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Toxicity of Selected Contaminants 57 METHOMYL ethanimidothioic acid, N-~(methylaminokarbonyI]oxy]-, methyl ester CAS No. 16752-77-5 o 11 CH3C = NOCNHCH3 1 SCH3 Methomyl was evaluated in the first volume of Drinking Water and Health (National Research Council, 1977, pp. 635-6431. The following ma- terial, which became available after the 1977 report was prepared, updates and, in some instances, reevaluates the information contained in the pre- vious reviews. Also included are some references that were not assessed in the earlier report. METAB O LISM Methomyl labelled with carbon-14 was rapidly metabolized and elimi- nated from the rat as carbon dioxide, acetonitrile, and unidentified uri- nary metabolites (Harvey et al., 1973~. It binds reversibly with blood cho- linesterase, which, in combination with its rapid rate of metabolism, may explain its high acute oral toxicity and much lower chronic oral toxicity (Kaplan and Sherman, 1977~. HEALTH ASPECTS Observations in Humans A growing number of case histories have indicated that methomyl is highly toxic to humans following acute exposure, frequently requiring hospital- ization as a result of blurred vision (Liddle et al., 1979; Morse et al., 1979; Smith, 1977). A committee of the National Research Council (1982) found no evidence that long-term health effects resulted from short-term exposure to a variety of anticholinesterase compounds. That committee did not specifically re- view methomyl, which is a member of that broad class of chemicals. None- theless, this conclusion provides reassurance that short-term exposure to methomyl is unlikely to produce long-term adverse effects on human health.
58 DRINKING WATER AND HEALTH Observations in Other Species Acute Effects The oral LDso of pure methomyl was 17 mg/kg for fasted male rats, 23.5 mg/kg for fasted female rats, and 37 mg/kg for rats on normal diets (Antal et al., 1979~. The minimum lethal dose of metho- myl was 15 mg/kg for the guinea pig, 30 mg/kg for the dog, and 40 mg/kg for the monkey (Kaplan and Sherman, 1977~. Chronic Effects A decreased weight gain was observed in male mice fed a nutritionally complete diet containing a methomyl concentration of 250 ppm for 90 days, whereas lower concentrations (10-125 ppm) had no effect (Kaplan and Sherman, 1977~. Further evaluation revealed that the entire range of treatments caused no clinical, hematological, biochemical, urinary, or pathological effects. Kaplan and Sherman also observed no evi- dence of toxicity in similar studies in dogs exposed for 90 days to doses up to 400 ppm in a nutritionally adequate diet. In a 22-month study of rats exposed to methomyl in a nutritionally ade- quate diet, there was a decreased hemoglobin level at 200 to 400 ppm along with a significantly (p ~ 0.05) higher testis to body weight ratio in the 400-ppm males and histopathological alterations in the kidneys of males and females at 400 ppm and in the spleens of females at 200 and 400 ppm (Kaplan and Sherman, 1977~. In dogs exposed to methomyl at 400 to 1,000 ppm, histopathological alterations were found in the kidneys and spleen. Consumption of diets containing 1,000 ppm was sufficiently toxic to result in lethality to several dogs in the treatment group. These authors suggested a chronic "no-effect" level of 100 ppm for rats and dogs. Methomyl (200 mg/kg) and ethanol (10370 aqueous solution) may inter- act to enhance the toxicity of methomyl in rats. Antal et al. (1979) reported that this interaction produced decreased growth, an increased ratio of ad- renal gland weight to body weight in both sexes, and several sex-specific changes, including increased hepatic triglyceride and free fatty acid levels in males and increased relative weight of kidneys and fasting glucose levels in females. Mutagenicity Methomyl induced anaphase bridge formation, prema- ture chromosome condensation, and a variety of mitogenetic effects in the broad bean Vicia faba. It was also found to induce mutations in the Ames Salmonella assay in the absence of a metabolic activation system (Gopalan and Njagi, 1981, abstract). A transplacental host-mediated hamster cell assay was used to study the ability of methomyl and its nitrosated deriva- ti~re to induce morphological transformation in fetal cell cultures. These cell cultures were also examined for growth in soft agar (0.3~o) and for
