example, that a jar of honey, if it is intended for medical use, or a container of vinegar and molasses or vinegar and something of that sort, as long as it 1s intended for use in the treatment or pre- vention of diseases, is a drug. Mr. Founratn. Do people buy honey as a drug ? Mr. Goonricu. It would depend on its use. Mr. Founrarn. Wouldn’t you think most people bought honey be- cause they wanted something sweet ? Mr. Gooprtcu. Most people would, but a lot of them bought it be- cause they thought it would cure a lot of diseases as Dr. Jarvis said in his book. But the point we had here was these products were recom- _ mended by this committee to be made available on a drug label basis for use by special patients. My conclusion, my advice to the Department, was if they were prominently labeled, honestly and forthrightly promoted for those conditions, they were properly classified as drugs. They would not be generally recognized as safe and effective, as the chairman has pointed out here, and therefore they were new drugs and required new drug approval. o Acting on the basis of the scientific advice of the medical advisory group, we took the steps to initiate the abbreviated new drug proce- — dure to be sure that the products were forthrightly labeled as drugs and marketed as drugs. ' This was the background of the total experience. Mrs. Dwyer. May [ask a question, Mr. Chairman? Mr. Founrarn. I yield to Mrs. Dwyer at this point. Mrs. Dwrer. Thank you, Mr. Chairman. I may be repetitious, but I want to clarify this point for the layman. What is the current HEW policy with regard to changing the Delaney amendment, especially since Mr. Finch is leaving ? I ask this in reference to the Washington Post article this morning on which I have gotten numerous phone calls on HEW trying to erase the law that outlaws cyclamates. There has been a lot of confusion. Back home in my district there are a lot of diabetics who are asking this question. I think perhaps this affects more people back home than many other things that affect anything in HEW. Now, would you try to tell me in layman’s language what you are trying to do? Dr. Epwarps. Mrs. Dwyer, I would say this. In regard to the posi- tion I took yesterday on the Delaney clause, it was certainly the posi- tion of Acting Secretary Veneman. While we are for any strengthen- ing of the bill, we certainly are not for repeal of the clause and, at this point in time, we are doing nothing in terms of attempting to change the Delaney clause. So far as we are concerned. Mrs. Dwyer. Have you positive proof that this is harmful to diabetics ? Mr. Goopricu. On the cyclamates, Mrs. Dwyer, there were two lines ‘of evidence. One, the results obtained in tests supported by Abbott Laboratories, the sponsor of one of the products, This showed that, at certain levels of feeding the test animals, the rats developed bladder tumors. : ''34 Later, after October, we had a series of rats under study—that is, the Food and Drug Administration had an ongoing study involving the feeding of cyclamates to rats, too. These animals were sacrificed after the October withdrawal of cyclamates and here we found that the tumors were arising in the animals at levels a good deal lower than had been observed by Abbott Laboratories. Now, we are in no position to say, proof positive, that taking some cyclamates in these drinks is going to cause a bladder tumor in a human being. But the prudent course, bearing in mind the observation in the animals, was to believe that the product was not generally recog- nized as safe and to put it off the GRAS list. It could not come back on because of the prohibitions against the approval of any food addi- tive if it has been shown to produce cancer in test animals. I know of no one in the Department from a scientific standpoint that would recommend cyclamates back into general purpose foods. They did recommend that the hazard was not one that should deprive diabetics who required cyclamates as part of the medical management of their diseases from the use of food sweetened with cyclamates. The only way those products could be sold was as drugs for manage- ment of the diabetic disease. The diabetic, of course, obtains insulin over the counter. He knows generally how to manage his disease. In- sulin is a unique drug and being an over-the-counter item, despite the knowledge that you have to have about using it safely. This was another part of our decision to make these so-called food drugs, the artificially sweetened products drugs in this sense and over- the-counter drugs. Mrs. Dwyer. The pill is also under suspicion now for diabetics, too, isn’t it? So, what are diabetics supposed to do today ? Dr. Epwarps. As we have indicated, Mrs. Dwyer, we have made cyclamates available to them. Taken as directed in the labeling, dia- betics can continue to appropriately use cyclamate-containing products. As regards the pill, we have recognized the inherent dangers of it and we have so warned the patients that are taking the pill. Weare attempting to, certainly. Mrs. Dwyer. Thank you. That is all. Mr. Fountarn. Inasmuch as Mrs. Dwyer has asked this question, Doctor, and has referred to the news story which I have in my hand— did you read that story ? Dr. Epwarps. Yes, I did. Mr. Founrarn. Yes. Dr. Epwarps. Yes, I did. Mr. Fountrarn. Would you state whether or not it is substantially correct ? Dr. Epwarps. Well, I would say this, that Mr. Fountain. Or wherein you differ with either the facts, the conclusions, or the quotes ? Dr. Epwarps. Well, again I don’t have the article directly in front of me. Acting Secretary Veneman did have a meeting with the staff— it was a routine meeting—to discuss the Delaney amendment, possible opportunities for us to strengthen the bill. I think that his position is now-—and I believe it is fair for me to say this with his concurrence— that until he is certain that anything that his administration would ''35 submit to Congress, it would have to show far greater evidence of strengthening the Delaney amendment than the particular one we were considering at our staff meeting several days ago. Mr. Fountain. I am always hesitant about putting newspaper articles in the record, not because I doubt that they are correct, but because I know how fast reporters have to write sometimes. They have deadlines like we do. Inasmuch as this article has been referred to, I think we should make it a part of the record. However, wr are express- ing no opinion as to whether it is correct. If you have any further comments after you have read it, we will be glad to have them. (The newspaper article follows :) [From the Washington (D.C.) Post, June 10, 1970] HEW iIs Tryine 'To Erase Law THAat OUTLAWED CYCLAMATES (By G. C. Thelen, Jr.) The Nixon administration has mapped a legislative strategy to erase the law that bars cancer-causing additives in foods. The strategy includes requesting admittedly unneeded but politically attractive additional authority to regulate other harmful additive effects. The proposed tactics were outlined Monday to a group of high officials in the Department of Health, Education, and Welfare by HEW legislative specialists. Authoritative administration sources said yesterday that Food and Drug Commissioner Charles C. Edwards and other participants in the meeting were so disturbed by the strategy they complained directly to John G. Veneman, Under Secretary of Health, Education, and Welfare. oo reportedly has ordered a delay on the controversial legislative changes. Robert H. Finch, retiring Secretary who will become a White House counselor, said he wanted the law changed after being forced to invoke it last October to remove the artificial sweetener cyclamate from drinks and some foods. Finch contended the law is unduly restrictive because it requires drastic action against any additive found to cause cancer when fed to animals in any amount. Cyclamates were linked to bladder cancer in rats. Some scientists and consumer protection advocates, notably Ralph Nader, argue for retention of the law, known as the Delaney clause after its sponsor, Representative James J. Delaney, Democrat of New York. The proposed strategy outlined by Creed Black, Assistant HEW Secretary for Legislation, calls for allowing cancer-causing additives in foods at a prescribed amount—or tolerance. It also calls for tolerance limits for additives shown to cause birth defects, genetic mutations, or other irreversible harm. “The approach is designed to anticipate and counteract criticism that the Department is merely trying to weaken existing safeguards against harmful sub- stances in food,” Black said in a briefing memorandum, a copy of which was ob- tained by the Associated Press. But Black conceded that new authority for the newer maladies is not needed because “present law is wholly satisfactory from a technical standpoint, as to pathological effects other than cancer * * *” Black attributed the legislative tactics to Dr. Jesse Steinfeld, Surgeon General and a Deputy Assistant HHW Secretary, and ‘to Steinfeld’s deputy, Winton B. Rankin. Rankin was removed as No. 2 man at the Food and Drug Administration when Finch reorganized the agency in December. The Nixon administration may be forced te reconsider its opposition to the Delaney clause when Elliott Richardson, now awaiting Senate confirmation, takes over as Secretary. It was Richardson, who, as Acting HEW Secretary, signed the 1959 letter spelling out the language of the clause. EX-FDA SCIENTIST DENIES ALTERING DATA Representative L. H. Fountain, Democrat of North Carolina, said yesterday that Dr. Arthur A. Nelson, a retired Food and Drug Administration scientist, has denied charges that he allowed a superior to alter his summary of data from a study made 20 years ago of rats on cyclamate, the artificial sweetener. ''36 The charges were made last year by Dr. Howard L. Richardson, an FDA pathologist, in internal FDA memos that surfaced recently and caused a furor. At a hearing of the House Intergovernmental Relations Subcommittee, Foun- tain said Nelson ‘told the staff that he alone had prepared the summary. Nelson told FDA investigators the same thing. They said that the superior, Dr. O. Garth Fitzhugh, denied that he had altered data. Dr. Epwaros. I think again some of the details are not exactly ac- curate, but its main point, that Acting Secretary Veneman is not con- templating any immediate action, is a very accurate statement. He is not satisfied with any of the reported changes or changes that have been reported to him, and there are no immediate changes contemplated. Mr. Founrarn. Let me ask you this: Is it or is it not true that the Surgeon General advocates the repeal of the Delaney amendment ? Dr. Epwarps. No; again I think that might be putting the Surgeon General in the wrong light. I believe that the Surgeon General cer- - tainly feels there are some things that could be done to strengthen the Delaney amendment. But I don’t, by any stretch of the imagination, believe he would like to have it totally amended. Mr. Founratn. He sees a need to strengthen the amendment ? Dr. Epwaros. I think he feels there are things that could be done to the amendment to give it greater strength. I think the only question was, in the departmental discussion on this, is whether what was being proposed would in fact strengthen or weaken it. Some felt it would weaken it, some felt it would strengthen it. I think the Acting Secretary is of the opinion that at this moment he is not certain that it would strengthen the amendment. Mr. Fountain. I am a little confused. When you say “strengthen,” what do you mean? In your opinion, how could the Delaney amend- ment be strengthened ? Dr. Epwarps. Well, I think that, first of all, we have to— Mr. Fountatn. It is an absolute ban at the present time. Dr. Epwarps. Absolute ban on any substance that is carcinogenic. There are a lot of factors that aren’t taken into consideration. The mutagenicity factor, the teratogenicity factor, a number of other factors that have a direct bearing on the health and well-being of the particular user of the food additive. Under the current amendment we are really only looking at one factor, carcinogenicity and there are other factors that obviously have to be taken into consideration. Even without the Delaney amendment we, in the Food and Drug Administration have to consider the total spectrum of toxic effects of the particular additive. Mr. Fountain. Did I hear you say you thought diabetics ought to use cyclamates in appropriate quantities ? Dr. Epwarps. I wouldn’t go so far as to say they should, I said I think they can take it, if their prescribing physician feels it is appro- priate. I wouldn’t want to go on record as saying they should. What we have really said is there is real reason to question the unlimited consumption of cyclamates. But again under medical supervision, I think it is all right. Mr. Founrarn. Then Mrs. Dwyer should tell her constituents to talk to their doctors. Dr. Epwarps. I think that would be wise for your diabetic friends. ''y 37 Mrs. Dwyer. What about saccharin now? Isn’t that under the gun, too? in Dr. Epwarps. Saccharin, I wouldn’t say it is under the gun, it is under investigation, very seriously by us. We have attempted to pull together as I said earlier this morning, all of the scientific information on saccharin. We have given it to the NAS/NRC and should be hearing from them in the relatively near future. We have no scientific evidence or at least we are not of the opinion that we have any that would cause us_to utilize the Delaney amendment as we have with cyclamates. Mrs. Dwyer. Dr. Edwards, I sat here yesterday and heard all of this testimony about oral contraceptives and very little about the pill for diabetics and cyclamates and saccharin. I am sure you know how many diabetics there are in the country how much concern is there © really in this field ? ; : i : Dr. Epwarps. This is under very serious consideration right now by our Bureau of Drugs. I might have Dr. Simmons address himself specifically to your question. ante Dr. Srumons. Mrs. Dwyer, this was to come up in questioning later. I don’t know if the chairman wanted to approach this whole subject now or not. Whichever way you would like to do it. What specifically is your question, Mrs. Dwyer, on Orinase? Mrs. Dwyzr. My question is we devoted a lot of time yesterday to the contraceptive pill and a little time to the diabetic pill and cycla- mates, which to me is just as important. Dr. Smwmons. Well, Mrs. Dwyer, most of my life in the past month has been devoted to the oral diabetic pill. I know exactly how you feel. — We have been under a tremendous amount of interest in the whole United States. Maybe in summary what I should tell you and through you to your constituents, is that fig entire therapy for diabetes is now open for reevaluation and many questions remain unanswered. I think the whole medical profession is much less confident now about its knowledge and approach than it was a year ago. When you say is the pill tolbutamide or Orinase safe, we always have to say compared to what, because we realize there isn’t any drug ever made that is effective and is in fact completely safe far everybody and doesn’t have side effects for some. Now our position at the present time is this: Having evaluated all of the evidence we have available to us now, and having consulted many, many experts on this subject, our opinion is this: The symp- tomatic diabetics need treatment because they don’t feel well and in fact they aren’t well. In that group of symptomatic adult diabetics who cannot or will not diet and if necessary lose weight or who can- not and will not use the insulin needed to control their symptoms, ora] agents are all we now have and are necessary in those circumstances because the patient has nothing else to turn to and needs relief. He must realize that that drug as any other drug in some people has undesirable side effects. That is the answer to your question, Mrs. Dwyer. I am sorry it was so complicated. Mr, Fountarn. What is symptomatic diabetic? Dr. Stumons. A symptomatic diabetic is one who has the symptoms of frequent urination, excessive thirst, weakness, weight loss, and ex- cessive appetite, Those are the classic symptoms of diabetes, ''38 Mr Founrarn. And it still may not show up in the blood or urine test ? - Dr. Smrmons. No, sir; when they have symptoms such as that they usually have urine sugar or elevated blood sugar. That is the sympto- matic diabetic, as opposed to that who goes in for a routine physical and by examination are found to have elevated sugar. Mr. Fountarn. What do you call the latter ones? Dr. Srarmons. Those are occult diabetics, which means by anything other than careful examination they would not know they had dia- — betes. We are talking about the diabetics with symptoms. Mr. Fountarn. Is that so-called onset diabetes ? Dr. Smrmons. The adult onset diabetes is that diabetes coming on- Mr. Fountatn. Between 40 and 60? Dr. Smumons. Yes. Mr. Fountain. Doctor, if you know, would you identify who ac- tually made the decision that cyclamate artificial sweeteners were to be considered drugs? Mr. Goopricu. I suppose I did. Mr. Fountarn. You recommended it ? Mr. Goopricn. If you put it this way. The committee recommended that they be drug labeled. The issue of whether this could legally be done, I decided, yes. ‘ sk Fountain. But who made the decision after you recommended it? Mr. GoonrtcH. Dr. Ley. Mr. Fountain. To what extent, if any, did Secretary Finch and his staff participate ? Mr. Goopricu. I guess Dr. Edwards signed the implementation document. Mr. Founrain. I realize the decision is quite often made by people who are supposed to have particular knowledge, but the man in charge has to bear the brunt of it whether it is good or bad. Mr. Goopricu. Yes. That is the reason I accepted the responsibility for making the decision. It was an issue of having this kind of a recommendation from an advisory committee of scientists, could it be done under the law, and how could it best be done to accomplish the purpose which was to be sure these products were drug labeled and sold on an over-the-counter, nonprescription basis. I made the deci- sion on how to do that. Mr. Fountain. Did Dr. Egeberg and his staff participate in the final decision ? Mr. Goopricx. No, other than to pass me this document and say how can it be done and I prepared the Federal Register document. Mr. Founrary. In other words, they wanted to make it a drug? Mr. Goopricu. Yes, that was the recommendation of the committee and they wanted it implemented, and I decided how it could be imple- mented. Mr. Founrarn. There is a story about the Governor of Virginia, and a strike in the public utilities. They were all about to close down, so he put the workers in the National Guard right quick, with one — stroke of the pen. The Attorney General came to see him and said, ''39 “Governor, you can’t do this,” and he replied, “Hell I can’t do it, [have | done it.” He said, “Your job is to find something to justify what I have done.” [Laughter. ] ae So to some extent you were called upon to find legal justification for a decision which they wanted to make. Mr. Goopricx. I was called upon to decide whether this could be done within the law and how best to accomplish a reasonable assur- ance that the products would be handled no longer as foods but as. drugs. Mr. Founrarn. Of course I am thinking primarily policywise. Was there any dissenting opinion expressed among the scientific or medical staff in the Food and Drug Administration with respect to the policy _ decision to permit the intended marketing of cyclamate artificial sweeteners and cyclamate-containing products as drugs ? Mr. Goopricu. Yes. You know Dr. Schrogie’s view as expressed in the October FDA Papers. There is a memorandum in the file which of course you have from Dr. Seife who is in the Medical Bureau raising an issue of whether or not Mr. Fountain. Could you tell us the nature of the dissent they expressed ¢ Mr. Goopricu. They simply took the view it wasn’t well enough documented that a diabetic really needed these artificially sweetened preparations. We chose to act on the advice of the outside consultants which Dr. Egeberg had called in. They made a report and we imple- mented the report. Mr. Founrarn. Who were those consultants ? Mr. Goopricn. Dr. Ivan Frantz, M.D., University of Minnesota; Dr. George C. Griffith of California; Dr. Harvey Knowles, Jr. of the University of Cincinnati; Dr. Edward Rosenow, executive director, American College of Physicians, Philadelphia; Dr. Henry Sebrell, Columbia University; Dr. Theodore Van Italie, M.D., St. Luke’s Hospital, New York. Ex officio were Dr. Levy, Commissioner of Food and Drug; Dr. Theodore Cooper, Director of the National Heart and Lung Institute; Dr. G. Donald Whedon, M.D., Director of the Na- | tional Institute of Arthritic and Metabolic Diseases; Dr. Ken Endi- cott, former Director of the National Cancer Institute; Dr. Steinfeld, Deputy Assistant Secretary for Health and Scientific Affairs. _ Mr. Founrarn. This was an ad hoc committee that was appointed ? Mr. Goopricn. This was an ad hoc committee. At the time of the announcement on October 18, Dr. Egeberg expressed the view there was a place for these products to remain available for use in the man- agement of diabetes and in certain cases of obesity. The Secretary di- rected him to empanel an ad hoc group that was especially knowledge- able in these diseases to see if there was a role to be played. The com- mittee was appointed in early November and reported back sometime in December. And the report you have and is available, of course. Mr. Founrarn. I do not have it here. Is there an indication of how many, if any, of those serving on the committee were diabetic specialists ? Mr. Gooprtcu. I don’t know, but we can get that for you readily, Mr. Chairman, and I don’t have any way to know whether there was any difference of opinion in the committee. ''ye < 40 (The information referred to follows :) “MepicaL SPECIALTIES OF THE MEMBERS COMPOSING THE SECRETARY’S MEDICAL ADyISsORY GROUP ON CYCLAMATES he “Members: Ivan D. Frantz, Jr., M.D., professor, depart- ments of medicine and biochemistry, medi- eal school, University of Minnesota. George C. Griffith, M.D., Emeritus Professor of Medicine, School of Medicine, University of Southen California. Harvey ©. Knowles, Jr., M.D., professor of medicine College of Medicine, University of Cincinnati, Cincinnati, Ohio. Edward ©. Rosenow, Jr., M.D., director, American College of Physicians, 4200 Pine Street, Philadelphia, Pa. William Henry Sebrell, M.D., Institute of Nutrition Sciences, 562 W. 168th Street, New York, N.Y. Theodoré B. Van Italie, M.D., professor of Medicine, Columbia College of Physicians and Surgeons, New York, N.Y. Ex officio members : G. Donald Whedon, M.D., director, National Institute of Arthritis and Metabolic Dis- eases, Bethesda, Md. Kenneth M. Endicott, M.D., (former Director, National Cancer Institute) now Director, Bureau of Health, Professions, Education and Manpower Training, National Insti- tutes of Health, Bethesda, Md. Jesse M. Steinfeld, M.D. (then Deputy Assist- ant Secretary for Health and Scientific Af- fairs) now Surgeon General, USPHS, Washington, D. C. Herbert L. Ley, M.D., (then Commissioner, FDA). Theodore Cooper, M.D., Director, National Heart and Lung Institute, NIH, Bethesda, Md. Specialty Biochemistry; enzyme _ ki- netics, protein and lipid metabolism. Cardiology, rheumatic heart disease; congenital heart disease. Diabetes : metabolic disorders. Internal medicine; gastro- enterology ; cardiology. Nutrition ; diabetes. Nutrition ; diabetes. Endocrine and metabolic dis- eases ; diabetes. Metabolic and degenerative diseases; cancer chemo- therapy. Oncology, hematology ; radio- active isotopes. Internal medicine; research. Experimental and _ clinical cardiovascular physiology and pharmacology. Those individuals considered experts in diabetes are: ae G. Donald Whedon, M.D. Kenneth M. Endicott, M.D. Henry Sebrell, M.D. Theodoreo Van Italie, M.D. Harvey C. Knowles, Jr., M.D. Mr. Fountarn. I believe most of the members were medical doctors. Mr. Goopricn. Yes. Mr. Fountarn. Dr. Edwards, who made the decision that the arti- ficial sweeteners containing cyclamates were to be regarded as “new drugs”? Mr. Goopricu. I did. Mr. Fountarn. You gave the legal opinion. Mr. Gooprtcu. I did. Mr. Founrarn. Dr. Edwards, I believe the order contained in sec- tion 130.40 which you signed on December 23, 1969, as Acting Com- missioner of FDA requires the submission of abbreviated new drug ei applications for cyclamate-containing artificial sweeteners intended solely for drug use. Where would such products be sold. Would they be found for sale in drugstores only ? ''41 Dr. Epwarps. No, not necessarily. They could be found in grocery stores. Mr. Founrarn. In other words, they would be available for sale to the public in grocery stores or supermarkets? Dr. Epwarps. Right. Mr. Fountarn. Dr. Goldberg reminds me to ask you just what you mean by the expression “intended solely for drug use.” Dr. Eywarps. I think Mr. Goodrich wrote that. Mr. Goopricu. Since I wrote it I guess I had better explain it. That is to make very sure that we have an understanding that these products _ are not to be made available as foods any longer, that they are strictly limited to medical use. I mean we were trying to emphasize that this was a special situation, that the product was not to be used as a food any longer but as a part of the medical management of diabetes or a few cases of obesity. Mr. Founvarn. Is there any requirement that these foods be placed in any particular place and so designated within a grocery store? Mr. Goopricu. No, sir. If we had made it a prescription drug, which of course was a possibility I discussed a while ago, then accord- ing to some State laws it would have to be sold only in a pharmacy, but there isn’t any Federal law that says where particular products would be sold. , Mr. Fountain. These products would be available then in any gro- cery store or supermarket that wanted to carry them ? Dr. Epwarps. That is right. Not unlike a number of other over- the-counter drugs. Mr. Fountarn. Do you have any other over-the-counter drugs that have been examined with the same findings? Mr. Goopricu. I am not sure I understand the question, Mr. Chair- man. The new label Mr. Fountain. The same findings with respect to their effect on test animals. Mr. Goopricu. Are there drugs i Dr. Epwarps. You mean food additives that have been relabeled as rugs? Mr. Goopricn. Are there any across-the-counter drugs that have been shown under some circumstances to create a cancer in test animals? Mr. Founratrn. Yes, and sold across the counter. Mr. Goopricu. Dr. Jennings says he does not know of any one that has exactly the same thing. But in general it can be said that drugs from their nature, if they are effective at all, have some side effects and adverse reactions. Bonine, as you know, meclizine and cyclizine which were big issues with us at one time in our past history—I hope now are behind us— were ones that were over the counter that had a possibility of terato- genicity and in that instance we required a warning that would prevent. their use by a person who might be pregnant. Now, this attempt is to restrict the cyclamate products to those diabetics and obese people whose doctor decides they have to have them for their health. This paper, Mr. Chairman, was published in the Journal of the American Medical Association, as I understand it, to be sure that the doctors got the whole message about this. This was our quickest way to communicate with them. ''42 Now, it may be that the whole thing is not going to pan out. I know from the recommendations of the committee that we were to make an annual review of this. The products are just now being introduced, and we will be following this and if we find an abuse, that they are really not being sold as drugs and are being sold and used as foods, of course we will have to take another action. We think, however, what we did was to have a strong enough warn- ing on the products that no one would use them without medical supervision. Mr. Fountarn. In other words, if I go into the grocery store and there is a shelf with low calorie peaches, if I pick those up I am pick- ing up a drug? Mr. Goopricu. If you get one that has cyclamate in it, yes. There are some mixtures being prepared now with saccharin alone or with saccharin and sugar combinations. So the way you distinguish the one intended for drug use, it has a box label on the front saying this is for medical use only and that medical supervision is essential for safe use, and it will identify it as containing cyclamates. I would hope you would look at that. Mr. Founrarn. So every grocery store of any consequence has be- come a drugstore. Mr. Gooprtcu. We don’t think so. The products, as I said, are just in the process of being introduced and labeled. It may be that they will be in a good many more stores than they should. But the label warning we have put on there is calculated to restrict their use to drug use only. Now, we think it is going to work. But obviously we can’t be 100 percent sure until we see the results. Mr. Fountarn. I notice some of the stores—I think Giant here in Washington—have a dietary section. Dr. Epwarps. And also even a drug section. Mr. Fountain. Yes. Of course there are a lot of good sized grocery stores that are not drugstores. The drug to which you referred a few moments ago, which was a subject of controversy, was sold in drug- stores, not grocery stores. So you don’t know of a similar example - of where food converted to drugs is sold in grocery stores. Mr. Goopricu. That is right. You would find a number of them sold in so-called health food stores. I think we would find some drugs there and Mr. Goldhammer has had experience with that. Mr. Founrarn. Grocery stores are going to have to be inspected. like drugstores, . Mr. Goopricn. We treat this problem as a special problem for a limited population and we are going to look at it again in October as the advisory committee recommended we do and if the product