THIOPHANATE-METHYL JMPR 1975 Explanation This systemic fungicide of the benzimidazole group was evaluated by the Joint Meeting in 1973 and an ADI of 0.08 mg/kg/day was recommended (FAO/WHO, 1974). Because an uncertain proportion of residues from thiophanate-methyl applications consist of methyl-benzimidazole carbamate (MBC), for which an ADI has not been established, only temporary tolerances could be recommended. Recommendations were made for a number of vegetable food crops, including some items for animal feeding purposes. Further information on the nature and fate of thiophanate-methyl in meat, milk and eggs was required before temporary tolerances could be confirmed. Since the previous evaluation, additional data have become available and are summarized in this monograph addendum. EVALUATION FOR ACCEPTABLE DAILY INTAKE BIOCHEMICAL ASPECTS Absorption, distribution and excretion Tissue distribution, excretion in urine and faeces of 14C-labelled thiophanate-methyl (phenyl - 14C) were investigated in female rats after administration of a dose level calculated to be equivalent to 45 mg/kg in the diet during a period of 20 days. An average of 89.60% of the 14C-TM radioactivity was excreted per day, 54.27% in urine and 35.38% in the faeces. After final administration diminution of radioactivity was fairly rapid in all tissues with the exception of thyroid, adrenal glands and liver in which organs it temporarily persisted. In addition to thiophanate-methyl the main metabolites or breakdown products identified in the faeces were 5-hydroxy methylbenzimidazole, 4-hydroxy thiophanate-methyl as well as 4-hydroxy-dimethyl-4,4'-O-phenylene bis-allophanate. In the urine the main metabolite identified was 5-hydroxy methyl benzimidazole (Kosaka et al., 1975). TOXICOLOGICAL STUDIES Special studies On effect on male reproductive system Thiophanate and thiophanate-methyl were administered by gastric intubation over a 5-day period in doses of 0, 295, 192 mg/kg respectively to groups of mature, male Swiss-Webter mice to investigate the in vivo effects on sex: organs, adrenal glands as well as the ability of the prostate gland to assimilate (3H) testosterone. Upon sacrifice, body, testes, prostate, seminal vesicles, and adrenal glands were weighed and the activity of testosterone was measured in the prostate glands upon removal from animals killed 5 minutes after a single dose of an intraperitoneal injection of (1,2-3H) testosterone 24 hours after final dose of these fungicides. The absolute weight of the adrenal glands was significantly increased in both groups; absolute weight of prostate was significantly increased in the group given thiophanate-methyl while body weights were slightly increased. No effect upon weight of the seminal vesicles was observed, The testes and adrenals / body weight ratios were significantly increased in both groups, the relative weight of prostate was significantly enhanced in the thiophanate-methyl group, while the relative weights of seminal vesicles were comparable to those of controls. The uptake of (3H) testosterone and its metabolism to (3H) dihydrotestosterone by the anterior prostate gland was not affected. Histological examination of the testes revealed no effect on spermatogenesis, and no evidence of sterile tubules or morphological changes of the Leydig cells were observed (Thomas and Schein, 1974). COMMENTS New data on the metabolism and on affects on the male reproductive system were submitted in response to the request for further work set forth by the 1973 Meeting. It was noted that thiophanate-methyl had no effect on the uptake and metabolism of testosterone and spermatogenesis in male mice. Based on the new data the previously allocated acceptable daily intake was reconfirmed. TOXICOLOGICAL EVALUATION Level causing no toxicological effect Mouse: 160 ppm in the diet equivalent to 23 mg/kg bw. Rat: 160 ppm in the diet equivalent to 8 mg/kg bw. Dog: 50 mg/kg bw/day. ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN 0-0.08 mg/kg bw. RESIDUES IN FOOD AND THEIR EVALUATION FATE OF RESIDUES In chicken and eggs New information on chicken feeding trials has been provided (Nippon Soda Co., 1975), Laying white Leghorn chickens were fed rations containing thiophanate-methyl at 10 mg/kg and 50 mg/kg levels for 30 days. In addition the birds were treated with daily doses of measured amounts of radioactive thiophanate-methyl, the amounts of which were related to the amount of unlabelled thiophanate-methyl through careful individual weighings and food consumption controls. Excreta and eggs were collected throughout the experimental period and analysed individually for total 14C-content. At the end of the 30 days feeding period animals were sacrificed and samples of muscle, fat, kidney and liver were obtained for radio-analysis. All 14C-activities were expressed as equivalent quantities of unaltered thiophanate-methyl. Results are given in Table 1. In no case had the treatment with thiophanate-methyl any deleterious effects an either the chickens or the egg production during the experiment. Total residues of 14C-containing material in eggs reached a plateau after three days of feeding, after which daily averages corresponding to 0.035 and 0.115 mg/kg of thiophanate-methyl were found in the two feeding groups. The highest levels in individual eggs were 0.080 and 0.377 mg/kg, respectively. Liver and kidney tissues from both test groups contained detectable amounts of 14C-activity. The average contents at the 10 mg/kg feeding level were 0.31 mg/kg in liver and 0.14 mg/kg in kidney and at the 50 mg/kg level 1.20 mg/kg and 0.72 mg/kg, respectively. Muscle and fat from both groups contained no detectable 14C-activity. It is noted that the excreta samples contained the majority of the radioactivity detected. An average of 5.42 mg/kg was found in the 10 mg/kg feeding group and 23.9 mg/kg was found in the 50 mg/kg group. TABLE 1. Thiophanate-methyl residues in eggs and chicken tissues Residues, 14C expressed as mg thiophanate-methyl per kg, from feeding level for 30 days of Sample 10 mg/kg 50 mg/kg Liver 0.31 (0.18-0.45) 1.20 (0.59-1.59) Kidney 0.14 (0.10-0.20) 0.72 (0.42-1.22) Muscle 0.00 (0.00-0.00) 0.00 (0.00-0.00) Fat 0.035(0.023-0.054) 0.00 (0.00-0.00) Eggs1 5.42 (2.93-8.99)2 0.115(0.050-0.187)2 Excreta1 - 23.87 (13.01-35.65) 1 Figures are averages from groups of five chickens. 2 Highest individual results for one egg were 0.080 at 10 mg/kg feeding level and 0.377 mg/kg at the 50 mg/kg level. APPRAISAL New data on thiophanate-methyl residues in chicken tissues and eggs have been made available. Feeding levels well above the maximum rates which can be expected in practice were found not to give rise to any detectable residues in meat and fat of chickens. In eggs residues near to the limit of detection of conventional gas chromatographic methods of analysis were found, while liver and kidneys showed residues up to 0.45 mg/kg. The latter residues may be expected to be eliminated after withdrawal of the thiophanate-methyl feeding. However, the length of a withdrawal period cannot be estimated owing to lack of experimental details. RECOMMENDATIONS The recommendations made in 1973 are confirmed as being no longer temporary and amended as follows: MAXIMUM RESIDUE LIMITS Commodity Limit mg/kg* Meat and fat of chicken 0.02** * Measured as the sum of thiophanate-methyl and carbendazim and expressed as the latter. ** At or about the limit of determination. FURTHER WORK OR INFORMATION No information required or desirable other than items listed in 1973 (FAO/WHO, 1974a, p. 41) with exception of items 1 and 2 of desirable information. REFERENCES Kosaka, S., Fujino, A., Tanove, T. and Mitsui, B. (1975) The balance and metabolic study of thiophanate-methyl on rats. Unpublished report from the Nisso Institute for Life Science, Oiso, Kanagawa, submitted to WHO by Nippon Soda Co. Nippon Soda Company, Limited. (1975) Further work and information on thiophanate-methyl for FAO/WHO JMPR 1975, July. Thomas, J. A. and Schein, L. (1974) Effects of thiophanate and thiophanate-methyl on the male reproductive system of the mouse. Toxicol. Appl. Pharmacol., 30:129-133.
See Also: Toxicological Abbreviations Thiophanate-methyl (WHO Pesticide Residues Series 3) Thiophanate-methyl (Pesticide residues in food: 1977 evaluations) Thiophanate-methyl (Pesticide residues in food: 1995 evaluations Part II Toxicological & Environmental)