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 DEMETON Chemical name Demeton consists of a mixture of two isomers; (X) Demeton-O and (II) Demeton-S. (I) diethyl 2-(ethylthio)ethyl phosphorothionate; O,O-diethyl O-[2-(ethylthio)ethyl]phosphorothioate. (II) diethyl S-[2-(ethylthio)ethyl]phosphorothiolate; O,O-diethyl S[2-(ethylthio)ethyl]-phosphorothioate. Synonyms (I) P=S systox; thiono systox; mercaptofos; systox. (II) P=O systox; isosystox; thiol systox; mercaptofos tiolovy. Empirical formula C8H19O3PS2 Structural formulaBIOLOGICAL DATA Biochemical aspects The thiono and thiol isomers of demeton are metabolized by plants and animals, degraded to a number of derivatives. In the mouse, 50-70% of an orally-administered dose is eliminated in the urine within 24 hours. The principal pathway of metabolism for both isomers is the oxidation of the mercapto sulfur of the ethyl mecapto ethyl moiety to the sulfoxide and sulfone. A secondary pathway involves the oxidation of the thiono sulfur to produce the phosphate and its sulfoxide and sulfone. Finally, both isomers and their metabolites are degraded by hydrolysis of the P-O- or P-S- bond to form the alcohol and acid, with the exception of the sulfone of demeton-S which gives ethyl vinyl sulfone and diethyl phosphorothioate (Fukuto et al., 1955; March et al., 1955). The demeton isomers and a number of derivatives are highly active in vivo and in vitro as cholinesterase inhibitors. In vitro: molar concentrations necessary to produce 50% cholinesterase inhibition expressed as I50 are as follows (Barnes & Denz, 1954; DuBois et al., 1956; Wirth, 1958). The sulfoxide and the sulfone of Demeton-O are less toxic than the parent compound (LD50 respectively for the rat, oral, 100 mg/kg and 90 mg/kg body-weight) (Wirth, 1958). The sulfoxide and the sulfone of Demeton-S have about the same toxicity as technical demeton, the oral LD50 for the rat being approximately 2.0 for both derivatives (DuBois et al., 1956; Wirth, 1958). Short-term studies Rat. Fifty ppm of demeton in the diet for 112 days produced the typical symptoms of depressed cholinesterase activity, especially in the first week. No histological changes were observed. Three ppm for 77 days caused only a small inhibition of cholinesterase (Schrader, 1957). Groups of 12 to 18 female rats fed 50 ppm (48% Demeton-S) for 16 weeks showed signs of poisoning and the growth-rate was affected. No histological changes were observed. Groups receiving 10 and 20 ppm showed severe inhibition of the brain and blood cholinesterase activity, while 3 ppm still gave 30% inhibition of blood cholinesterase activity. One ppm did not cause significant inhibition (Barnes & Denz, 1954). The daily administration of 0.75 mg/kg of Demeton-S for 3 days caused a progressive decrease in the cholinesterase activity of the brain, serum and submaxillary glands (DuBois et al., 1956). Groups of 5 rats were given 65 oral doses of 0.4, 0.66 and 1.89 mg/kg body-weight of technical demeton over a period of 90 days. One animal at the highest dose level died. No other signs of intoxication were seen (Deichmann & Rakoczy, 1955). Guinea-pig. With daily doses of 2.5 mg of demeton (30% Demeton-S per kg body-weight) for 48 days, no toxic changes were observed (10 animals), but there was an inhibition of blood cholinesterase activity (Bär, 1954). Dog. Groups of 2 dogs (one female and one male) were given technical demeton for 24 weeks. No significant depression of plasma cholinesterase activity was found with 0.025 mg/kg body-weight per day. With 0.047 mg/kg body-weight per day significant plasma inhibition was found after 16 weeks (Frawley & Fuyat, 1957). I50 × 10-6 M in 30 minutes at 37°C Rat Human Human Rat References brain serum erythrocyte plasma cholinesterase cholinesterase cholinesterase cholinesterase Demeton-S (48%) 4.0 2.4 Mühlmann & Tietz, 1956 Demeton-O 4.26* 1.9* 4.65* DuBois et al., 1956 Sulfoxide 4.75* 3.1* 6.2* " Sulfone 48.30* 17.2* 51.0* " Demeton-S 