cannot be really sold and really used as a drug, then we will have to take it off the market. Mr. Founrarn. On the other hand I would hate to have to go to the drugstore to get some peaches. I don’t know, but there might be some controversy between the grocery men and drugstores, as we now have between different groups with conflicting interests. Dr. Goldberg? Dr. Goutpperc. Where a grocery store as was described a moment ago has both a drug section and a dietary food section, where would you anticipate these products would be located 2 ''43 Mr. Goopricu. I would anticipate in the dietetic food section, but I don’t know. I would have to look. Dr. Gotppere. Yet they are drugs, and I think I assume correctly that the dietary section would have no other drugs in it. : Mr. Goopricu. It depends on the grocery store you deal with. I happen to deal with a Safeway that has the dietetic goods and Anacin and aspirin, all of that stuff, side by side. Mr. Founrarn. We are going to get into this a little later on. I was getting ahead of myself. : A staff member said he saw Sucaryl containing a label declaration required in the order of December 23 in the dietetic food sections of grocery supermarkets. Has an abbreviated new drug provision been approved for that product ? Mr. Goopricn. It is my understanding that it has. But in going over the preparation for this hearing we were not able to locate that par- ticular letter and we will just have to try again. What happened on that, I had some discussions with Abbott’s counsel about both the issue of labeling the existing stocks that were around on the date of the recall and the abbreviated new drug applica- tion and wrote him a letter of the conditions that we would require for the approval. It was my understanding in talking orally over the telephone with the Bureau of Drugs that it had been approved. But I must say we could not locate that letter. It is my belief that it was approved. Our filekeeping is not the best, as you know. Mr. Founraty. Dr. Edwards, would you say that artificial sweet- eners containing cyclamates offered for sale in diet food sections of supermarkets are at that point intended solely for drug use? Dr. Epwarps. I would answer that question “Yes.” Mr. Fountain. Is it not possible and perhaps even probable that any person who has been accustomed to using cyclamates or artificial sweeteners in tablet form or liquid form for use in the home to sweeten his coffee, as I have done, or to put on grapefruit—although I have dis- covered grapefruit is sweeter without anything if you try it long enough—or to be used in cooking or baking, whether under the care of a physician or not, will continue to buy the product when he sees it on the shelves in the same location as in the past ? Dr. Epwarps. It certainly is a possibility, that is right. Mr. Fountatn. What control is the Food and Drug Administration exercising at the present time, and what controls, if you don’t have any, are you planning, over the sale of such products to be sure that they are at all times intended solely for drug use as contemplated by your regulation ? Dr. Epwarps. I know of no specific plans but I would like to ask our Associate Commissioner for Compliance. Mr. Fre. I don’t know how you can control an over-the-counter drug. If someone chooses to buy aspirin and misuse it, they are going to misuse it. You have a label that tells the individual what it is and we trust that he will follow the label. Mr. Fountarn. It would be wonderful if we could really trust our- selves to follow labels. Dr. Epwarps. It obviously is not going to solve the problem. I think that certainly consideration must be given to the possibility of requir- ''44 ing it to be sold in the appropriate place at least within the store, things like this. But I think our hands are somewhat tied. Our alter- natives are somewhat limited. __ Mr. Founrarn. Do you regard it as important that controls of some kind are worked out to maintain or to be sure this solely intended drug use will actually be carried out ? Dr. Epwaros. I think we definitely have to look into this. Mr. Good- rich just said that is the reason we put in the abbreviated NDA. If we are going to contemplate doing this in the future, we have to de- velop a system that will insure this drug being utilized and sold in the proper way. Mr. Fountarn. I think it is just natural, and maybe regrettably so, for people who purchase products of this kind to maybe assume too much. They see it on the grocery shelf, they know we have all sorts of © food inspection laws, and they assume it wouldn’t be put there if it - was not proper. There are many people for whom it is not intended who will buy it even though it may be put on the diet counter. Shouldn't it also specity, if it is going to be put in the grocery stores, that it is a drug? Perhaps the container should indicate this is not a food but it is a drug, or it is a combination, something like that. Mr. Fine. That is the purpose of the labeling. It spells out it is a drug. Mr. Fountain. I have forgotten precisely what the labeling says. Mr. Goopricu. It is a box label on the front of the container, in a box to set it out Mr. Founratn. I know diet colas have that because I used some. It has a big sign on the box. But sometimes you don’t get the box. Some people may pick up three or four bottles. I notice the cap says one thing, the bottle says another. Mr. Goopricu. But each individual container of these products has on the front of it a box warning that it is for use only as an adjunct in a calorie-controlled diet by diabetics and certain obese patients under medical supervision, not by just everybody who wants to lose a few pounds. Mr. Fountain. It doesn’t say it isa drug. Mr. Goopricu. It says for medical use only. Mr. Fountarn. Yes. But everybody knows what the word “drug” means. Mr. Goopricu. That may be a good suggestion for us. Mr. Founrarn. I don’t think it says for medical use only. ___Mr. Frye. Yes; it does. I have the wording here. “For use only by diabetic or obese patients under medical supervision” and in a box the statement “Caution, medical supervision is essential for safe use.” So we have both statements. Mr. Fountain. But it does not say for medical use only. _ Mr. Five. No; it says medical supervision is essential for safe use. Mr. Founrarn. And it does not say it is a drug. Mr. Fine. No; it does not. Mr. Fountain. There may be a lot of similarities, but there is a difference. Dr. Epwarps. The point is well taken. We might give that serious consideration. ''4 5 Mrs. Dwyer. This question may be repetitious, but, Dr. Edwards, have you made any attempt to study in depth FDA’s role with regard to both regulated food and drugs and to how such products are mar- keted as it affects diabetics? As I listened to this testimony today, I am not so ‘sure that we have gone in depth into it, and I am not criticizing you or your role or the’ Department, but do you realize how big this role really is and the responsibility ? i Dr. Epwarps. I know exactly what you are saying. I do not know of anything, any studies that we have or have immediately contem-_ plated, Maybe Dr. Wodicka could respond to this. We are moving in the direction of accomplishing what you are suggesting. But not specifically as it relates to the diabetic. This certainly falls into the general area of the great need for the Food and Drug Administration to play a much greater role in the labeling of food, the identification of the quality of food, and so forth. Whether it be for diabetics or just the ordinary healthy person, I think our role certainly has to be much greater than it has been in the past. Obviously for those that have special illnesses we even have a greater responsibility to see to it they know what they are getting and par- ticularly if it is treated as a drug, no question about that. Mrs. Dwyzr. I don’t envy you your job. I think you are doing a fabulous job just the same. Thank you, Mr. Chairman. Mr. Founrarn. Doctor, section 201(s) of the Federal Food, Drug, and Cosmetic Act defines the term “food additives” as meaning “any substance, the intended use of which results or may reasonably be ex- pected to result directly or indirectly in its becoming a component or otherwise affecting the characteristics of any food.” Now that the cyclamates have been banned in general purpose foods do you regard cyclamates as food additives if by their use they become a component of a food or otherwise affect the characteristics of a food ? Dr. Epwarps. No; they are a drug. We have made the decision to classify these, this particular substance, as a drug and we have to move in that direction. Mr. Fountarn. Mr. Goldhammer? Mr. GotpHammer. Dr. Edwards, may a new drug also have a food additive purpose use ? Dr. Epwarps. I would think so. Mr. Goopricu. Yes, particularly in the case of an animal feed. Mr. GotpHammer. Then let’s get back to the cyclamate sweeteners which are drugs. Now that the cyclamates have been banned from gen- eral purpose food, do you regard cyclamates as food additives? They are new drugs, but do you regard them as food additives, if by their use they become a component of food or otherwise affect the charac- teristic of a food ? Dr. Epwarps. I understand your point. I still would have to stick with my initial answer to that, that we have made the decision to categorize them as drugs. Mr. Gorpyamner. All right. Then tablets of diethylstilbesterol pel- ets are drugs, are they not? And new drug applications were filed. But the principal use was as a substance to go into the feed of chickens. I believe under those circumstances this was held to be a new drug. Now, 48-798—70——_4 ''46 I ask again, if this new drug, the cyclamate artificial sweetener, is used in such a way that by its use it becomes a component of a food, would you regard it as a food additive? i : Dr. Woprcxa. I think the thrust of the decision in this instance is that while cyclamate is indeed a drug, that by the decision let’s say canned - food with cyclamate is also a drug and the food, therefore, is no longer a food. Mr. Goopricx. Similarly because of its intended use. oak Mr. GotpHammer. What is the answer to the question? No, it is not a food additive? Is the answer to the question “No”? Dr. WonrcKa. It is not a food additive because it is not added to food. In other words, the food containing the cyclamate is itself a drug and no longer a food. Mr. GorpHamnerr. All right. If I were to take the cyclamate sweet- ener home and sweeten some baked goods that I made, have the cycla- mates become a component of food ? y Mr. Goopvricu. No, Mr. Goldhammer. What you are doing there is ou are using a product as a drug to control calories in obese and dia- hotis people. Now, if it is intended solely for that use, it is by definition a drug and not a food. : I recognize, of course, as you do, that a product can in some circum- ‘stances be both a food and a drug. This is why we emphasize they are intended solely for drug use, that the product could be sold. Now, there are circumstances, as you know, in which drugs are taken by incorporating them into milk, or taking them with meals, or things of that kind. And this will have te be of that kind. Of course we understand the anomaly of what was in use as a food, now having a different role. This is wy we decided to implement it through these procedures to have a sharp break with the past in the intended use. Mr. GotpHammer. I have not made myself clear apparently. May I take a drug intended solely for drug use and use it in such a way that it becomes a food additive in my home? Mr. Goopricu. Not that I know of. In the episode you gave with the diethylstilbesterol pellets, of course, the pellet in treating the chickens was a drug. It affected the growth and everything about the chicken. It was a food additive when the chicken was killed and you had a tissue residue in some of the flesh, you were selling a food and the food con- tained a residue of the drug which was a food additive under those circumstances. Now, I do not think that is comparable. Mr. GotpHamner. Let’s go back to the definition of food additive. T hate to argue this point but I haven’t gotten a clear answer which is appealing to me or reasonable. Getting back to the definition under section 201(S), the act defines a food additive as any substance, the intended use of which may result or may reasonably be expected to result directly or indirectly in it ote a component or otherwise affecting the characteristic of a ood. Now, to come back to those tablets, which are new drugs, legally on the market, as you have stated, and I take that and put it on my grapefruit or into my coffee, has this become a component of a food? Mr. Goopricu. Yes; in a sense of course, sir, it has become a com- ''47 ponent of a food. But it is also a drug, and in this instance, because it was intended for drug use, the two are mutually exclusive in our opinion. Mr. GotpHammer. But you do concede, then, that under those cir- cumstances it falls within the scope of that definition, it has become a component of a food ? Mr. Goopricu. In literal terms, yes; but not in terms of the overall interpretation of the differentiation between a drug and food. ; Mr. GorpyamMer. I mean under the statutory definition it has become a component of a food and therefore a food additive. Mr. Goopricu. Not the way we interpret it, The way we interpret that is that this is a drug, its intended use was to be used ina calorie- restricted diet, therefore it had to be taken with food, it was nonetheless a drug because of its intended use and it is not a food additive as long as it is intended for drug use. At least this is our judgment. Mr. Founrain. It says a food additive means any substance, the intended use of which results or may reasonably be expected to result directly or indirectly in its becoming a component or otherwise affecting the characteristic of a food. Mr. GorpHammer. Mr. Goodrich, can you conceive of any use for Sucaryl tablets in which it does not become a component of a food 2 Mr. Goopricu. I just said I did not. It is intended for use as a part of a calorie-controlled diet as a drug. Mr. GorpHamMer. What if it is intended for that use by label decla- ration but it is so displayed and because of traditional use is purchased for other than drug use? Supposing I went into a grocery store and bought a jar of honey and without any knowledge on my part there was a statement on that label which said for removal of corns. Now I bought the honey to use to make honeycake. Have I purchased a drug or have I purchased a food ? Mr. Goopricu. You purchased a drug. The intention is the intention of the person who introduced that product in interstate commerce and therefore you have purchased it for your own food use, of course, and your intention is that it be used for food use, where as its label is for drug use. What we did here was not that kind of a situation, but plainly and blatantly forthrightly put on the front of the label that these were intended solely for or intended for medical use and medical supervision was essential. Mr. Fountain. Don’t you think it would be more accurate to say this food is intended for that purpose ? Mr. Goopricu. We don’t think so. As a matter of fact it could not legally be classified as a food. This was essential to our decision. Mr. Founrarn. We have a vote on the House floor, so we will have to recess. But I want to read this aloud again for emphasis and for my own benefit as well as for yours. Section 201(S) defines the term food additive as being “any substance, the intended use of which re- sults or may be reasonably, expected to result directly or indirectly in its becoming a component or otherwise affecting the characteristic of any food.” That is a pretty broad definition of food additive. Mr. Goonprticu. It is, indeed. Mr. Founrarn. Was this a means of getting around the Delaney amendment ? ''aR 48 Mr. Goopricu. No; this was a means of implementing the ad hoc re- port. It was necessary to classify the product as a drug to make it available to diabetics, otherwise the Delaney clause would have for- bidden that. We faced that forthrightly. Mr. Founrary. The committee stands in recess until 2 o’clock. (Whereupon, at 12:52 p.m. the subcommittee was recessed, to recon- vene at 2 p.m., this same day.) AFTERNOON SESSION Mr. Fountarn. Let the committee come to order. Dr. Edwards, do not your regulations under food additives have special provisions for new drugs which have food additive uses ? Dr. Epwarps. Yes; they do. Mr. Founrarn. I would like to put in the record at this time a copy of regulation 121.7 under food additive section of the law. (The document referred to follows :) § 121.7. Food additives or pesticide chemicals for which new-drug applications are required (a) A substance that is a new drug within the meaning of section 201(p) of | the act may also be a food additive within the meaning of section 201(s) by reason of the fact that its intended use results or may reasonably be expected to result, directly or indirectly, in its or its ingredients’ conversion products be- ' coming a component or otherwise affecting the characteristics of a food. When an application for a new drug that is intended for administration to a food-pro- ducing animal is submitted, it will also be evaluated under section 408 or 409 of the act (giving due consideration to data previously filed by the applicant) when there is a reasonable possibility that a residue of the drug may be present or otherwise affect the characteristics of the edible products of such animals, and a regulation issued where necessary. Where a substance is both a new drug and a food additive, the submission of a new-drug application in accordance with the regulations appearing in Part 130 of this chapter will also be construed as a petition for the establishment of a regulation for the use of the substance as a food additive. A new-drug application will not be approved for a use that results in the substance becoming a food additive until a regulation is established under section 408 or 409 of the act. A food-additive regulation under section 409 of the act will not be established when the additive results from the use of a new drug for which a new-drug application cannot be approved. The new-drug ap- plication and the establishment of a regulation respecting the food additive or pesticide chemicals use will be acted upon simultaneously. (b) With respect to those uses of a new drug that result in its becoming'a food additive, the provisions of these regulations shall apply concerning the procedure to be followed in establishing a food-additive regulation. Upon deter- mination that a new-drug application contains a petition for the establishment of a food-additive regulation, the Division of New Drugs of the Food and Drug Administration shall so notify the applicant prior to the date of approval of the application, and shall inform him that his application with respect to the uses of the new drug which result in its becoming a food additive will be processed under the regulations in this part. Upon the issuance of the food-additive regula- tion, the Division of New Drugs will notify the applicant that his application is approved to the extent allowed by the regulation. In the event the proceeding for the food-additive regulation results in the denial of a regulation allowing the use of the new drug as a food additive, the applicant shall be notified that the refusal to approve his new-drug application is final with respect to the use of the new drug for uses resulting in its becoming a food additive. [24 F.R. 2434, Mar. — 28, 1969, as amended at 26 F.R. 12249, Dec. 22, 1961; 28 F.R. 14311, Dec. 27, 1963] Mr. Founratn. And I will read the paragraph as follows: A substance that is a new drug within the meaning of section 201(p) of the act may also be a food additive within the meaning of section 201(s), by reason of the fact that its intended use results or may reasonably be expected to result directly in its or its ingredients’ conversion products becoming a component or otherwise affecting the characteristics of a food. '' Reading further— Where a substance is both a new drug and a food additive, the submission of a new drug application in accordance ‘with regulations appearing in part 130 of this chapter, will also be construed as a petition for the establishment of a regu- lation for the use of a substance as a food additive. A new drug application will not be approved for a use that results in the sub- stance becoming a food additive until a regulation is established under section 408 or 409 of this act. Quoting further— The new drug application and ‘the establishment of a regulation respecting the food additive will be acted upon simultaneously. Now in view of that, the question I would like to ask you is this: has the Food and Drug Administration established a food additive regula- tion for the use of artificial sweeteners containing cyclamates ? Dr. Epwarps. No. Mr. Founatn. Is it possible to prepare a food additive regulation for cyclamates in view of its established capacity to induce cancer in animals and in view, further, of the existence of the Delaney amendment ? Dr. Epwarps. No. Mr. Founrarn. In the absence of a food additive regulation for -cyclamates, I wonder if you would give us, as you see it, the justification for your approving new drug applications submitted for cyclamates-containing sweeteners? Dr. Epwarps. I think the only justification that we would have under your interpretation is that it 1s intended strictly for drug use. That would be the only justification. Mr. Founrarn. Would you agree then that if the law says it is both, it can’t be strictly a drug? Mr. Goopricu. A product can be both a food and a drug, if it is in- tended for both uses, Mr. Chairman. If it is intended solely for drug uses, then it comes, under the drug definition and is properly handled under the drug definition, in my judgment. Mr. Founrarn. Isn’t it bordering somewhat on the absurd to hold an article added to food and drinks, taken home for one purpose only, for the sole purpose of sweetening food, is not a food additive? Mr. Goopricu. We didn’t think so, Mr. Chairman. We thought that the restricting of this product to medical use as a part of a calorie- controlled diet, on the advice of experts that this was necessary for certain people’s health, was a proper application as a drug. Of course, we can argue the other points, we recognize. Mr. Founrarn. I am not attempting to express an opinion here. I am raising a question. But would you tell us what other substances or ‘products consumed in this way are also drugs? Mr. Goopricu. Oh, there are several nutritional-type things that would qualify as drugs, but in a cruder sense, I gave you the example of the honey, which the court of appeals has held, even though it was a common article of food, when it was intended solely for medicinal Be Pose came under the drug labeling provisions of the law and was a drug. This is a well established principle under our law. After all, the definition of a drug that we are dealing with here is a congressionally defined concept, and as the Supreme Court. recently emphasized, the definition of drug was a statutory definition and was to be applied to ''50 accomplish the purpose of the law, of protecting the public. We thought we did that by implementing this report. Mr. Founratrn. Is section 121.7(b) interpreted by the courts? _Mr. Goopricu. Not that I recall offhand. But this is a useful concept which we do apply. It was put in the regulation primarily to deal with a situation such as a medicated feed in which you would have a medi- cated drug feed for an animal and expect some residue in the flesh as the produce of the animal was marketed. Mr. Fountain. Mr. Goldhammer ? Mr. GotpHammer. Mr. Goodrich, if there had been an accidental con- tamination of food with cyclamates, but not enough to charge that a poisonous and deleterious substance had been added, could you not al- lege the product to be adulterated because of the presence of food additives for which there is no regulation ? Mr. Goopricu. In the development of the food additive amendment, the Congress kept section 406, which deals with added poisonous and deleterious substances, in to deal with accidental contaminants. If we could prove that cyclamates were a poisonous and deleterious substance which of course I believe we can, and it were accidentally contaminat- ing food, in my best judgment it would be a violation of section 406 and a comparable provision of section 402(a), which declares it adulterated rather than a food additive thing; but in pursuing that a little bit, if you are talking about an incidental additive, which I be- lieve is the line you are following, that would come under the food additive provision. My justification for dealing with these products as I did was that they were to be intended for use and used strictly as drugs, and that in my judgment doesn’t raise the food issue. __ Mr. Gorpuamner. If I understand you correctly, if it is an inci- dental contamination, with the cyclamates, the contaminant is a food additive ? Mr. Goopricu. It would be, yes. Mr. GotpHammer. But if you added it directly to the food, it is not a food additive? Mr. Goopricu. It would come under the definition just as well, whether intentional or incidentally. Under both circumstances it would come under the literal language of that definition. My belief is that where the product was intended solely for medical uses, it was not a food by any definition, and didn’t come under the food additive definition. — Mr. GotpHammer. What would you do about a product which was a drug solely for drug uses, which some manufacturer of a food found had some properties which were of advantage in the manufacture of the food, and this was a drug and the drug was solely for drug use. Would you regard the use by the food manufacturer as a use of a food additive? Mr. Goopricu. Yes; if it were intended by him as a food additive use. Yes. But if you had a drug that was intended—sold, offered, and intended for use as a drug, and shipped by the manufacturer on that basis, and some other person intended it for food use, then the status would change, dependent upon the intention of the person responsible for the handling at that time. The regulations you have before you deal with that issue of intended use. ''~ 51 Mr. Gorpammer. What if a nondiabetic person, or one not under the care of a physician for treatment of overweight, purchased sucaryl, as it is currently labeled, with the intention of using it in his food at home. Would the article then be a food additive ? Mr. Goopricx. No. In the sense that you mean would his change of intention lead the product to be adulterated while held for sale, or something like that? This is possible as an interpretation, but the real critical point with us, I believe, is the intention of the person re- sponsible for the labeling. : This is what we are dealing with here, and this is why I thought that the “intended solely for use,” and the prominent labeling “solely for use,” and this is why I insisted on the box label on the front, all to be sure that it was intended solely for drug use and not food use. We hope that a person who is just fat and wants to lose a few pounds would read and heed the label. If he doesn’t, then we are going to have to take more stern action with respect to cyclamate products. The committee that advised us recommended an annual review of these products which is due in October, and you have our assurance that we are going to follow that. The new articles under the abbreviated new drug applications are just beginning to appear and how they are going to be marketed re- mains to be seen. We think that by putting a strong box warning on these products that they can be kept for diabetics and for limited ae of obese without the hazards that go with their general use in food. This is our hope and expectation. This is the reason for our inter- pretation. Dr. Gotpperc. How do you plan to find out whether your objectives are realized? Are you going to do market studies, or Mr. Goopricu. Both. We will have to have some of both, Dr. Gold- berg. As you probably know, there was a very substantial volume of these canned fruits and vegetables just hitting the market when the October announcement was made. There has been a problem of dis- posing of those stocks. We allowed until September 1, 1970 to dispose of those stocks and after that it will become important whether or not they can be marketed under the new drug label within the limited areas of usefulness defined within our regulations. Dr. Gotpperc. Have you given consideration to placing a limit on the amount of these products that can actually be sold in commerce, in relation to the population that you estimate would need them ? Mr. Goopricu. We haven’t tried to fix a quota on it, but it’s cer- tainly pertinent to our evaluation of whether or not the products are really being sold and used by diabetics and for the limited use of obese for whom it is intended. This remains to be seen. I am told that it is highly unlikely that the products will have much market with this kind of a box on it, but it remains to be seen. Dr. Gotpgere. Do you think it is possible to get an accurate reflection of who the purchasers of these products are, and the uses to which they put them? Mr. Goopricu. I think so, because they will be displayed in grocery stores, as you indicated, and I think it will be possible for us to follow ''02 their marketing history by really rather minimal inspectional tech- niques, Dr. Gorppere. I am not really clear how the inspector is going to obtain that information. Could you spell that out a little more? Mr. Goopricu. Sales volume will be the first indicator. Dr. Gorpgrre. Well, sales volume is one of the criteria. But wouldn’t it be important to put a quota on it in the first place? Mr. Goonricu. It might. That certainly is worth considering. But we wouldn’t have any basis at the moment of deciding how to quota it. And instead we have to go with this warning, which we think will work, and see what happens. Dr. Gotpsere. I would