FAO/PL:1967/M/11/1 WHO/Food Add./68.30 1967 EVALUATIONS OF SOME PESTICIDE RESIDUES IN FOOD THE MONOGRAPHS The content of this document is the result of the deliberations of the Joint Meeting of the FAO Working Party of Experts and the WHO Expert Committee on Pesticide Residues, which met in Rome, 4 - 11 December, 1967. (FAO/WHO, 1968) FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS WORLD HEALTH ORGANIZATION Rome, 1968 OXYDEMETON-METHYL This pesticide was evaluated by the 1965 Joint Meeting of the FAO Committee on Pesticides in Agriculture and the WHO Expert Committee on Pesticide Residues (FAO/WHO, 1965) under the name of demeton-S-methyl sulfoxide, a commercially produced isomer of demeton-S-methyl. Since the previous publications, the results of additional experimental work have been reported. This new work has been summarized, combined with that previously published, and discussed in the following monograph. All toxicological studies discussed in this monograph were conducted with the commercially produced metabolite, oxydemeton-methyl (the currently accepted ISO name of the compound). EVALUATION FOR ACCEPTABLE DAILY INTAKES Biochemical aspects Demeton-S-methyl sulfoxide is produced in plants from the metabolism of demeton-methyl. The sulfoxide is further broken down by plants and animals. After injection into mice, 97-98 percent is rapidly eliminated (Niessen et al., 1963). In vitro: Molar concentrations necessary to produce 50 percent inhibition of sheep erythrocyte cholinesterase, expressed as I50 in 30 minutes at 37°C, are as follows (Heath and Vandekar, 1957) : demeton-S-methyl P=0 isomer 6.5 × 10-5 demeton-S-methyl sulfoxide 4.1 × 10-5 demeton-S-methyl sulfone 2.3 × 10-5 Acute toxicity LD50 mg/kg Animal Route body-weight References Mouse Oral 30 DuBois and Plzak, 1962 Mouse Intraperitoneal 8-12 DuBois and Plzak, 1962 Rat Oral 30-75 Mühlmann and Tietz, 1956; Schrader, 1963 Rat Intraperitoneal 20 DuBois and Plzak, 1962 Rat Intravenous 47 Heath and Vandekar, 1957 (cont'd) LD50 mg/kg Animal Route body-weight References Guinea-pig Oral 120 DuBois and Plzak, 1962 Guinea-pig Intraperitoneal 30 DuBois and Plzak, 1962 Short-term studies Rat. In groups of 20 rats, administration of the sulfoxide by mouth in doses of 5 mg/kg body-weight daily for 3 months caused no signs of intoxication or pathological changes, and 10 mg/kg body-weight for 21 days caused an inhibition of cholinesterase activity after 4-6 days (Wirth, 1958). Groups of 6 males and 6 females received concentrations of 20 ppm or less in the diet for a period of 16 weeks: no significant influence on growth-rate or food consumption was observed. Ten ppm or less caused no significant depression of erythrocyte cholinesterase activity. Gross and microscopic examination of the tissues of rats revealed no indication of toxic effects except for fatty changes in the livers of some of the rate fed 10 ppm and 20 ppm (Bär, 1963). 50 ppm for 6 months had no effect on weight gains in a group of 6 rats and showed no pathological changes attributable to the action of the compound. The brain and blood cholinesterase activity was strongly inhibited. Concentrations of 100 and 200 ppm produced signs of intoxication in the first 3 weeks of the experiment (Vandekar, 1958). In a three-generation reproduction study at dietary levels of 0, 10, 25 and 50 ppm, groups of 10 males and 20 females of each generation, except the third filial, were maintained through two successive matings. Second litter animals were used for composing the succeeding generation groups. The third filial generation was maintained only to weaning age. At 50 ppm in all generations, the number of pregnancies and the number of young per litter were significantly reduced. Histological examination of the second filial generation animals disclosed only reduced oögenesis in 3 of the 10 in the 50 ppm females, with no apparent effect at 25 ppm. 10 ppm was without effect on the number of pregnancies, the number of young per litter, the number of surviving young up to 21 days and microscopic appearance of major organs. Erythrocytic cholinesterase activity, expressed in percentage of controls, was reduced to 83 per cent in males and 67 per cent in females in the third filial generation, after 21 days; and in the second generation, after 27 weeks, to 83 per cent in the males and to 61 per cent in the females. Erythrocytic cholinesterase activity was more consistently reduced, in proportion to the test level, at the two higher levels. No gross abnormalities nor effect on food consumption or body-weight gain were seen at any test level (Taylor, 1967). Dog. Diets containing 5, 10 and 20 ppm have been fed to male and female beagle dogs for periods of 12 weeks. None of these dose levels produced significant changes in food consumption or body-weight or gave rise to cholinergic signs. Levels of 10 ppm or less did not cause significant inhibition of serum or erythrocyte cholinesterase activity (Root et al, 1963). Long-term studies No data available. Comments For the establishment of the ADI short term studies on rats and dogs can be taken into consideration. In the rat 10 ppm, equivalent to 0.5 mg/kg/day causes no toxicologically significant inhibition of serum or erythrocyte cholinesterase activity and no adverse effect on reproduction in three successive generations. In the dogs 10 ppm, equivalent to 0.25 mg/kg/day, did not show any effect. TOXICOLOGICAL EVALUATION Level causing no significant toxicological effect Rat 10 ppm in the diet equivalent to 0.5 mg/kg/day Dog 10 ppm in the diet equivalent to 0.25 mg/kg/day. Estimate of acceptable daily intake for man 0 - 0.0025 mg/kg body weight. Further work desirable Observations of the effect in man. EVALUATION FOR TOLERANCES Not considered at the 1967 Joint Meeting. REFERENCES PERTINENT TO EVALUATION FOR ACCEPTABLE DAILY INTAKES Bär, F. (1963) Personal communication Unpublished report. DuBois, K. and Plzak, G.J. (1962) Toxicol. Appl. Pharmacol., 4, 621 FAO/WHO. (1965) FAO Mtg. Rpt. PL.1965/10/1; WHO Food Add./27.65 Heath, D.F. and Vandekar, M. (1957) Biochem. J., 67, 187 Mühlmann, R. and Tietz, H. (1956) Höfchen-Briefe, 9, 116 Niessen, H., Tietz, H., Hecht, J. and Kimmerli, G. (1963) Arch. Toxikol., 20, 44 Root, M., Gowan, J. and Doull, J. (1963) Unpublished report. Schrader, G. (1963) Die Entwicklung neuer insectizider Phosphorsäure-Ester, Verlag Chemie GMBH, Weinheim. Taylor, R.E. (1967) Unpublished report submitted by Chemagro Corporation Vandekar, M. (1958) Brit. J. industr. Med. 15, 158 Wirth, W. (1958) Arch. exp. Path. Pharmacol., 234, 352
See Also: Toxicological Abbreviations Oxydemeton-methyl (JMPR Evaluations 2002 Part II Toxicological) Oxydemeton-methyl (FAO/PL:1968/M/9/1)