PESTICIDE RESIDUES IN FOOD - 1982 Sponsored jointly by FAO and WHO EVALUATIONS 1982 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 Rome, 23 November - 2 December 1982 Food and Agriculture Organization of the United Nations Rome 1983 PARATHION METHYLExplanation Parathion methyl was evaluated by the Joint Meeting in 1968, 1975, 1929 and 1980 (FAO/WHO 1969, 1976, 1980 and 1981)1 and a temporary ADI of 0 - 0,001 mg/kg bw/day was allocated. Reproduction study in species appropriate to such a test and results of adequate long-term study reported to be in progress then were required by the 1980 Meeting. These studies, as well as other additional toxicological data, have been received and are reviewed in this monograph addendum. EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOCHEMICAL ASPECTS Absorption, Distribution and Elimination In male rats, treated with a single oral dose of 14C-parathion methyl (benzene ring-labelled) at 0.1, 1.0 or 5 mg/kg bw and in female rats given a single oral dose of 1 mg/kg bw, over 99% of the administered dose was excreted in the urine and the faeces within 48 hours. Elimination in the faeces accounted for only 5 - 7% after 1 or 5 mg/kg bw, but amounted to about 20% after 0.1 mg/kg bw. Male rats treated with an intravenous dose of 1 mg/kg bw excreted about 99% of the administered radioactivity in the urine within 48 hours, and approximately 1% of the dose in the faeces. Total radioactive residues recovered in the 12 tissues analysed (excluding the gastrointestinal tract) from rats given a single oral dose of 5 mg/kg bw were about 11% of the administered dose 1 hour after treatment, declining to 0.3% at 24 hours, about 0.1% at 48 hours and to only 0.04% 6 days later. The kidney had the highest relative activity up to 8 hours post-treatment. The 14C activity in the plasma was initially about 5 times higher than that in the erythrocytes. However, from day 2 to day 6 after dosing, the 14C-activity in the erythrocytes was greater than that in the plasma and remained constant. Following an intraduodenal dose of 1 See Annex 2 for WHO and FAO documentation. 1 mg/kg bw, male rats with fistulated bile duct excreted only 3% of the radioactive dose in the bile with the remainder being eliminated primarily (95%) in the urine within 24 hours (Weber et al 1979). The elimination of parathion methyl was rapid in the dog. A terminal half-life of 7.2 hours was estimated in dogs given an intravenous dose of 10 mg/kg bw (Braeckman et al 1980). TOXICOLOGICAL STUDIES Special Studies on Reproduction Rat Groups of 10 male and 20 female rats (SPF-Wistar W74 strain, 5-6 weeks old) were fed a diet containing technical parathion methyl (95% pure) at 0, 2, 10 or 50 ppm for 77 days and then mated to initiate a standard 3-generation (2 litters/generation) reproduction study. Pups of the second litters (F1b and F2b) provided the parents of the next generation. Through the parental generations, there was no mortality related to compound. Treatment at the top dietary level (50 ppm) induced convulsions in F1 parents, growth retardation in both F0 and F1 adults (both sexes) and significant adverse effects on litter size and pup weight at birth and through lactation practically through all progeny generations. All F2b pups at 50 ppm died 5 days after birth, resulting in the absence of data on F3a and F3b litters for this dosage group. Fertility rate was slightly decreased at 10 ppm in F2 generation (both mating trials, i,e. F3a and F3b litters). A reduction in litter size occurred at 10 ppm in F3a litters at birth, in F1b litters after 5 days and in F2a and F2b litters at 5 weeks. At 2 ppm, a non-dose-related decrease in litter size at birth and a slightly depressed survival of pups to 5 days were observed in F2b litters. These findings, occurring in a single progeny generation, were not believed to be attributable to parathion- methyl in the diet. Gross examination of F2b and F3b pups at birth and during rearing revealed no malformations. Histopathological evaluation of reproductive tract plus liver and kidney from 5 males and 5 females per group of F2 parents and of a set of about 15 tissues including the reproductive tract from 10 male and 10 female F3b weanlings per group showed no microscopic changes associated with treatment. The no-effect level in the study was 2 ppm (Lösen and Eiben 1982; Glaister 1981). Special Studies on Mutagenicity Parathion methyl (94.3 - 94.5% pure) was tested for its mutagenic potential in in vitro microbial assays with and without the presence of a metabolic activation preparation (S-9 fraction from liver of rats induced with Aroclor 1254). The indicator organisms used were Salmonella typhimurium strains TA 1535, TA 100, TA 1537 and TA 98. Positive mutagenic response was obtained with and without metabolic activation in strain TA 1535 at concentrations at and above 1 000 µg/plate and in strain TA 100 at and