personally doubt that even sales volume would tell you very much. It might signify that the persons for whom it is not intended are purchasing it, and those you have in mind for the consumption of it are avoiding it. Mr. Goopricu. It might well do that, but these might be gross indi- cators. Was the product being continued as a food instead of as a drug as we intended. Mr. Fountarn. Mr. Goodrich, I asked you the question if you ap- proved any new drug applications for artificial sweetners containing cyclamates, and you said “yes.” And I asked you if it was possible to prepare the food additive regulation for cyclamates in view of their established capacity to induce cancer in animals and further, the existence of the Delaney amendment, and I believe you answered that nai"? Mz. Goopricn. That’s right. Mr. Fountain. How can you reconcile that with the law as I read it? Mr. Goopricx. By following the line that these are drugs, Mr. Chair- man. This is our only justification. Mr. Fountain. Notwithstanding what the result may be, you are basing it on the intention ? Mr. Goopricu. The intended use is the touchstone of the decision _ on whether a product is a drug ornot. Mr. Founrarn, The language says, anything that may result in being a component. Mr. Goopricu. Yes, but that definition stands in the same chapter with the definition of drug, which says any article, the intended use of which, or intended for use in the cure, mitigation, or treatment of man, isa drug. Mr. Fountarn. May I ask you your interpretation of this language, “where a substance is both a new drug and a food additive, the sub- mission of a new drug application in accordance with the regulation will also be construed as a petition for establishment of a regulation for the use of the substance as a food additive: the new drug application will not be approved for the use that results in the substance becoming a food additive until a regulation is established under section 408 or | 409 of this act.” And then the new drug application and the establishment of a regu- lation respecting the food additive will be acted upon simultaneously. Mr. Goopricu. That was to deal with a situation such as I posed to _ you of the drug intended for treating an animal, which results in a tissue residue in the edible flesh, or things of that kind. When that regulation was placed into effect the food additive law was new. The ''53 medicated feeds and drugs for animals had been approved in the past, and the residue problem was being posed for us, and this was to cope with that problem. pine Mr. Founvarn. In approving the abbreviated new drug applications for such sweeteners, I take it that you feel you have not violated your _ own regulation 121.7, promulgated under the food additive section of the law? Mr. Goopricu. That is our belief, sir. Mr. Founrarn. Would you disagree with the statement that it is clear that regulation 121.7 has a definite requirement for FDA to con- sider the new drug applications for food additive use simultaneously with the establishment of food additive regulations ? Mr. Goopricn. Yes, I agree that it says that, and I can assure you that we did consider all of that when this policy or decision was made, that the consequences of the Delaney clause were well known and understood. They were recognized by me that the article could not be approved except strictly for drug use and this is the basis on which I acted. Mr. Fountain. I would like to go into some questions relating to the March 17, 1970 order, from the Federal Register of March 24, 1970, requiring the filing of abbreviated new drug applications for cycla- mates-containing products, and requiring labeling statements limiting the use to diabetic or obese patients under medical supervision, and further requiring a boxed label which I referred to earlier, reading, “Medical supervision is essential for safe use.” The implications of that order and the seemingly extreme departure from normal processing of abbreviated new drug applications will, I think, be covered in these questions. The products covered by the order have been traditional foods such as artificially sweetened peaches, and are covered by food standards still in effect. Yet the Food and Drug Administration has declared such foods to — be new drugs. Dr. Edwards, I would like to refer now to the order, Regulation No. 130.48, relating to the conditions for marketing cycla- mates-containing products as drugs, which appeared in the Federal Register, volume 35, No. 57, on Tuesday, March 24, 1970 I have already placed the Federal Register statement in the record. The regulation, in subsection (a), states in part, “Products that are useful in regulating the intake of protein, fats, carbohydrates, or calories, for the purpose of maintaining or reducing volume weight under medical supervision, or that are useful in the diet of diabetics, may be marketed on the basis of an approved abbreviated new drug application.” Now under part D of the order, dietetic jams, jellies, desserts and ice creams are specifically mentioned as products within the scope of the order. And FDA, according to this order, will permit cyclamates in these products under an approved abbreviated NDA. Do the Canadian officials permit such use in Canada? Dr. Epwarps. I would like to ask Mr. Fine to answer that question, _Mr. Chairman. Mr. Frvr. I believe you still have my copy of the Canadian order there, that they are not going to permit such products with drug labels, as of April 1. ¢ ''54 _.. Mr. Founrarn. We will put in the record a copy of a memorandum dated March 31, 1970 from Dr. Edwards to the Surgeon General, Dr. Steinfeld, which bears on the March 24 Federal Register notice, and on the attitude of the Canadian officials regarding cyclamates-containing products. (The document referred to follows:) Marcu 31, 1970. To: Dr. Jesse L. Steinfeld, Surgeon General. From: Commissioner of Food and Drugs (OC-1). Subject : Cyclamates in foods. The Medical Advisory Group to the Secretary expressed the unanimous opinion that under appropriate medical management of individuals with diabetes (par- ticularly in the case of juvenile diabetics) and of patients in whom weight re- duction and control are essential for health, cyclamates provide medical benefits which outweigh the hazards. Further, the group also recommended that cycla- mates continue to be made available for such patients on medical advice and ‘on a nonprescription, drug-labeled basis. The Federal Register of March 24, 1970, sets forth the conditions for marketing cyclamate-containing products as drugs (exhibit A). At the ninth annual meeting of the Society of Toxicology, Atlanta, Ga., March 15-19, 1970, a paper was presented entitled, “Myocardial Lesions Induced by Calcium Cyclamate in Syrian Hamsters.” An abstract is attached as exhibit B. Significant is the statement that: ‘‘Alloxan-diabetic hamsters were much more sensitive than healthy ones to the adverse effect of Ca-cyclamate” and the state- ment, “It seems that cyclamate enhances the toxicity of Ca as well as of Na with either of which it forms a stable, water-soluble salt.” This paper was re- ported on in Food Chemical News of ‘March 23, 1970. On March 6, 1970, the Canadian Food and Drug Directorate issued Trade Information Letter No. 328. (Exhibit C.) You will note that Canada has as of April 1, 1970, a total ban on cyclamates in the following commodities: Soft drinks, beverage bases and mixes. Fruit spreads. Puddings. Bakery products. Frozen and other desserts. Confectionery. Table sirups. Dressings. Toppings. You will recall that following the Secretary’s press conference in October of 1969, it was agreed with the Canadian authorities that the interdependence of the Canadian and U.S. markets necessitated similar policies relating to food products containing cyclamates. It is obvious that the two Governments no longer have similar policies. In light of the trade press report of March 23, 1970, on the paper presented at | Atlanta (exhibit B) and the Canadian Trade Information Letter No. 328 (ex- hibit C), it is most likely that embarrassing questions may be asked in the lay press about why the United States continues to permit cyclamates in foods, while Canada is phasing them out. : CHARLES C. Epwarps, M.D. Mr. Founrarn. The following is in part declared in this letter, and I quote: On March 6, 1970, the Canadian Food and Drug Directorate issued Trade In- formation Letter Number 328. You will note that Canada, as of April 1, 1970, has a total ban on cyclamates in the following commodities: soft drinks, beverage bases, and mixes, fruit spreads, pudding, bakery products, frozen and other desserts * * * You will recall that following the Secretary’s press conference in October 1969, it was agreed with the Canadian authorities that the interdependence of the Canada and U.S. markets necessitated similar policies relating to food products containing cyclamates. It is obvious that the two governments no longer have similar policies. ''5d In light of the trade press report of March 23, 1970, and the paper presented at Atlanta, the Canadian Trade Information Letter Number 328, it is most likely that embarrassing questions may be asked in the lay press about why the United States continues to permit cyclamates in food while Canada is phasing them out. Why did you feel that the questions might be embarrassing if your decision to permit cyclamates in foods was correct, and a scientific one? Dr. Epwarps. Obviously, we had up until this time attempted to keep our policies reasonably alike but at this point we started out in our own direction without specific regard for what they were doing. Again, I think it boils down, or goes back to the fact that basically our policies were the same, with the exception that we had declared these as drugs, and put ourselves in a certainly different position than the Canadians. Mr. Fountatn. That is the reason you figured the lay public would be expressing concern ? Dr. Epwarps. Right. I think that with our geographic closeness to Canada, we have to be reasonably realistic or similar in what we pro- vide the public, or the consumer. Mr. Fountain. Is it intended that the cyclamates-containing prod- ucts which will now be permitted on the market are to be sold as drugs only to those persons with diabetes and to patients in whom weight re- duction and control are essential for health ? Dr. Enwarps. That is what our hope is. Mr. Founrary. But you have no way at the moment of assuring that that hope will be realized ? Dr. Epwarps. No. As I think Mr. Goodrich said a few moments ago, Mr. Chairman, we certainly are not in a position where we can say we have made a real fast ruling on this particular subject, and ig- nore it. In the very near future we have to reassess our position and maybe we made the wrong decision. Only time will give us that, and I don’t think it is going to take a great deal of time to make that judg- ment. Mr. Fountarn. I think that the important thing is that the general public and everyone understands where we are and what is involved, regardless of what your decision is. Dr. Enwarps. That’s right. Mr. Founratn. This would then exclude, would it not, the use of these preparations except when they are essential to health ? Dr. Epwarps. That’s right. Mr. Founratn. Will you explain the circumstances under which diatetic jams and jellies and desserts and ice creams, and canned fruits and vegetables containing cyclamates are essential to health ? Dr. Epwarons. As I recall, the report of the committee that Dr. Ege- berg appointed in the fall, late in the fall, to advise on this whole subject of cyclamates stated the following : Although the use of cyclamates is not absolutely necessary in any disease, it is recognized that it can be useful in the medical management of individuals with diabetes or patients in whom weight reduction and control is essential to health. Especially in juvenile diabetics where sweets and soft drinks are special problems, nonnutritive sweetened foods may be an essential part of the pre- ventive therapy. ''56 This was the basic decision of the medical expert committee, and it was the reason for our categorizing some of these products as essen- tial to medical management of some of these diabetic patients and in the cases of obesity as well. Mr. Founratn. Did I understand your previous testimony that it was unanimous that these items be made available essentially for health reasons ? Dr. Epwarps. Yes, that was the only reason for making these par- ticular items available. Mr. Founratrn. Was that a unanimous opinion ? Dr. Epwarps. The unanimous opinion of the advisory committee? Mr. Fountain. Yes. Dr. Epwarps. I don’t know. Mr. Goopricu. I know of no conflict, Mr. Chairman. Mr. Founratrn. I understood the opinion was unanimous. Mr. Goopricu. What we have to go on is the report that they unani- mously supported the Secretary’s view. This is published as a special communication in the Journal of the American Medical Association, February 23, 1970. Now when they get over to discussing the medical uses, there is cer- tainly no indication of any disagreement at all. Dr. Epwarps. They merely unanimously supported his position in regard to the general purpose foods. ; Mr. Fountarn. I believe item 2 of the regulation said it endorsed the prohibition of cyclamates in beverages for general use, and then it expressed the unanimous opinion that under appropriate medical man- agement of individuals, with diabetes, particularly in the case of ju- venile diabetics, and patients with weight reduction problems, cycla- mates provide medical advantages which outweigh their hazards. Now what was your interpretation, that it was a unanimous opinion 2 Mr. Goopricu. Yes. Mr. Founvatrn. I have here a memorandum from Dr. H. F. Kray- bill, Ph. D., assistant director for biological sciences research, bureau of science, to the deputy assistant administrator for research and de- velopment, dated December 19, 1969, in which he says in part—and the whole memorandum will put in the record— For those who can regiment themselves, neither cyclamates nor saccharin are necessary. One presumably faces an issue of benefits versus risk, although one physician in the group advised me that he felt that hypoglycemics and hyper- glycemics might well avoid the use of cyclamates. , (The document referred to follows :) DECEMBER 19, 1969. To: Deputy Assistant Administrator for Research and Development. From: H. F. Kraybill, Ph. D., Assistant Director for Biological Sciences Research, Bureau of Science (SC 4). Subject: Congenital defects, diabetes, and cyclamates (reference to Medical Advisory Group on Cyclamates). In your memorandum of December 9 to Director of Division of Pharmacology and Toxicology, this Bureau, you raise some interesting points. It is hopeful that I might clarify some of these points, which my memorandum of November 20 did not adequately cover, without extending discussion too much beyond points within which we are in agreement. '' , 57 Your concern, I take it, is whether the Medical Advisory Group on Cycla- - mates, which Secretary Finch convened on November 17-18, adequately covered those areas of carcinogenesis and teratogenesis as they apply to the human population. You are aware of the fact that Dr. Schrogie and I were present only part time in those sessions and not as commentators on key issues, although Dr. Schrogie did have a chance to see some of the original notations and recommend changes. ‘ : ; : You are quite correct in your concern about the diabetics and offspring of dia- betics with reference to cyclamate stress. A paper by Watanabe et al. (Diabetes, vol. 12. No. 4, 1963, pp. 66-72) stresses the intimations of a teratogenic effect of diabetes extending back into the 19th century and now with indications of birth defects (chick embryo) caused by cyclamates, this takes on a more serious aspect to be looked for in relation to cyclamates. The need for epidemiological studies in this area was discussed fully by our NAS/NRC Committee in review of cycla- mates on October 16. Since last discussing this matter with you, I have had a chance to see a pre- liminary draft of minutes of the Medical Advisory Group on Cyclamates meeting and a member of Dr. Steinfeld’s staff has informed me that full discussion was held on the matter of birth defects and bladder cancer. Apparently with reference to the matter of bladder cancer there was some divergent viewpoints with NCI member particularly concerned about the impact of cyclamate. The other mem- bers of the group, however, made a strong plea for cyclamates feeling that in clinical management of a juvenile diabetic some “carrot” must be provided to those who have an unrelentless craving for sweets or sweetening agents. For those who can regiment themselves, perhaps neither cyclamates nor saccharin are necessary. One presumably faces an issue of benefit versus risk, although one physician in the group advised me that he felt that hypoglycemics or hypergly- cemics might well avoid the use of cyclamates. You are quite correct in insisting that a followup on those exposed in the sixties might be in order to establish causal relationship between bladder cancer and cyclamates. In my memorandum of November 20, I was emphasizing the fact that hyperglycemics, of course, would be a population group at high risk unless their metabolic aberration puts them in a different category then the nondiabetic population for their propensity toward tumor induction. There is indeed a basis for the view in experimental carcinogenesis that a stress agent given as an insult to an animal once or twice becomes the activator for induction of a carcinoma at a later time (case in point, aflatoxin induction of liver cancer in the rat). At a meeting of our Epidemiology Advisory Panel to an FDA Advisory Group on December 9, bladder cancer was discussed in terms of environmental agents. It was their opinion that bladder cancer is an event of low frequency (Dr. Schneiderman estimated about 1,200 cases per annum in the United States of America), as compared with cancer at other sites. Perhaps cyclamates or cycla- mate exposure might elevate that frequency, who knows? The matter of birth defects presents an interesting problem for exploration. Again I was informed that this matter was fully discussed in terms of all groups of the population and reference will be made in the forthcoming report from the Medical Advisory Group that the aspect of teratogenesis, mutagenesis, and car- cinogenesis was fully considered. This report should be available soon. The Medi- cal Advisory Group were particularly concerned about groups such as teenagers, nondiabetics, and diabetics who may have higher intakes of eyclamates. We shall _have to wait to see their final report as to what recommendations have been advanced. Mr. Founrarn. Now, the physician referred to was a member of that advisory group, was he not ? Dr. Epwarps. Yes. Mr. Fountarn. So that would indicate the opinion was not unani- mous. Dr, Epwarps. I don’t think that that is necessarily contrary to the unanimous opinion of the group. If I am interpreting what you read correctly, Mr. Chairman, what he is saying is that if one exercises the proper amount of willpower, one can get along without this. There are many diabetics that can get along on diet alone. ''58 Certainly in the case of obesity, if one has the willpower one needn’t use any cyclamates in terms of attempting to cut down his caloric intake. ‘ So I don’t think it is necessarily contrary to what has been said. Mr. Fountain. Are diabetics hyperglycemics ? Dr. Wopicxs. Yes. Mr. Goopricu. What we went by, Mr. Chairman, is the statement on the first page of the report, where it summarizes the committee’s find- ings and the sentence was that the advisory group was of the opinion— and it didn’t mention any dissent—that the medical benefits in these instances outweigh the possibility of harm and recommended that cyclamates and products containing cyclamates be continued to be made available to such patients on the advice of their physicians and on a nonprescription drug labeling basis. This I believe is what is re- flected in that Federal Register document. I interpreted this to mean that there was agreement on this point and this document was shown to both Dr. Ley and Dr. Steinfeld, who were ex officio members of the committee, and certainly neither one of them indicated to me any dissent. : I am not surprised that one member there would have perhaps some question, but it is not necessarily dissent from the recommendations. Dr. Epwarps. The recommendation that should be emphasized, Mr, Chairman, is that we are talking about some diabetics, not all diabetics. Mr. Fountrarn. Mr. Goodrich, did you write these regulations ? Mr. Goopricu. Yes, I did, sir. Mr. Founrarn. They are pretty clear to me, although there are some differences in interpretation. You did a good job of writing meaningful regulations. ~Mr. Goopricu. Well, what was given me, Mr. Chairman, was the report of the committee and the request from Dr. Steinfeld and the Food and Drug people, to prepare a document within the limits to. the law that could implement this decision, or tell them it couldn’t be done. I told them it could be done this way, and I accept full responsi- bility for it. Mr. Fountarn. Would you summarize again—I think you answered this question, but I will ask it again—your explanation of the circum- stances under which diabetic jams, jellies, desserts, ice creams, and so forth, containing cyclamates, are essential for health? Dr. Epwarps. If I may, Mr. Chairman, I will read again— Although the use of cyclamates is not absolutely necessary in any disease, it ean be useful in the medical management of individuals with diabetes and patients in whom weight reduction and control is essential 'to health. Particularly ‘iin juvenile patients, who have diabetes, where sweets and soft drinks are a special problem, non-nutritive sweetened foods may be an essential part of preventive therapy. Mr. Fountain. Are you talking about juvenile diabetes? _ Dr. Epwarps. They relate right here in this particular article to juvenile diabetes, but the same basic principle would hold true in adult diabetes as well, although juvenile diabetics are more difficult to control, it’s more difficult in getting them to stick to a diet and so forth. But the basic principle in terms of treatment of diabetes is basically the same. / ''09 Dr. Gotppere. Just so that I understand what you are saying, you are testifying that jams, jellies, desserts and ice cream, and so on do have an essential place in the management of adult diabetes? Dr. Epwarps. I am not exactly saying that, no. I am saying that jams, jellies, et cetera, are foods with an abnormally high caloric con- tent, and in terms of developing for the diabetic patient a well rounded, pleasant, easy to take diet, it is important to be able to include certain of these food elements. Dr. Gotppere. Is it necessary for people in that category to have desserts at all? Dr. Epwarps. Probably not, no. Again, let me make it clear this is | not my medical opinion. It is the opinion of the medical experts com- mittee that Dr. Egeberg put together. I think the point you make is certainly valid. There is no reason for any dessert, but as you know, in children and in many adults, that is easier said than accomplished. Dr. Gotpeerc. I appreciate the distinction you are making between your own expression and that of the committee. What prompts me to ask the question is the fact that I know many people who have elevated cholesterol levels and find it possible to avoid eating desserts on the advice of their physicians. These people can follow that course, I can see no medical justification for considering jams, jellies, et cetera, as . being essential for diabetics. Dr. Epwaros. I think certainly it would principally be the juvenile, not the adult, where a true appreciation of sticking to a rather rigid diet is more difficult to come by. Dr. Gorpsere. If we grant that there is a need for these foods for the juvenile diabetic, are you not in effect exposing the whole popula- tion to the use of a cyclamate product just to satisfy the craving of that one small group ? Dr. Epwarps. If our label isn’t accomplishing the purpose that we hope it is accomplishing, you are right. Although here again the amount of cyclamate exposure plays a very important role. I think some of these jams, jellies, et cetera, are not going to be probably utilized on a frequent enough basis to be of a significant health hazard. On the other hand, I am hopeful that our drug label on these par- ticular products will accomplish the purpose that we have intended it for. That this produce will not be consumed by the general public. Mr. Fountain. Are the words essential for health in the medical advisory committee’s report or, is that in the statute ? Dr. Epwaros. I will read the two parts, Mr. Chairman. “Although the use of cyclamates is not absolutely necessary for any disease”—I think that is a fair statement—and at the bottom of the same paragraph it says, “nonnutritive sweetened foods may be an es- sential part of preventive therapy.” Again that can be interpreted in several different ways. Mr. Founrarn. May be essential. Dr. Epwarps. Yes. Mr. Fountain. I believe the second paragraph says that the patients in whom weight reduction and control are essential for health, eycla- mates provide the medical benefit which outweight the hazards. Mr. Goopricu. What we are trying to emphasize there, Mr. Chair- man, is just that anyone should not have access to these products. That ''60 e they should be only for an obese person under medical supervision. That is an obese person who has a weight control problem that brings him to the doctor. Now there again we will have to see how this works, but our inten- tion is honorable, I believe. Mr. Founrarn. But they are permitted to be sold for extremely restricted use ? Dr. Epwarps. We hope it is restricted. If it isn’t, we have to make sure that it is restricted or eliminate the use of these altogether. Mr. Fountarn. Are you satisfied that your decision to permit the sale of cyclamates for restricted use was a wise decision ? Dr. Epwarps. I think, Mr. Chairman Mr. Founrarn. Even for restricted use ? Dr. Epwarps. My reaction at this moment is yes, but I may have to change that opinion in a very short period of time if we find that in fact this is not a restricted use but is being utilized by the public generally. Mr. Founrarn. I really have not intended the question that way. But in other words, there is no question that you made a wise decision when you went as far as you did? That is the point I want to make, Do you think that was a wise decision in limiting the sale of cyclamates to these restricted uses even though you may decide to go even further? Dr. Epwarps. I think so. Again this is under the advice of our specialists, _ Mr. Fountarn. And based upon the data you have ? Dr. Epwarps. Yes, and the advice that we obtained from these so- called experts, I think we made the right decision. Now again whether it is or isn’t remains to be seen. Mr. Founrartn. I think you have, to some extent, answered this question, but maybe you can add something to it. Are these diabetic jams, jellies, desserts and so forth in a true sense essential for health in that they help to stop the spread of a disease or have a positive effect on the disease by ameliorating or curing it ? Dr. Eywarps. No. Mr. Fountain. Doctor, would you say there is a difference of opin- ion, or two schools of thought at least, as to whether artificially sweetened foods are necessary for the diabetic or the obese individual ? Dr. Epwarps. I think there are two schools of thought, yes. Mr. Fountain. Now I would like to put in the record a copy of memorandum of February 5, 1970, to John Jennings, Acting Director, Bureau of Medicine, on the subject of cyclamate foods and it is signed by Dr. Marvin Seife, Acting Associate Director for Marketed Drugs, Bureau of Medicine and from which I would like to quote. (The document referred to follows :) '' 61 DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, Pusiic HEALTH ‘SERVICE, Foop AND ‘DruG ADMINISTRATION, February 5, 1970. Reply to attention of : MD-800. Subject : Cyclamate foods (see Mr. Fine’s memo of January 2, 1970). To: John Jennings M.D., Acting Director, Bureau of Medicine/MD-1. 1. Strictly speaking, there is no medical necessity for any artificial sweeteners, even saccharin. Diabetics and overweight patients should be adhering 'to a diet that is calculated for their ideal weight, taking into account their sex, height, age, and physical activity. This type of diet ‘will contain proportionate amounts of carbohydrate, protein, and fat foodstuffs to be well balanced for nutritive - value and palatability. 2. The artificial sweeteners have actually contributed to a general disregard of the above principles in medical management of such patients by an over- | emphasis on the carbohydrate elimination from the diet and a substitution with other caloric, albeit noncarbohydrate, foodstuffs. 3. In only rare situations, specifically the young children and the very aged, where a lack of appetite may contribute to excessive weight loss and thus mal- nutrition, the artificial sweeteners have been helpful. To the vast majority of people, be they patients or not, these sweetening agents have been purely a matter of convenience. 4. It would be reasonable to suggest that cyclamate-containing foods be labeled so as to include a warning that the artificial sweetener is not a nutritive or — medical necessity and that medical advice should be sought and followed. 5. Cyclamate agents per se should be treated as other nonprescription drugs to be used on the advice of a physician. MARVIN SEIFE., Acting Associate Director for Marketed Drugs, Bureau of Medicine. Mr. Fountarn. Now I would like to quote from this document. 1. Strictly speaking, there is no medical necessity for any artificial sweeteners, even saccharin. Diabetics and overweight patients should be adhering to a diet that is calculated for their ideal weight, taking into account their sex, height, age, and physical activity. This type of diet will contain proportionate amounts of carbohydrate, protein, and fat foodstuffs to be well balanced for BLS value and palatability. 