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 PIRIMICARBExplanation Pirimicarb was evaluated by the Joint Meeting in 1976 and 1978 (FAO/WHO 1977 and 1979)1. The temporary ADI established in 1976 was re-assessed in 1978 and 0-0.01 mg/kg bw was recommended. The Joint Meeting concluded that, although it was not unduly concerned about the carcinogenic potential of pirimicarb, it wished to see a further carcinogenicity study undertaken in an appropriate mammalian species using a current accepted protocol. A mouse oncogenicity study was performed and is reviewed in this monograph addendum. EVALUATION FOR ACCEPTABLE DAILY INTAKE TOXICOLOGICAL STUDIES Special Study for Carcinogenicity Groups of Alderley Park Swiss derived mice (60/sex/group) were fed diets containing pirimicarb at levels of 0 (2 groups), 200, 400 and 1 600 ppm for up to 96 weeks. Animals were examined throughout the study for abnormal clinical or behavioural conditions, body weights were determined and food consumption was measured at regular intervals. Complete histopathology, including bone marrow smears, were performed on all animals. There was no evidence of bacterial, viral or parasitic infections in any of the animals examined during the study. Body weights of the 1 600 ppm male and female rats were significantly decreased (p <0.01) throughout the study. Food consumption and food utilization were variably decreased throughout the test, as well as increased food wastage, primarily in the high dose group animals. Mortality rates for males were comparable among all treatment and control groups, whereas, mortality was significantly increased for high dose females. There was a significant increase in the finding of lymphosarcoma among the high dose females during weeks 27-52, but the incidence of lymphosarcoma overall was comparable among all treatment and control groups. 1 See Annex 2 for WHO and FAO documentation. The incidence of pulmonary tumours (pulmonary adenomas) in the high dose males and females is not biologically significant when compared with historical control data and the considerations from the first mouse study (Palmer and Samuels 1974). Hepatocellular nodules, classed as Type A or Type B, were significantly increased in the high dose group when compared to controls. No consistent trend in either Type A or B nodule was determined, and therefore, total incidence of liver nodules, per se, was evaluated. The incidence of these tumours was not significantly increased among groups through week 78 of the study, as determined by intercurrent deaths, but became significantly different from week 79 to termination. There was no clear dose response, the mortality rate was increased for low and high dose males from weeks 76 to termination, and there was no previous identification of liver involvement or target organ toxicity to the liver. These support the conslusion that pirimicarb was not oncogenic in mice under the conditions of this study (Litchfield et al 1980). Special Studies on Mutagenicity Rat - cytogenetic study Six-week-old, Wistar-derived outbreed male rats (180-220 g) were administered pirimicarb dissolved in maize oil (10, 50 and 100 mg/kg) by oral gavage. There were five experimental groups with eight animals/group. The negative and positive (EMS) control groups consisted of a total of 12 animals at each dosing regime. Six or 24 hours after a single dose and 6 hours after the five consecutive daily doses of the test compound, animals were given a single IP treatment of 3 mg/kg colchicine and sacrificed two hours later by cervical dislocation. Chromosome slides were prepared and 50 cells from each animal were examined and scored for chromatid or chromosome gaps, chromatid breaks, fragments and other complex abnormalities. Pirimicarb did not induce chromosomal alterations in bone marrow cells of Wistar-derived outbred male rats when administered via oral gavage (Anderson et al 1980). Salmonella/microsome reverse mutations Pirimicarb, dissolved in DMSO at five concentrations (4, 20, 100, 500 and 2 500 µg/plate), was evaluated in two separate studies for mutagenic activity by the plate-incorporation method of the Ames Salmonella reverse mutation test, in the presence and absence of mammalian metabolic activation from rat liver enzymes. Five histidine- requiring strains of Salmonella typhimurium for detecting base-pair substitution, (TA 100, TA 1535) and frameshift mutation (TA 98, TA 1537 and TA 1538) were used in the histidine-reversion assay. The in vitro mammalian metabolic activation system consisted of liver homogenate fraction "S-9" from Aroclor 1254 treated Sprague-Dawley albino rats and the co-factor solution described by Ames. Pirimicarb did not demonstrate a dose-related increase in the number of histidine-independent colonies, failed to induce any biologically significant change in the reversion frequency to histidine independence with or without the addition of metabolic activation preparation in the study, and thus, was not mutagenic at the dose levels tested (4 through 2 500 µg/plate) (Trueman 1980; Longstaff 1978). COMMENTS Pirimicarb was last evaluated by the JMPR in 1978, when the Meeting expressed concern for the previously conducted rat and mouse oncogenicity studies. An additional long-term evaluation was requested and has been submitted and reviewed. It was concluded that pirimicarb was not carcinogenic in the rodent species tested, under the conditions of the study. Pirimicarb was also evaluated for mutagenic activity in a battery of in vivo and in vitro studies and all results were negative. In the absence of positive findings in the mutagenicity and carcinogenicity studies, the concerns previously expressed have been resolved and an ADI has been established. TOXICOLOGICAL EVALUATION Level Causing no Toxicological Effect Monkey : 2 mg/kg bw/day, Rat : 175 ppm in the diet, equivalent to 9 mg/kg bw Dog : 1.8 mg/kg bw/day. Estimate of Acceptable Daily Intake for Man 0 - 0.02 mg/kg bw. REFERENCES Anderson, D., Richardson, C.R., Howard, C.A., Bradbrook, C., Salt, 1980 M.J. and Cook S.K. Pirimicarb: a cytogenetic study in the rat. Report by ICI Central Toxicology Laboratory No. CTL/P/525, submitted by ICI to WHO. (Unpublished) Litchfield, M.H., Sotherson, M.F. and Jackson, D.G. Pirimicarb: 1980 Lifetime feeding study in the mouse. CTL Study No. PM 0002, submitted by ICI to WHO. Longstaff, E. Pirimicarb; short-term predictive tests for 1978 carcinogenicity results from the Salmonella/microsome reverse mutation test. Report by ICI Central Toxicology Laboratory, No. CTL/P/428, submitted by ICI to WHO. (Unpublished) Palmer, S.M. and Samuels, D.M. Pirimicarb: 80-week carcinogenic study 1974 in mice. CTL Study No. HO/CTL/P121/B, submitted by ICI to WHO. Trueman, R.W. An examination of pirimicarb for potential mutagenicity 1980 using the Salmonella/microsome reverse mutation assay. CTL Report No. Y00032/001/002, submitted by ICI to WHO.
See Also: Toxicological Abbreviations Pirimicarb (Pesticide residues in food: 1976 evaluations) Pirimicarb (Pesticide residues in food: 1978 evaluations) Pirimicarb (Pesticide residues in food: 1979 evaluations) Pirimicarb (Pesticide residues in food: 1981 evaluations)