Document XR7807Njv5jpVrNeXe38vDXrB

c August 18, 1967 Mr. Morgan H. Hoovar Food, Drug and Cosmetic Chanicals Committee Manufacturing Chemists Association, Inc. 1825 Connecticut Avenue, N.W. Washington, D.C. 20009 Dear Mr. Hoover r Pursuant to your letter of August 1 on reproduction' studies, attached herewith are unpublished data on an organic phosphate which showed progressing effects with succeeding generations such that lowest feeding level ultimately showed some effect. ^ While most of these data are in the hands of the Food and Drug Administration, they should remain confid ential until our toxicologist (outside laboratory) has had opportunity to publish. They are submitted here as an unfortunate demonstration that single generation reproduction studies may not be adequate to demonstrate reproductive effects. Very truly yours WAK:dmk Encls. Original Signed X.. A. Knapp W. A. Knapp Consultant-Toxicology *SI 002lli Ott'd* QUESTIONNAIRE FOR DATA ON REPRODUCTION STUDIES Material! (chemical or common name optional) Use, or Anticipated Use* s (.g.) A Food Additive or Insecticide Is REPEATED DOSES TO RATS Longest period fed Lowest dosage level with measurable effect Criteria affected at this level Highest non-measurable effect level 2 years 2 gmAg body weight 1 gm/kg REPRODUCTION STUDY Maximum no. of generations to rats 1st or 2nd litter used to establish next generation? Highest level fed with no effect Any effect at any level? If yes, describe. Generation (s) in which seen 3 1st 1 gra/kg no TERATOLOGY STUDY To rats, rabbits, or both? Did some receive it throughout gestation? Did some receive it during a portion of gestation period? What portion? Highest level with no effect Any effect at any level? If so, describe. Rats Yes Yes Middle 5gm/kg no ' 1/3 REGULATORY STATUS Does material have tolerance or limitation under Food Additive or Miller Pesticide Amendments? no If yes, at what levels and for what foods or crops? __ ******** Circulated by Manufacturing Chemists' Association Food, Drug, and Cosmetic Chemicals Committee > J O a f/a c A / ASI 00002113 Industrial Chemicals Division Allied Chemical C >ortion DATA OW REPRODUCTION STUDY Compound - An organic phosphate 4" ,. ? Anticipated Use - Pesticide Chronic Feeding Study - Rats TWo-ycar feeding study at 10, 30, 100 and 300 ppm In the diet produced no clear-cut effect, excepting that on red-blood cell and plasma cholinesterase which were depressed at 10 ppm in females end at 30 ppm In males. There was some growth depression In females during study but final weights were not significantly different from controls. Also, liver to body weight ratio was shown in males at 100 ppm but not.ag 300 ppm. Reproduction Study run using feeding levels of 30, 100 and 300 ppm. All levels showed deleterious effect which might be roughly summarized as follows. Complete table of results is attached Criteria Weanling Survival Fertility Index Gestation Index Viability Index ijl Mm? If* Effect Depressed In all litters at 100 and 300 ppm. Depressed In 2nd. generation at 30, 100 and 300 ppm. Unaffected at any feeding level. Depressed In 2nd. litter of each generation at 100 and 300 ppm. -- Questionably depressed in 2nd., litter of each generation at 100 and 300 ppm. Rotei: - A repeat of this study haa been made using feeding levels of 1 and 3 ppm. Results are not yet availeble. WAR 8/18/67 ASI 00002114 Table 6 Summary of Reproduction Data for Control Rats and Rats on Various Dietary Levels of for Two Matings Through Three Generations Generation Diet level (ppm) /*** *o \ lb g_ / 2a Fib' \ * V F2b^3* \ *3b 0 30 100 300 0 30 100 300 0 30 100 300 0 30 100 300 0 30 - 100 0 30 100 Number of rats Preg Whelped Mated nant 20 17^ 16 20 18 18 20 20 20 20 17 17 19 15 15 20 20 20 19 19 19 20 17 17 20 14 14 20 12 12 11 4C 3 72 2 20 16 16 19 15 15 10 5 5 62 