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 PHOSPHAMIDON CH3O O CH3 O C2H5 \" ' " / P - O - C = C - C - N / ' \ CH3O Cl C2H5 Explanation This pesticide was evaluated toxicologically at the Joint Meetings in 1965, 1966, 1968 (FAO/WHO 1965, 1967, 1969)1, and an ADI was established at the 1966 Meeting on the basis of no-effect levels taken exclusively from data reported by Industrial Bio-Test Laboratories (IBT). Additional data have become available and are summarized and discussed in this monograph addendum. EVALUATION FOR ACCEPTABLE DAILY INTAKE TOXICOLOGICAL STUDIES Special Studies on Carcinogenicity Mouse Groups of 5-week old B6C3F1 mice (10 male and 10 female controls, 50 males and 50 females/treated group) were fed dietary levels of technical phosphamidon at 0, 80 or 160 ppm for 62 weeks (160 ppm- group) or 71 weeks (80 ppm-group) in males and 80 weeks in females (both treated groups). The male animals were then placed on control diet for 28 weeks (160 ppm-group) or 19 weeks (80 ppm-group) and female animals, 11 weeks (both treated groups). Pooled controls, consisting of 85 male and 85 female control mice from similar bioassays of 8 other chemicals and the 10 male and 10 female controls concurrent to the present study were used for statistical comparison. Moribund animals and terminal survivors at 91 or 92 weeks were sacrificed for necropsy and microscopic examination of major tissues and all gross lesions. Necropsies were also conducted on all animals found dead. There was no compound-related effect on mortality. Between 84-92% treated males and females, 70% control males and 100% control females survived to termination. Generalized tremors, rough hair coats and poor physical condition were seen in some males of both treated groups after 60 weeks. Dose-related growth depression was apparent in males at both 80 and 160 ppm practically throughout the study. Treated 1 See Annex 2 for WHO and FAO documentation. animals exhibited no non-neoplastic lesions that could be associated with the compound. Tumour data indicate no significant difference between control and treated groups in incidence of any particular type of tumour. Under the conditions of the experiment, there was no indication of carcinogenicity of phosphamidon in B6C3F1 mice (NCI 1979). Rat Groups of 5-week old Osborne-Mendel rats (10 male and 10 female controls, 50 males and 50 females/treated group) were fed technical phosphamidon in their diet at 0, 80 or 160 ppm for 80 weeks and then maintained on control diet for additional 30 weeks (males) or 31 weeks (females). For statistical comparison, pooled controls were used, which consisted of 85 male and 85 female controls from similar bioassays of 8 other chemicals and the 10 male and 10 female controls from the current study on phosphamidon. Moribund animals and terminal survivors at 110 or 111 weeks were sacrificed for necropsy and microscopic examination of major tissues and all gross lesions. Necropsies were also conducted on all animals found dead. Survival was not affected by treatment. Between 50 to 72% males and 78 to 90% females of all groups, including the controls, survived to the end of the experiment. Growth was depressed in both sexes at 160 ppm for most of the study. Hyperexcitability and tremors were seen in some animals in both treated groups between weeks 6 and 16. Histopathologically, except for a seeming increase at 160 ppm in incidence of focal cellular changes in the liver and follicular cell hyperplasia of the thyroid in males, there were no non-neoplastic lesions attributable to the compound. A variety of tumours were detected in the treated animals. Such neoplasms, either not dose- related or comparable to controls in incidences, were likely to be spontaneous in nature. However, tumours of the spleen and thyroid seemed to occur more frequently in treated groups than in controls at incidences as reported in Table 1. It was indicated in the report that statistical analyses showed a significant increase in combined incidence of spleen haemangioma and haemangiosarcoma at 160 ppm and a significant dose-related trend with respect to the combined