above 500 µg/plate. There were no indications of mutagenic activity in assays with tester strains TA 1537 and TA 98 at concentrations of 20 to 2 500 µg/plate with or without metabolic activation (Herbold 1982a). Parathion methyl (96.8% pure) was shown to induce a significant increase (dose-related) of sister chromatid exchanges and cell cycle delay in Chinese hamster cell line V79 and in two human lymphoid cell lines (Chen et al 1981). In a micronucleus test, groups of 5 male and 5 female mice were intubated with parathion methyl (95.6%) at 0, 5 or 10 mg/kg bw/day for 2 consecutive days with an interval of 24 hours between doses. The animals were sacrificed 6 hours after the second dose and femoral bone marrow smears were prepared. Results of examination of the smears did not indicate any significant increase in incidence of micronucleated polychromatic erythrocytes in the treated groups (Herbold 1982b). Special Studies on Eye and Skin Irritation Results of irritation studies with New Zealand White rabbits indicated parathion methyl (96.1%/95.6%) to be slightly irritating to the skin. The compound was not an irritant to eyes (Thyssen and Lorke 1982). Long-Term Studies Rat Groups of 5 to 6 weeks old male and female rats (SPF, Wistar TNO/W74 strain; 100 male and 100 female controls, 50 males and 50 females/treated group) were fed parathion methyl (94.8% pure) in their diet at 0, 2, 10 or 50 ppm for 2 years. Additional groups of 10 males and 10 females per group were included for interim sacrifice of 5 males and 5 females/group after 6 and 12 months. Mortality was increased in females at 50 ppm during the first year but about 79-90% males and 58 - 78% females of control and treated groups still survived at the end of the study. Animals (both sexes) in the top dosage group exhibited cholinergic symptoms (tremors) at times during the study and growth retardation throughout the experiment. Haematology, clinical chemistry and urinalysis carried out at five intervals during the study indicated deviations from control values essentially only at 50 ppm in a number of parameters. These included an increase in reticulocyte counts and a decrease in hematocrit and haemoglobin values in both sexes after 6 and/or 24 months, depressed plasma protein levels in females at all intervals, elevated serum urea in females at most intervals and in males after 24 months, increased plasma alkaline phosphatase activity in females after 3 and 6 months and a rise in urinary protein level in females after 1 and 6 months. (Plasma protein level was also depressed in females at 10 ppm but only after 1 month.) Cholinesterase in plasma and erythrocyte, assayed nine times over the course of the study, was consistently inhibited (>20%), in a dose-dependent pattern, at 50 ppm at all intervals and at 10 ppm frequently during the study. The extent of depression was greater with plasma cholinesterase than with erythrocyte cholinesterase. Terminal brain cholinesterase was inhibited (>20%) in males at both 10 and 50 ppm and in females at 50 ppm. Gross pathological findings in animals dying or sacrificed in moribund condition during the study and in those sacrificed at interim or terminally were comparable to those in the controls. A reduction of absolute weight, but not organ/body weight ratio, of several organs was demonstrated in animals at 50 ppm. Histopathological evaluation of a wide range of tissues from animals of control and top dosage groups only revealed a significant increase in frequency of males at 50 ppm (33% vs 4% in controls) displaying very slight to moderate degree of "excessive Oil Red 0(ORO)-positive substance in hepatocytoplasm". A no-effect level on this particular liver lesion could not be defined due to the absence of data on microscopic findings in the liver of treated animals below 50 ppm. No other non-neoplastic histopathological changes attributable to treatment were evident. Notably, histopathological data were available for only half of the animals in the control group. When histopathological and tumour data from only 50 male and 50 female controls were used as the basis of comparison, there did not seem to be any significant difference between the control and top dosage groups in the incidence of animals with tumours (benign and/or malignant), malignant tumours, benign tumours or multiple primary tumours. However, there appeared to be an increase in incidence at 50 ppm of thyroid adenoma in males (11/45 vs 4/43 controls) and of uterine adenocarcinoma (8/42 vs 3/44 controls)2. The increase was not statistically significant if incidence for the respective tumours in 43 and 44 concurrent controls were used for comparison. Whether the control incidence for the tumours in question would be significantly altered, if histopathological findings in all 100 male and 100 female concurrent controls were taken into consideration, is not known. The incidence of