2. The artificial sweeteners have actually contributed to a general dusreaabe of the above principles in medical management of such patients by an over- emphasis on the carbohyd:ate elimination from the diet and a substitution with other caloric, albeit noncarbohydrate, food stuffs. Now I would also like to put into the record at this time a copy of a memorandum of a conference dated January 28, 1970, on the subject of the labeling of foods containing cyclamates. (Tp document referred to follows: ) MEMORANDUM OF CONFERENCE, JANUARY 28, 1970 x (Present: Dr. John Palmer, Bureau of Medicine; Miss Mary McEniry, Bureau of Medicine; Mr. Walter R. Moses and Mr. Taylor H. Quinn, Division of Case Guidance, Bureau of Compliance; Sam D. Fine, Acting Associate Commissioner for Compliance; and Robert O. Bartz, Office of the Associate Commissioner for Compliance. ) SUBJECT: LABELING OF FOODS CONTAINING CYCLAMATES On this date a discussion was held concerning the labeling of food products containing cyclamates. Dr. Palmer opened the meeting by discussing a meeting held within the ELureau of Medicine where it was suggested that a package be put together on labeling. This package then would be provided to interested parties for their views. Comments would be solicited from these specific groups: NAS/ 48-798-—70——-5 ''62 NRC, the American Diabetics Association, American Clinicians, the American Medical Association, the National Institutes of Health, and the Medical Advisory Group to the Secretary. Dr. Palmer stated the medical community had two schools of thought relative to dietary management of diabetics. Some physicians manage diets with no sweets, while others try to simulate as closely as possible the regular type diet with sweets. Additional points brought out by the Bureau of Medicine included the diffi- culty of setting a daily limit on cyclamate consumption. The American Diabetics Association has suggested 200 mg. per day as a possible figure. It was also suggested that possibly food manufacturers could formulate products without cyclamates and provide instructions for consumers to add their own sweeteners. - This was ruled out because of the Secretary’s statement indicating that cycla- mate containing foods would continue to be available. Mr. Fine brought out that we should keep in mind that cyclamate containing foods will be available, not only for diabetics, but also in dietary management for obesity. He also mentioned an answer must be forthcoming for those products falling within the February 1, 1970 deadline. It was pointed out that at this stage we are receiving large numbers of inquiries on labeling for which no ready answers are available. ‘ The submission of NDA’s for cyclamate containing foods was also discussed. Mr. Fine pointed out that the abbreviated NDA approach used for table sweet- eners set a precedent and Mr. Goodrich believed this same procedure should be utilized for other food products with cyclamates. The Bureau of Medicine repre- sentatives said the Bureau could not physically handle the number of NDA’s which would be received. It was then suggested that consideration be given to rule out certain foods. 4 Messrs. Moses and Quinn proposed three factors that the Bureau of Medicine might consider in this regard. Foods containing cyclamates may be marketed if manufacturers demonstrate the following : 1. Evidence to establish that the products are necessary. 2. That a reduction of calories be at least 50%, if cyclamates are used. (This would rule out bakery products but would permit canned fruits, jams, and jellies, and gelatin desserts). 3. That non-nutritive substitutes have been tried and do not work. Mr. Fine mentioned that Commissioner Edwards and he would be meeting with Dr. Egeberg on Friday, January 30, 1970, at 11:30 A.M. to discuss cyclamates. Mr. Fine asked Dr. Palmer and Miss McEniry to consider the proposals men- tioned and make recommendations prior to the meeting time. The question con- cerning what cyclamate containing foods are we going to have on the market and what labeling will be utilized requires prompt answers. The Bureau of Medicine was requested to make the medical decisions on this issue. Roser? O. BARTZ. Mr. Founratn. I will quote from the second paragraph : Dr. Palmer stated the medical community had two schools of thought relative to dietary management of diabetics. Some physicians manage diets with no sweets, while others try to simulate as closely as possible the regular type diet with sweets. Now Dr. Edwards, is it true or is it not true that there is a serious question as to the efficacy of cyclamate-containing foods in weight re- - duction or calorie intake control ? Dr. Epwarps. Will you repeat that question, Mr. Chairman, please ? Mr. Fountain. I will ask it this way. Is it true that there is a serious question as to the efficacy of the cyclamate-containing foods in weight reduction or caloric intake control ? Dr. Epwarps. J think that is—there is a question, yes. Mr. Founratn. In reference to the matter of efficacy of cyclamate- containing foods and weight reduction or caloric intake contro] I would now like to put into the record a memorandum from Dr. Edwin L. Hove, then acting director, division of nutrition to Dr. H. F. Kray- bill, Ph. D., assistant director for biological sciences research. This is dated October 6, 1969, and discusses the benefits of cyclamates. I will quote. - ” ''63 (The document referred to follows :) OcTOBER 6, 1969. To: H. F. Kraybill, Ph. D., SC-4, Assistant Director for Biological Sciences Research. ne From : Edwin L. Hove, Ph. D., SC—-700, Acting Director, Division of Nutrition. Subject : Comments on Dr. Schubert’s letter re cyclamates. Benefits of cyclamates (p.5, par. 1, of the Schubert letter) Dr. Schubert is probably correct in stating that no benefits with regard to weight reduction have been scientifically demonstrated for the cyclamates. The attached chart bears on this subject. It shows that during the rapid increase in the production of cyclamates (1962 to date) there was no discernable change in the per capita consumption of sugar in the U.S.A. Other USDA information indi- cates that the sugar equivalence of artificial sweeteners consumed in 1968 was 8.5 lbs. per person. This included both cyclamates and saccharin. There was no corresponding drop in refined sugar consumption for that year. A report in Nature (Dalderup & Visser, Nature 221 :91, 1969) does show that cyclamates stimulated | the appetite of rats causing greater weight gains and more eflicient utilization of food. Fetal mortality in pigs (p. 4, par. 8, of the Schubert letter ) The data obtained by WARF were not statistically significant. As I recall their figures, the 500 mg dose level had a probability of only 0.35, whereas the lower dose of 100 mg per kilo had a slightly better probability figure. Even when the numbers were ballooned by combining two experiments, the data still fell short of statistical significance. Conversion to CHA (p.1, par. 3, of the Schubert letter) A recent report by Dr. Pawan of London found that only 8 of 52, or about 15%, of a group of normal volunteers converted cyclamates to CHA with a maximum 24 hour excretion of CHA being 4.6 mg. This indicates that the conversion to CHA is not universally at the 30% level and that in some cases the maximum con- version is only in the neighborhood of 0.2%. I do not feel in a position to speak directly about other points raised in the Schubert letter. °° CYCLAMATE PRODUCTION ve “16 \ 6G 7) a Ze ce / Se es Mo] Oo at: QO. 2 . — 8 a © ee ° if ae t ee Le me A ‘ i A | | A RK if . 2 -o-~ ee ra me “ BIT OT O. Om ON ar a PNA ot REFINED SUGAR USED t | | i 935 1940 1945 1950 Les 1960 1965 1970 PATA SCURCE: USDA '' Mr. Founratn. The quotation is, “Dr. Schubert is probably correct in stating that no benefits with regard to weight reduction have been scientifically demonstrated for the cyclamates. The attached chart bears on this subject. It shows that during the rapid increase in the production of cyclamates—1962 to date—there was no discernible ‘change in the per capita consumption of sugar in the United States. Other USDA information indicates that the sugar equivalence of artificial sweeteners consumed in 1968 was 8.5 pounds per person, This included both cyclamates and saccharin. There was no corresponding drop in refined sugar consumption for that year. A report in Nature— Dalderup & Visser, Nature 221:91, 1969—does show that cyclamates stimulated the appetite of rats causing greater weight gains and more efficient utilization of food.” ava T am also putting into the record a report in Nature magazine, vol- | ume 221, of January 4, 1969; the article is entitled “Effects of Sodium Cyclamate on the Growth of Rats Compared With Other Variations in the Diet.” (The document referred to follows :) Errecrs or SoptuM CYCLAMATE ON THE GROWTH OF Rats COMPARED WITH OTHER VARIATIONS IN THE DIET We have studied the effects on rats of sodium cyclamate in amounts corres- ponding to those consumed by man. Malle rates were chosen because differences in weight, food consumption, and food efficiency (growth per calorie of food) are usually more distinct in males than in females. 101 weanling albino rats. divided into six groups, were given a human type diet in a drier and ground form, com- — posed according to the data on the food consumption of the Dutch population in 1961 (refs. 1 and 2). This ‘“Ran-1961” diet was varied by substituting different compounds for bread and potato starch in isocalorically proportionate amounts. | The protein lost by replacing potato and bread was resupplied with cooked potato protein and wheat gluten. Sodium cyclamate was substituted for two-thirds of the sugar in the original diet so that the sweetening effect was the same; that is, in an amount 1/30 of the weight of the sugar. The sugar content of the Ran-1961 diet is 15 kealories percent. ; The six rations are: I, Ran—1961 control; II-V, Ran—1961 with 15 kealories percent of sugar, butter, sunflower oil, and lean dried beef, respectively, instead of starch; VI, Ran-1961-cyclamate, containing 4.26 milligrams of sodium cycla- mate/gram of food. Table 1 gives the weight, gain in weight, food consumption, and food efficiency data for a 6-week-experimental period. There is little difference between groups I-V, whereas the animals in group VI gained appreciably more weight than any in the other groups. Wilcoxon’s parameter-free ranking tests*® was applied to calculate the bilateral ‘tail errors (P:). For tthe difference between group 1 and group VI, P:=0.01. The data for consumption of food showed a similar pattern from the first weeks onward: over 6 weeks P2=$.045. Even the food efficiency was significantly higher than that of the control group (P2=0.002). The only remarkable point in the results from the other groups was the rela- | tively low food consumption—in kealories—of the animals receiving extra meat, although their weight gain did not differ from that of groups I-IV. Their food efficiency was high, however, and differed significantly from that of the butter and sunflower oil groups (P=0.03) though not from the control group. 1Dalderup, L. M., Keller, G. H. M., Visser, W., de Vries, J. E., and van Haard, W. B., Netherl, J. Nutrit. (Voeding), 28, 556 (1967). i 245 (1968) L. M., Visser, W., and Keller, G. H. M., Netherl. J. Nutrit. (Voeding), 29, (ase ae 3 Wilcoxon, F., Biometrics, 1, 80 (1945) ; Mann, H. B., and Whitney, D. R., Ann. Math. oe Stat. 18, 50 (1947). a '' 4 ‘ } TABLE 1.—AVERAGE WEIGHT, WEIGHT GAIN, FOOD CONSUMPTION, AND FOOD EFFICIENCY DATA ‘ Sunflower Dried Sodium Control Sugar extra Butter extra oilextra meat extra cyclamate Group I il i IV V Vi Number of animals___.._.-___- pibd: 17 7 17 16 LES ie Initial weight (g.)__-._- 48-6 48-5 48-6 48-5 49-1 48-2 » aang [CREE chasse 37-64 36-66 32-64 33-59 34-65 35-64 Weight after 6 weeks (g.)___-_- 158-6 158-5 147-0 148-5 145-3 188-2 | Range(gJer ro 22. 95-218 119-207 99-198 91-222 76-208 150-237 Weight gain (g.)-_ 110-0 110-0 98-4 99-6 96-2 139-9 ANGE one es eae a 58-161 74-158 58-149 48-163 42-14 99-173 Total food consumption in the first 6 weeks (g.)--.-.------- 469.7 421-4 424-9 372-9 509-6 EE SE 376-5-573 329-5-524-5 355-5-541 = 249-471-5 359-608, Calorie content per g. food 4-21 4-51 4-59 4-29 , 4185, a Tota! food consumption in the first 6 weeks (calories) .._-._. 1, 936 1,974 1,900 1, 943 1,600 ALB) Range (calories) _-__._____ 1, 500-2, 358 1,585-2,412 1, 486-2,366 1,632-2,360 1,068-2,023 1,502-2, 546. k Food eee: growth in g. / s per 100 calories_____________ 5-61 5:57 5-12 5-09 5-97 6-55. a4 (g. per 100 calories). 3-87-7-02 3-90-7-61 3-74-6-42 2-94-6-91 3-19-8-40 5-11-7-39 Statistically significantly differ- ent from control group: Weight after 6 weeks and Mates re th Sh Ec ee ek Oe Ne P2=0-01 Food consumption___- P2=0-045 Growth per calorie of foo P,=0-002 1 Although not significantly different from the control group, the differences from the butter and the sunflower oil groups were both significant at the 3 percent level. Sodium cyclamate in the quantity given (0.48 percent) seems to stimulate appe- tite, and thus a rise in weight. It is surprising that the food efficiency is also betas higher than in the controls. If this is also true for man, then weight reduction ee will be more difficult if the diet contains cyclamate. The small variations in total a food composition between diet VI and ithe control can scarcely be significant, for the far greater variations in rations II-V had no substantial effects. } Fitzhugh et al.t have studied the effects of cyclamate in higher doses. One percent cyclamate mixed in food had no siguificant effect on the growth of rats, although males showed a tendency to gain weight and the females a tendency to growth inhibition—up to adulthood (1 year old). Higher doses—5 or even 10 percent of the food given—resulted in a distinct retardation of growth.>” The dose given—although based on possible human consumption—is rather high for the animal in relation to its weight. It amounts to 70 mg/rat/day, which is 565 mg/kg body weight in the 6th week of the study ; the maximum permissible 4 amount for man is 50 mg/kg body weight. A dose of 5 percent of the food is = equivalent to more than 10 times the dose administered in our experiment (750 een mg/rat/day ). x Tt is clear that it is not sufficient to give only extremely large doses of certain : compounds to test animals ‘to discover their effects; administration of lower doses also provides useful information. We are continuing these studies with rats of both sexes. L. M. DALpERvP. ie j W. VISSER ee Netherlands Institute of Nutrition, Wageningen. iv Received Oct. 28 ; revised Nov, 18, 1968. Mr. Fountain. This states in part, “Sodium cyclamate in the quan- ae if tity given (0.43 percent) seems to stimulate appetite, and thus a rise in weight. It is surprising that the food efficiency is also higher than ait AS leis, G., Nelson, A. A., and Frawley, J. P., J. Amer. Pharmacol. Assoc., sci. ed., ,» 588 (1951). 5 Nees, P. O., and Derse, P. H., Nature, 208, 81 (1965). ® Nees, P. O., and Derse, P. H. (Wisconsin Alumni Research Foundation, Calcium Cycla- mate Feeding Study, Madison, 1965.) 7 Ferrando, M. R.. and Hacket, B., Bull. Acad. Nat. Med., 3/4, 36 (1968). ''66 in the controls. If this is also true for man, then weight reduction will be more difficult if the diet contains cyclamate.” And I would also like to put into the record a copy of several pages _ (pp. 73, 74, and 75) of the Medical Letter on Drugs and Therapeutics, vol. 6, No. 19, September 11, 1964, from which I will quote. Tue MEDICAL LETTER ON DRUGS AND THERAPEUTICS ARTIFICIAL SWEETENERS AGAIN The use of the artificial sweeteners—saccharin (2,3-dihy dro-3-0xobenziso- sulfonazole) and cyclamate (N- yclohexylsulfamate)—separately or in com- bination, as substitutes for sugar in a great variety of beverages and foods (coffee, tea, soft drinks, baked goods, desserts, canned fruits, vegetable juices, and syrups) has become more widespread since the last Medical Letter report on this subject (5:96, 1963). Since 1957, the use of cyclamate in bacon and later in ham as a substitute for sugar has been permitted by the Meat Inspection Division of the U.S. Department of Agriculture. Originally intended for special dietary purposes, as in the management of severe diabetes, the use of artificially sweetened food and drink has become the vogue even when there is no need to limit caloric intake. Television ads regularly proclaim the virtues and con- veniences of artificial sweeteners for cooking and baking and for desserts, syrups, and beverages prepared at home, as well as in commercial soft drinks. Effectiveness in a weight-reduction program ven for weight reduction, the use of noncaloric sweeteners is of questionable. value. In a study of their effectiveness among 247 obese and 100 diabetic persons (M. B. McCann, et al., J. Amer. Diet. Assoc. 32 : 327, 1956), the authors found “No significant difference * when the weight loss of users and nonusers of these products was compared: No correlation was found between the length of time these products were used and weight loss. * * *” Except where intake of sugar must be limited, as in some diabetic patients, the unrestricted use of artificial sweeteners makes little sense, especially since their safety is not beyond ques- tion. It should also be remembered that sugar is an important source of energy in children. Safety of artificial sweeteners The National Research Council’s Food Protection Committee judged that the use of the sweetening drugs for special dietary purposes was not hazardous in view of the low daily intake in such use (Policy Statement on Artificial Sweeteners, Food Protection Committee of the Food & Nutrition Board, 1955, revised 1962). Most of the studies on the metabolism, excretion, and toxicity of saccharin were made in the earlier part of the century. Large amounts of saccharin were used during wartime periods of sugar shortages, and no adverse effects were reported. A fresh examination of the effects of saccharin on human subjects in health and disease is, however, needed. On a weight basis, cyclamate is one-thirteenth as sweet as saccharin, and is the chief agent used in commercial foods and drinks. When the use of cyclamate was less widespread, the Medical Letter estimated that a child or adult could ingest about 3 grams a day from consumption of popular beverages and foods. The only published study of the metabolic, excretory, and toxic effects of cyclamate in man was that of J. A. Schoenberger, et al. (Amer. J. Med. Sci., 225: 551, 1953). It disclosed no disturbance in nitrogen, sodium, or potassium balance : there was no evidence, when cyclamate was used over a period of months, of toxic injury to the blood, vascular, liver, and renal systems. An average of 37 percent was excreted in the urine after oral administration of cyclamate. There was no clear indication how the remainder was disposed of in each subject. This study was, moreover, limited to a few healthy males. Studies in chronically ill patients have not been reported. Safety of cyclamate The Food Protection Committee said, in its 1955 report, The Safety of Artificial Sweeteners for Use in Foods, “Although ingestion of cyclamate in amounts of 5 or more g. per day is capable in healthy adults of inducing in some individuals ''\s 67 the formation of soft or mushy stools, there is no evidence of direct functional change in the gastrointestinal tract. It is not unlikely that per capita daily con- sumption of cyclamate will exceed 5 g. in a significant segment of the popula- tion if the full potential usage of this material in foods and beverages is exploited. * * * While the studies made on the toxicology and pharmacology of the cyclamate indicate that this substance is relatively nontoxic, it must be borne in mind that in the human there has been study of its effects only in adult males. * * * Additional information on the physiology of excretion of ¢ycla- mate is needed. Study of renal clearance is especially pertinent since we have no data on the effects of the use of cyclamate during pregnancy, in children, or in cases of renal dysfunction. Observations on mammary secretion of cyclamate would be of value. The possibility of deleterious effects in cases of lower bowel disease should be considered.’ Even more important, no studies have appeared on the effects of saccharin and cyclamate on the human fetus or in persons with chronic disease, and such studies should be undertaken. As the National Research Council’s Committee points out, these materials “* * * should be subject to continuing observation for possible deleterious effects under prolonged and varying conditions of use and should be reappraised when- ever indicated by advances in knowledge.” In the light of the wide and indis- criminate use of these sweeteners, a reappraisal of the toxicology of artificial sweeteners, in sick as well as healthy persons and in pregnancy and lactation, is in order. The statement of a manufacturer of cyclamate that 14 years of continuous experience and usage of cyclamate “without evidence of harmful effects” should be considered an adequate reply to questions about its safety betrays a naivete about adverse effects of drugs and chemicals. For example, substantial cigarette smoking began in 1910, but it was not until 1950 that systematic inquiries began which ultimately implicated cigarette smoking as a major cause of lung cancer; aspirin was marketed in 1899, but it was not until the present decade that gastric bleeding was shown to be an important side effect. CONCLUSION Until the many unanswered questions with respect to the toxicity of saccharin and cyclamate have been answered, The Medical Letter regards the current pro- motion and extension of use of these agents as against the public interest and believes that action by the medical profession, health authorities and Federal agencies to inform and protect consumers is in order. It would also be desirable for the FDA and the National Research Council to undertake independent in- vestigations of the safety of saccharin and cyclamate under all conditions of human use, including use during pregnancy. Mr. Fountarn. This is the quote: Effectiveness in a weight-reduction program.—Kven for weight reduction, the use of noncaloric sweeteners is of questionable value. In a study of their effec- tiveness among 247 obese and 100 diabetic persons (M. B. McCann, et al., J. Amer. Diet Assoc., 32:327, 1956), the authors found “No significant differ- ence * * * when the weight loss of users and nonusers of these products was compared.” : Lalso refer to the article on artificial sweeteners by John J. Schrogie, M.D., previously placed in the record and I cite the last paragraph of the article which IT quote: Although many questions about the safety of artificial sweeteners have been raised, few have been resolved. Largely left out of the public controversy has been the issue of their effectiveness in weight reduction. None of the few controlled studies reported to date have established a useful role for nonnutri- tive sweeteners as weight reducting except under the most carefully controlled circumstances. Finally, in the same connection I would like to put in the record a memorandum of January 30, 1970, from the files of the FDA entitled, “Cyclamates. The problem—Handling foods containing cyclamates as drugs,” from which I quote. '' ia 68 wet (The document referred to follows :) Rey NoTE.—DO NOT USE THIS ROUTE SLIP TO pare) Bast | SHOW FORMAL CLEARANCES OR APPROVALS vs oy 0 TO: ia AGENCY @LDG. ROOM pe gags a ¥ HS » ay / ee zt ; = ae arti ne ( APPROVAL CO REVIEW 1 PER CONVERSATION mee ‘ Co SIGNATURE =]. NOTEAND SEE ME =) AS REQUESTED ne é } CO COMMENT =$©(_ NOTE AND RETURN _([)_ NECESSARY ACTION pi Beads - © For Your INFDRMATICN a (C) PREPARE REPLY FOR SIGNATURE OF be | ; | Ces fees ie Anat Bet Boel [re Gow ge ie Mt tae ® ve (1228 a ee, cn ee i, J (Fold here for return) Le eo We Ro. From Mary A. McEniry (Mp-3) PHONE BUILDING “Krnoom i i For’ HEW-30 Rav. 11/56 ROUTE SLIP GPO : 1988 —O-408608 . CYCLAMATES THE PROBLEM Handling foods containing cyclamates as drugs. BACKGROUND The’ Department has stated that cyclamates will remain on the market. In the press conference of October 18, 1869, the Secretary stated that “* * * my order does not require the total disappearance from the market place of! soft - @rinks, foods, and nonprescription drugs containing cyclamates.” Bek The policy published in the Federal Register on December 31, 1969, quoted Ret _ the following statement from the Department’s Medical Advisory Group on Cycla- fee’ mates: “Expressed the unanimous opinion that under appropriate medical man- ~ agement of individuals with diabetes (particularly in the case of juvenile dia- betes, and of patients in whom weight reduction and control are essential for '' 69 health, cyclamates provide medical benefits which outweigh their hazards.” The Bureau of Medicine, in supporting the Department’s statements that cycla- mates should remain on the market with proper labeling as drugs, finds that additional policy decisions are necessary to establish a position that can be reasonably supported scientifically. To approve cyclamate containing foods as safe and effective drugs within the concept of our enforcement of the new drug provisions of the act is unten- able. We are aware of no evidence that cyclamate-containing foods are safe or effective for use in the treatment of obesity or diabetes. Under the principles we strongly adhere to in permitting drugs to be marketed, these products should not be allowed on the market. To approve an NDA for these products is not sup- portable medically or legally. Thus if cyclamate containing products are to ‘yemain on the market, as we have stated, an alternate position shouid be explored. RECOMMENDATION We propose that these products be allowed on the market under tthe following conditions: \ 1. They contain labeling including appropriate warnings; declaration of cyclamate content; number of calories per appropriate unit or serving; are limited to use under directions of a physician ito use in obesity or diabetes ; and a statement as to the maximum amount of cyclamate that should be con- sumed in a 24-hour period. 