0.078* 0.078* 0.31* " 0.21 Barnes & Denz, 1954 Sulfoxide 3.58* 1.5* 2.56* DuBois et al., 1956 2.2 Barnes & Denz, 1954 Sulfone 2.86* 0.52* 1.69* DuBois et al., 1956 2.0 Barnes & Denz, 1954 * In 40 minutes at 37° celsius Animal Route Substance LD50 mg/kg References body-weight Mouse Intraperitoneal Demeton (Demeton-S) 5.6-7 DuBois et al., 1956 Mühlmann & Tietz, 1956 Oral Demeton (technical) 2.5-14 Barnes & Denz, 1954 (diverse mixtures) Borgmann & Hunold, 1954 Gaines, 1960 Metcalf, 1955 Schrader, 1957 Oral Demeton (Demeton-O) 7.5-30 Metcalf, 1955 Schrader, 1957 Wirth, 1958 Oral Demeton (Demeton-O) 1.5-16.2 Borgmann & Hunold, 1954 DuBois et al., 1956 Metcalf, 1955 Schrader, 1957 Wirth, 1958 Intraperitoneal Demeton 3 DuBois & Coon, 1955 Intraperitoneal Demeton (Demeton-S) 1.5 DuBois et al., 1956 Guinea-pig Intraperitoneal Demeton (Demeton-S) 5.5 DuBois et al., 1956 Acute toxicity Cattle. Technical demeton (0.1 mg/kg body-weight) fed in capsules to a cow for 3 consecutive days caused severe symptom of poisoning. After feeding demeton-treated hay containing an average concentration of 41 ppm to 3 cows for 56 days, no adverse effects on weight changes and milk production were observed, but during the last 6 days of feeding them was a decrease in erythrocyte cholinesterase activity (Dahm & Jacobson, 1956). Man. Groups of 5 subjects were given demeton for 30 days, in the following amounts: 4.125 mg, 4.5 mg, 4.875 mg per day. Each period was followed by a second control period of 30 days. The plasma and erythrocyte cholinesterase activity remained within 20% of the control values during the administration of demeton (Moeller & Rider, 1965). Long-term studies No data available. Comments on experimental studies reported Long-term toxicity tests on rats using demeton have not been carried out. The toxicity of technical demeton is dependent upon the proportion of each isomer in the mixture. The toxic effect of demeton results from the action of the unchanged isomers and, moreover, of different metabolic products. Demeton-S and its metabolic products are more toxic than Demeton-O. EVALUATION Level causing no significant toxicological effect in animals Rat. The estimated maximum no-effect level is 1 ppm, equivalent to 0.05 mg/kg body-weight. Dog. 0.025 mg/kg body-weight seems to be the no-effect level. Man. In man a dose equivalent to approximately 0.07 mg/kg body-weight per day showed no effect. Estimate of acceptable daily intake for man 0-0.0025 mg/kg body-weight per day. This value is based on experiments carried out with specimens of technical demeton and does not therefore take account of the chemical changes in the crop. Further work desirable Chemical composition and toxicity of the residues. Reproduction studies in the rat. REFERENCES Bär, F. (1954) Arzneimittel-Forsch., 4. 668 Barnes, J. M. & Denz, F. A. (1954) Brit. J. Industr. Med., 11, 11 Borgmann, W. & Hanold, G. A. (1954) Report from Max von Pettenkofer Institute Dahm, P. A. & Jacobson, N. L. (1956) J. Agric. Food Chem., 4, 150 Deichmann, W. B. & Rakoczy, R. (1955) Arch. industr. Hlth, 11, 324 DuBois, K. P. & Coon, M. J. (1955) Arch. industr. Hyg., 6, 9 DuBois, K. P., Murphy, S. D. & Thursh, D. R. (1956) Arch. industr. Hlth., 13, 606 Frawley, J. P. & Fuyat, H. N. (1957) J. Agric. Food Chem., 5, 346 Fukuto, T. R., Metcalf, R. L., March, R. B. & Maxon, M. G. (1955) J. econ. Ent., 48, 347 Gaines, Th. B. (1960) Toxicol. Appl. Pharmacol., 2, 88-99 March, R. B., Metcalf, R. L., Fukuto, T. R. & Maxon, M. G. (1955) J. econ. Ent., 48, 355 Metcalf, R. L. (1955) Organic Insecticides, Interscience, New York Moeller, H. C. & Rider, J. A. (1963) Fed. Proc., 22 (171), 187 Mühlmann, R. & Tietz, H. (1956) Höfchen-Briefe, 9, 116 Schrader, G. (1957) Communication to Farbenfabriken Bayer AG, Leverkusen, Agnew. Chemie, 69, 86 Wirth, W. (1958) Arch. exp. Path. Pharmacol., 234, 352
See Also: Toxicological Abbreviations Demeton (FAO/PL:1967/M/11/1) Demeton (WHO Pesticide Residues Series 5)