Toxicity of Selected Contaminants 59 their ability to induce tumors in nude mice. Only the nitrosated methomyl was found to elicit cell transformation and growth in soft agar (0.3~o) (Quarles et al., 1979b) as well as tumorigenicity in nude mice (Quarles et al., 1979a). The data indicate that methomyl is mutagenic in one microbial muta- genicity assay. It also interferes with the cell cycle of one plant system. Negative results were obtained in a transplacental host-mediated hamster cell assay and in a transfo~n~ation assay. Carcinogenicity No new data were found by the committee. Teratogenicity New Zealand white rabbits were fed methomyl at die- tary levels of 0, 50, and 100 ppm on days 8 through 16 of gestation. When the fetuses were examined, there was no evidence of teratogenic effects. Alizarin-stained skeletons revealed no abnormalities in bone structure. A three-generation reproduction study in rats showed that methomyl did not have any adverse effects on various reproductive performance indices that could be attributed to feeding dietary levels of 50 and 100 ppm (Kaplan and Sherman, 1977~. After reviewing the data, the committee concluded that methomyl is not teratogenic to rats or white rabbits. CONCLUSIONS AND RECOMMENDATIONS Suggested No-Adverse-Response Level {SNARL) Chronic Exposure The findings from a chronic oral exposure study by Kaplan and Sherman (1977) suggested that 100 ppm is a "no-effect" level for rats (5 mg/kg bw) and dogs (2.5 mg/kg bw). Using this level from the dog for a 70-kg human consuming 2 liters of water daily, which contributes 20~o of total intake, and an uncertainty factor of 10(,, one may calculate the chronic SNARL as: 2.5 mg/kg X 70 kg X 0 2 = 0.175 mg/liter. 100 X 2 liters The toxicity of methomgl has been charactenzed in acute, subacute, and chronic toxicological investigations, principally in rats and dogs. Addi- tional infotmation has been pro~rided in clinical toxicology literature based on occupational exposures. Of greatest significance in the chronic animal studies was the consistent occurrence of histopathological changes in the kidneys of rats and dogs.
60 DRINKING WATER AND HEALTH Future research in animal models should be directed toward evaluating the physiological significance, if any, of the histopathological changes in- duced by methomyl in kidney tissue. PICLORAM 2-pyridinecarboxylic acid, 4-amin~3,5,6-trichloro- CAS No. 1918-02-1 NH2 Cl N COOH Picloram is a broad spectrum, persistent herbicide used on forage grasses. It is readily soluble in organic solvents (20,000 ppm in acetone) and water (430 ppm) (Johnson, 1971~; it is degraded by ultraviolet light (Wirthgen and Raffke, 1977~; and it is decomposed in water to negligible levels within 180 days (Johnson, 1971~. In the study by Johnson (1971), a standing pond was sprayed at a rate of 4 pounds/acre, which resulted in 2,400 ppb at time zero, 700 ppb at day 1, and 6 ppb at 180 days. METAB OLISM Picloram is rapidly absorbed from the gastrointestinal tract and is excreted virtually unchanged in the urine and feces of male Fischer 344 rats within 48 hours (Nolan et al., 1980~. Following a 10 mg/kg ~4C-picloram intra- venous dose, the isotope was cleared biphasically and excreted in the urine. The half-time for rapid and slow clearance from plasma was 6.3 and 128 minutes, respectively. Oral administration of the same dose resulted in comparable half-times of 29 minutes and 3.8 hours, respectively. At higher (1,400 mg/kg) oral doses, the plasma levels remained constant for 3 hours, then slowly declined. Balance studies in rats indicated that 98.4~o of the dose was recovered. Urinary excretion resulted in an 80~o to 84~o recovery, fecal excretion re- sulted in approximately 15~o recovery, less than 0.5~o was recovered in the bile, and virtually no radioactivity was recovered as trapped SCOT or as other volatile compounds (Nolan et al., 1980~.
