PESTICIDE RESIDUES IN FOOD - 1981 Sponsored jointly by FAO and WHO EVALUATIONS 1981 Food and Agriculture Organization of the United Nations Rome FAO PLANT PRODUCTION AND PROTECTION PAPER 42 pesticide residues in food: 1981 evaluations the monographs data and recommendations of the joint meeting of the FAO panel of experts on pesticide residues in food and the environment and the WHO expert group on pesticide residues Geneva, 23 November-2 December 1981 FOOD AND AGRICULTURE ORGANIZATION OF THE UNITED NATIONS Rome 1982 OMETHOATE Explanation Omethoate was evaluated in 1971 and reviewed in 1975, 1978 and 1979 (FAO/WHO 1972b, 1976b, 1979b and 1980b).* A temporary ADI was established in 1971 and the submission of a long-term study required. In addition to the report of the long-term study in rats, the results of a multi-generation study in rats, of an acute oral study, of a mutagenicity study, degradation in soil and data on residues from supervised trials have been received and are included in this monograph addendum. DATA FOR THE ESTIMATION OF ACCEPTABLE DAILY INTAKE TOXICOLOGICAL STUDIES Acute toxicity LD50 of omethoate metabolite in male rats, dosed orally with aqueous solution, was 908 mg/kg (Flucke 1978). Long-term studies Rat Four groups of 50 male and 50 female Wistar rats were maintained for 24 months on a diet containing omethoate at concentrations of 0.3, 1, 0, 3 and 10 mg/kg. The control group consisted of 100 males and 100 females. Omethoate did not clearly affect behaviour, body weight, survival rate, food intake, haematological parameters, clinical chemistry and urinalysis. Plasma and erythrocyte cholinesterase activities, measured in 5 males and 5 females of each group at 1, 2, 4, 8, 13, 26, 52 and 78 weeks and at the end of the study, were statistically significantly depressed in both sexes at 10 mg/kg diet. Erythrocyte cholinesterase activity was also inhibited in both sexes in the 3 mg/kg diet group. The suppression of brain cholinesterase, as measured in 10 males and 10 females per group, was dose-related in the 3 and 10 mg/kg diet group in both sexes. In addition, brain cholinesterase was also significantly affected in females in the 1 mg/kg group, which can be considered as a marginal no-effect level. * See Annex II for FAO and WHO documentation. Gross and microscopic examination revealed no indication of a diverse effect of omethoate. The tumour incidence was not clearly affected by treatment (Bomhard et al 1979). Special studies on reproduction Groups of FB30 Long Evans rats (10 males and 20 females per group) were fed omethoate (94%) in the diet at concentrations of 0, 1, 3 and 10 ppm for about 10 weeks, after which they were mated to initiate a standard 3-generation, 2-litter-per-generation, reproduction study. Four days after birth, the litters were reduced to 10. Immediately after birth, litters were examined for malformations. At the age of 8 weeks, the offspring were sacrificed and subjected to gross examination. Ten males and 10 female rats of the F3b generation of all dose groups were examined histopathologically 4 weeks after birth. There were no clear effects either on mating performance and pregnancy rate, mortality, or type and distribution of abnormalities. In the second generation the litter size was reduced in the 3 and 10 ppm groups. In the F2b litters, litter size was reduced at both 3 and 10 ppm after 4 days and at 10 ppm only after 28 days. Since this effect was observed only in a single progeny generation, 3 ppm could be considered as a no-effect level with regard to reproduction (Löser 1981). Special studies on mutagenicity In a micronucleus test, male and female mice were given 2 × 6 mg/kg bw or 2 × 12 mg/ kg bw at 30 and 6h before necropsy. Omethoate did not increase the frequency of micro-nucleated erythrocytes in the bone marrow. The animals, especially those in the high-dose group, showed clear clinical symptoms (Herbold 1981). Omethoate was examined for mutagenic activity in a series of in vitro microbiological assays, using the Salmonella typhimurium strains TA 1535, TA 100, TA 1537 and TA 98. Each plate was run with and without liver homogenate (S-9 mixture). Omethoate was mutagenic in strain TA 1535 (2 experiments), TA 100 (2 experiments) and TA 98 (1 experiment). No mutagenic activity could be observed in strain TA 1537 (Herbold 1980). RESIDUES IN FOOD RESIDUES RESULTING FROM SUPERVISED TRIALS Some information was provided (Bayer 1981) on residues of omethoate occurring on potatoes and sugarbeet following repeated (3 or 4) treatments at recommended levels. In all cases, residues at harvest (about 35 and 80 days after last treatment respectively) were below the level of determination of 0.01 mg/kg. Steadily declining residues were found on sugarbeet leaves (3, 0.9, 0.4, 0.2 and 0.1 mg/kg at 0, 14, 28 and 35 days respectively); at harvest (85 days) no detectable residue remained. FATE OF RESIDUES In soil Omethoate is rapidly degraded in soil. By 16 days after application