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SCIENTIFIC BASIS FOR INTER-INDUSTRY PROPOSAL The fundamental position of the scientific advisors to the Inter-Industry Committee on Indirect Food Additives is that government cannot protect the public from every conceivable hazard to health. Because of limitation of scientific manpower and the priority of other national programs potential health hazards must be assigned relative probability factors and available resources applied to those with highest potential return in health protection. The eleven years since enactment of the Food Additives Amendment and the millions of dollars spent on toxicology of food packaging materials have established that potential health hazard from food packaging materials is extemely remote and that a significantly reduced effort in this area would be in the best interest of public health. Without exception, all non-government scientists who presented their views at the National Conference on Indirect Food Additives (February 13-14, 1968) felt that the current system of regulation of indirect additives was diverting scientific effort from more important health problems. A specific proposal to help alleviate this problem was outlined by one of those scientists, Dr, John P. Frawley, of Hercules Incorporated. The over whelming majority of other scientists speaking at the National Conference endorsed Dr. Frawley's proposal. In brief, the derivation of Dr. Frawley's proposal can be summarized as follows: a) An examination of all available chronic toxicity studies (24S compounds) revealed that except for heavy metals and compounds developed because of their toxicity -* as pesticides, all.compounds were safe to TV1 TUJV' '7 ';y* v*ir sljwi SI 0000061S Page 2 experimental animals when fed for a lifetime at 40 ppm in the total diet. Applying unusually conservative margins of safety, it was concluded that a dietary level of 0.1 ppm of any chemical suitable for use in food packaging can be considered toxicologically insignificant for man.* b) Any food packaging component which can be shown by suitable migration studies to contribute no more than 0.1 ppm to the diet of man should be considered non-migratory and exempt from regulatory control. c) Based on extensive migration studies using uncoated paper and actual food packaging conditions, it was demonstrated that if all food were packaged in the uncoated paper, use of an additive at a level of 0.05% by weight of the container or its coating could not contribute more than 0.1 ppm to the diet. d) Uncoated paper is the most permeable type of food packaging material and consequently its components are most susceptible to migration. Therefore, components of other types of containers will migrate less than those used in paper. e) No more than 25% of the human diet is in contact with any specific food packaging additive. f) Therefore, any food packaging component (except heavy metals and pesticides) used at a level of 0.2% or less by weight of the container or its food dontact surface *Because the rat consumes from two to four times the amount of food per kilogram of body weight as man, this represents approximately a 1000-fold margin of safety. ASI 00000619 \ can contribute no more than 0.1 ppm to the human diet and should be exempt from regulatory control. All of the major industry representatives endorsed the above proposal at the time of the National Conference. The Inter-Industry Committee still endorses these proposals as being scientifically sound and safe for public health. Since the time of the National Conference, additional evidence has been accumulated which supports the steps in the derivation of the proposal. These are presented below: a) The initial compilation of two-year chronic studies published by Dr. Frawley (Food ^ Cosmetic Toxicol. Vol. 5_, 293, 1967) contained 220 compounds. Since then it has been extended to 252 compounds. Table 1 presents the 32 compounds and the "no effect" levels which have been added since Dr. Frawley's publication. All additions support