2. The products represent a reasonable reduction in calories when com- pared to the same products prepared in the usual fashion. ‘ 3. They meet other appropriate food labeling regulations. Cay In view of the recommendation of the Secretary’s Medical Advisory Group to review the data on cyclamates on a yearly basis, we recommend that serious consideration be given to limiting these guidelines to be in effect on a year-to-year basis, with their continued effectiveness dependent on a re-review of data on safety and effectiveness. We should also set a 2- or 3-year limit for interested manufacturers to submit data to establish the safety and efficacy of the cycla- mates in the treatment of obesity and diabetes. A 5-year period should be the very maximum period that we should consider. At the end of the period estab- lished, the products will: 1. Be removed from tthe market if adequate data are not presented, or 2. Remain on the market as drugs along the lines proposed above, with safety and efficacy established by adequate data, or 3. Remain on the market with cyclamate as a food additive with a safe level of cyclamate established by available data, if the Delaney amendment is modified ‘to make this approach possible. This approach would not require a determination of specific cyclamate con- taining foods which should be excluded from ‘the market on the basis that they are not needed in the diet management of obese or diabetic patients. Many would | be excluded on the basis of requiring a reasonable caloric reduction. To require abbreviated new drug applications for these foods in addition to placing us in an untenable position would place an impossible workload on the Bureau at a time when we can least absorb it. These comments do not apply to the cyclamate sweeteners themselves for which we are already handling abbreviated new drug applications. We would be prepared to consider handling those products on an individual basis, on their merits, which could not meet the criterion which requires a reasonable reduction in caloric content (candies, cookies, and so forth). We recommend that a set of guidelines be prepared for marketing these prod- ucts along the lines discussed in this memorandum and circulated to the members of the Secretary’s Medical Advisory Group, the American Medical Association— Council on Foods and Nutrition, American Society for Clinical Nutrition, National Institutes of Health, National Academy of ‘Sciences-National Research Council, and other expert individuals or groups for review and comment prior to pub- lishing. This would enable us to establish a recommended daily intake of cycla- mates. The establishment of a daily intake is a major remaining problem. Mr. Founrtarn. “To approve cyclamate containing foods as safe and effective drugs within the concept of our enforcement of the new drug provisions of the act in untenable. We are aware of no evidence that i t , a [eee tas ea ''70 eyclamate-containing foods are safe or effective for use in the treat- ment of obesity or diabetes.” This document also states, “Under the principles we strongly adhere to in permitting drugs to be marketed, these products should not be allowed on the market. To approve an NDA for these products is not supportable medically or legally. And, Doctor Edwards, the document from which the last quotation was read appears to be a position statement in opposition to the pro- posal that cyclamate-containing foods be handled as new drugs. Attached to it is a copy of a routing slip dated February 2, 1970, addressed to Dr. Palmer from Mary McEniry and declaring, “This didn’t issue—but the content apparently was discussed upwards.” Are you familiar with this document ? Dr. Epwarps. No, Iam not. Mr. Founrarn. Mr. Goodrich ? Mr. Goopricu. Yes, I am familiar with it. Mr. Founrarn. Will you comment upon it ? Mr. Goopricu. Yes. I don’t know who wrote this. I imagine Miss McEniry did. She is _ wrong on her legal position and from the standpoint of the scientific decision we decided to implement the recommendations of the advisory committee. The Commissioner and the Surgeon General and Assistant Secretary for Health accepted that report, and directed me to act on it, Mr. Fountain. She isin New Drugs? Mr. Goopricu. Yes, Miss McEniry is a lawyer, she is in the regula- tion writing part of the Bureau of Drugs, and she is a thoroughly competent person. The views expressed here on Jegal and policy Mr. Fountary. These are her opinions ? Mr. Goopricn. I assume they are. It is not signed, the one I have, but I rather expect that she had a hand in this, do you know, John? Dr. Jennies. Yes. Mr. Fountarn. Would you say that statement is based upon scien- tific thinking within the Bureau? Mr. Gooprics. J expect so. Mr. Founrarn. She didn’t write as a lawyer, did she? Dr. Epwarps. Dr. Jennings was Director of the Bureau and it might be appropriate, Mr. Chairman, if he would comment on this. Mr. Fountain. Doctor? Dr. Jenninos. Well, I think the Bureau had several problems when they were given the task of implementing the decision to label cycla- - mate-containing foods as drugs. And I think that is what is coming through here. We had spent a long time in establishing a position that only certain types of drugs would be approved by the Food and Drug Adminis- tration. We were in the throes of an extremely difficult legal battle which is establishing these principles and some of the people in the Bureau felt that the approval of the cyclamate drugs through the new drug procedures was contrary to the position that we had been attempting to establish and to sustain for so long. We recognized fully the right of the Secretary and Surgeon Gen- eral to rely on expert opinion other than that within the agency and T think that was what were asking of our General Counsel and others, ''71 that some way be found to implement this decision without appearing to violate the standards and procedures which we had striven so hard. to establish for new drugs. Mr. Founrarn. Well, would you say you disagree or you agree with Miss McEniry ? Dr. Jennines. I would have to say that I agree with the concept that we did not have the substantial evidence that we usually require for the approval of a new drug. I yield of course to Mr. Goodrich’s superior knowledge as to whether this was legal or not. Mr. Fountain. We understand that. But did your group come to the conclusion that to approve an NDA for these products is not sup- portable medically and legally ? Now you say medically, and leave Mr. Goodrich the question of the legality. Dr, Jennrnos. I can’t say medically without speaking somewhat of the legal context. Mr. Founrarn. The two are together, you are right. Dr. JENNINGS. Since 1962 we have been attempting to establish only those drugs where there is substantial evidence for safety and efficacy. In this instance the kind of well-organized clinical trials that would provide the basis for such approval were not known to us. Therefore, the labeling of these products as drugs had to be via a pathway other than the usual evaluation of substantial evidence con- sisting of adequate and controlled studies. This is the problem that had to be resolved. Mr. Fountarn. Would it be your opinion today ? Dr. Jennines. My opinion today is that there is not as yet developed the kind of evidence that we would require for the routine approval of a new drug. TI said in opening, however, we fully recognize the authority of the Surgeon General and the Secretary to rely on other evidence. Mr. Founratn. I am not so sure, Mr. Goodrich, whether you have answered all of my question relating to the copy of a routing slip dated February 2, 1970, addressed to Dr. Palmer from Mary McEniry and I quote, “This didn’t issue—but the contents apparently were dis- cussed upwards.” Can you comment on that, as to what she had in mind ? Mr. Goopricu. I never saw this memorandum until I saw it in the files after we produced it for your committee. I do know that this issue was discussed. I do know that the Bureau of Medicine did not want to handle any kind of new drug application for this type of product. I do know that the Bureau of Medicine was just as conscious as I was of the need if the product was to stay on the market, to have ac- chia labeling restraints. I believe they concur in what was finally one. Dr. Jenninas. Yes, we had offered an alternate method that didn’t involve use of the NDA, but Mr. Goodrich, as he pointed ont, had persuaded all concerned that since the products were not generally recognized as safe and effective they had to be processed as new drugs. Mr. Founrarn. The committee will recess for 10 minutes, 2 (Recess. ) Mr. Founrary. Let the committee come to order. '' 7 72 Dr. Edwards, would you detail the events in the decisionmaking | process which led to the order of March 17, 1970, requiring the sub- mission of abbreviated NDA applications for cyclamate-containing products? Dr. Epwarps. Mr. Chairman, would you repeat that question please ? Mr. Founrarn. I asked if you would outline or detail the events in the decisionmaking process which led to the March 17, 1970, order — requiring the submission of an abbreviated NDA for cyclamate-con- taining products? Dr. Epwarps. Possibly Mr. Fine would address himself to that. Mr. Fine. We had a discussion with Dr. Jennings and with Mr. Goodrich which was written up—I don’t have that particular right now. I think I can find it here. We made certain recommendations to the Secretary and the Secre- | tary agreed with our recommendations. The only reservation was expressed to Mr. Goodrich about the size of the label area. He and I worked out that final language one day in my office. Mr. Goodrich, is that as you recall ? Mr. Goopricu. Yes. Mr. GorpHamner. Dr. Edwards, the decision to permit the market- ing of cyclamate products as drugs was surely made sometime prior to the October 17, 1969, order which appeared in the Federal Register. It was referred to in Secretary Finch’s statement of October 18 which -is in the record. What were the events that transpired which led to the decision by October 17 that these cyclamate containing products would be available as drugs? Dr. Epwarps. I obviously don’t have the answer to that. Maybe Mr. Goodrich can address himself to that. Mr. Fountarn. Mr. Goodrich ? Mr. Goopricu. Yes. The Food and Drug Administration sometime before October 18, had prepared a complete compilation of all avail- able scientific evidence on the cyclamates to submit to a food protec- tion committee of the NAS/NRC group. This was done I believe about 30 days prior to October 18 and the committee was to meet here in Washington on the 16th and 17th to go over this data. It included Dr. Richardson’s reevaluation of the slide from the 1951 material. It included Dr. Varett’s study on egg embryos. All that was known — about the cyclamates was accumulated in one volume prepared by the Food and Drug Administration for the submission to the ad hoc ~ committee. And as I say, the committee was scheduled to meet here in Wash- ington on the 16th and 17th of October. ia Early that week, on Monday I believe, Abbott Laboratories pre- sented to the Surgeon General through, I believe, Dr. Saffiotti at the National Cancer Institute. The results of some animal studies that have been conducted in | Food and Drug were submitted. Dr. Ozer’s laboratory in New York was represented. : These slides were interpreted—or tissue slides from the investiga- tion of animals were evaluated by the Food and Drug Research Lab- oratories sometime during the prior week as having shown cancer in the bladders of the test animals. beh a (ess ''73 : Die Abbott Laboratories brought those results into the Department on Monday of the week of October 18, as I recall. Dr. Saffiotti got in touch with Dr. Steinfeld and Dr. Steinfeld brought in Dr. Ley and the first move was to obtain the slides and eval- uate it by the best available means, drawing on the National Cancer Institute resources as well as our own, and to obtain a consultation with an expert in bladder tumors, human bladder tumors, a gentleman whose name escapes me at the moment. But he was an expert in this area from New Orleans. He flew here and the data were reviewed by about Wednesday of that week. On Wednesday there was concurrence by the inside group that the new data were indeed highly relevant. The ad hoc committee on cyclamates was scheduled to meet the next day to study the total package that Food and Drug had presented. They did meet on Thursday and on Friday the Abbott material was presented. I believe the Abbott people as well as Food and Drug peo- ple and Dr. Steinfeld, Dr. Egeberg, they were in attendance, That afternoon they concurred in the finding that cyclamates had shown to produce cancer in animals, test animals and that the Depart- ment had decided by that time what its course of action would be, Now the people involved were Dr. Egeberg, Dr. Steinfeld, Dr. Ley and limited number of other people in the Department. But the scientific expertise came from those people. The Secretary made a decision to announce this on Saturday morning the 18th. In preparation of the statement that was read, the issue came up about whether these products would continue to be available for medical use. The medical advise was that they should be and that statement was put into the document. Now whether the decision was made on Thursday or Friday or Wednesday I am not sure. But in the total evaluation of this issue the decision was made, It was also decided that this would be submitted _ to an outside group to see what the role was because we knew there was a difference of opinion medically in view of Dr. Slager’s work of course about the importance of cyclamates in obesity and in diabetes, As a matter of fact at the press conference on the 18th one of the reporters raised the quote from the medical legal issue raising an issue whether or not this was an effective drug. So the Department decided on the course of bringing in the outside consultants. This was done in November. The report came in December and it was implemented late in Decem- ber when we got the report. Those are the events. I hope that answers your question. Mr. Gotpuamnen. It is my recollection that when the announcement was made there seemed to be some statement minimizing the hazard which might be involved here, Do you have any information on the background leading to those minimizing statements ? Mr. Goopricn. T have the statements. I would be glad to present them. I believe there was a transcript kept of what was said orally. I don’t have that but I believe there is one. My recollection is that there is. I was present at the meeting and I was present at some other meet- ings. And what its message was was that there was no medical emer- gency but that a prudent course required the elimination of these products from general purpose foods and that was announced effective ''74 on the dates that you have, January 1 and February 1. Those dates were later relaxed to some extent. Mr. Gotpnammer. Thank you. Mr. Fountary. Then, Mr. Goodrich, you assume the responsibility for determining whether or not this legally could be done. I believe Dr. Edwards, you signed the order although you more or less inherited . the situation, but the actual decision and the announcement was made by the Secretary ? Mr. Gooprrcit. Yes, the Secretary made the basic statement. Dr. Steinfeld has a what runs to about six pages giving in some detail what had happened during that week in his consultation with the experts to whom I referred a moment ago. And then Dr. Ley made a short statement about what steps would be necessary to implement this program. Mr. Fountary. Coming back to the position statement of Janu- ary 30, 1970, which I have already put in the record, I call your atten- tion to the statement appearing in that document namely, “to approve an NDA for these products is not supportable medically or legally”. We had some questions about that. I think the subcommittee would like to examine to some extent the question of legality in connection | with the March 17, 1970, order. Am I correct in the interpretation that as foods, cyclamate-containing products would be adulterated within the meaning of the act and subject to seizure ? Mr. Goopricu. Yes. Mr. Founratrn. However, as drugs the same products could be mar- keted free of any such charge of adulteration, is that correct ? Mr. Goopricu. Yes, if approved through the New Drug procedures in this instance. The definitions of adulteration of foods and drugs are somewhat different. Mr. Founrtarn. It seems to me, in view of this, that if FDA wanted for whatever reason to continue the marketing of cyclamate-contain- ing foods, this could be done with the simple expedient of calling them drugs. There are in the supermarkets today, large stocks of cyclamate- containing products which are labeled as foods. As I understand your order, many of these will be labeled as drugs by September 1, is that correct ? Mr. Goopricu. Yes, Mr. Chairman, when the October 18 announce- ment was made there was a practical problem of phasing out of the market very large inventories of foods and drugs that contained cyclamates. The time of the announcement came just at the completion of the canning season for canned products in California and so there was— on the west coast—a substantial stock of canned fruits and vegetables with cyclamates on hand. Our figure showed that 90 percent or so of the total cyclamates, how- ever, were found in carbonated beverages and in table sweeteners and mixes. This was the maximum use of the cyclamates. On that basis the Secretary decided to phase those out of the economy by January 1, 1970, and that was done. The next was to deal with existing stocks of jams, jellies, ice creams, and the other things that have been mentioned here. Plus the canned fruits and canned vegetables. ''X 79 It was first announced that they would be phased out by February 1, 1970. However, the Canadians then adopted the April 1 and Septem- ber 1 dates, and we became consistent with them. : : Then we received in December a report from this committee on handling the continued sale of these products as drugs. This was implemented in the Federal Register announcement and we made it effective to coincide with the last day of the phaseout for the food. This _is why you get the September 1, April 1 dates for the filing of the abbreviated new drug application. Mr. Founrary. But for the moment these foods are items which are adulterated for food purposes, but not as drugs? Mr. Goopricu. Right. Mr. Fountain. Will they cease to be foods as of the date an ab- breviated new drug application is approved and new labels applied? Mr. Goopricu. As of the date they are marked clearly and intended clearly for drug use. _ Mr. Founrarn. Does the fact these products have been sold as foods for probably decades, during which time they were not sold as drugs, have any bearing in your opinion on the identity of such products as foods or drugs? Mr. Goopricu. Certainly. That is why we were so insistent on the strong box warning on the front of the package. I am sure the canners would like to have it on the bottom or the back, or someplace besides the front, but we were insistent that the new status come through forth- rightly and gave notice to the users that the status had changed. Mr. Fountatrn. It is interesting—you didn’t mention it, but I guess you are aware of the fact that you did have a precedent in a way back in 1911. Mr. Goopricu. That.was before my time, Mr. Chairman. Mr. Fountain. The Secretary of Agriculture held that foods con- taining saccharin were dangerous. I understand in those days the legal aspects of the matter were not as difficult as is true today. Mr. Goopricu. They were tied by some other historical factor. Mr. Founrary. While that decision didn’t last, I note it was pro- mulgated by Food Inspection Decision 135 signed by the Secretary of the Treasury, the Secretary of Agriculture, and the Secretary of Com- merce and Labor on April 26, 1911. These products, however, will continue to be sold in food stores after September 1, will they not? Mr. Goopricu. Yes. Mr. Founrarn. And they probably will be sold from the same shelves and the same departments as they are today? Mr. Goopricu. They may, but we don’t think so. They may well be. Mr. Fountarn. How do you intend to handle that ? Dr. Gotpserc. You say you don’t think so, will you explain why? Mr. Gooprtcu. I don’t believe, Dr. Goldberg, they will have the prime space that the canned fruits now have. My belief is that they will have such a limited market that they will go to a different part of the store. There is great competition for shelf space in supermarkets as you know and our belief is that they will move from the high frequency purchase items such as canned fruits, to a less conspicuous place and a more definitely more drug place. This remains to be seen, but we think this will be the effect of the box warning. '' %6 ‘Dr. Gotpperc. When we discussed this earlier, if my recollection is correct, you did not anticipate that they would be put in the drug section of a supermarket if the supermarket had a drug section. Mr. Gooprrcx. I think they will be put in the so-called dietetic food section which is my best judgment. That may or may not happen, but that is what I believe. Dr. Gotpperc. That is a food section ? Mr. Goopricu. Yes. Dr. Gotpserc. Thank you. Mr. Founraty. And anyone is free to purchase the product for his or their use whether under the care of a physician or not? Mr. Goopricu. Yes, sir; we would hope that they would read and heed the label. Mr. Fountain. This may be repetitious to some extent, but I want to be certain of your answer. The subcommittee’s staff has looked at this situation in retail stores and has found that most of the super- markets have a dietetic food department which consists of a number of shelves for display of special dietary foods of all types. “Tn fact, right now some of the dietary foods are being sold at re- _ duced prices at. some stores, Does the Food and Drug Administration at this time have any plans to prohibit the display and availability of cyclamate-containing prod-_ ucts in the dietary food departments in supermarkets or take any action in that respect ? \ Dr. Epwarps. We have at this point, Mr. Chairman, formulated no plans in this regard. Mr. Fountain. Dr. Goldberg? Dr. Goipperc. It appears to me that in various parts of the United States there are substantial Spanish-speaking populations who don’t read English. Now, I assume these people buy canned peaches and products of that sort by looking at the identification of the food on the can. Has any consideration been given for their protection ? Dr. Epwarps. No, not to my knowledge. Mr. Goopricu. The whole problem of labeling to satisfy the needs ‘of the Mexican Spanish-speaking Americans is a problem with us, more particularly in, say, hazardous substances than with this. We have not been able to really work out a perfectly satisfactory solution to it. In places like Puerto Rico where Spanish is the predominant lan- guage we do, as you know, have a regulation calling for Spanish labeling. We would like to have a situation in which the labeling could be in tune with the minority group—or the Mexican Spanish-speaking groups using the products. We have a provision that allows this dual language but have not discovered any means to require that for special kinds of audiences. This is a broader problem with us to a considerable extent than what you have outlined. It has come up more specifically with hazardous substances which have warning and precaution state- ments on them, and so forth. We simply have not been able to develop something. Dr. Gotpsere. It probably is virtually impossible to do that in the continental United States, but you can do it where you have a high concentration of these people, as in Puerto Rico. ; Dr. Epwarps. Right. = Soe Cer '' tr. Dr. Gorpserc. It would be difficult to obtain Spanish language labeling even for California, New York, and Texas, because produc- tion is for a national market. Mr. Goopricu. This is the magnitude of the problem that we have wrestled with. But we are aware of what you are saying, where we need to have labeling that is understandable. Mr. Founvary. Dr. Edwards, as a matter of fact, aren’t most of the cyclamate products on the market today foods within the statutory definition for food, and I quote, “Food means articles used for food or drink or for man or other animals.” Dr. Epwarps. That is right. Mr. Founrarn. I think we have included this in our question, but we have been disturbed by the dual coverage containing cyclamate products. The FDA is now declaring them to be drugs but under another more specific section of the law they are defined as foods. Congress enacted section 403(j) dealing with foods for special dietary uses to deal with just such products as the FDA has declared to be drugs. Is it not, Mr. Goodrich, a general rule of law that where you _ have a specific section of law covering a product and a general section of the law which may also cover the same product, that coverage of that product would be given the specific section of the law under which it falls? Mr. Goopricn. Yes, that is one of the rules of construction. But in this case, Mr. Chairman, aside from the cyclamate thing, we are in the process of revising, as you know, our regulation for special dietary _ uses and one of the problems there over the years has been drawing a clear line between a product that is intended for drug use and one intended for special dietary uses. In our 1941 regulations, for example, we provide that an article is a food for special dietary use if it is intended in the management of diabetes and a number of other medical conditions. een Experience has shown us that this kind of a product deserves to be in the drug category and we proposed as long as 1966 when these regulations were first revised to make clear that articles intended for medical management of disease, even nutritional adjuncts, should be labeled with the more comprehensive drug information than food. This is one of the issues in the dietary food regulations. _ Mr. Founrarn. The regulations that the Food and Drug Adminis- tration itself adopted concerning special dietary foods seems to cover specifically the cyclamate-sweetened products. I have already put into the record regulation 1.11 which defined the term “special dietary uses” as applied to food for man and these uses are uses for supplying par- ticular dietary needs which exist by reason of the physiological, path- ological, or other conditions but not limited to the conditions of dis- eases, convalescence, lactation, pregnancy, hypersensitivity—and it lists underweight and overweight. Would you not agree then, Doctor, that this definition of special dietary uses covers especially cyclamate- containing products for use by diabetics and obese persons ? Dr. Epwarps. Would you go ahead ? Mr. Goopricu. May I respond to that? This is the regulation you just mentioned which was under revision. And to a sense; yes. It would cover that. But where the article was intended solely for drug use, 48—798—70—_- 6 ''78 it would not be under those regulations in our judgment. And this is the line—that is, the new regulations are defining it and it originated a long time before cyclamates, to be sure that those things intended for medical management would be treated as drugs, approved for safety and effectiveness as new drugs and label with a more comprehensive direction for use, This is one of the issues in the dietary hearing on which I believe there is no real difference of opinion. _ Mr. Fountain. Regulation 125.6 for special dietary food, under section 403J of the act states in the first paragraph, “Ifa food purports to be or is represented for special dietary uses by man by reason of its use as a means of regulating the intake of carbohydrates, fats, or calo- ries for the purpose of controlling body weight or for the purpose of dietary management with respect to disease, the label shall bear a state- ment of * * *” and then follows, of course, the language. Now, Dr. Edwards, did you compare that wording which I have just read with the order of March 17, 1970, declaring cyclamate prod- ucts new drugs and requiring abbreviated new drug applications? I think you will see that the special dietary regulation, 125.6 which I read is almost word for word the same as paragraph A of your March 17, 1970, order. What I would like to know is whether it is your belief— maybe Mr. Goodrich can comment upon this—that by taking the word- ing from the special dietary regulation and transferring it to the March 17, 1970, order it may have the effect of nullifying the status of the product as a drug since the product is also covered by the legally valid special dietary regulation 125.6? Mr. Goopricn. The regulation you read from, Mr. Chairman, is the one that was revised and the revision is in a controversial situation with the hearings that must take place before the order can be placed finally into effect. The regulations were revised to take out the concept of the drug from the dietary food regulations and it has been held up by the procedures that are underway at the public hearings. The hear- — ing has lasted ad infinitum, but the Department decided long ago that a_ product of this kind ought to be handled as a drug on a clearly defined basis or a food on a clearly defined basis. What we did with the imple- mentation to carry out the ad hoe committee’s recommendation was to _ classify the article as strictly a drug in our judgment. Mr. Fountain. If it does not nullify regulation 125.6, do not then the cyclamate products fall squarely within the scope of special dietary regulation 125.6, and under the same circumstances as foods? Mr. Goopricn. Until relabeled in September, of course they are still foods intended for special dietary use, and they are labeled in general to comply with those provisions. The new labeling is going to classify them as drugs, which will not make them subject to this regulation, and in addition this regulation is under revision. Mr. Founrarn. Another point here which occurs to us in the con- sideration of the legality of cyclamate-containing products, that is the question of the effect of the standards of identity for artificially sweetened products which permit the use of cyclamates as optional ingredients. As I understand it, there are many such standards which are in effect today ; is that not true, Dr. Edwards? Mr. Goodrich ? ow ''a I have reference to artificially-sweetened food standards as well as other such things as jams and jellies. Mr. Gooprtcu. There are a number of those standards, Mr. Chair- man, which have been the subject of our statement of policy on the interim handling. Mr. Founvatn. Are they still in effect ? Mr. Goopricu. Yes; they are. They are still in effect and they can be repealed through the publication procedures under section 701 (e). In order to deal with the interim status of these products, we have published a statement of policy on them which in effect says we will not initiate regulatory action pending the revision of the standards provided they meet the interim requirements of the special dietary food regulations. Mr. Fountatn. Continuing for the record, since the standards have not been repealed and are still in effect for artificially sweetened canned foods and other products, such products are to be considered foods by definition under the valid regulations; are they not ? Mr. Goopricu. Yes. Mr. Founrarn. Since the cyclamates are no longer generally recog- nized as safe standardized products, it would be adulterated today, I think ? Mr. Goopricn. Yes. Mr. Fountarn. Does this present FDA at the moment with a legal inconsistency ? Mr. Goopricu. It presents us with the problem of phasing these products out. This is what thedeadlines were all about. Understand- ably, when the Secretary made his announcement on October 18, 1969, that did not overnight remove all the products from the marketplace. The courts have held where the status of the product changes it is within the discretion of the agency to order a phaseout time. This was done in October. That is the January 1 and February 1 dates which were announced. We have explained in our statement how the February 1 date changed to June 1 for jams, jellies, desserts, and so forth; and Sep- tember 1 for artificially-sweetened canned vegetables, and this was to be consistent, in part, with the Canadian action. We also have a July 1 phaseout date for drugs. We have had some discussion and some orders affecting the phaseout of drugs containing cyclamates, too. That is, by drugs, I mean in that connection the pedi- atrics, preparations, antibiotics sweetened with cyclamates. Mr. Fountarn. I realize it presents you with a problem, but doesn’t it result in actually conflicting regulations? Mr. Gooprrcn. Yes; in technical violation, that is the reason we pub- lished the statement of policy saying we would not initiate regulatory action if these conditions were met on an interim basis. This was a bridge between the existing standards and the development of labeling of the new product. Mr. Gorpmaaer. Mr. Goodrich, that statement of policy was issued, and it doesn’t state anything about cyclamates. It is just for combina- tions of sweeteners, isn’t that so? Mr. Goopricu. Right, there is one on cyclamates, Mr. Goldhammer, that gives the phaseout dates. September 1 is that date and by that '' 80 - time you have to have new drug applications for the products if cycla- “mates are to be continued. The others are dealing with the new products. Mr. Gorpnammer. Mr, Goodrich, the standards of new products will continue in existence because as of now there has been no statement of policy with respect to them, isn’t that so? Mr. Goopricn. Yes; but if they complied with the standards they would still be adulterated, Mr. Goldhammer. Mr. GorpHAamm™enr. But they