incidence of splenic tumours in male rats when compared to pooled controls. The comparison with concurrent controls was not significant. Background incidence in the testing laboratory of such splenic tumours in untreated male Osborne-Mendel rats was reported as 6/240(3%), with incidences in individual groups as high as 3/9 (33%) and 2/9 (22%). No tumours of the spleen occurred in females of the current study. As for thyroid tumours, there was a statistically significant dose-related trend for the combined incidence of C-cell adenoma and carcinoma in female rats when compared to pooled controls. Incidences of these tumours in the female treated groups were also significantly higher than in the pooled controls. Table 1. Tumour Incidence in Rats Treated with Phosphamidon Males Females 0 80ppm 160 ppm 0 80ppm 160 ppm Spleen Haemangioma 1/50(2) Haemangiosaracoma 1/7(14)1 2/50(4) 5/49(10) Haemartoma 1/50(2) Thyroid Follicular cell carcinoma 1/47(2) 0/10 1/50(2) C-cell adenoma 7/48(15) 5/47(11) 0/10 8/50(16) 7/46(15) C-cell carcinoma 1/8(13) 0/10 1/50(2) 1/46(2) 1 The numerator denotes the number of animals with the lesion and the denominator the number of animals with the specific tissue examined microscopially. Figure in parentheses indicates incidence in %. However, according to the historical records of the testing laboratory, incidence of the particular thyroid tumours in untreated females of Osborne-Mendel strain was 16/235(7%), with incidences in individual control groups as high as 3/9(33%) and 3/10 (30%). In males the incidence of thyroid tumours was not statistically significant. The conclusion was made that "the data obtained in this bioassay with Osborne-Mendel rats are insufficient to allow the interpretation that technical-grade phosphamidon is carcinogenic in this species". Following a review of the report on the current carcinogenic study of phosphamidon, members of the Data Evaluation/Risk Assessment Subgroup of the Clearinghouse on Environmental Carcinogens in the United States were of the opinion that "the results from the assay should be considered to be equivocal and, therefore, no conclusion drawn on the carcinogenicity of phosphamidon" (NCI 1979). COMMENTS Phosphamidon was last reviewed by the 1968 JMPR. Additional data now available included two carcinogenicity studies in rodents, one of which (mice) was negative, and the other (rat) was inconclusive. It was noted that no data on delayed neurotoxic potential had ever been submitted. An ADI was established at the 1966 Meeting on the basis of the no-effect levels taken exclusively from IBT data, which have been found to be invalid. The Meeting was informed that a number of essential replacement studies had been commissioned. The Meeting decided to change the ADI to a temporary status and requested that the studies be submitted at the earliest possible date. TOXICOLOGICAL EVALUATION Level Causing no Toxicological Effect Rat : 2 ppm in the diet, equivalent to 0.1 mg/kg bw Dog : 0.5 mg/kg bw/day Estimate of Temporary Acceptable Daily Intake for Man 0 - 0.001 mg/kg bw FURTHER WORK OR INFORMATION Required (by 1985) 1. The following replacement or new studies: a. 2-year rat study; b. 12-month dog study; c. 2-generation reproduction study in rats; d. Teratology studies in rats and rabbits; e. Mutagenic studies. 2. An appropriate delayed neurotoxicity study. Desirable Further toxicity studies on the metabolites of phosphamidon. REFERENCES NCI Bioassay of phosphamidon for possible carcinogenicity, National 1979 Cancer Institute, Carcinogenesis Technical Report Series No. 16, D.H.E.W. Publication No.(NIH)79-816. Report of a study performed at Gulf South Research Institute, Louisiana and prepared at Tracor Jitco, Inc., under the direction of NCI.
See Also: Toxicological Abbreviations Phosphamidon (ICSC) Phosphamidon (PIM 454) Phosphamidon (FAO Meeting Report PL/1965/10/1) Phosphamidon (FAO/PL:CP/15) Phosphamidon (FAO/PL:1968/M/9/1) Phosphamidon (FAO/PL:1969/M/17/1) Phosphamidon (WHO Pesticide Residues Series 2) Phosphamidon (WHO Pesticide Residues Series 4) Phosphamidon (Pesticide residues in food: 1986 evaluations Part II Toxicology)