Dr. Frawley's conclusion that any compound suitable for use in food packaging can be considered toxicologically insignificant at a level of 0.1 ppm in the diet. b) After the National Conference, the National Academy of Sciences, Food Protection Committee appointed an Ad Hoc Committee on Toxicological Insignificance. This Committee of scientists recommended a number of quantitative guidelines on insignificance, one of which was that "if a ASI 00000620 Page 4 chemical has been in commercial production for a substantial period, e.g. 5 years or more, without evidence of toxicological hazard incident to its production or use, if it is not a heavy metal or a compound of heavy metal, and if it is not intended for use because of its biological activity, it is consistent with sound toxicological judgment to conclude that a level of 0.1 ppm of the chemical in the diet of man is toxicologically insignificant". This level is the same level proposed by Dr. Frawleyas the appropriate level of toxicological insignificance for food packaging components. c) Dr. Frawley's original extrapolation from maximum quantity migrating to food to maximum concentration in the container was based on rosin size migration to food from uncoated paper. Since that time, comparable data have been obtained for a plasticizer migrating from polyvinyl chloride film.. These data are summarized in Table 2, and confirm the conclusion that the uncoated paper used in Dr. Frawley's calculation represents the extreme condition. d) In Dr. Frawley's extrapolation to the container, he made the "assumption" that no more than 25% of the diet would be in contact with any specific food packaging component, In an effort to obtain * '* ASI 00000621 Page S a more quantitative measure of the maximum dietary percentage which might be in contact with a specific substrate type, a survey of food packaging practices was conducted in four supermarkets. The 106 food items which compose the basis of the U. S. Department of Agriculture survey of food consumption were tabulated with the type or types of food contact surface. These data are presented in Table 3. The total for each category of container is presented. The grand total exceeds 100% because foods which are commonly packaged in two or more types of containers are listed under all appropriate types. The absolute maximum of the average diet which may be in contact with a specific substrate is 45% for all types of plastics and plastic coatings. Other categories were 34% for glass, 32% for paper, 23% for can, 10% for cellophane and 6% for metal foil. About 23% of the diet is bulk packaged or not in sufficient contact to be considered packaged. With the unlikelihood that any individual would consistently choose one type of container over another for food offered in several types of containers, and with the improbability of any minor component of Page 6 food packages being universally used in all of a container type, Dr. Frawley's estimate of 25% is reasonable and conservative.* e) The proposal to exempt from regulation components present in containers at 0.2% or less by weight of the container or its coating has been formally endorsed by at least 23 other scientists who addressed letters to the Hearing Clerk expressing their personal professional conclusions. Table 4 lists the names of the experts who have officially stated that this level of use of additions is generally recognized as safe. It is apparent that the Food and Drug Administration is reluctant to establish a level of insignificance in the total diet, or in the food container. Because of difficulty of enforcing a level in the total diet, the Committee agrees with the Food and Drug Administration proposal to establish a level of toxicological insignificance in the packaged food. However, starting with a level of 0.1 ppm in the diet which has been recommended by the National Acadmey of Sciences as insignificant, and using the conservative dietary exposure of 25%, an extrapolation to 0.4 ppm in specific foods is apparent as a level of exemption rather than 0.05 ppm as proposed by the Food *In other areas of safety evaluation, it is customary to make reasonable assumptions concerning human exposure. Uses of most pesticide tolerances would exceed the ADI if the tolerance level was assumed to be present on 100% of the agricultural commodity. Many direct food additives would exceed th ADI if used at the maximum level in all permitted foods. In the case of food packaging, it is even less likely that a single chemical will be used by all manufacturers of even one type of substrate, much less all types. .