would be a food by definition ? Mr. Goopricn. Depending on what they were intended for, If they were offered for general purpose food they would be indeed an adul- _ terated food. The only way they could be so after those dates is to comply with a new intended use of drugs, honestly, forthrightly labeled for that. condition. Otherwise they are going to violate the adulteration provision even though they might comply with the exist- - ing standards with which we are concerned here. Mr. GorpHamner. Do you not think existing standards should be revised to reflect the changed status of cyclamates ? Mr. Goopricu. I sure do. Mr. GorpHammenr. This is now June 10, and the order banning cycla- mates was sent out October 17, 1969, and it really is not much of a job to get a notice out, is it? Mr. Goovricn. You are correct. You are absolutely correct. Mr. Founrarn. It has been 8 months. Mr. Gooprtcn. This should have been done, but we have been dealing with this on a more direct basis through these other things, and there isn’t any misunderstanding between us and the canners about the status of these products. But you are absolutely right that those stand- ards should be repealed, and they will be. Mr. Fountatrn. Your order of March 17, 1970, is intended to limit the sale of cyclamate-sweetened products, isn’t it? Dr. Epwarps. That is right. Mr. Founrain. The Modi Advisory Group on Cyclamates estab- lished by the Secretary of Health, Education, and Welfare, concurred that cyclamates should be made available under proper medical man- agement on a nonprescription drug-labeled basis, as we have brought out. Do you believe you have confined the uses of cyel amate-containing products to those intended by the Medical Advisory Group on Cycla- mates under the method of distribution and sale of cyclamate- containing products in grocery stores and food shops everywhere? Dr. Epwarps. I doubt it. Mr. Fountarn. I do not believe you have a program as yet. You do not have a program to assure that cyclamate-containing products will be used as contemplated by the Advisory Group on Cyclamates. Dr. Enwarps. I think the real answer to this will probably come September 1 and January 1 of this year. After January 1 or Sep- tember 1, we are going to obviously have to take a good hard look at the sale of these products. If the sale of the products looks out of line _ with the number of potential users, medical users of these products, then I think we either have to move in the direction of putting severe restrictions on their sale far more than there are now, or eliminating from the market, one or the other. '' ecu. oe 81 _ Mr. Founrvarn. As a layman, and a Member of Congress, I am in no position to pass judgment upon the validity of many of these decisions. SS But once a decision is made, as it has been made here, it seems to me “fh er that every effort ought to be made to do something to be sure that Ni these products are used for the purpose for which they were intended. ae IT wonder how much supervision you plan to exercise, and when, over the sale of these products? Dr. Epwaros. As I say, the decision unfortunately will have to wait until September, and then through a sales survey, or market survey. ee If we are convinced that they are not being handled or sold in the Beles proper way, I think we will have to take some rather stringent actions. al ay Mr. Founrarn. Dr. Edwards, I understand that the words “medical = supervision is essential for safe use,” are required to appear on the labels of cyclamate-containing products. This actually means that these products are unsafe unless there is medical supervision; is that correct ? ; Dr. Epwarps. Congress has said so in a sense. I think again it is a eae benefit-to-risk ratio. Depending upon medical conditions involved, aia: which you are speaking of, I think one can justify the use of this product in certain cases. But certainly not across the board. Mr. Fountarn. I am talking about without medical supervision now. Dr. Epwarps. They should not be taken except under medical Bere Ks, supervision. Mr. Founratn. So without medical supervision then, am I correct in mM assuming that your decision means they are unsafe? Not your de- eh cision, but the decision that was made. ie ae ls “s Dr. Epwarps. That was the decision that was made, that is right. Mea, Mr. Fountary. Have you found any reason to disagree with it? Not ips ih in finality, but in the fact there haven’t been any limitations? ue" miss Dr. Epwarps. I would go so far as to say there are exceptions to this 2°73 as particular rule. eee pe Mr. Founvarn. In your opinion, Doctor, do the cyclamates have any Ge toxicity or other potential or harmful effects ? HO Dr. Epwarps. Again, do these cyclamates have toxicity ? Mr. Fountary. Or other potential for harmful effect on human beings? Dr. Epwarps. Yes. Mr. Fountain. Can you elaborate ? ; Dr. Epwarps. Well, it has been demonstrated rather specifically if ae taken in adequate amounts it is toxic to the GI tract. There is a diarrhea that is formed by taking too much in the way of cyclamates. There is _ evidence that exists and shows the suspicion of metabolic effects, but ae some of these other areas are not as specific, to my knowledge. Be st Mr. Founrary. Are any collateral measures necessary in connection : ee with the use of these products by diabetics and these obese people who ; have to use these for their health? By that I mean are there any spe- - cial diets necessary for these people? Dr. Epwarps. Well, depending upon the severity of the diabetic, the | . particular case of diabetics, there are various diets that are prescribed. eae In the early asymptomatic diabetic, it is more a matter of caloriesthan Bae. anything else. But as you move up in severity, more specific diets are pes. indicated: fe ''82 ’ Mr. Founrarn. At this point I would like to place in the record a number of documents. One is a paper from the files of the Food and Drug Administration entitled “Medical Effects of Cyclamates and Cyclohexylamine.” It is taken from the Advisory Group report on cyclamates. (The document referred to follows :) MEpIcAL EFFECTS OF CYCLAMATES AND CYCLOHEXYLAMINE Cyclamates produce stool softening and diarrhea in humans when relatively large amounts are ingested. This is apparently the result of an osmotic effect; there is no evidence that cyclamates exacerbate organic gastrointestinal diseases. A number of cases of photosensitivity have also been reported in users of arti- fically sweetened products. Various other pharmacologic effects of cyclamates and cyclohexylamine may influence the action of certain commonly used drugs and thus interfere with therapeutic regimens. Cyclohexylamine produces weak pressor effects when ad- ministered to animals, raising the possibility that hypertensive reactions might result in humans, particularly those being treated with monoamine oxidase inhibitors. In animals, cyclamates reduce insulin release and the hypoglycemic effect of tolbutamide is decreased while that of chlorpropamide is increased. Thus, when these drugs are employed in the treatment of diabetes mellitus, control may be less certain especially in the case of the “brittle” patient. Cyclamates may potentiate the diuretic effects of the thiazide drugs and resultant excess loss of potassium should be guarded against. Studies in some animal species indicate that cyclamates potentiate the anticoagulant effect of the courmarin drugs sug- gesting that exaggerated responses in patients under anticoagulation regimens may occur. Cyclamates bind moderately strongly to plasma protein and might displace other drugs similarly bound with resultant modifications in pharmacologic effect. Other studies have shown that the absorption of the antibiotic lincomycin is re- duced by cyclamates; there is no evidence suggesting effects on the absorption of other similar drugs. The presently available data suggest that special care should be taken when cyclamates are used in patients under treatment with other drugs. Because of the paucity of reported clinical experience with cyclamates, it is recommended that instances of known or suspected adverse effects of the cyclamates as out- lined above be reported promptly to the Director, Bureau of Medicine, Food and Drug Administration, Washington, D.C. 20204. REFERENCES 1. (Effect of Cyclamates on Tolbutamide and Chlorpropamide) Dixon, R. L. Presented at Seminar on Non-Nutritive Sweetening Agents, Albany Medical College, June 12-13, 1968. : 2. Lomonova, G. V. Toxicity of Cyclohexylamine and Dicyclohexylamine, Gigiena Truda i Professional ’niya Zabolevaniya 7 (No. 11) : 95-98, 1961. Mr. Founvrarn. This document lists the various pharmacologic effects of cyclamates and cyclohexylamine. Various other pharmacologic effects of cyclamates and cyclohexylamine may influence the action of certain commonly used drugs and thus interfere with thera- peutic regimens. Cyclohexylamine produces weak pressor effects when adminis- tered to animals, raising the possibility that hypertensive reactions might result in humans, particularly those being treated with monoamine oxidase inhibitors. In animals, cyclamates reduce insulin release and the hypoglycemic effect of tolbutamide— It isa little difficult with some of these terms— is decreed while that of chlorpropamide is increased. Thus, when these drugs are employed in the treatment of diabetes mellitus, control may be less certain especially in the case of the “brittle” patient. Cyclamates may potentiate the diuretic effects of the thiazide drugs and resultant excess loss of potassium should be guarded against. Studies in some animals species indicate that cycla- mates potentiate the anticoagulant effect of the courmarin drugs suggesting that exaggerated responses in patients under anticoagulant regimens may occur. ie ''83 Cyclamates bind moderately strongly to plasma protein and might displace other drugs similarly bound with resultant modifications in pharmacologic effect. Other studies have shown that the absorption of the antibiotic lincomycin— Is that what it is? Dr. Epwarps. Yes, lincomycin. Mr. Goopricu. Lincomycin. Mr. Fountain. Some of these words are not spelled right. It is not all my pronunciation that is wrong. —is reduced by cyclamates; there is no evidence suggesting effects on the absorption of other similar drugs. Also, a memorandum of August 19, 1968, to Herbert L. Ley, Com- missioner of Food and Drugs, from H. F. Kraybill, Ph. D., Bureau of Science, and Dr. John Schrogie, Bureau of Medicine. This memo lists aberrant responses of animals and man to cyclamates and cyclo- hexylamine. (The document referred to follows :) Foop AND Drug ADMINISTRATION MEMORANDUM, AuGusST 19, 1968 To: Herbert L. Ley, Jr., M.D., Commissioner of Food and Drugs, OC-1. From: H. F. Kraybill, Ph. D., Bureau of Science, SC-4; John Schrogie, MD., Bureau of Medicine, MD-430. Subject: Briefing report on nonnutritive sweetening agents. An increasing concern about the safety of nonnutritive sweeteners in foods, beverages, and drugs has stimulated an acceleration and expansion of research on the cyclamates and saccharins in Japan, Europe, and the United States. Russia, Great Britain and such international organizations as the FAO/WHO have adopted certain restrictions on their utilization in foods and beverages. The attached briefing report presents, in detail, some of the adverse responses recorded by various investigators in experimental animals and clinical studies with man. A brief résumé of the aberrant responses of animals and man to saccharin, cyclamates and cyclohexylamine (sec. III of report) is given below. a. Growth retardation and reproductive impairment in animals.—Doses of cal- cium and sodium cyclamate, ranging from 500 mg./kg. to 8,000 mg./kg. produced growth retardation in rats and swine and fetal resorption in swine (500 mg./kg.) ; fetal resorption and/or death in mice (75 to 300 mg./kg.) and sterility in rats (10 percent cyclamate )—section IIIA and IIIB, pages 13-14. b. Nonuniform rate of conversion of cyclamate to cyclohexylamine in animals — and man.—Information on rate of conversion of cyclamate to cyclohexylamine in various animals and man is quite variable, reflecting uncertainties as to metabolic fate, organ and tissue retention and potential impact of such agents on long- term toxicity—section IIIC, pages 14-17. c. Bowel function and stool consistency in animals and man.—Studies with experimental animals parallel those with man in that increasing intakes of cycla- mates lead to softening of stools and diarrhea. The threshold level in man appears to be 5 grams/day with stool softening and this effect increases until a dose of 10 grams/day where diarrhea ensued quite readily—section IIID, page 18. d. Protein-bound iodine increase in man.—Levels of cyclamate at 10 and 18 grams per dose daily to human test subjects increased PBI values from the normal range of 4 to 7 microgram percent to 14 to 18 microgram percent. Among the placebo group supranormal concentrations of PBI in serum prevailed in 11.5 percent of this group and in a high cyclamate intake group (18 grams/day) the occurrence was 46.7 percent of that group. e. Alteration in serum enzymes in animals and man.—Austrian studies with guinea pigs indicate that 2 percent solutions of cylamate in the diet, given for 120 days, produced significant changes in LDH and SGPT and lesser changes in alkaline phosphatase. There are less significant changes in these serum enzymes at 0.5 percent level of cyclamate. Home studies (Abbott Laboratories) also showed changes in SGOT and alkaline phosphatase when 4 to 4.5 gms. of cycla- mate and 0.45 gms. of saccharin were given to diabetic patients for 7 months. The clinical investigator indicated that these serum enzyme level increases were statistically significant but not clinically so because of small magnitude of change '' 84 and by comparison with deviations in control group—section IIIF, pages 19-21. f. Coagulation factors in animals and man.—Cyclamates administered as 2- percent solutions in diet to rabbits at level of 1.1 mg./kg. of body weight increased the prothrombin time (Quick) and reduced Factor VII in blood after 4 weeks on this compound. The “r” and “k” times of the thromboelastogram were prolonged by ingestion of this level of cyclamate. Lower levels of cyclamate did not have this effect on blood coagulation, however, when the anticoagulant ‘“Marcoumar” was given with 0.5 percent cyclamate, similar effects were produced. This observed - potentiation is relevant to anticoagulant therapy—section IIIG, pages 21-24. g. Drug interaction in man.—Blood levels of lincomycin were decreased in human test subjects who continuously consumed cyclamate-sweetened soft drinks—section IIIH, page 24. h. Serun cortisol alteration in monkeys.—Monkeys receiving 4 to 8 gms./kg. of body weight of cyclamate exhibited an increase in serum cortisol after acute and chronie exposure—section IIIJ, page 25 and section IV, 3b, page 31. i. Chromosome alteration in man.—Levels of cyclamate at 40 to 500 »g/ml intro- duced into human cell cultures at 200 ug/ml concentration caused an increase in chromosome breaks from 8 to 6 to 8 percent. (Normal value 3 percent.) One heavy consumer of cyclamates exhibited 15 percent break in chromosomes—section IITK, page 25. j. Photosensitivity to cyclamates in animals and man.—Rats exhibited photo- sensitivity to cyclamate when given in a 5 percent solution in diet. One human case of photosensitivity recorded where an individual drank 72 ounces of cyclamate- sweetened beverages for 2 months. Since 1950 there have been three cases of - human photosensitivity reported in medical literature. Saccharin apparently does not induce this photoallergy—section IIII, page 26. k. Cyclohexylamine toxicity in animals and man.—Cyclohexylamine (CHA) formed in beverages or foods on processing and on standing is a direct exposure to man when consuming cyclamate-sweetened products. CHA is also formed in ~ feces and occurs in serum and tissues. CHA has an effect on mitochondrial respi- ration, contracts guinea pig and frog muscles and is the probable agent for the photosensitization reaction. CHA is highly toxic, produces CNS excitation and irritation of visible mucous membranes. Most important effect of CHA is the marked “pressor response” in man when intravenous doses of 1, 3 and 10 mg./kg. of body weight are administered. Pressor response potentiated by monamine oxidase inhibitors. Tolerances for CHA in foods and beverages may be important matter for consideration. JoHN ScuHroeiz, M.D. Acting Director, Division of Research and Liaison, Bureau of Medicine. H. F. Kraysicz, Ph.D., Assistant Director for Biological Sciences Research, Bureau of Science. Mr. Founrarn. We also have a Memorandum of Conference dated December 17, 1969, attended by Dr. Charles C. Edwards, Acting Com- missioner, FDA; Mr. W. B. Rankin, special assistant; Mr. T. M. Quinn, Division of Case Guidance: and Dr. John F. Palmer, Assistant for Scientific Coordination, regarding cyclamate-containing nonnutri- tive sweetener products. This discusses the need for warning statements concerning possible drug interaction with cyclamates, ingestion of eyclamates during pregnancy, and the absence of a box for a warning statement. (The document referred to follows :) MEMORANDUM OF CONFERENCE, DECEMBER 17, 1969 Present: Dr. Charles C. Edwards, Acting Commissioner, FDA; Mr. W. B. Ran- kin, Special Assistant: Mr. T. M. Quinn, Division of Case Guidance, RC-120; and Dr. John F. Palmer, Assistant for Scientific Coordination, MD-5. The purpose of the meeting was to resolve existing issues in labeling prepared to appear in an S.P.I. regarding cyclamate-containing artificial nonnutritive sweetener products. '' Labeling had been prepared in FDA which reflected the recommendations found in the report from the Medical Advisory Group on Cyclamates resulting from their meeting of November 17 and 18, 1969. Certain changes in the proposed label- ing introduced by Mr. William Goodrich, CPH, were the subject of consideration -at the present meeting. These included warning statements concerning possible drug interaction with cyclamates, ingestion of cyclamates during pregnancy, and - the absence of a box for a warning statement. Pharmacological effects of cyclamates and cyclohexylamine demonstrated in animal experiments reveal a possible drug interaction with such prescription drugs and drug classes as monoamine oxidase inhibitors, oral anti-diabetic drugs ‘(tolbutamide and chlorpropamide), the thiazide drugs and lincomycin. Based on these data, and the lack of adequate clinical information in this area, the Ad- visory Group suggested that special care should be taken when cyclamates are used in patients under treatment with other drugs. The Bureau of Medicine advised against a statement in the O—T-C labeling for eyclamates directing the user to consult his physician when using cyclamates at the same time he is on other drugs. It was felt that such a warning statement would tend to confuse the patient rather than inform him. In similar situations even where a known Clinical effect might be anticipated, the approach has been to inform the physician through labeling of the prescription drug rather than to attempt to advise the patient by O-T-C label warning statements. Such an approach also would appear to comply fully with the Advisory Group’s recommendations. The use of a pregnancy warning statement on the cyclamate O-T-C labeling also was felt not to be informative to the laity, but that it also may lead to con- fusion. The deletion of such a statement does not appear to conflict with the Advisory Group’s recommendations. In this regard, a memorandum of November 25, 1969, from Dr. Ley to Dr. Egeberg was considered. This memo includes cer- tain labeling recommendations for cyclamate-containing products and includes: use of a pregnancy warning statement. It was felt that the proposed cyclamate labeling now under consideration adequately reflects or accounts for the recom- mendations in this November 25, memorandum. The Commissioner accepted the recommendations that these warning state- ments not appear on the cyclamate O-T-C labeling. He also concluded, with con- -eurrence, that the warning statement appear boxed. However, the Commissioner felt strongly that FDA act in a positive and timely manner to assure that the physician be adequately informed of available information concerning cyclamates in the areas of possible drug interaction and teratogenicity. The discussion ex- tended to the desirability of informing physicians generally on all recently ac- quired scientific information on cyclamates, including animal carcinogenetic and mutogenic data. Besides appropriate prescription drug labeling revisions reflect- ing possible drug interaction and the possibility of the use of cyclamate brochures going to physicians, the discussion touched on the issuance of a ‘Dear Doctor” | letter by FDA and the possibility of securing assistance from the AMA and organized osteopathy to inform physicians in this area dealing with cyclamates. The Commissioner directed the Bureau of Medicine to assist in developing pos- sible approaches aimed at informing physicians on the scientific aspects of the cyclamates. JOHN F. PALMER, M.D. Mr. Founrarn. Another memorandum dated October 15, 1969, ad- dressed “For the Record,” from Arthur H. Wolff, Assistant Surgeon General, on the subject “Association of Congenital Defects with Diabetes During Pregnancy.” (The document referred to follows :) CONSUMER PROTECTION AND ENVIRONMENTAL HEALTH SERVICE MEMORANDUM, OcrToBER 15, 1969 To: For the Record. From: Deputy Assistant Administrator for Research and Development. Subject: Association of congenital defects with diabetes during pregnancy. If the recent concern about the possible deleterious effects of cyclamates should lead to stricter controls on the use of non-nutritive sweeteners, I suggest that the above subject be kept in mind. It occurs to me that one possible continued recommended use would be for diabetics. If so, consideration should be given to the particular contraindication of cyclamates for diabetics during pregnancy. ''86 In view of this, I think it is important to bear in mind that the diabetic state itself appears to be etiologically associated with a higher prevalence of con- genital defects as well as still births and neonatal mortality. In the book “Diabetes” by R. H. Williams, 1965, he points out that congenital defects are six times more common in births from diabetic mothers. In the “Text Book of Endocrinology,” 1968, Williams indicates that fetal anom- alies are 10 times more frequent. “Clinical Endocrinology” by Paschkis, et al., 1967, indicates that major congenital malformations occurred in 17 percent of births in diabetic mothers as opposed to 2 percent in non-diabetic. Warren and others, in “Pathology of Diabetic Mellitus,” 1966, refers to a higher prevalence of congenital defects in diabetic mothers with difficulties of the lower spine being unduly frequent. The relationship noted above leads me to wonder whether the diabetic con- dition results in endocrinologice factors that may interact, either additively or synergistically with teratologic agents, in the induction of congenital anomalies. A related question is whether experimental work should be initiated on the pos- sible “co-teratogenic” relationship of cyclamates and diabetes. It is noted that in Diabetes 12, 66, 1963, Wantabe and Ingalls report the experimental induction of congenital defects (cleft palate) in rates following inducing a diabetic con- dition with alloxan. Another question that may be raised is whether this association of congenital defects with diabetes can be etiologically associated with the probably higher intake of non-nutritive sweeteners in the diabetic as compared to non-diabetic pregnant women. i doubt if this is the case, because many of the references cited in the text books noted indicate that the association has been known for many years predating the extensive use of cyclamates. ARTHUR H. Wo trr, Assistant Surgeon General. Mr. Founrarn. In that document it says: If the recent concern about the possible deleterious effects of cyclamates should lead to stricter controls on the use of nonnutritive sweeteners, I suggest that the above subject be kept in mind. It occurs to me that one possible con- tinued recommended use would be for diabetics. If so, consideration should be given to the particular contraindication of cyclamates for diabetics during pregnancy. T would also like to place in the record a copy of the report to the Secretary of Health, Education, and Welfare from the Medical Ad- visory Group on Cyclamates, published in the Journal of the Ameri- can Medical Association, dated February 23, 1970, volume 211, No. 8. (The document referred to follows:) — [From JAMA, Feb. 23, 1970] Report TO THE SECRETARY OF HEW From THE MepicaL ADvIsoRY GRouP ON (CYCLAMATES _ (Roger O. Egeberg, M.D.; Jesse L. Steinfeld, M.D. ; Ivan Frantz, M.D.; George C. Griffith, M.D.; Harvey Knowles, Jr., M.D.; Edward Rosenow, M.D.; Henry Sebrell, M.D. ; and Theodore Van I'tallie, M.D.) The Medical Advisory Group on Cyclamates appointed by Secretary Finch met on November 17 and 18, 1969, with representatives of the Food and Drug Administration and the National Institutes of Health to review the currently available data on the possible harmful effects of these nonnutritive sweeteners in relation to their potential benefits. The group considered the data on carcinogenic, mutagenic, teratogenic, enzymatic, osmotic, and growth effects of cyclamates and on their possible adverse influence in interaction with other drugs. After carefully reviewing the evidence currently available, the Medical Ad- visory Group on Cyclamates unanimously supported the secretary’s prohibition of the inclusion of cyclamates in beverages for general use, and in the future proc- essing of general purpose foods and vegetables. It recognized, however, that in the medical management of individuals with diabetes (and particularly in the case of juvenile diabetes) or patients in whom weight reduction and control are essential for health, nonnutritive sweeteners such cyclamates can be a useful dietary adjunct. The advisory group was of the opinion that the medical benefits ''87 in these instances outweighed the possibility for harm and recommended that cyclamates and products containing cyclamates continue to be made available to such patients on a nonprescription drug-labeled basis and should be used only on the advice of a physician. The advisory group recommended further (1) that products containing cycla- mates display a cautionary label that includes the cyclamate content in an average serving; (2) that cyclamates no longer be used as an excipient (Sweeten- er or inactive ingredient in drug manufacture) ; (3) that research be continued on cyclamates and other nonnutritive sweeteners to reproduce and expand the present findings: and (4) that FDA annually carry out a review of data on cyclamates and other nonnutritive sweeteners to determine whether research developments require a revision or addition to these recommendations. BACKGROUND The substitution of nonnutritive sweetening agents for sugar began with the discovery of saccharin in 1879 (sweetening power 350 times sugar) and was greatly extended when tthe sweetening properties of cyclamates (sweetening power 30 times sugar) were noted in 1944. Combinations of cyclamates and saccharin (30 to 100 times as sweet as sugar) avoid the objectionable aftertaste of saccharin but take advantage of its sweetening properties. In 1968, 17 million pounds of cyclamates were manufactured: 69 percent were used in beverages, 19 percent in table sweeteners, 6 percent in foods, 4 percent in nonfood items, and 2 percent were exported. The Food Additives Amendment (1958) to the Federal Food, Drug, and Cos- metie Act (1938) specifically exempted from the law substances generally re- garded as safe (GRAS) but authorized the Food and Drug Administration to alter or ban the use of such substances on the basis of safety evaluation. The negative findings on toxicity in earlier FDA studies (1951), other than stool softening and diarrhea in rats, and the finding (1955)* by the National Acad- emy of Sciences-National Research Council (NAS-NRC) Food Protection Com- mittee of no nutritional or public health problem from regulated use of cyclamates in special purpose foods, prompted the inclusion of cyclamates and saccharin in the 1959 GRAS list. At this time, cyclamates were not used so extensively nor in such a wide array of foods as today. Although the NAS-NRC committee report concluded that a maximum intake of 5 grams daily would be acceptable, a ‘‘no limit” recommenda- tion was accepted, as the sweetener was used primarily in tablets which contained only 0.05 grams of cyclamate so that more than 100 tablets a day would have to be taken to exceed the 5 grams maximum intake. However, the increased number | of people using cyclamate sweetened food in an attempt to control weight greatly increased cyclamate consumption. In response, the NAS-NRC committee in 1962 issued a revised policy statement saying that cyclamates could safely be used in limited amounts as a nonnutritive substitute for sugar in special purpose foods. In both 1965 and 1967, scientists of FDA evaluated available information on cycla- mates and concluded that there was no evidence that use levels at that time pre- sented a hazard to health. In 1967, the joint Food and Agriculture Organization- World Health Organization FAO-WHO Expert Committee on Food Additives * established an unconditional acceptable daily intake of 0 to 5 milligrams/kilogram of body weight for saccharin, and a temporary acceptable daily intake of 0 to 50 milligrams/kilogram for cyclamate until additional studies, including those on the toxicity of cyclohexylamine, could be carried out within the next 3 years. The NAS-NRC in 1968 evaluated all available data, including the FAO-WHO report, and recommended an acceptable daily intake of 75 milligrams/kilogram of body weight for cyclamate. Total daily doses of 1 gram of saccharin or 5 grams or less of cyclamate were considered