PESTICIDE RESIDUES IN FOOD - 1980 Sponsored jointly by FAO and WHO EVALUATIONS 1980 Joint meeting of the FAO Panel of Experts on Pesticide Residues in Food and the Environment and the WHO Expert Group on Pesticide Residues Rome, 6-15 October 1980 PARATHION-METHYL Explanation Parathion-methyl was evaluated by the Joint Meeting in 1968, 1972, 1975, and in 1979 (FAO/WHO 1969, 1973, and 1976; FAO, 1980). In 1979, based on the consideration that parathion-methyl was neither teratogenic nor embryotoxic in rats and that previously requested long-term studies were in progress, the Meeting extended the temporary Acceptable Daily Intake. Further information on the toxicological hazards associated with the use of parathion-methyl under actual field conditions in India and short-term studies were made available to the Meeting. These data are reviewed in this monograph addendum. DATA CONSIDERED FOR DERIVATION OF ACCEPTABLE DAILY INTAKE TOXICOLOGICAL STUDIES Special studies on potentiation In an effort to evaluate the possible acute interaction of parathion-methyl and other toxic insecticides, acute studies with DDT and parathion-methyl in rats were performed. Male rate were orally administered fractions of the LD50 of each material. The ratio of LD50 value calculated to that observed in the study suggested a less than additive effect when the two insecticides are administered simultaneously (i.e., the acute toxicity was less than anticipated based on preliminary toxicity data with each material alone) (Kimmerle, 1975 ). An additional trial in male rats administered parathion-methyl and parathion-ethyl (parathion) showed the combined toxic effects to be additive (Flucke and Kimmerle, 1977). Special studies an carcinogenicity Mice In a dose range-finding study, groups of mice (5 male and 5 female, B6C3F1, mice/group) were fed parathion-methyl at dosage levels of 0, 20, 40, 60, 80, 100, 125, 250 or 500 mg/kg for 7 weeks. After 1 week of control diet (following parathion-methyl dosing) the animals were sacrificed and tissues of some of the upper dosage groups were examined microscopically. The criterion of 10% weight loss was chosen to develop the dosage levels of the chronic study (the data were not reported in detail enough to determine whether the 10% weight loss would be the criterion for the high or low dosage groups in the chronic study). Mortality was noted in the study; the high dose group had no survivors and the 250 mg/kg group had only 1 female of 10 mice surviving the 7-week trial. Mean body weights were not substantially reduced (maximum was 6% at week 7). From these data the initial dosage levels for the chronic study were chosen as 0, 62.5 or 125 mg/kg. Groups of mice, 50 male and 50 female (20 of each sex were used as controls) B6C3F1 mice/group, were fed parathion methyl for 102 weeks. All animals were 6 weeks of age at the inception of the study and were fed parathion-methyl diets 7 days per week. Animals were housed in groups of five under clean, but not SPF conditions, and were in rooms where other chemicals were administered to mice in chronic studies. The animals were weighed every two weeks during the initial phase of the study and monthly for the remainder of the study. At the conclusion of the study all animals were sacrificed and necropsied. Histopathologic evaluations were made on all major tissues and organs and on all lesions, noted on gross examination. There was a substantial decrease in growth of male mice, such that the dosage levels had to be reduced at 38 weeks from 125 and 62.5 mg/kg to 50 and 20 mg/kg respectively. Thereafter, the males grew normally. The 125 mg/kg dose in females was responsible for a slight weight loss over the entire course of the study. There were no differences in mortality with respect to control groups. Sufficient survivors were available for an adequate study on the development of neoplastic and non-neoplastic lesions. On pathologic examination, a variety of lesions were observed in both treated and control animals. The incidence and type of each neoplasm was not attributable to the presence of parathion-methyl in the diet. All lesions encountered were attributed to the common ageing process in this strain of mice. Statistical evaluation of the data concurred with the gross and pathological findings. It was concluded that under the conditions of this bioassay, parathion-methyl was not carcinogenic to the B6C3F1 mouse. These conclusions were confirmed by a Data Evaluation/Risk Assessment Subgroup of the Clearinghouse on Environmental Carcinogens (NCI, 1979). Rats In a dose range-finding study, groups of rats ( 5 female and 5 male, F344 (Fischer) rats), were fed parathion-methyl in the diet at dosage levels of 0, 10, 20, 30, 40, or 50 mg/kg for 7 weeks. At the conclusion of the dietary trial, all animals were maintained on control diets for one week and sacrificed. Growth had been measured twice a week for the 8-week trial. Abnormalities noted on gross and microscopic analyses of tissues and organs and a 10% growth reduction were chosen as requisites for the dosage levels to be used in the chronic study. There was no mortality in the male rats and survival of the females mixed. There were no serious lesions noted on sacrifice and based on growth the dosage levels of 0, 20 or 40 mg/kg were chosen for the chronic study. Groups of rats (50 male and 50 female (20 of each sex were used as controls, F344 (Fischer) rats per group) were fed parathion-methyl in the diet, 7 days per week for 105 weeks at dosage levels of 0, 20 or 40 mg/kg. Groups of rats were housed together (4 of each sex per cage) in a clean room where several other chemicals were being studied. The animals were not maintained under SPF conditions. Body weight data were recorded periodically over the course of the study as were chemical analyses of the dietary content. At