PESTICIDE RESIDUES IN FOOD - 1984 Sponsored jointly by FAO and WHO EVALUATIONS 1984 The monographs 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, 24 September - 3 October 1984 Food and Agriculture Organization of the United Nations Rome 1985 BENDIOCARB Explanation Bendiocarb was evaluated by the Joint Meeting in 1982 at which time a temporary ADI was allocated. 1/ The 1982 JMPR required submission of 1) historical data of total lymphoreticular tumours in the CFY strain of rats used in the long- term study, and 2) a short-term (28 days) study in dogs to clarify the relationship between dietary intake of Bendiocarb and terminal erythrocyte and brain cholinesterase activity, using an appropriate method for cholinesterase determination. Additional data have been submitted and are reviewed in this monograph addendum. Corrigenda: The NOEL for the dog in the 1982 evaluations is incorrect. It should be 0.7 mg/kg bw/day. EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOCHEMICAL ASPECTS Absorption, Distribution and Excretion Man An area on the forearm of each of six male volunteers was exposed for 3 h to 14C- Bendiocarb (as an aqueous suspension) at a dosage of 0.01-0.02 mg/kg bw under occluded conditions in a warm environment and non-occluded conditions in a cooler environment. The data indicate that Bendiocarb was absorbed (as measured by 14C- urinary excretion) more rapidly and to a greater extent (18 percent total urinary excretion) under an occlusive dressing than on non-occluded skin (6 percent total urinary excretion). The study also showed that Bendiocarb was incompletely removed by washing and formed a depot in the skin. Some Bendiocarb (generally less than 1 percent of that applied) remained on or in the skin 48 h after treatment. The only urinary metabolite formed was 2,2-dimethyl-l,3-benzoxodiol-4-ol in conjugated forms (Challis, 1982). 1/ See Annex 2 for FAO and WHO documentation TOXICOLOGICAL STUDIES Special Study on Carcinogenicity Rat Evaluation by trend analysis of historical data on the incidence of total lymphoreticular tumours was done in the CFY strain of rats used in the long-term study. It demonstrated that the incidences of lymphoreticular tumours in treated and untreated groups of each sex were not significant, with a calculated chi-square value of 2.45 at one degree of freedom. None of the tumour types was observed more than twice in one sex at any dose level, indicating the absence of any consistent tendency for the recurrence of tumourigenicity in a particular organ, and there was no demonstrated decrease in latency. There was no evidence that tumours adversely affected survival. Moreover, as shown in Tables 1 and 2, the incidence of lymphoreticular tumours among untreated control groups in concurrent studies, at the same laboratories (Huntingdon Research Centre) and in the same CFY rat strain, are comparable to the overall incidences observed among treated groups in the present study and, therefore, are not compound- related. Short-term Toxicity Dogs A series of investigations of the factors influencing assessment of effects of Bendiocarb on blood and brain cholinesterase in the dog, including controlled alterations of feeding conditions, sampling times, sample storage and the analytical method, led to the development of an experimental model for monitoring cholinesterase effects of Bendiocarb. The principal features of this test system are: 1. A 1-h feeding period following overnight fasting recording the dose ingested. 2. Blood samples within 1.5 h after the end of the feeding period. 3. Blood samples rapidly chilled and assayed virtually immediately for whole blood cholinesterase. 4. Brain samples within 2 h after the end of the feeding period, with chilled homogenate prepared and assayed immediately after death. 5. Reference (normal) activity for whole blood obtained from pre-exposure sample and for brain from 24-h recovery sample at room temperature. 