2 20 18 18 20 9 9 71 1 20 14 14 20 6 6 71 1 Born alive 157 193 174 149 133 193 165 119 116 71 22 13 137 139 32 8 161 94 10 125 74 3 Total number of pups Born Alive Discard* dead day 5 1 152 15 5 188 23 13 140 12 8 96 0 8 130 17 17 185 25 12 55 0 18 39 2 4 93 5 17 66 2 1 17 0 1 10 0 14 129 14 3 129 11 4 13 0 7 00 7 149 19 1 91 12 2 10 0 19 118 13 0 67 8 0 00 Weaned 137 160 102 63 103 114 27 19 87 62 15 0 112 111 10 0 101 69 9 84 40 0 Weanlings Mean wt. (8) 34 32 29 28 34 32 34 29 31 33 34 0 35 31 34 0 36 35 27 41 34 0 Survival (X) 97 94 63 42 89 68 16 16 78 90 68 0 91 . 86 31 0 71 84 . 90 75 61 0 F.I.^ 85 90 100 85 79 100 100 85 70 60 36 29 80 79 50. 33 90 45 14. 70 30 14 Indices (%) G.I.* V.I.f 94 97 100 95 100 80 100 64 100 98 100 96 100 33 100 33 100 80 100 93 75 77 100 77 100 94 100 93 100 41 100 0 100 93 100 97 100 100 100 94 100 91 100 0 L.I.8 100 97 80 66 91 71 49 51 99 97 88 0 97 94 77 0 78 87 90 . 80 68 0 a. Number of pups discarded on fifth day to reduce litter size to 10. b. One rat died with 14 fetuses in utero. c. One rat died with 5 fetuses In utero. d. Fertility index *(pregnancies/matings) 100. e. Gestation index (litters cast/pregnancies) 100. f. Viability index " (pups surviving 5 days/pups born alive) 100. 8> Lactation index " (pups weaned/live pups on day b less discards) 100. ASI 00002115 TELEPHONE HUDSON 3-6126 Manufacturing Chemists' Association, Inc. (FOUNDED 18721 1825 Connecticut Avenue, N. W, Washington, D. C. 20009 August 1, 1967 TO: Members of the Food, Drug, and Cosmetic Chemicals Committee and All Others Receiving This Memo Including Drs. Oser (Food and Drug Laboratories), Treon (Atlas), and Zapp (DuPont) SUBJECT: Request for Data on Three-Generation Rat Studies Gentlemen: To assist in preparing MCA recommendations to be presented to the Panel on Reproduction Studies of the FDA Advisory Committee (ref. minutes of the June 13, 1967 FDCC Committee meeting), you are re quested by Dr. C. P. Carpenter (Chairman of the Reproduction Studies Group within the FDCC Committee) to send in to me the enclosed questionnaire on three-generation rat studies in the event your toxi cologists have carried out or contracted out such studies. Hopefully, these data will enable the FDCC Committee to decide whether or not to support the requirement for three-generation studies in addition to the usual two-year feeding tests on rats and dogs which are partial requirements to obtain clearances for direct food additives If your data have been used by the National Agricultural Chemicals Association Toxicology Committee, please so state and do not resubmit. Data are needed by August 22, 1967. Sincerely yours. MMH:sjg Enclosure Morgan M. Hoover ASI 00002116 QUESTIONNAIRE FOR DATA ON REPRODUCTION STUDIES Material: (chemical or common name optional) Use, or Anticipated Use: (e.g.) A Food Additive or Insecticide B C REPEATED DOSES TO RATS Longest period fed Lowest dosage level with measurable effect Criteria affected at this level Highest non-measurable effect level REPRODUCTION STUDY 2 years 2 gm/kg body weight 1 gm/kg Maximum no. of generations to rats 1st or 2nd litter used to establish next generation? Highest level fed with no effect Any effect at any level? If yes, describe. Generation (s) in which seen 3 1st 1 gm/kg no TERATOLOGY STUDY To rats, rabbits, or both? Did some receive it throughout gestation? Did some receive it during a portion of gestation period? What portion? Highest level with no effect Any effect at any level? If so, describe. Rats Yes Yes Middle 1/3 5gm/kg no _______ REGULATORY STATUS Does material have tolerance or limitation under Food Additive or Miller Pesticide Amendments? If yes, at what levels and for what foods or crops? no ******** Circulated by Manufacturing Chemists' Association Food, Drug, and Cosmetic Chemicals Committee ASI 00002117