FAO Meeting Report No. PL/1965/10/1 WHO/Food Add./27.65 EVALUATION OF THE TOXICITY OF PESTICIDE RESIDUES IN FOOD The content of this document is the result of the deliberations of the Joint Meeting of the FAO Committee on Pesticides in Agriculture and the WHO Expert Committee on Pesticide Residues, which met in Rome, 15-22 March 19651 Food and Agriculture Organization of the United Nations World Health Organization 1965 1 Report of the second joint meeting of the FAO Committee on Pesticides in Agriculture and the WHO Expert Committee on Pesticide Residues, FAO Meeting Report No. PL/1965/10; WHO/Food Add./26.65 THIRAM Chemical name Bis(dimethylthiocarbamoyl) disulfide; tetramethylthiuramdisulfide. Synonyms TMTD, thiuramyl Empirical formula C6H12N2S4 Structural formula BIOLOGICAL DATA Biochemical aspects There are investigations on tetraethyl thiuram disulfide (TETD, Disulfiram), a homologue of thiram. Experiments on TETD (tagged with 35S) showed that in rats 80-95% of an oral dose in absorbed, elimination is delayed and a remarkable storage of 35S in the tissue occurs (mainly in the adrenals, liver and spleen) (Eldjarn, 1950). The compound was distributed in different tissues in a similar way to carbon disulfide. The liver is important in the detoxication of the compound. Animal tissues have been found to degrade TETD to diethyldithiocarbamate (Harzlick & Irvine, 1921), which in turn decomposed to carbon disulfide and diethylamine (Prickett & Johnston, 1953). Investigations on the fate of thiram in the digestive tract of ruminants revealed a similar degradation by micro-organism, which was not complete (Robbins & Kastelic, 1961); 4.0% of the ingested thiram appeared in the faeces and 1.5% in the urine. The metabolic fate of thiram absorbed into the body from the gastro-intestinal tract probably depends to some extent on the species of animal (Robbins & Kastelic, 1961). Thiuram disulfides can act as inhibitors of liver enzymes (Owens, 1953). Thiram acts in vivo in a similar way to tetraethyl thiuramdisulfide, i.e., it inhibits the acetaldehyde oxidation enzyme systems. Some authors believe that it is the first stage of alcohol metabolism, i.e, the oxidation to acetaldehyde that is mainly inhibited and only to a less extent the conversion of aldehyde into acetic acid (Hald & Jacobson, 1948; Thorn & Ludwig, 1962). Acute toxicity Animal Route LD50 mg/kg References body-weight Mouse Oral 1500-2000 Kirchheim, 1951 Mouse Intraperitoneal 250 Hald et al., 1952 Rat Oral 780-865 Lehman, 1951 Handbook of Toxicology, 1959 Rabbit Oral 210 Lehman, 1951 Handbook of Toxicology, 1959 In man oral doses of 0.5 g of Arasan (containing 75% thiram) were not toxic (Domingo, 1952). Short-term studies Fowl. 80 ppm of thiram in the diet of laying hens resulted in misshapen or soft-shelled eggs, retardation or even cessation of production of egg. Chicks showed retarded growth, reduced feed efficiency and increased mortality (Johnson et al., 1955). Thiram was toxic to chicks at 40 ppm (approximately equivalent to 6.8 mg/kg body-weight) in the diet and goslings at less than 150 ppm, but turkey poults tolerated 200 ppm. The symptoms of poisoning were leg deformities, weight loss, crooked and curled toes, enlarged hocks and some slipped tendons and spraddles (Waibel et al., 1957). Dog. Groups of 3 male dogs were fed diets containing 10, 50 and 200 ppm of thiram for one year. No abnormalities or effects on growth were observed and no gross or microscopic changes at any level (Fitzhugh, 1963). Long-term studies Groups each of 24 rats (12 males and 12 females) were given a diet containing 48 ppm of thiram over 3 generations. No effects on growth, reproduction, blood picture and mortality rate were found. No gross or histological changes were observed (van Esch, 1956). In another experiment, 12 female and 12 male rats