the conclusion of the study, all animals were sacrificed for gross and microscopic analyses of tissues and organs. There was no substantial effect of parathion-methyl on growth, although the 40 mg/kg dosage level decreased female growth and increased the mortality rate of females. Survival of females was significantly reduced at 40 mg/kg. A variety of neoplastic and non-neoplastic lesions were noted in rats over the course of the study. Each type of neoplasm had been noted previously in this strain of rat. The incidence by type and site and by test group and sex was reported to be unaffected by parathion-methyl in the diet. Based on the chronic bioassay data, there was no evidence that parathion-methyl was carcinogenic to this strain of rat. The conclusion was confirmed by the Data Evaluation/Risk Assessment Subgroup of the Clearinghouse on Environmental Carcinogens (NCI, 1979). OBSERVATIONS IN MAN In three supervised trials in India, groups of agricultural workers, either wearing protective clothing or clothing normal to the area, were examined before, during and after exposure to three different formulations of parathion-methyl applied by hand in different agricultural situations indigenous to India. Two concentrations of parathion-methyl as an emulsifiable concentrate in water and one trial with parathion-methyl as a 2% dust were used in these trials. The duration of exposure for the individuals participating was four hours per day for four successive days. Pre-exposure, exposure, and post-exposure examinations with respect to physical determinations, cholinesterase measurements and haematological parameters ware performed on the individuals. As might be expected from this type of experiment, the most significant data reported were cholinesterase depression levels reflective of exposure. In the trial with the high concentration parathion-methyl emulsifiable concentrate, there was no substantial difference with respect to cholinesterase depression in the individuals wearing protective clothing from those wearing normal clothing. Cholinesterase depression data suggested that exposure had, indeed, occurred although cholinesterase depression levels rarely exceeded the 25% level that would be indicative of excessive exposure. In the trial where a lower concentration of the parathion-methyl emulsifiable concentrate was used, none of the workers showed any substantial inhibition of cholinesterase activity during the course of the experiments. Differences in the two trials with emulsifiable concentrates were probably reflective of the differences in concentration of the technical material and in the crop upon which the technical material was sprayed (in the higher concentration the crop was a high span of cotton that presumably increased the exposure from drift). In the third trial, a 2% dust formulation of parathion-methyl did not induce cholinesterase activity in any of the exposed workers regardless of whether protective clothing was used. In none of the above trials were there any of the variations in haematological parameters or significant side effects noted with some other insecticides (Anonymous, 1976). EVALUATION COMMENTS Parathion-methyl was previously evaluated by the Joint Meeting in 1968, 1972, 1975 and 1979 (FAO/WHO, 1969b, 1973b, 1976b, 1980b) and a temporary ADI of 0-0.001 mg/kg bw/day was allocated. Some data were submitted to the meeting and reviewed. An extensive study of agricultural field workers exposed to different formulations of parathion-methyl under agricultural conditions in India showed that, following good agricultural practices, occupational exposure would not result in significant adverse short-term effects. While these data were sufficient to relieve concerns about the short-term hazards associated with short-term occupational exposure, the meeting decided to extend the temporary ADI and request that reproduction and long-term studies be made available. Level causing no toxicological effect Man: 0.3 mg/kg bw/day. Estimate of temporary acceptable daily intake for man 0-0.001 mg/kg bw/day. FURTHER WORK OR INFORMATION Required (by 1982) 1. Reproduction study in species appropriate to such a test. 2. Results of adequate long-term study reported to be in progress. REFERENCES Anonymous. Studies on the Toxic Hazards of Methyl-Parathion Preparations to Human Workers When Engaged in Agricultural Pest Control Operations Under Indian Field Conditions. (1976) Unpublished report from the Haffkine Institute for Training Research and Testing (Bombay) submitted by Bayer (India) Limited to the World Health Organization. Flucke, W. and Kimmerle, G. Studies on Acute Toxicity of Simultaneously Administered Parathion-Methyl (Parathion-M) and Parathion-ethyl (Parathion-A). (1977) Unpublished report from Bayer AG Institut für Toxicologie submitted to the World Health Organization by Bayer, AG. Kimmerle, G. Acute Toxicity of DDT in Combination with Parathion-Methyl and Penithrothion to Rats. (1975) Unpublished report from Bayer AG Institut für Toxicologie submitted to the World Health Organization by Bayer, AG. NCI. Bioassay of Methyl Parathion for Possible Carcinogenicity. National Cancer Institute, Carcinogenesis Technical Report Series #157. D.H.E.W. Publication No. (NIH 79-1713). Report of a study performed at the Fredrick Cancer Research Center, Fredrick, MD, and prepared by Tracor Jitco, Inc. for the National Cancer Institute.
See Also: Toxicological Abbreviations Parathion-methyl (FAO/PL:1968/M/9/1) Parathion-methyl (WHO Pesticide Residues Series 2) Parathion-methyl (WHO Pesticide Residues Series 5) Parathion-methyl (Pesticide residues in food: 1978 evaluations) Parathion-methyl (Pesticide residues in food: 1979 evaluations) Parathion-methyl (Pesticide residues in food: 1984 evaluations) Parathion-methyl (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)