FAO Meeting Report No. PL/1965/10/1 WHO/Food Add./27.65 EVALUATION OF THE TOXICITY OF PESTICIDE RESIDUES IN FOOD The content of this document is the result of the deliberations of the Joint Meeting of the FAO Committee on Pesticides in Agriculture and the WHO Expert Committee on Pesticide Residues, which met in Rome, 15-22 March 19651 Food and Agriculture Organization of the United Nations World Health Organization 1965 1 Report of the second joint meeting of the FAO Committee on Pesticides in Agriculture and the WHO Expert Committee on Pesticide Residues, FAO Meeting Report No. PL/1965/10; WHO/Food Add./26.65 METHOXYCHLOR Chemical name 1,1,1-trichloro-2,2-di-(p-methoxyphenyl) ethane; 2,2-di-4-anisyl, 1,1,1,trichloroethane, di-(p-methoxyphenyl)-trichloromethyl methane; 2,2-di(p-methoxyphenyl)-1,1,1,-trichloroethane. Synonyms DMDT; dimethoxy-DT; marlate. Empirical formula C16H15O2Cl3 Structural formulaBIOLOGICAL DATA Biochemical aspects Methoxychlor is not excreted intact, and appears to undergo metabolize yielding hydroxyphenyl derivatives (von Oettingen & Sharpless, 1946). Methoxychlor is very rapidly detoxicated in the liver, yielding a metabolite which is excreted into the intestine and removed from the body in the faeces. This rapid detoxication, together with fairly slow gastro-intestinal absorption, explains the low mammalian oral toxicity and low tissue storage of methoxychlor (Weikel, 1957). Some tissue and fat storage takes place and reaches a maximum in 4 weeks; the stored material is mobilized in 2-4 weeks after exposure ceases (Kunze et al., 1950; Metcalf, 1955). Methoxychlor showed very little tendency to be excreted in the milk even when dietary concentrations up to 7000 ppm were given to dairy cows. At 800 ppm and 7000 ppm the amounts found in the milk were 0.13 ppm and 2.14 ppm respectively at 16 weeks (Gannon et al., 1959). The rate and completeness of methoxychlor metabolism may account for the low storage and accumulation. Acute toxicity Animal Route LD50 mg/kg References body-weight Mouse Oral 1850 Domenjoz, 1946 Rat Oral 5000-7000 Hodge et al., 1950 Lehman, 1951 Smith et al., 1946 Sheep Oral >2000 Negherbon, 1959 Welch, 1948 Steer Oral >500 Negherbon, 1959 Welch, 1948 Short-term studies Rat. Groups of weaned rats, each of 10 males and 10 females per group, were fed for 45 days on a ration containing 100, 1000 and 30 000 ppm methoxychlor. At 100 ppm there was no effect on growth; at 1000 ppm growth was slightly retarded; at 30 000 ppm very little growth occurred. At 10 000 ppm, rats in paired-feeding tests over 30 days showed marked growth reduction attributed to a reduced food intake. There were no deaths in the 100 ppm and 1000 ppm groups; 8 of 10 rats died in each of the male and female groups receiving 30 000 ppm. The blood picture was normal. At autopsy there was no significant difference in the organ-weights of the rats on 100 ppm and 1000 ppm. The 30 000 ppm group showed uniformly smaller organ-weights than the controls. In the case of the testes, the decrease in weight was very marked. There was no evidence of histopathological change in the organs examined, except in the testes, which showed apparent suppression of spermatogenesis beyond the spermatogonial phase; the spermatogonia and Sertoli cells were relatively normal; the primary spermatocytes were variable in number, usually with evidence of necrosis. The more mature germ cells were absent (Hodge et al., 1950). In paired-feeding experiments in which 10 000 ppm of methoxychlor were added to the diet of weanling male rats, a marked reduction in the weight of the testes, seminal vesicles and prostate was found. These effects