\ in . , i `V -h- . jit-gyp ' .'* ASI 00000623 Page 7 and Drug Administration, For practical reasons, a level of 0.5 ppm is proposed by the Inter-Industry Committee, in light of the fact that the original calculations by Frawley employed a 1000-fold margin of safety. This additional 10-fold margin of safety beyond the conventional 100-fold safety factor also allows for any possible exposure to a chemical from other environmental sources than food. It is also the firm recommendation of the Inter-Industry Committee that a level of exemption be established in the food container and its food contact surface. Scientifically, this is the most readily enforced point of addition of a chemical and practically the most useful for industry and government. With the restrictions placed on such an exemption as contained in the preamble of the Food and Drug Administration proposal, the level of 0,2%, as proposed by Dr. Frawley and supported by the scientific community is eminently justified and supported. August 27, 1969 ASI 00000624 TABU: 1 ADDITIONAL NO-EFFECT LEVELS ESTABLISHED BY TWO-YEAR FEEDING STUDIES* Compound No-Effe Level (^ppm Acetone peroxides treated flour* Alkyl (Cg-C^c) tolyl methyl trimethyl ammonium chloride (Hyamine 2389)2 200 Alkyldimethylbenzyl ammonium chloride (Roccal)5 1,200 Alkyldimethylbenzyl ammonium chloride (unspecified)^ < 630 Arsanilic acid5 1,000 2H-l-Benzopyron-2-one (Coumarin)6 1,000 Butoxy polyethylene polypropylene glycol (UCON 50 HB260)7 10,000 4-tert-Butyl-2-chlorophenyl methyl methylphosphoramidate (Ruelene)8 Butyl stearate 1* 1.000 Chlorine (free in ^0)*^ 100 Dibutyl sebacate9 .. 62,500 2,6-Dichlorobenzonitrile (Dichlobenil)1 100* (3-[3,4-Dichlorophenyl]-1-methoxy-l-methylurea) (Linuron)12 125* Diethyl carbonaia*3 3,000b Di-isobutyl phenoxy ethoxy ethyl dimethyl benzyl ammonium chloride (Hyamine 1622)2 200 3- Ethoxy-4-hydroxybenzaldehyde (Ethyl vanillin)0 20,000 4- Hydroxy-3-methoxybenzaldehyde (Vanillin) 20,000 Isosafrole5 < 1,000 6-Methyl-2H-l-benzopyran-2-one (6-Methylcoumarin)6 3,500 1.2- Methylenedioxy-4-allylbenzene (Safrole) ^ < 100T 1.2- Methylenedioxy-4-propylbenzene (Dihydrosafrole)0 < 1,000 Methyl ethyl cellulose*^ 10,000 Monochloroacetaldehyde 2,4-dinitrophenylhydrazone (Olin 1763)15 100* Nonyl phenoxy polyethylene (9) glycol ether (Tergitol nonionic TP-9)7 2,700 Phenyldimethylurea* 1,250* Polyalkylene glycol ether (Tergitol nonionic XD)7 2,700 Polyethylene glycol homolog, containing 90,000 ethoxyl groups terminated by hydroxyls (Polyox WSR301)7 50.000 Polyethylene polypropylene glycol (UN0C 75 H1400)7 10.000 Polyethylene polypropylene glycol (UN0C 25 H200 5)7 2.000 Sodium arsenate*' 255 (62.5 ppm As) Sodium arsenite*7 54 (31.25 ppm As) Sodium 2-ethyl hexyl sulfate (Tergitol anionic 08)7 6,400 aDiet contained 77% flour treated with 0.045% acetone peroxides comprised of 85 to 95% 2,2 dihydroperoxy propane and 5 to 15% bis-(l,l-hydroperoxy-l,l'-methyl) diethyl peroxide *Pesticide b3000 ppm concentration in drinking water T-Tumors at higher levels *Supplemental List to that published in Food 8 Cosmetic Toxicol. Vol. 5, 293-308 (1967) ASI 00000625 TABLE 1 (CONTINUED) REFERENCES 1. Food Cosmetic Toxicol. Vol. 5, 309 (1967) 2. Soap 8 Chem. Specialties Vol. 30, 147 (1954) 3. J. Am. Pharm. Assn., Scientific Edition, Vol. 40, 263 (1951) 4. J. Am. Pharm. Assn., Scientific Edition, Vol. 37, 29 (1948) 5. Proc. 12th World's Poultry Congr., Sidney, Australia, 234 (1962) 6. Food 6 Cosmetic Toxicol. Vol. 5, 141 (1967) 7. Mellon Institute, Pittsburgh, Pa., Unpublished Data 8. Food 6 Cosmetic Toxicol. Vol. 6, 185 (1968) 9. AMA Arch. Ind. Hyg. 5 Occup. Med. Vol. 7, 310 (1953) 10. Food 6 Cosmetic Toxicol. Vol. 6, 147 (1968) 11. Food 8 Cosmetic Toxicol. Vol. 6, 261 (1968) 12. Food 8 Cosmetic Toxicol. Vol. 6# 171 (1968) 13. Arch. Tox. Vol. 22, 98 (1966) 14. Food 8 Cosmetic Toxicol. Vol. 6, 449 (1968) 15. Toxicol. 