safe. In this same year, the FDA proposed a maximum limit of 3.5 grams of cyclamate for a 70 kilogram (154 pound) adult and 1.2 grams for a 25 kilogram (54 pound) child. In the following year, FDA proposed that labeling be modified to permit the consumer to determine easily if his intake was below recommended limits. EVIDENCE OF POSSIBLE HAZARD eesinaine in 1967 and extending to the present, a number of research findings have raised questions as to the safety of the cyclamates. The discovery of bladder tumors in animals is directly responsible for the removal of cyclamates from the list of substances generally recognized as safe for use in foods. On June 5, 1969, '' te & scientists at the University of Wisconsin reported to Abbott Laboratories, who were supporting the studies, that a significant incidence of bladder tumors had been found in white Swiss mice in two experiments in which pellets of cholesterol and cyclamates were implanted into the lumen of the urinary bladder. Represent- - atives of Abbott Laboratories carried out discussions with representatives of the National Cancer Institute and the Food and Drug Administration, and all con- cerned agreed that carcinogenicity demonstrated by the pellet implantation tech- nique did not provide relevant information as to the hazards of orally ingested compounds, a position which had previously been taken by an NAS-NRC Ad Hoe Committee on Nonnutritive Sweeteners in 1968. However, these studies did stim- ulate new experiments and encouraged scientists conducting studies then in ‘progress to give special attention to the bladder as a site of neoplastic transformation. Y On October 8, 1969, an Abbott scientist was notified that there appeared to be bladder lesions in rats fed a 10:1 mixture of cyclamate sodium: saccharin sodium over a 2-year period in their contract-supported experiments at the Food and Drug Research Laboratories, Long Island, N.Y. During this study, many of these rats were shown to be able to convert cyclamate to cyclohexylamine (CHA). In the 79th week, half of the animals in each treated group were given supplemental GHIA in the diet. On October 9, pathologists of Abbott Laboratories examined slides from an experiment initiated by Abbott in 1967 and conducted at Industrial Bio-Test Laboratories, Inc., Northbrook, Ill. In these experiments cyclohexylamine (CHA), a known impurity of commercial cyclamate and a metabolic breakdown product of cyclamate, was fed to rats at various levels over a period of 2 years. One tumor was found in the bladder of one of the 17 surviving rats on the highest daily dosage of 15.0 mg/kg of CHA. On October 13, representative of Abbott Laboratories met with scientific per- sonnel of the Food and Drug Research Laboratories to review the study of cyclamate sodium and saccharin sodium. Of the 240 rats receiving the cyclamate sodium: saccharin sodium mixture, seven males and one female showed papillary — lesions of the urinary bladder, a tumor rarely observed in rats. However, the tumors were seen macroscopically in only two animals. All lesions occurred in the group of 35 males and 45 females fed 2.5 gm/kg/day of the cyclamate sodium : saccharin sodium mixture, and none were found at 1.00 gm/kg/day or below. Of the eight tumors, four to eight were diagnosed as carcinomas by different path- ologists. Three of the animals with bladder tumors had received supplemental CHA and five had not. With one exception, tumors developed in rats found to convert cyclamate to CHA. On October 14 representatives of Abbott Laboratories, National Cancer Insti- tute, FDA, and the Department of Health, Education, and Welfare met to dis- cuss these preliminary findings, and it was agreed that the scientific personnel present would report the findings to the NAS-NRC Ad Hoe Committee on Non- nutritive Sweeteners the morning of October 17. At this time the committee recommended cyclamates be removed from the GRAS list. 7 On October 18, 1969, HEW Secretary Robert H. Finch, because of the demon- stration of urinary bladder tumors in rats fed cyclamate throughout their life span, ordered the artificial sweetener cyclamate removed from the GRAS list. This action was taken in accordance with the Delaney amendment and on the advice of medical consultants to the Secretary. The Secretary emphasized in the strongest possible terms that there was no evidence that cyclamate causes cancer in humans. Further, there was no evidence that the use of cyclamates had caused malformation in children or any other abnormality in humans, other than a rare skin hypersensitivity.*? Since the October 18 announcement by the Secretary, additional evidence has come to light. In an FDA feeding study, originally designed to determine the conversion of cyclamate to cyclohexylamine, infiltrating bladder tumors were found at 88 weeks in three of 23 rats of the Osborne-Mende! strain. The rats had been fed cyclamate without saccharin at daily rates as low as 400 mg/kg of body weight. This is about one-sixth the dosage fed to the different strain of rats used in the Abbott study. No tumors were found in the control groups. Bladder tumors were found by the FDA study in two rats, one male and one female, even in those animals receiving 400 mg/kg daily. The minimum dosage used. At this time, therefore, the lowest dosage of cyclamate capable of producing bladder carcinoma in rats is not known. A '' 89 7 Although the action taken by the Secretary of HEW in regard to. cyclamates was based solely on the finding of carcinogenicity in animals, consideration of other research findings also is important. In these studies, toxicity of cyclohexyl- amine (CHA), as well as cyclamates, must be considered since most species fed cyclamates develop the capacity to convert cyclamates to CHA and most foods containing cyclamates also contain small quantities of CHA. Humans capable of converting cyclamates to CHA will metabolize 0.1 percent to 38 percent of the ingested cyclamate to CHA.° Cyclohexylamine has a 50 percent lethal dose (LDso) in rats of 200 mg/kg and in humans‘ will cause dermatitis and convulsions at high doses. It has been reported * that the addition of cyclamate (200 ug/ml) to leukocyte cultures produced chromosome breaks. Using kidney cells from a marsupial (rat. kangaroo) Sidney Green, MS, et al. (unpublished data) found that similar con- centrations of cyclamate di dnot inhibit mitosis or produce chromosome ab- normalities, but cyclohexylamine at concentrations as low as 1 wg/ml produced single chromatid breaks. In vivo experiments in rats ® showed that cyclohexyl- amine, 1 mg/kg, injected daily for 5 days produced a significant increase in single chromatid breaks (discontinuity of the chromatin of at least the width of its chromosome) in spermatogonial cells and that injected doses of 10 mg/kg of cyclohexylamine for 5 days showed a significant increase in chromatid breaks in bone marrow cells. Injection of various compounds including cyclamates, CHA, sucrose, and alcoholic solvents into the air sacs of eggs have shown that cyclamates cause almost six times as many, and CHA causes 60 times as many deformities of the embryo as sucrose.” i The significance of these experiments and what relevance, if any, they have to- man cannot be evaluated with present knowledge. MEDICAL EFFECTS OF CYCLAMATES AND CYCLOHEXYLAMINE Cyclamates produce stool softening and diarrhea in humans when relatively large amounts are ingested. This is apparently the result of an osmotic effect ; there is no evidence that cyclamates exacerbate organic gastrointestinal dis- eases. A number of cases of photosensitivity have also been reported in users of artificially sweetened products. Various pharmacologic effects of cyclamates and cyclohexylamine may influence the actions of certain commonly used drugs and thus interfere with therapeutic regimens. Cyclohexylamine produces weak pressor effects when administered to animals, raising the possibility that hypertensive reactions might result in hu- mans, particularly those being treated with monoamine oxidase inhibitors. In rats, pretreatment with cyclamate (100 milligrams/kilogram body weight subcutane- ously) reduces the hypoglycemic effect of tolbutamide, but similar pretreatment increases the hypoglycemic effect of chlorpropamide.” Cyclamates may potentiate the diuretic effects of the thiazide drugs and excess loss of potassium may occur. Studies in some animal species indicate that cyclamates potentiate the anticoagu- lant effect of the coumarin drugs suggesting that exaggerated responses in pa- tients under anticoagulation regimens may occur.” Cyclamates bind moderately strongly to plasma protein and may displace other drugs similarly bound with resultant modifications in pharmacologic effect. Other studies have shown that © the absorption of the antibiotic lincomycin is reduced by cyclamates ; there is no evidence suggesting effects on the absorption of other similar drugs.* : Presently available data suggest that special care should be taken when cycla- mates are used in patients under treatment with other drugs. Because of the pau- city of reported clinical experience with cyclamates, instances of known or sus- pected adverse effects of the cyclamates as outlined above should be reported promptly to the Director, Bureau of Medicine, Food and Drug Administration, Washington, D.C. MEDICIAL USES OF CYCLAMATES Although the use of cyclamates is not absolutely necessary in any disease, it can be useful in the medical management of individuals with diabetes of patients in whom weight reduction and control is essential to health. Particularly in juvenile patients who have diabetes, where sweets and soft drinks are a special problem, nonnutritive sweetened foods may be an essential part of preventive therapy. Excessive glucosuria may cause symptomatic polyuria, moniliasis, and pruritus with bacterial infection of the urologic system leading to pyelonephritis. Hyper- ''90 glycemia is thought by some to be related to angiopathy, neuropathy, cataracts, and pregnancy abnormalities. Although it is not known for sure whether obesity adds to the risk of angiopathy in the patient with established diabetes, certainly all agree that obesity is an undesirable physical state whether diabetes is present or not. Therefore, a sugar substitute can be helpful in the dietary management of the young diabetic and the overweight patient. oe 2 3 As cyclamates are withdrawn, care must be taken by physicians that diabetic or obese patients carefully note the sugar content of diet drinks since these drinks may be sweetened with combinations of saccharin and sugar. It is emphasized that cyclamates will continue to be allowed only in special purpose foods. The restriction on cyclamate use in marketed beverages will be absolute, beginning Jan. 1, 1970. In all cases where cyclamates are used in foods, the lowest exposure possible for each individual seems the most reasonable course. There is no medical justification for cyclamates as an excipient for drug formu- lation. For the present, cyclamate will be available on a drug labeled, nonpre- scription basis and should be used only on the advice of a clinician. iOver the last several decades there has been a slow, steady increase in inci- dence, but not mortality rate, from bladder cancer in the United States. But it should be emphasized that there has been no significant change in this trend during the period that cyclamates have been used as an artificial sweetener. Further updating of such data will be accumulated and reported as soon as possible. REFERENCES 1. “National Academy of Sciences-National Research Council: The Safety of Artificial Sweeteners for Use in Foods,” publication 384, 1955. 2. “Specifications for the Identity and Purity of Food Additives and Their Toxicological Evaluation; Some Flavoring Substances and Non-nutritive Sweetening Agents,” 11th report, publication 44. Rome, Food and Agricul- ture Organization and World Health Organization Hxpert Committee on Food Additives, 1968. 3. Boros, E: “An Experience With Artificial Sweeteners. JAMA 194 1571-572, 1965. 4. Kobori, R., Araki H: ‘“‘Photoallergy. “J. Asthma Res. 3 1213-215, 1966. 5. Lamberg, 'S. I.: “A new photosensitizer : The artificial sweetener cyclamate.” JAMA 201 :747-750, 1967. 6. Coulston, F. V., Goldberg, L.: “FDA Progress Report on Contract 69-7.” _ Albany Medical College, Union University, Institute of Experimental Pa- thology and Toxicology, 1969. 7. Lomonova, G. V.: “Toxicity of cyclohexylamine and dicyclohexylamine.” Gig Tr Prof Zabol 7 :95-98, 1961. 8. Stone, D., Lamson, E., Chang, Y. S., and others: “Cytogenetic Effects of Cycla- mates on Human Cells in Vitro.” Science 164 1568-569, 1969. 9. Legator, M. S., Palmer, K. A., Green, S., and others: “Cytogenetic Studies in Rats of Cyclohexylamine, a Metabolite of Cyclamate.” ‘Science 165 :1139- 1140, 1969. 10. Verret, M. J.: “Teratogenic Effects of Cyclamate and Related Compounds in the Chicken Embryo: Report on Non-nutritive ‘SSweeteners.” Bureau of Science-Bureau of Medicine, Food and Drug Administration, III-24, 1969. 11. Lockwood, R. R.; Dixon, R. L.: “The Effect of Cyclamate on the Hypogly- cemic Response of Tolbutamide and Chlorpropamide in Rats.” Food Cosmet Toxic 7 :1-7, 1969. 12. Holeenberg, J. S.; Bidgood, M.; Dixon, R. L.: “Possible Interaction Between Cyclamate and Warfarin.” Curr Ther Res 11 2577-584, 1969. 13. Wagner, J. J. : “The Bitter Sweeteners.” Sciences 9 :20-25, 1969. Mr. Founrarn. I have already placed in the record a memorandum of December 19, 1969, from Dr. H. F. Kraybill, Assistant Director for Biological Sciences Research, Bureau of Science, to Deputy Assistant Administrator for Research and Development. This is on the subject “Congenital Defects, Diabetes and Cyclamates,” and I quote from this memorandum : _You are quite correct in your concern about the diabetics and offspring of diabetics with reference to cyclamate stress. A paper by Watanabe et al (Dia- betes, Vol. 12, No. 4, 1963, pp. 66-72) stresses the intimations of a teratogenic we ''91 effect of diabetes extending back into the 19th century and now with indications of birth defects (chick embryo) caused by cyclamates, this takes on a more serious aspect to be looked for in relation to cyclamates. The need for epidemio- logical studies in this area was discussed fully by our NAS/NRC Committee in review of cyclamates on 16 October. . Since last discussing this matter with you, I had had a chance to see a pre- liminary draft of minutes of the Medical Advisory Group on Cyclamates meeting and a member of Dr. Steinfeld’s staff has informed me that full discussion was held on the matter of birth defects and bladder cancer. Apparently with reference to the matter of bladder cancer there was some divergent viewpoints with NCI member particularly concerned about the impact of cyclamate. The other members of the group, however, made a strong plea for cyclamates feeling that in clinical management of a juvenile diabetic some ‘carrot’ must be provided to those who have an unrelentless craving for sweets or sweetening agents. For those who can regiment themselves, perhaps neither cyclamates nor saccharin are necessary. This is the part, I believe, the quotation we have already referred to: One presumably faces an issue of benefits versus risk, although one physician in the group advised me that he felt that hypoglycemics or hyperglycemics might well avoid the use of cyclamates. (The document referred to will be found on pp. 56 and 57.) Mr. Founrarn. I would like to refer to another memorandum al- ready in the record; namely, the memorandum of Mar. 31, 1970, from Commissioner Edwards to Dr. Jesse Steinfeld, Surgeon General. I quote from this document : At the ninth annual meeting of the Society of Toxicology, Atlanta, Ga., March 15-19, 1970, a paper was presented entitled “Myocardial Lesions Induced by Calcium Cyclamate in ‘Syrian Hamsters.” Significant is the statement that “Al- loxan-diabetic hamsters were much more sensitive than healthy ones to ‘the ad- verse effect of Ca-cyclamate” and the statement: “It seems that cyclamate enhances the toxicity of Ca as well as of Na with either of which it forms a stable, water-soluble salt.” This paper was reported on in Food Chemical News of March 238, 1970. Mr. Fountary. Dr. Edwards, by declaring cyclamate-containing products to be new drugs within the meaning of the law, have you not in effect, or has FDA not in effect, declared that such substances are not generally recognized as safe for the uses for which they are intended ? Mr. Epwarps. That is right. Mr. Fountarn. Reading from section 503-B-1(b), we find: A drug intended for use by man which because of its toxicity or other poten- tiality for harmful effect, other methods of its use, other collateral measures necessary for its use, is not safe for use except under the practitioner licensed by law to administer such drug. Since medical supervision is declared to be necessary for safe use for cyclamate-containing drugs, wouldn’t you say they fall within the scope of section 503-B-1(b), which I just read, and are therefore pre- scription drugs? Dr. Epwarps. Let me make this point first. I think in theory, yes. I think we have an inconsistency in the law, however, indicating that the case of insulin is an example where it is not a prescription drug primarily because I presume it is felt that diabetics understand their disease sufficiently well that they don’t particularly have to have this on a prescription basis. I believe maybe this inconsistency with insulin had something to do with making this not a prescription drug. Dr. Wodicka? Mr. Founratn. Do you want to add to that, Doctor ? Dr. Woprcka. I would like to comment on that if you don’t mind, ''92 Mr. Chairman. The cyclamate-containing products that are under dis- cussion are almost unique as drugs in the quantity of intake per day. So that the channels of distribution would be inadequate for those used in prescription drugs to handle the drugs without having a lot of disruptive changes. Now if you are sure these considerations entered into this matter of the existing market, that until evidence of abuse was clearly shown, I — don’t think we should enter that area. But if these abuses are shown, - that disruptive change would have to be faced up to. Mr. Founratn. I can appreciate your point of view. Of course, there are economic and other factors that enter into this. But I am asking these questions, among other reasons to get on the record a number of questions that are raised and the extent to which you have gotten yourself into an inconsistent position as a result of the decisions which were made. Now, if you wanted to, in spite of the label declaration that their safe use requires medical supervision, you could use these products without being under the supervision of a physician? Dr. Epwarps. I think you could. No question about it. Mr. Founrarn. And, as you say, you have a practical problem with distribution. Dr. Wopicxa. Yes. Mr. Founvarn. Of course, if you declared these to be prescription drugs, unless you make other changes in the meantime, you would cer- tainly avoid what may well one day turn out to be an enormous enforcement problem to insure the proper use of cyclamate-containing products, is that right ? Dr. Epwanrps. That is correct. Mr. Founvarn. It certainly appears that the scheme of distribution for the cyclamate-containing products which you have devised, unless it is closely controlled in some way, will be ineffective, and cyclamate products will be as freely available to any person who wants to buy them just as they were before the ban was imposed. A This to us would have nullified your order with a breakdown in pro- tection for the consumer. Now your order of March 17, 1970, also pro- vided for the abbreviated new drug application for these products to be mailed to the district offices of the Food and Drug Administration, Has this ever been done before ? Dr. Epwarps. Not to my knowledge, no. Mr. Founratn. Is this being done in this instance possibly because you feel the hazard involved in cyclamate-containing products is minor? Are the district offices staffed with medical people? Mr. Fine. The review that the district offices will do will be only of the labeling. The medical decisions are already made here in Washing- ton on the cyclamates. All the district offices will do will be to review the labels submitted to see if they comply with the order. Mr. Founrarn. So that will be the only responsibility ? Mr. Fine. That is correct. Mr. Fountarn. Since you have classified cyclamate-containing prod ucts as drugs, will it be necessary for all the manufacturers of such products to register as drug manufacturers? Mr. Finr. The answer is yes. Mr. Founrarn. Any special requirement? Is there a lot of bureaucratic redtape? ''93 Mr. Fine. The registration form is quite simple. ~ Mr. Fountain. The registration form is quite simple ? Mr. Fine. Yes, it is. Mr. Founrarn. All the drug manufacturers do have to register under the law, is that true? Mr. Fins. Yes, sir. Mr. Fountain. Have all of the manufacturers of cyclamate- containing products been advised of the need to register? Mr. Fine. Not specifically. I think that they realize that this is implicit in the order as soon as they see that this is a drug. Mr. Fountain. You will have many more people manufacturing cyclamate products than you have manufacturing drugs, will you not? Mr. Fre. I am not so sure that some people will stay in this business with this kind of drug labeling based on conversations I have had. I I think many of the people that in the past have done this when they see that drug labeling required, the drug labeling requirements, they may decide to get out of the business. Mr. GorpHammer. Mr. Fine, do you think that Del Monte Food Packing Co., just to mention one, knows that it has to register? Mr. Fine. I believe they do. Mr. GorpHammner. I have a copy of the National Canners Associa- tion letter to the members relating to their meetings with you and de- cisions arrived at and procedures to be followed. There is no reference in that communication to the fact that registration of the manufacturer of these products is required. There is considerable discussion of pro- cedures and the new drug provisions they will have to meet. But Ihave run through that letter rather carefully and I find no reference to the need for registration. Have you had communications with the canning organizations on that point? Mr. Frvz. Specifically on that point, no, I have not. Have you, Dr. Wodicka, sir ? Dr. Wonicxa. No, I have not, but in this specific instance of Del Monte, I believe, to my knowledge, they have two technically trained people who spend full time on regulatory matters and I think they would be sufficiently familiar with the law and the regulations to be well aware of the requirements. Mr. Gotpnammer. The drug regulations ? Dr. Woptcxa. They have copies of the complete law, sir. Mr. Founrarn. Is there any necessity of getting out a communica- tion to all these people? Mr. Five. We can do this. : Mr. Fountain. Have you done it ? Mr. Fine. No, I say we can do this. Dr. Epwarps. We will do this. ee Mr. Founrarn. I assume you won’t approve a new drug application of a cyclamate-producing manufacturer if the manufacturer has not _registered as a drug manufacturer by law ? Dr. Epwarps. That is correct... _ x _ Mr, Founrarn. Have you advised -your field districts of the re- quirements for registration by producers of .cyclamate-producing . manufacturers ? By cy : : Dr. Epwarps, That is correct, too. _ sit 48-798—70—_7 ''94 Mr. Founrarn. Section 502(f) (2) requires warnings for protection of the users for OTC products; are there contra-indications that the purchaser should be made aware of these matters ? Dr. Epwarps. No, there are not. Mr. Founrarn. For instance, documents have been put in the hear- ing record which make reference to the high incidence of birth defects for diabetics who become pregnant. Don’t you think that 502(f) (2) would require warning of harm to offspring if cyclamates are ingested by pregnant diabetic women ? Dr. Epwarps. This is obviously not on the labeling. We have tried to get this information in the proper medical journals. It is not on the labeling. Mr. Fountain. Also, the documents show that cyclamates may inter- fere with the desired action of certain commonly used drugs, including antidiabetic drugs—in which case it seems to me the diabetic ought to be informed. of this potential hazard by labeling declarations of some kind. Dr. Epwarps. Mr. Chairman, all these pharmacological effects are under intensive study by our. Bureau of Drugs and, as noted a little earlier, many of the suspected pharmacological effects are those that have been noted in animals. I think the only specific pharmacological effect which has been proven in the human being is in the case of lino- mycin. Dr, Jennings has just informed me, however, that a later study indicates that cyclamates used in linomycin did not interfere with the drug’s absorption. So, again, the rest of these things are being closely watched and studied by:the Bureau and appropriate action will be taken as soon as we are convinced scientifically there is a relationship. Dr. Jennings also makes the point that all of this information was provided to this expert committee when they made their recommendations. Mr. Founrarn. Are you through ? Dr. Epwarps. Yes. Mr. Founrarn. Where does the NDA application go after it goes to the regional office ? : Dr. Epwarps. In the case of cyclamates? . Mr. Fountain. Yes. Are they sent there for the purpose of inspect- ing labeling only ? : Dr. Epwarps. For cyclamate-containing foods it would first go to the District Office in whose territory it is located. Mr. Founrarn. From there to the Bureau of Drugs? Dr. Epwaros. That’s right. The NDA goes to the District Offices where they can then begin their checks, and from there it goes to the Bureau of Drugs. I presume, Dr. Jennings, it would go through the NDA process, would. it not? Dr, Jennrnas, There are several reasons these were being handled in this fashion. One is that they are abbreviated NDA forms which will contain no scientific safety and efficacy questions, that question being resolved for better or worse on a higher level. _ The applications will essentially consist, of labeling to make sure it is in accord with what we have ordered. And we feel that the District Offices have adequate staff to do this, especially since the Bureau of Drugs has developed a set of guidelines and instructions for the ap- proval of these abbreviated ND A’s. ''95 Certain of the NDA’s are being processed in the usual fashion or more nearly the usual fashion in the Bureau. They are the table-top sweeteners which are cyclamates alone. Sucary] tablets, the things that you are familiar with. Our requirements are such that we are confident that through the applications that are processed in the Bureau, we will have access to any data relating to safety and efficacy that might develop and which we might not otherwise be aware of. So that this was an administrative decision designed, among other things, to spare the personnel now in the Bureau of Drugs for more urgent duties at this time. Mr. GorpHammer. Dr. Jennings, will district make the decision as to whether the NDA is to be approved ? Dr. Jennrnes. Yes, sir, based on the Federal Register publication and a rather comprehensive set of instructions and guidelines which I believe have now been issued to them. Mr. GotpHamner. All right. Dr. Jennings, do you believe that the safety of cyclamates has been established ? Dr. Jennines. I think I spoke to that a little earlier, Mr. Gold- hammer, not in the sense required by the Food and Drug and Cos- metic Act for new drugs that are processed in the usual manner. We discussed that to some length previously. I want to point out Dr. Edwards referred to it a little earlier, that the action taken regarding the cyclamates as drugs entails a yearly review of data and so it is essentially an interim action. The first yearly review is upcoming in October. I anticipate that one of these days we will have to decide whether we can continue these as drugs with the substantial evidence of safety and efficacy as for other drugs or whether perhaps through other developments they might be included in the food additive list or perhaps eliminated completely because of the inability to establish safety standards. Mr. GorpHammer. Well, in the light of what you have just said, are i es in approving any NDA for a cyclamate-containing food or drug? Dr. Jennrnos.. That becomes, I think, essentially a legal question and we have been told that in order to implement the recommenda- tions of the Advisory Committee, in view of the lack of general recog- nition or safety and efficacy, that the new drug application route was the only one available. Mr. GorpHammer. Thank you. Mr. Founrarn. Did I interpret what you just said, Dr. Jennings, to mean that on the basis of current medical knowledge you could not approve any new drug application for a cyclamate-containing product? Dr. Jennines. Yes, sir. If cyclamates, for instance, were introduced to us completely without any previous experience, the amount and kinds of data available relating to both safety and efficacy, in my opin- ion, would be insufficient and inadequate to warrant approval under the usual new drug procedures. This is why we have made so much of the point that this was essentially an interim procedure pending the review of data as it develops. That doesn’t mean that we have persua- sive data that the products are unsafe but simply that the kinds of sub- stantial evidence ordinarily required for approval of a new drug ap- plication are wanting. ''96 Mr. Fountarn. So what you are doing, then, is making available ab- breviated NDA forms that:could not be approved otherwise ? Dr. Jennies. I think that is correct; in an effort to implement the recommendation of the Secretary’s committee. Mr. Founrarn. I would like, before we recess, to make a brief state- ment. I think we have covered the subject of cyclamates about as thorough- ly as we can. We have put into the record a number of things which were quite