uterine adenocarcinoma at 50 ppm was indicated in the 2 According to "Table: Tumour hosts with descriptions of all tumours" included in the report, 4 female controls had adenocarcinoma of the uterus. An examination of "histopathological single finding" in Tables 344-347 revealed the uterus of one (animal No.149) of the 4 supposedly affected control animals was not examined microscopically. report to "remain within the variability of untreated animals of this strain observable in other virtually parallel studies". Background incidences of this particular malignancy and thyroid adenoma were not given (Bomhard et al 1981). Observations in Humans In 15 healthy male workers (with blood cholinesterase level <75% of presumably the mean normal levels) in a pesticide plant who were repeatedly or chronically exposed to parathion methyl for durations ranging from 1 week to 7 years, but with intermittent periods of non-exposure, there was no increased frequency of chromosome aberrations in lymphocyte cultures, as compared to 13 matched controls (having a blood cholinesterase level of 100%) not occupationally exposed to any chemical (Stocco et al 1982), COMMENTS The reproduction and long-term studies required by the 1980 Joint Meeting and other additional studies have been made available. A no-effect level of 2 ppm on re-production capability was demonstrated in the 3-generation rat reproduction study. Parathion methyl was mutagenic in the in vitro microbial assays to 2 of the 4 Salmonella typhimurium tester strains and in sister-chromatid exchanges and cell cycle delay studies with Chinese hamster cell line V79 and with 2 human lymphoid cell lines. On the other hand, a micronucleus test in mice was negative. Also, workers exposed to parathion methyl occupationally for long periods exhibited no increased frequency of chromosome aberrations in lymphocyte cultures. In the case of the 2-year feeding study in rats, the available data did not permit a complete evaluation of the carcinogenic activity of the compound or the determination of a definite no-effect level in the species. The Meeting, therefore, decided to extend the temporary ADI and requested that additional data pertaining to the study be provided. TOXICOLOGICAL EVALUATION 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 FURTHER WORK OR INFORMATION Required (by 1984) Additional data on the 2-year feeding study in rats including: a. Historical data on incidences of thyroid adenoma and adenocarcinoma of the uterus in the particular strain of rats (SPF Wistar TNO/W74) used in the study. b. Histopathological data, not presently available, on the remaining 50 males and 50 females in the control group or satisfactory and acceptable explanation for the absence of such data. c. Results of microscopic examination of the liver from treated males below 50 ppm. REFERENCES Bomhard, E., Löser, E. and Schilde, B. E605-Methyl (parathion-methyl) 1981 chronic toxicological study on rats (feeding experiment of two years). Report from Bayer AG submitted to the World Health Organization by Bayer AG. (Unpublished) Braeckman, R.A., Godefront, M.G., Blondeel, G.M., Belpaire, F.M. and 1980 Williams, J.L. Kinetic analysis of the fate of methyl parathion in the dog. Arch. Toxicol. 43: 263-271. Chen, H.H., Haveh, J.L., Sirianni, S.R. and Huang, C.C. Induction of 1981 sister-chromatid exchanges and cell cycle delay in cultured mammalian cells treated with eight organophosphorus pesticides. Mutat. Res. 88: 307-316. Glaister, J.R. E605-methyl rat breeding study (histopathology). Report 1981 from Hazleton Laboratories Europe, Ltd., England, submitted to the World Health Organization by Bayer AG. (Unpublished) Herbold, B. E 120 parathion-methyl ( Salmonella/microsome test to 1982a evaluate forepoint mutation. Report from Bayer AG submitted to the World Health Organization by Bayer AG. (Unpublished) Herbold, B. E 120 parathion-methyl micronucleus test on the mouse to 1982b evaluate for mutagenic effect. Report from Bayer AG submitted to the World Health Organization by Bayer AG. (Unpublished) Löser, E. and Eiben, R. E 605-methyl multigeneration studies on rats. 1982 Report from Bayer AG submitted to the World Health Organization by Bayer AG. (Unpublished) Stocco, R. de Cassia, Becak, W., Gaeta, R. and Rabello-Gay, M.N. 1982 Cytogenetic study of workers exposed to methyl-parathion. Mut. Res. 103:71-76. Thyssen, J. and Lorke, D. Parathion-methyl (E120) tests for irritant 1982 effects on the skin and eye. Batch No. 23010618. Report from Bayer AG submitted to the World Health Organization by Bayer AG. (Unpublished) Weber, H., Patzschke, K. and Wegner, L.A. (14C)methyl-parathion 1979 (benzene ring-labelled compound) biokinetic studies on rats. Report from Bayer AG submitted to the World Health Organization by Bayer AG. (Unpublished)
See Also: Toxicological Abbreviations Parathion methyl (Pesticide residues in food: 1984 evaluations)