given 200 ppm in the diet for 8 months showed no appreciable changes in growth and mortality rate, and 300 ppm for 65 weeks did not give rise to specific evidence of poisoning (Tollenaar, 1951). Groups of 24 rats, 12 females and 12 males, were fed diets containing 100, 300, 1000 and 2500 ppm of thiram. Rats with 300 and 1000 and 2500 ppm in the diet for 65 weeks showed weakness, ataxia and various degrees of paralysis; also histological changes (calcification in the brain stem and cerebellum and dystrophic changes in the leg muscles) were found, and at 2500 ppm there was an increased mortality rate (Lehman, 1952). Groups of 20 young rats were placed on diets containing 100, 300 and 500 ppm thiram for 2 years (Bär, 1959). Small reductions in the growth rate were seen at all concentrations. At concentrations of 300 and 500 ppm an increased mortality rate was seen, while at 500 ppm convulsions, thyroid hyperplasia (Griepentrog, 1962) and calcification in the cerebellum, hypothalamus and medulla oblongata were observed (Griepentrog, 1961). Comments on experimental studies reported There are long-term studies in rats, but no other species has been studied. Dose levels of 100 and 300 ppm in the diet of the rat had a questionable effect on the thyroid but at 48 ppm no changes were seen. Chicks appear to be especially susceptible to thiram. Before these results can be taken into account, confirmation is needed with detailed information; and because long-term reproduction studies with 3 generations of rats did not show any abnormalities in the litters, the rat was selected for evaluation. It is known that TMTD in a dose of 0.5 to 1.5 g per day can be taken by man for many weeks without ill-effect unless alcohol is consumed. EVALUATION Level causing no significant toxicological effect in animals Rat. 48 ppm in the diet, approximately equivalent to 2.5 mg/kg body-weight per day. Dog. 5 mg/kg body-weight. (Note. An effect was found in the chick at 6.8 mg/kg body-weight.) Estimate of acceptable daily intake for man 0-0.025 mg/kg body-weight. Further work desirable Biochemical studies. Extension of the experiments in chicken. REFERENCES Bär, F. (1959) International Union of Pure and Applied Chemistry Congress, München, September Domingo, A. F. (1952) Rev. Med. vet. (Caracas), 11, 335 Eldjarn, L. (1950) Scand. J. Clin. Lab. Invest., 2, 198 van Esch, G. J. (1956) Versl. Volksgezondh., 166 Fitzhugh, O. G. (1963) Personal communication Griepentrog, F. (1961) Arch. Psychiat. Nervenkr., 202, 412 Griepentrog, F. (1962) Beitr. Path. Anat., 126, 243 Hald, J. & Jacobson, E. (1948) Acta pharmacol. (Kbh.), 4, 305 Hald, J., Jacobson, E. & Larsen, V. (1952) Acta pharmacol. (Kbh.), 8, 329 Handbook of Toxicology (1959) vol. 3, Saunders, Philadelphia Hanzlick, P. J. & Irvine, A. (1921) J. Pharmacol. exp. Ther., 17, 349 Johnson, E. L. Waibel, P. E. & Pomeroy, B. S. (1955) Proc Amer. vet. med. Ass., 92, 322 Kirchheim, D. (1951) Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak., 214, 59 Lehman, A. J. (1951) Quart. Bull. Assoc. Food and Drug Officials U.S., 15, 122 Lehman, A. J. (1952) Quart. Bull. Assoc. Food and Drug Officials U.S. 16, 47-53,126-32 Owens, R. G. (1953) Contr, Boyce Thompson Inst., 17, 221 Prickett, C. S. & Johnston, C. D. (1953) Biochim. biophys. Acta, 12, 542 Robbins, R. C. & Kastelic, J. (1961) J. Agric. Food Chem., 9, 256 Thorn & Ludwig (1962) The dithiocarbamates and related compounds, Elsevier Mongraphs Tollenaar, F. D. (1951) Neth. Milk and Dairy J., 5, 46 Waibel, P. E., Johnson, E. L. & Pomeroy, B. S. (1957) Poultry Sci., 36, 697
See Also: Toxicological Abbreviations Thiram (ICSC) Thiram (FAO/PL:1967/M/11/1) Thiram (Pesticide residues in food: 1984 evaluations) Thiram (Pesticide residues in food: 1992 evaluations Part II Toxicology) Thiram (IARC Summary & Evaluation, Volume 53, 1991)