8 Appl. Pharmacol. Vol. 8, 472 (1966) 16. Allied Chemical Corporation, Unpublished Data 17. Toxicol. 8 Appl. Pharmacol. Vol. 10, 132 (1967) ASI 00000626 TABLE 2 MAXIMUM MIGRATION OF ROSIN SIZE1 AND 2-ETHYLHEXYL DIPHENYL PHOSPHATE2 3T4O TOTAL DIET _____ Approx. 1 of z Commodity Group Diet Aqueous 8 Wet Foods Fats, Oils Dry Foods M at, Poultry 8 Fish 43 3 39 15 Average Mijjration (ppm) Rosin Size^ Santicizer 1415 * 3.1 32.8 2.1 2.2 120 36.2 60 TOTAL Contribution to Total Diet IPm-i Rosin Size Santi (ter 141 1.3 0.9 1.0 3.6 0.8 5.4 9.0 8.5 13.5 Rosin Size 2.1 ppm/% Santicizer 141 0.5 ppm/% 1. Rosin Size - 4% in paper 2. 2-Ethylhexyl Diphenyl Phosphate - Santicizer 141 - 28% in PVC Film 3. Commodity Groups Taken From Table 3 and Consolidated 4. Food 8 Cosmetic Toxicol. Vol. 5, 293 (1967) and TAPPI Vol. 48, 433 (196S) 5. AMA Arch, Ind. Hyg. 8 Occup. Med, Vol. 8, 281 (1953) b 'nv t, J,f ASI 00000627 ; & ASI 00000628 TABLE 3 AVERAGE QUANTITY OF FOOD USED IN AMERICAN HOMES1 AND TYPE OF PACKAGING SURFACE CONTACTING FOOD2 FOOD CONTACT SURFACE3 Food Group and Major Items Quantity Percent None Glass Can Plastic per Week of Diet or Plastic (lbs)Coating Paper Foil Cellophane Milk, Cream, Cheese, etc. Fresh fluid milk Evaporated milk Non-fat dry milk Cream Frozen milk dessert Cottage cheese Other cheese 'ats, Oils Butter Margarine Lard Vegetable shortening Salad, cooking oil Salad dressing 'lour. Cereal Flour Prepared flour mix Breakfast cereal Rice Commeal, grits Macaroni, other pastas Other cereal, pastas lakery Products Bread Crackers Rolls Cake Pie 19.13 0.62 0.13 0.32 1.68 0.48 0.68 18.8 0.6 0.1 0.3 1.6 0.5 0.7 0.42 0.80 0.26 , 0.34 ' 0.36 0.53 > 1.56 0.48 1.06 0.44 0.61 0.42 0.11 0.4 0.8 0.3 0.3 0.4 0.5 1.6 0.5 1.0 0.4 0.6 0.4 0.1 4.36 0.51 0.34 0.47 0.33 4.3 0.5 0.3 0.5 0.3 X X X X X X X X X X X XX X X X X X vA X X X X XX XX X X X X XX X X X XX X X XX XX X X Food Group and Major Items Quantity per week civs)' Percent of Diet Bakery Products (Cont'd) Cookies Coffee Cake Doughnuts other 0.89 0.31 0.44 Beef Beef steaks Beef roasts Ground beef Other beef 2.23 1.42 1.34 0.43 Pork Pork chops, hams, loins Sausage Smoked hams Bacon Other pork 1.25 0.34 ` 0.79 0.80 0.42 Variety Meats Veal Lamb Liver, brains, tongue, etc. Frankfurters Other lunch meats 0.16 0.18 0.26 0.56 0.86 Poultry Chicken Other poultry 2.62 0.19 Fish Fresh fish Frozen fish Canned fish Shellfish 0.64 0.13 0.28 0.15 0.9 0.3 0.4 2.2 1.4 1.3 0.4 1.2 0.3 0.8 0.8 0.4 0.2 0.2 0.3 0.5 0.8 2.6 0.2 0.6 0.1 0.3 0.1 Page 2 FOOD CONTACT SURFACE3 None Glass Can Plastic Paper Foil Cellophane or Plastic Coating X X X X X X X X X X X X X X X X X X X X XX X X X X X X X X X X X X X X X X Y X X X AST 0 0 0 0 0 6 2 9 Food Group and Major Items Quantity per Week (lbs) Percent of Diet Eggs Fresh eggs Sugar and Sweets Sugar Sirups, molasses, etc. Jelly jam Candy Potatoes Fresh potatoes Canned potatoes Frozen potatoes Chips, sticks Other Fresh Vegetables'* Dark green leafy Carrots, pumpkin, squash Tomatoes Cabbage Lettuce Com Onions Beans Celery Cucumbers Other Fresh Fruits^ Citrus Cantaloupe Apples Bananas Melons 2.69 2.33 0.40 0.45 0.52 4.82 0.10 0.17 0.22 0.06 0.35 0.56 1.09 0.65 1.30 0.51 0.82 0.46 0.33 0.30 0.96 2.51 0.37 1.38 1.45 1.28 2.6 2.3 0.4 0.4 0.5 4.7 0.1 0.2 0.2 0.1 0.3 0.5 1.1 0.6 1.3 0.5 0.8 0.5 0.3 0.3 0.9 2.5 0.4 1.4 1.4 13 Page 3 FOOD CONTACT SURFACE5 None Glass Can Plastic Paper Foil Cellophane or Plastic Coating_____________________________________ X X XX X XXX X X X X XX X XX X X X X X X X X X X X X X XXXXX w AS! 00000630 f .'J >------a t - i -. --- 1 XXX ASI 00000631 Food Group and Major Items 4 Fresh Fruits (Cont * d) Peacnes Berries Other Quantity Percent per Week