of 14C-labelled omethoate to a standard soil, 48% of the 14C activity had been eliminated as 14CO2 (Wagner et al 1978). As intermediates in this degradation, the following conversion products, shown in Figure 1, were isolated and identified by NMR and MS: I Omethoate II (Phosphonothio)acetic acid III O-Methyl S-methylcarbamoylmethyl hydrogen phosphorothioate IV 2-Mercapto-N-methylacetamide V N, N'-Dimethyl-2,2'-dithiodi(acetamide) VI 2-(Methylcarbamoylmethyldithio)acetic acid VII N-Methyl-2-methylsulphinylacetamide VIII N-Methyl-2-methylsulphonylacetamide IX N,N' -Dimethyl(thio-oxamide) X N,N'Dimethyloxamide XI N-Methyloxamic acid XII Dimethyl hydrogen phosphateOf the compounds identified, amounts of I, II, III, V, VI and VIII were measured over a period of 112 days as shown in Table 1. The other materials listed were shown to be labile intermediates in the degradation of omethoate in soil. Similar information is being obtained on the degradation of omethoate in plant tissue. TABLE 1. Degradation pattern of 14C-omethoate in soil % of 14C applied Days I II III+ VI1 V VIII Total 9 37 3.4 4.2 2.6 <0.1 49 21 29 5.2 4.0 2.3 0.8 45 49 17 6.3 4.9 1.3 1.8 32 85 2.4 0.7 3.9 0.2 2.4 11 112 <1 <0.3 3.5 <0.1 2.7 7 1 III and VI were not separated in these determinations. EVALUATION COMMENTS AND APPRAISAL In a long-term study in rats, at levels of 3 and 10 ppm in the diet, a clear indication of cholinesterase inhibition was evident in brain, plasma and red blood cell cholinesterase. At the 1 ppm level, no clear effect was observed on cholinesterase activity in plasma or red cells in either sex. However, in females receiving 1 ppm omethoate in the diet a slight depression (ca. 12%) of brain acetylcholinesterase was observed. A no-effect level of 3 ppm in the diet could be estimated from a rat 3-generation reproduction study. Omethoate was mutagenic in strains TA 1535, 100 and 98 of Salmonella typhimurium used in the Ames test. However, no activity was observed in TA 1537. No mutagenic activity was detected in a micronucleus test and a dominant lethal test previously evaluated. A long-term rat study did not indicate carcinogenic potential. In this study, the highest dose level (10 ppm) failed to elicit any effect other than cholinesterase depression. The relatively low dose levels used in this study preclude adequate carcinogenicity evaluation. Therefore, the temporary ADI has been extended. Submission of results of carcinogenicity studies at higher levels in a rodent species is required by 1985. Information regarding the degradation of omethoate in soil was reviewed, together with a limited amount of additional data on residues from supervised trials on potatoes and sugarbeet. Levels causing no toxicological effect Rat: 1 ppm in the diet equivalent to 0.05 mg/kg bw/day Dog: 1.6 ppm in the moist diet equivalent to 0.12 mg/kg bw/day. Estimate of temporary acceptable daily intake for man 0 - 0.0005 mg/kg bw. RECOMMENDATIONS OF RESIDUE LIMITS No change is suggested in the maximum residue limits previously recommended. FURTHER WORK OR INFORMATION Required (by 1985) Carcinogenicity studies in a rodent species at higher dose levels. Desirable Clarification of the mutagenic potential in micro-organisms, in respect to the "marginal effect" of omethoate in some strains of Salmonella. REFERENCES Bayer Reports on omethoate residue trials. Data from Bayer AG, 1981 Leverkusen. (Unpublished) Bomhard, E. S-6876 - Chronische Toxizität an Ratten 22 Oktober, 1980 Stellungnahme zu Bericht Nr. 8607. Report of the Bayer AG Institut für Toxikologie, submitted to WHO by Bayer AG. (Unpublished) Bomhard, E., Löser, E. and Kaliner, G. S-6876 - chronic toxicity study 1979 on rats (two-year feeding experiment). Report of the Bayer AG Institut f. Toxikologie, submitted to WHO by Bayer AG. (Unpublished) Flucke, W. Akute orale Toxizität "Omethoat-Metabolit" 23 Oktober. 1978 Report of the Bayer AG Institut für Toxikologie, submitted to WHO by Bayer AG; (Unpublished) Herbold, B. S-6876-Salmonella/Mikrosomen-Test zur Untersuchung auf 1980 punktmutagene Wirking. Report of the Bayer AG Institut für Toxikologie, submitted to WHO by Bayer AG. (Unpublished) Löser, E. S-6876-Folimat-Wirkstoff Multigenerationeversuche an Ratten 1981 21 Januar, Bericht Nr. 9731. Report of the Bayer AG Institut für Toxikologie, submitted to WHO by Bayer AG. (Unpublished) Addendum: Histopathology - Consultox Laboratories Ltd., London. Wagner, K., Neitzel, H. and Oehlmann, L. Metabolismus von Omethoat im 1978 Boden. Report submitted by Bayer AG, Leverkusen. (Unpublished)
See Also: Toxicological Abbreviations Omethoate (WHO Pesticide Residues Series 1) Omethoate (WHO Pesticide Residues Series 5) Omethoate (Pesticide residues in food: 1978 evaluations) Omethoate (Pesticide residues in food: 1979 evaluations) Omethoate (Pesticide residues in food: 1980 evaluations) Omethoate (Pesticide residues in food: 1984 evaluations) Omethoate (Pesticide residues in food: 1985 evaluations Part II Toxicology)