6. Modification of the Ellman analytical technique, adjusting sample volume and buffer strength. TABLE 1. Observed Incidence of Lymphoreticular Tumours Tumour Type Sex Dose Level (ppm) 0 2/10 20 200 No. Examined/Group 200 100 100 100 Reticulum cell sarcoma M 1 1 1 2 F 0 1 0 0 Myeloid leukaemia M 1 0 2 1 F 1 0 0 0 Lymphatic leukaemia M 0 0 1 2 F 0 0 0 0 Thymic lymphosarcoma M 1 2 1 1 F 0 1 0 0 Mediastinal lymphosarcoma M 0 0 0 0 F 0 1 0 0 Mast cell leukaemia M 0 1 0 0 F 0 0 0 0 Total L.R. Tumours (%) M 3 8 10 12 F 1 6 0 0 M+F 2 7 5 6 TABLE 2. Historical Incidence of Lymphoreticular Tumours Study 1 2 3 4 5 6 7 8 9 Males 0/35 2/40 0/48 1/49 0/38 2/38 1/50 1/49 1/49 % 0 5 0 2 0 5 2 2 2 Females 0/50 0/50 1/48 1/50 1/49 1/49 3/50 3/50 1/50 % 0 0 2 2 2 2 6 6 2 These features were developed during successive studies on Bendiocarb. The refinement of cholinesterase monitoring is evidenced by the consistency of the effects on cholinesterase activity observed in the chronic dog study, i.e. recurrent reductions over the 2-year treatment period of whole blood cholinesterase activity at least 30 percent below pre-exposure levels in individuals administered 500 ppm Bendiocarb in the diet. Previous acute and sub-chronic studies demonstrated complete recovery from anticholinesterase effects following feeding at dietary levels of 500 or 1000 ppm. Brain cholinesterase activity was also similarly decreased after 52 and 104 weeks of treatment at 500 ppm and complete recovery was observed after 24 h at room temperature. No consistent effects were detected at 100 or 20 ppm. All animals were fasted overnight at each monitoring stage in order to minimize the expected and unavoidable wide variation in the amount of diet ingested by individuals in the same group. A uniform dose-effect correlation can be demonstrated when the amount of Bendiocarb actually ingested in the feeding period is considered, with statistically significant reductions in cholinesterase activity repeatedly associated with doses greater than 5 mg/kg. This uniformity of response to a given dose of Bendiocarb can also be shown to extend to the degree of effect, with more than 70 percent of all instances of ingestion of at least 5 mg/kg being associated with anticholinesterase activity falling within a narrow range that equates to 2-5 percent cholinesterase inhibition per mg/kg Bendiocarb dose. It is further evident that the individual variation in response within and between dose groups observed in both the 16-week and chronic dog studies was related to the amount of Bendiocarb ingested rather than to the dietary level, given uniform conditions of feeding, sampling, analysis, etc. The variability in individual food intake during short feeding periods is a consequence of normal daily fluctuations in appetite and can produce very different degrees of cholinesterase inhibition. Thus, both the daily variation in amount of food ingested, as well as the pattern of eating, present limitations to the uniformity of response achievable experimentally in dogs. However, since blood samples were taken 1.5 h after feeding, and considering the rapid reversibility of cholinergic effects from methyl carbonates, it was considered adequate to evaluate the inhibitory effect on cholinesterase enzymes in the dog. Therefore, the original concerns of the 1982 Meeting were alleviated. COMMENTS Bendiocarb was evaluated in 1982, at which time a temporary ADI was allocated with a request for further information on historical data on the incidence of total lymphoreticular tumours in rats in the long-term study, and for a short-term study in dogs. Historical control data and considerations on the statistical analysis of incidences of lymphoreticular tumours provided indications that the observed differences among control and treated groups are of insufficient extent and consistency to indicate any treatment-related effect on tumourgenicity. Furthermore, according to the 1982 Evaluation, the latency period of these tumours was not modified by the treatment. The required short-term dog study was not provided. However, clarifications made available to the meeting alleviated the concerns expressed by the 1982 Meeting with respect to the cholinesterase activity determination, and a dog study is no longer required. The meeting agreed to estimate a full ADI. TOXICOLOGICAL EVALUATION Level Causing no Toxicological Effect Rat: 10 ppm in the diet, equal to 0.38 mg/kg bw Dog: 20 ppm in the diet, equal to 0.7 mg/kg bw Estimate of Acceptable Daily Intake for Man 0 - 0.004 mg/kg bw FURTHER WORK OR INFORMATION Desirable 1. Further investigations on the cataractogenic activity of Bendiocarb at low dosage levels in rats. 2. Observations in humans. REFERENCES Challis, J.R. Dermal absorption of Bendiocarb in man. Report 1982 Method/12/35 submitted by FBC Limited to WHO, (Unpublished)
See Also: Toxicological Abbreviations Bendiocarb (Pesticide residues in food: 1982 evaluations) Bendiocarb (Pesticide residues in food: 1984 evaluations)