obvious, but I think they more clearly indicate just what the situation is. It is hard for me to really understand the rationale behind the han- dling of this matter. FDA is making the manufacturer go to the trou- ble of filing a new drug application, albeit an abbreviated one, and thereby, insofar as the intent of the law is concerned, is supposedly imposing upon him the obligation to establish the safety and efficacy of his product. The evidence we have heard today tends to establish that there is a question both as to the efficacy and safety of these products. I think it is under just such circumstances that the new drug provisions were in- tended to come into play. These provisions placed the burden upon the Food and Drug Ad- ministration to keep questionable drugs off the market. It seems to me that until safety and efficacy have been established, this should be done. And yet the FDA makes no demand on anyone interested in market- ing cyclamate-containing products which are now called new drugs, thus acknowledging that they are not generally recognized by the ex- perts as safe and effective. Instead the new drug application is directed to the field offices of the Food and Drug Administration. They have no responsibility other than to inspect the labeling. They have no drug function. There are no physicians there. Without specific inquiry, people would think a much more responsible function was being performed there than that which is going on, which is somewhat of a rubber-stamping operation. It seems to me the new drug provisions of the law, and their in- tegrity and their importance, are being eroded. I do not believe the Congress ever intended that when new drug applications are filed they would be given perfunctory treatment with- out the required scientific data review. Whether or not so intended, the action taken by the Food and Drug Administration clearly gives the appearance of being a subterfuge to keep cyclamates in foods and thereby circumvent the law. I think it is regrettable, but these are obvious conclusions which I, as a layman and a lawyer also, would have to draw. IT am glad to hear you say, Doctor, that this whole process, is cur- rently being reevaluated and that an effort will be made to improve the situation for the future. Before we recess, I have a statement submitted to the subcommittee by Congressman Joseph G. Minish in connection with cyclamates. The statement will be included in the hearing record at this point. ''97 (The statement referred to follows :) PREPARED STATEMENT OF Hon. JOSEPH G. MINISH, A REPRESENTATIVE IN CONGRESS FROM THE STATE OF NEW JERSEY Mr. MinisH. Mr. Chairman and members of the Subcommittee on Intergovern- mental Relations, thank you for affording me the opportunity to make known my views concerning the operation of the Food and Drug Administration, most particularly with regard to the cyclamate situation. The FDA, as the overseer of foods, drugs, pesticides, cosmetics, and various other types of consumer products, is charged with a most important responsibility. Any dereliction or delay on the part of this agency in carrying out its obligations fully will result in detriment to a large portion of the populace. With respect to the partial removal from public sale of cyclamates, I remind the committee that the National Academy of Science concluded in December of 1968 that it had a serious suspicion about the sweetener’s effect on humans. At that time, the Academy set maximum intake levels for adults and children, demon- strating its doubts about the possibility of overuse. Nonetheless, the FDA did not insure that buyers of products containing cyclamates were prevented from mis- using or overindulging them. Although there was a warning somewhere on a prod- uct containing cyclamates that the product was to be used by persons who must restrict their intake of sugar, there was not a warning concerning the maximum amount to be consumed in accordance with NSA findings. Moreover, cyclamates were used in children’s vitamins and products geared for children such as pow- dered soft drinks. It is extremely doubtful that many children using these products required a sugar-free diet. I believe, Mr. Chairman, that when there is any doubt about public safety, the question should be resolved in favor of the public. Obviously, the FDA could have developed a more effective policy to avoid the massive use of cyclamates before they were ordered removed from public sale. We all know that at some time it may be necessary to ingest a potentially dangerous substance; that is, when the substance will do more good than harm. Such is the case with medicine. Although many medicines may have some un- pleasant or unhealthful side effects, nonetheless, they are prescribed because they are more beneficial than the ailment they are intended to mitigate. However, the removal of an artificial sweetener from public sale is less harmful to the public than wide usage of one that is potentially dangerous. I believe that the FDA should have made a determination that would have protected the public from the possibility of harmful or deleterious effects from cyclamates much earlier than it did. Perhaps it is time to seek substantial improvement in the agency’s operation, to insure that the public is protected as fully as Congress intended. Recent de- motions and departures from the agent would suggest that it might be more intent on stilling criticism than in making progress. If this is true, and if it is allowed to continue, the FDA would be serving a shriveled public service. Thank you for permitting me to add my testimony to that of your other witnesses. Mr. Founrarn. The subcommittee will not meet tomorrow. In view of our need for sufficient time to complete this series and the short time that would be available in the morning, and the nonavailability of sub- committee members, we will recess subject to call of the Chair and resume next month at a time to be announced. We will get in touch with you, Doctor Edwards, to arrange a mu- tually convenient time for resuming the hearings. It will be following the July 4th recess. The committee stands recessed subject to call of the Chair. (The following letters were received subsequent to the conclusion of the hearings :) ''98 ABBOTT LABORATORIES, North Chicago, Iil., July 13, 1970. Hon. L. H. FounrTAIN, Rayburn House Office Building, Washington, D.C. Dear Mr. Fountain: Neither the statement of Commissioner Edwards, nor the testimony of the Food and Drug Administration personnel at the hearing on Food and Drug Administration activities before the Subcommittee on Intergov- ernmental Relations, Committee on Government Operations, on June 10, 1970, completely covered the subject of the safety of cyclamate. We would, therefore, like to correct the unfortunate impression that the safety of cyclamate has not been demonstrated by valid and adequate scientific studies. First it would be well to establish for the record the manner in which the information regarding carcinogenicity was developed and presented to the Gov- ernment. Abbott Laboratories has for many years submitted all of the scientific data coming to its attention regarding cyclamates to Dr. O. G. Fitzhugh, Toxico- logical Adviser, Food and Drug Administration. However, this matter was han- dled in a different way. A brief historical excursion to June of 1969 is necessary. On June 5, 1969, Dr. Bryan of the University of Wisconsin advised us of the results of his bladder implantation studies. Upon hearing of his results, we informed him that we felt compelled to discuss his findings with the Food and Drug Administration. During a telephone report to Dr. Ley on June 10, by Dr. James M. Price, vice president, experimental therapy, Abbott Laboratories, Drs. Ley and Price agreed that the Bryan report should be evaluated by Dr. Endicott, Director, National Cancer Institute and his associates at the Institute. Appointments were made with the Commissioner and Dr. Endicott for June 20, 1969, and Dr. Price again related Dr. Bryan’s findings. After the scientists at the National Cancer Institute made their evaluation on June 20, it was the judgment of the three physicians (Ley, Endicott, and Price) that the bladder implantation studies were possibly indicative but hardly con- clusive that carcinogenic properties could be demonstrated for orally ingested cyclamate. This conclusion had been anticipated because earlier bladder im- plantation studies done in England on saccharin several years ago had also resulted in bladder carcinomas, without, of course, saccharin being deemed to be a carcinogen on that basis. In fact, when those earlier saccharin findings were reviewed by the National Academy of Sciences-National Research Council in 1968, it was concluded that, “* * * there is no evidence from the work reviewed that saccharin * * * pre- sent(s) (a) carcinogenic hazard * * *”. However, because Dr. Bryan’s work on cyclamate embraced a much larger number of animals than the earlier British work on saccharin, it was considered by us to be a superior study as a screening test and therefore warranted further interest. Dr. Ley asked that a written summary of Dr. Bryan’s work be addressed to him personally to avoid premature discussion of the subject in nonscientific channels at the FDA. He also asked us to keep the National Cancer Institute apprised of any additional data which we might acquire. At about the same time a study sponsored by Abbott Laboratories at the Food & Drug Research Laboratories (a private research laboratory), under the direc- tion of Dr. Bernard Oser, had just been completed. In this study the rats had been on a daily diet which included a mixture of cyclamate and saccharin, and in some cases, cyclamate, saccharin, and cyclohexylamine (CHA). The protocol was designed to measure the long-term toxicity of the mixture and was not designed to investigate the possible carcinogenicity of any one of those sub- stances. Still, in the light of the Bryan work, we arranged to have the urinary bladder of the animals inflated and sectioned so that microscopic examination could be made to ascertain whether the test groups had an abnormal incidence of bladder tumors. 4 Upon review of the slides, the pathologist for Food & Drug Research Labora- tories concluded that carcinomas were observable in the bladders of some animals fed at the highest level; namely, 2,500 milligrams per kilogram of body weight of a mixture of 10 parts cyclamate to one part saccharin. This would not in itself be indicative of carcinogenicity of cyclamate since the animals, in all cases, received both cyclamate and saccharin, and in all but one case received large doses of CHA as well. The colony, incidentally, was not free of bladder mites and bladder worms, which some scientists believe predispose the animals to ''99 pladder carcinoma: Although such nematode infestations are common, the im- portance of this factor has not been appreciated until quite recently. Further investigation of this factor is indicated. Coincidentally, Abbott scientists received from Industrial Bio-Test Labora- tories of Northbrook, Ill., a series of slides of the bladders of rats fed cyclo- hexylamine in their daily diet. A carcinoma was observed microscopically in the slides of one bladder. Putting the information from the two tests together, we concluded that in accordance with our agreement with Commissioner Ley a second visit with the National Cancer Institute was appropriate, to determine the scientific significance of the data. After the scientists at National Cancer Institute had reviewed the data and the slides, Dr. Saffiotti, Associate Scientific Director, NCI, requested us to take the matter up with Dr. Jesse Steinfeld, Deputy Assistant Secretary for Health, Department of Health, Education, and Welfare. Dr. Steinfeld told Dr. Ley that the subject of our intended conversation was additional data on the possible carcinogenicity of cyclamate and requested his attendance at the meeting. We had also told Dr. Ley the subject of the impending meeting and had offered to brief him. It was not necessary to do so because he accepted Dr. Steinfeld’s invitation. Those persons at the FDA concerned with the events of October 18, 1969, and the days immediately preceding it, were Dr. Ley, then Commissioner, Kenneth Kirk, then Associate Commissioner for Compliance, and Winton B. Rankin, then Deputy Commissioner. None of these people is now with the FDA. The personnel from the Department of HEW with whom we discussed the problem were Dr. Egeberg, Assistant Secretary for Health, Dr. Steinfeld; and Robert Mardian, General Counsel, HEW. t should be borne in mind that even at this date no conclusive evidence that cyclamate is carcinogenic in man or other animals has been forthcoming. The study done at Dr. Osler’s laboratory has not been repeated to show that the same results would occur a second time. Nor has any study been done under an ade- quate protocol to demonstrate that cyclamate alone would show a carcinogenic effect. We understand that the National Cancer Institute ig, with other cooperat- ing parties, working on the design of such a protocol. ; Cyclamate has been one of the most intensively studied substances in the human diet. Its safety was widely and justifiably recognized in the scientific community. The safety data on cyclamate was reviewed by three Ad Hoc Com- mittees (1955, 1962, and 1968) of the National Academy of Sciences-National Research Council. The latest such Committee composed of nine highly regarded scientists of broad experience and unquestioned qualifications, completed an exhaustive review of all data available in 1968 and in a report provided to the FHA in November of that year said: “In summary, observations to date have not revealed any apparent systemic toxic effect in normal children or adults or in persons with preexisting diseases, such as diabetes or liver or renal disease, when the daily intake is of the order of 5 grams per day or less. As the dose is increased above this, softness of stools or diarrhea may occur in some persons. Relatively rare skin rashes have been re- ported and appear to be in the nature of a photosensitiivty. There is no clinical evidence of significant interference with the action of common medications such as insulin, antibiotics, or diuretics. There is no evidence to date of any effects on human fertility or embryonic development although specific studies are lacking. Some aspects of the metabolism in humans have not been completely defined.” The committee, in the preface to its report, acknowledges access to scientific studies, published and unpublished, complete and in progress. “The committee has been able to review a large body of unpublished informa- tion based on very recent studies as well as progress reports of work still in progress. This information was made available to the committee by the principal sponsors, both Government and commercial, of current research work in the United States, and through direct conference with many investigators. In addi- tion, of course, published literature in the field has been reviewed.” The adequacy of the data to make a judgment was unquestioned. There were unanswered questions, as there always will be in any scientific inquiry. But Con- gress recognized that at the time they adopted the food additives amendment. Each of the prior reviews of the safety of cyclamates by NAS/NRC Committee suggested areas of unanswered questions and areas in need of additional research, yet each of the prior reports found that cyclamates were safe within both an overall limit (5 grams every day) and within existing consumption patterns. ''100 The fact that the present evaluation also found additional areas for study cannot detract from its basic finding that cyclamates are safe in use. AS was well recog- nized in Congress at the time the food additive amendment was adopted, the statute does not require and cannot require proof beyond any doubt of the safety of an ingredient; all that is required is a reasonable certainty, and this reason- able certainty is reflected in the Ad Hoc Committee’s report. “* %& %* there seemed to the Committee no reason to differ materially with the earlier implied conclusion of the Food Protection Committee and the Food and Nutrition Board, viz: That intakes of 1 gram or less per day of saccharin or 5 grams or less per day of cyclamate by the adult should be no hazard. * * * In the case of the cyclamates [the Committee] concludes that daily intakes of 70 milligrams-kilograms or less per day are safe.” This judgment of the Committee is amply supported and documented in the extensive body of the report, which demonstrates clearly that cyclamate was safe under its conditions of use. Even with some areas of research not yet com- pleted, the Committee’s conclusion and judgments underlying that conclusion provide the reasonable certainty as to safety clearly specified by Congress. Little further data have been reported since the NAS/NRC 1968 interim report. Dr. Verrett, an FDA scientist, recently was quoted as suggesting, on the basis of a study done at the University of Washington on mice, that cyclamate inter- feres with the action of oral antidiabetic agents in man. This in the face of a comment by Dr. R. R. Dixon, the investigator, that the results of his experiments © could not be extrapolated to man. Such a disclaimer is well taken because in two studies in human beings it has been shown that no such interference occurs. Reference is made to these human studies in the interim report of the NAS/NRC Committee. On page 8, Summaries and Conclusions, the Committee said, “Throughout these investigations there was no evidence of interference with the effects of any of the drugs with which the patients were being treated.” The reports of these human studies were in the files of the FDA, as was the interim report. x There have been suggestions, based upon the results of experiments done by Dr. Legator, an FDA scientist and by others, that cyclamate may be mutagenic. The question of mutagenesis arises from relatively recent chromosome study techniques which have not yet been demonstra'ted to be correlative with muta- genic activity. Furthermore, when chromosome studies are done with human leucocytes, damage to the cells is not found. Moreover, the studies done by Dr. Legator which received such great national publicity were done with cyclo- hexylamine and not cyclamate. Efforts to corroborate his studies on CHA have been unsuccessful. His studies with cyclamate did not reveal any chromosome abnormalities. Allegations of possible fetal malformations have been based on chick embryo studies by Dr. Verrett, employing a test system considered to be only of screen- ing value. If any notice should be taken of this type of studies, it would be as an indication of the necessity to start teratogenic, fertility and reproduction (TFR) studies under the guidelines established by the FDA for doing such studies. Those guidelines require studies in two mammalian species, and as the NAS/NRC Ad Hoc Committee reported to the FDA, “* %* * studies have been conducted with mice, rats, rabbits, dogs, and swine and no evidence has been presented, nor has any investigator made ‘the claim that sodium saccharin or the cyclamates are teratogenic.” Curiously, if the screening test with chick embryos had been done first, the feeding studies in those several mammalian species would have overcome any suspicion of possible adverse effects on formation of the fetus. However, because the screening test was done after the studies in mammalian species, those studies are sometimes disregarded and it is assumed that the bare suspicion raised by the screening test is conclusive proof of tera'togenicity. Such a position is not sound— such a position is not scientific. With respect to Dr. Verrett’s work with chick embryos, which has been so cere in lay reports, Dr. Steinfeld in his prepared statement on October 18, 1969, said, “The NAS/NRC Ad Hoc Committee on nonnutritive sweeteners of the Food Protection Committee yesterday concurred in this department’s position of 2 ''101 weeks ago that chicken egg injection teratogenic experiments cannot be extrap- olated to man. in the face of other mammalian feeding experiments in which no evidence of fetal malformation was found.” No instance of serious or irreversible effects in man can reasonably be attrib- uted to cyclamate. Its removal from general purpose foods is solely on the basis of findings that bladder cancer occurs in some rats receiving a dosage every day of their lifespan that is far in excess of any that might be ingested by any human being on even a single day. Dr. Steinfeld has said, “There is absolutely no evidence-to demonstrate in any way that the use of cyclamate has caused cancer in man.’” The fact that Abbott Laboratories yielded to what many may think to be the antiscientific dictates of the Delaney clause cannot in any way be considered an endorsement of that statutory provision by our company. We strongly disagree with any suggestion that that clause should be expanded to include teratogenesis and mutagenesis because we are not aware that any test procedure in animals shows. sufficient correlation with effects in. man that suspension of scientific judg- ment can be countenanced. No substance can be shown to be absolutely safe. Even those generally recog- nized as safe are so recognized by the absence cof significant adverse findings. The data available on cyclamates indicate to us that it is'a safe compound. We agree that it cannot be classified as a food additive, not because of lack of evidence of safety, but because of the Delaney clause. However, all of the safety data has been submitted to the FDA with our New Drug Applications on our Sucaryl® brand sweeteners, Approval of those applica- tions would in no way be inconsistent with the new drug provisions of the Federal Food, Drug, and Cosmetic Act. Questions of the claims of efficacy of the cyclamates are readily resolved. Only two claims are made: 1. the cyclamates are nonnutritive and 2. the cyclamates ~ are sweet. Neither claim has ever been disputed, sericusly or frivolously. Confusion arises when the premise that cyclamate has a positive anticaloric effect is injected into the discussion. Of course, the addition of cyclamate to the diet does not reduce calories already present. Of course, eating large quantities of low calorie products which have a total caloric value exceeding that. of products which would otherwise be consumed does not lower caloric intake. But, the substi- tution of a noncaloric substance for a caloric substance does reduce caloric intake. Thus the substitution of one Sucaryl tablet for one teaspoon of sugar eliminates 16 calories that would otherwise have contributed ‘to the problem of obesity. Also, such a substitution aids the diabetic in avoiding an unwanted and at times dangerous carbohydrate—sugar.) ae fact that sugar can be dangerous should not be ignored. It is curious that seldom has the question of the safety of cyclamates been put in terms of the alternatives available to the American public, namely the relative safety of vari- ous sweeteners, nutritive and nonnutritive. Putting it another way, one might ask—is sugar immune to question simply because its dangers have been accepted for many years? If we apply the criteria set forth in Mr. Goodrich’s statement regarding the GRAS status of cyclamates in his memo of January 4, 1966 (hear- ing transcript, p. 215), “It (cyclamate) could not be generally recognized as safe, if there were indeed a sharp difference of opinion about its safety’; sugar is not generally recognized as safe.) The medical profession has expressed concern over the increasing intake of sugar because of sugar’s apparent association with excessive concentrations of fat in the blood stream which may be related to coronary atherosclerotic heart dis- ease. Sugar has long been criticized as a source of “empty calories” contributing to obesity and as a source of fermentable carbohydrate that may contribute to dental caries formation! The per capita intake of sugar has been steadily increas- ing whereas the percentage of total carbohydrates in the American diet is now about a fourth lower than at the beginning of the century. The share of carbo- hydrate provided by sugars has steadily increased from 31.7 percent in 1909-13 to 51.2 percent in 1965. In 1965, the annual per capita intake of sugar was 96.5 pounds according to Agriculture Economic Report No. 113 of the USDA; this is equivalent to more than 4 ounces per person per day, or approximately one-fifth the dry weight of the American diet. ''; 102. Con tte basis of the scientific evidence, cyclamate is probably safer than sugar. Perhaps Abbott Laboratories did a disservice to itself and the American con- sumer by not demanding that cyclamate be judged on the basis of its safety as compared with sugar’s. After all, the sugar industry spent the better part of a decade in a vigorous assault on the cyclamates, What was Abbott’s attitude during this attack on the safety of cyclamate which lasted from about 1962 to 1970? First, we provided every bit of data which came to our attention, negative as well as affirmative, to the World Health Organization, 'to the Food and Drug Administration and to the National Academy of Sciences-National Research Council. Furthermore, we were willing to live by the results of scientific studies. As has been indicated, conclusive proof of carcino- genicity from cyclamate, even in the lower species, has not been developed. Never- theless, with the full expectation that the Delaney clause would be invoked, we reported what we knew to be damaging evidence from studies that were not in the least relevant to human consumption. We are, and always have been, willing to comply with the Federal Food, Drug, and Cosmetic Act; but we will not and cannot let our compliance with the act be misconstrued as an indication that cyclamate was or is unsafe as used. Very truly yours, R. W. KASPERSON, Vice President, Corporate Regulatory Affairs. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE, Foop AND DruG ADMINISTRATION, Rockville, Md., August 5, 1970. Hon. L. H. FountrvAIN, Chairman, Subcommittee on Intergovernmental Relations, Committee on Govern- ment Operations, House of Representatives, Washington, D.C. DEAR Mr. Fountain: This is to comment on a letter of Mr. R. W. Kasperson, vice president, corporate regulatory affairs of Abbott Laboratories, addressed to you concerning issues of safety and efficacy of the cyclamates. In general, Mr. Kasperson dismisses the question of safety by finding the avail- able evidence inconclusive and that of efficacy by explaining that the utility of the cyclamates is self-evident. He emphasizes the timeliness of reports submitted by Abbott Laboratories concerning these issues. In fact, much of the present controversy about artificial sweetners could prob- ably have been minimized if the last statement was completely correct. Abbott Laboratories did not keep its new drug application up to date and only episo- dically submitted data to various unrelated offices of the Food and Drug Adminis- tration; there was no attempt to communicate or organize this information effec- tively. A meeting with Food and Drug Administration staff in 1965 led to certain recommendations for further study but these were never implemented. Much of the data reported to Abbott Laboratories from contracts under its support re- mained in its files instead of being published in the open literature as would the reports of any work of quality. This latter statement is documented by the bibliography cited in the review article prepared by scientists of Abbott Labora- tories which appeared in the American Journal of Clinical Nutrition during 1968. Finally, its scientific attack did not represent an organized approach to the prob- lem but rather a reaction to the various unfavorable studies which had been generated through support by the Sugar Research Foundation. Mr. Kasperson then turns to this relatively scanty data to raise questions about its validity in regard to the biological effects of cyclamates and cyclohexylamine. That the picture is not fully coherent or complete is admitted by all. The Food Protection Committee of the National Academy of Sciences/National Research Council in its report which Mr. Kasperson quotes extensively indeed did not find evidence for lack of safety, but, as Mr. Kasperson fails to point out, neither was it ~ satisfied that sufficient and adequate evidence exists; eight detailed recommen- dations for further study are given iin its report. A late report made last October concurred in the Department’s conclusion that cyclamates have been shown to produce cancer in test animals and should not be used in general purpose foods. Because the various tests for carcinogenesis, mutagenesis, or tetratogenesis are controversial, they are summarily dismissed by Mr. Kasperson. The impor- tance of these findings will not be resolved by debate but by further study. The ''od aw 103 issue is: are cyclamates sufficiently important to even temporarily disregard cer- tain warning signs of toxicity in which the mechanism or dose level effects are unknown? (further, it is specious reasoning to separate the effects of cyclamate from cyclohexylamine which occurs both in finished products and as a metabolic transformation product) The role of the latter substance in producing toxic effects is unknown. on (While cyclamates may have been one of the most intensively studied substances in the human diet, such a statement has no practical meaning. Data have been often inappropriate, uneven in quality, slow in coming, and not adequate to estab- lish ‘the safety of these substances.) As promised, steps have been initiated to re- view all the scientific data bearing on the effectiveness of cyclamates for use by diabetics and certain obese patients who are under medical treatment. We will advise you further. Sincerely yours, M. J. Ryan, Director, Office of Legislative Services. (Whereupon, at 5:35 p.m., the hearing was adjourned, subject to the call of the Chair.) O '' '' C. BERKELEY LIBRARIES WN €028997704 '' ''