could be mediated through an oestrogenic action inhibiting the production of anterior pituitary gonadotrophins with consequent deficiencies in the development of the male reproductive system. Cystic tubular nephropathy was also observed (Tullner & Edgcomb, 1962). Rabbit. Daily oral doses of 200 mg/kg body-weight killed the rabbits after 4 to 15 days. The only symptoms noted were diarrhoea and anorexia (Smith et al., 1946; Von Oettingen, 1955). Dermal application of 2 or 3 ml of a 30% solution (in dimethyl phthalate) 5 days a week for 13 weeks was toxic; growth was depressed and paralysis of the forelegs occurred in some cases. Histopathological examination showed some fatty degeneration of the liver and lesions of the central nervous system. Applications of 1 ml or less had no effect (Haag et al., 1950). Dog. Groups, each of 2 dogs, were maintained for one year on doses of 20, 100 and 300 mg/kg body-weight per day. There were no deaths; the blood picture and organ-weights were normal; there were no histopathological changes (Hodge et al., 1952). Long-term studies Rat. Groups each of 25 male and 25 female rats were fed for 2 years on diets containing 25, 200 and 1600 ppm of methoxychlor. There was no effect on growth at doses of 25 ppm and 200 ppm in the diet, but there was moderate reduction in growth at 1600 ppm. There was no decrease in life-span; organ-weights and blood picture were essentially normal and histopathological examination revealed no significant changes (Hodge et al., 1952). Comments on the experimental studies reported From the studies reported the rat appears more sensitive than the dog. Experiments with the rat covered the life-span and may be used to estimate the acceptable daily intake for man. EVALUATION Level causing no toxicological effect in the rat The maximum no-effect level in rat was 200 ppm in the diet, equivalent to 10 mg/kg body-weight per day. Estimate of acceptable daily intakes for man 0-0.10 mg/kg body-weight Further work desirable Additional biochemical studies. Long-term toxicity studies in another species than the rat. Reproduction studies. REFERENCES Domenjoz, R. (1946) Arch. int. Pharmacodyn., 73, 128 Gannon, N., Link, R. P. & Decker, G. C. (1959) J. Agric. Food Chem., 7, 829 Haag, H. B., Finnegan, J. K., Larson, P. S., Riese, W. & Dreyfuss, M. L. (1950) Arch. int. Pharmacodyn, 83 (4), 491 Hodge, H. C., Elliott, A. M., Thomas, J. F., Blanchet, H. J., Wilt, W. G. & Mason, K. E. (1950) J. Phamacol. exp. Ther., 99, 140 Hodge, H. C., Maynard, E. A. & Blanchet, H. J. jr (1952) J. Pharmacol. exp. Ther., 104, 60 Kunze, F. M., Laug, E. P. & Prickett, C. S. (1950) Proc Soc. exp. Biol. (N.Y.), 75, 415 Lehman, A. J. (1951) Quart. Bull. Assoc. Food and Drug Officials U.S., 15, 122 Metcalf, R. L. (1955) Organic insecticides, Interscience, New York Negherbon, W. O. (1959) Handbook of Toxicology, vol. 3., Saunders, Philadelphia Smith, M. I., Bauer, H., Stohlman, E. F. & Lillie, R. D. (1946) J. Pharmacol, exp. Ther., 88, 359 Tullner, W. W. & Edgcomb, J. H. (1962) J. Pharmacol. exp. Ther., 138 (1), 126 Von Oettingen, W. F. & Sharpless, N. (1946) J. Pharmacol. exp. Ther., 88, 400 Von Oettingen, W. F. (1955) The halogenated hydrocarbons, toxicity and potential dangers, United States Department of Health. Education and Welfare. Public Health Service Bull. No. 414 Weikel, J. H. (1957) Arch. int. Pharmacodyn., 110 (4), 423 Welch, H. L. (1948) J. econ. Ent., 41, 36
See Also: Toxicological Abbreviations Methoxychlor (ICSC) Methoxychlor (Pesticide residues in food: 1977 evaluations) Methoxychlor (IARC Summary & Evaluation, Volume 5, 1974) Methoxychlor (IARC Summary & Evaluation, Volume 20, 1979)