FAO Meeting Report No. PL/1965/10/1
    WHO/Food Add./27.65


    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

    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


    Chemical name

           Bis(dimethylthiocarbamoyl) disulfide;


           TMTD, thiuramyl

    Empirical formula


    Structural formula



    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,

    Acute toxicity

    Animal        Route        LD50 mg/kg    References

    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


    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

    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.


    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,

    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)