of Diet (lbs) 0.24 0.51 0.45 0.2 0.5 0.5 Canned Vegetables Fruits Vegetables Fruits 2.93 1.59 2.9 1.6 Frozen Vegetables Fruits V getables Fruits 0.62 0.05 0.6 0.1 Juices Canned vegetables Canned fruit Frozen fruit Fresh fruit - 0.54 1.41 0.42 0.46 0.5 1.4 0.4 0.5 Dried Vegetables Fruits Vegetables Fruit 0.37 0.10 0.4 0.1 Beverages Coffee Tea cocoa Cola Fmit Ginger ale, seltzer diet Fruit ade 5 punch Beer $ ale Whisky, gin, rum, brandy Wine 0.74 0.19 3.06 0.91 1.12 1.02 1.94 0.18 0.12 0.7 0.2 3.0 0.9 1.1 1.0 1.9 0.2 0.1 Page 4 FOOD CONTACT SURFACE3 None Glass Can Plastic Paper Foil Cellophane or Plastic _________________________ Coating____________________________________ X X X XX X X XX XX XX XX XX XX XX XX X X X X XX X X X XX X Page 5 Food Group and Major Items Quantity per week (lbs) Percent of Diet Soups Other Mixtures Soups, sauces, gravy Puddings, popsicles, etc. Baby foods 0.92 0.85 0.17 0.9 0.8 0.2 Nuts Condiments Shelled nuts Unshelled nuts P anut butter Catsup sauces Pickles, olives, relish Salt Vinegar other 0.09 0.03 0.30 0.38 0.49 0.29 0.23 0.1 0.1 0.3 0.4 0.5 0.3 0.2 TOTAL 101.77 None Glass Can Plastic Paper Foil Cellophane or Plastic Coating XX X XX X X X XX X XX X XX XX X XX X x . 23% 34% 23% 45% 32% 6% X 10% FOOTNOTES 1. Average Quantity of Food Used in American Homes derived from "Food Consumption of Households in the United State Spring 1965" U. S. Department of Agriculture HFCS- 1965-1966 Report No. 1. 2. Packaging Surfaces Contacting Food based on 1969 practices observed in survey of supermarkets: Food Fair, Acme, Hearns, Penn Fruit. 3. Many foodsare occasionally packaged in every type of food contact surface. For example, sugar flavored wt'~ cinnamon is sometimes packaged in glass. Because of the insignificance of these uses, only the more cor., container surfaces have been listed.4 4. For fresh fruits and fresh vegetables, some items, as onions or lettuce are sometimes packaged in plast': paper and all are carried home in paper bags. Because of the small surface or short durat5^ these have been listed under "None"--meaning not in contact with any pa igi:ig jurf.; :*, I1 AS 0 0 0 0 0 6 3 2 i TABLE 4 EXPERTS WHO ADDRESSED LETTERS TO THE HEARING CLERK DECLARING COMPONENTS OF FOOD PACKAGING USED AT A LEVEL OF 0.2% OR LESS AS GENERALLY RECOGNIZED AS SAFE A. M, Ambrose, Ph.D, Frank R. Blood, Ph.D. Joseph C. Calandra, Ph.D., M. D. Sal M. Cannavo Charles P. Carpenter, Ph.D. Steven Carson, Ph.D. William B. Deichmann, Ph.D. Daniel M. Dent David W. Fassett, M. D. Leon Golberg, D.Sc., Ph.D. Richard L. Hall, Ph.D. William H. Hunt, Ph.D. Jo}in H. Kay, Ph.D. R. Emmet Kelly, M. D. M. L. Keplinger, Ph.D. Donald D. McCollister Professor of Pharmacology Medical College of Virginia Director, Division of Toxicology Professor of Biochemistry Vanderbilt University Hospital President Industrial Bio-Test Laboratories, Inc Senior Research Chemist L. A, Dreyfus Company Administrative Fellow Mellon Institute Vice-President Food and Drug Research Laboratories, Inc. Professor of Pharmacology University of Miami For the Scientific Staff The Borden Company Director, Laboratory of Industrial Medicine Eastman Kodak Company f Research Professor of Pathology Albany Medical School Director of Research and Development McCormick Company, Inc. Toxicologist Monsanto Company Director Lifestream Laboratories, Inc. Medical Director Monsanto Company Toxicologist University of Miami Manager, Plant Science and Animal Health Registrations The Dow Chemical Company tt'V . "i.'.t ivy's . i." i ' ---- .iip.i. --L,i,| . s! ASI Q0000633 Bernard L, Oser, Ph. James L. Ritchie Henry F. Smyth, Jr., Ph.D, Andrew A. B. Swan, M, Joseph F. Treon, Ph.I Carrol S. Weil Geoffrey Woodard, Ph. D. Page 2 President Food and Drug Research Laboratories, ic. President American Paper Institute Advisory Fellow Mellon Institute Director, Industrial Hygiene Research Labs. Imperial Chemical Industries Limited Manager, Toxicology Division ` Atlas Chemical Industries Senior Fellow Mellon Institute President Woodard Research Corporation y; ASI 00000634