DITHIOCARBAMATES       JMPR 1974

    Explanation

         The dimethyl and the ethylene-bis-dithiocarbamates were evaluated
    by the Joint Meeting in 1965, 1967 and 1970 (FAO/WHO 1965, 1968,
    1971). These meetings listed requirements for information on methods
    of analysis, pathways of breakdown or metabolism in plants and in
    animals, studies on possible carcinogenic effects, effects on thyroid
    function, effects on reticuloendothelial and haematopoietic systems
    and effects on reproductive physiology. Much of the latter information
    had not become available for consideration at the Meeting.

    EVALUATION FOR ACCEPTABLE DAILY INTAKE

         For the dimethyldithiocarbamates (ferbam, thiram, and ziram), new
    data showing a teratogenic effect with ziram and thiram and
    chromosomal aberrations with ziram (Antonovic et al., 1971) have
    become available. Ziram, thiram and ferbam have also been shown to be
    nitrosated in vitro and in vivo and may therefore be capable of
    forming nitrosamines (IARC Monograph, 1974).

         In the case of the ethylenebisdithiocarbamates (mancozeb, maneb,
    nabam, and zineb), reports have been received that these fungicides
    may be teratogenic (Petrova-Vergieva and Ivanova-Chemishanska, 1973).
    Furthermore, ethylenethiourea, a major breakdown and metabolic product
    of these pesticides (FAO/WHO, 1971; Truhaut et al., 1973), is
    teratogenic, mutagenic, and produces thyroid carcinomas and liver
    tumours in mice and rats (Graham et al., 1973; Sram and Benes, 1974;
    IARC Monograph, 1974). There has been a suggestion that with prolonged
    oral administration zineb, maneb, and ziram induce pathological
    alterations resembling precancerous changes in the lung of rats
    (Antonovic et al., 1971).

         The Meeting recognized that current needs for these pesticides in
    food production entail their extensive use. Until methods of residue
    analysis that distinguish between the two groups of dithiocarbamates
    come into general use, the Meeting decided to allocate a new temporary
    ADI to all dithiocarbamate fungicides.

         On the basis of the above findings it was decided to lower the
    value of the temporary ADI. The new lower temporary ADI of 0.005 mg/kg
    is based on a larger safety margin from the no-effect levels specified
    by the 1970 Meeting, (FAO/WHO, 1971). In extending the temporary ADI
    for the dithiocarbamates until 1977, the Meeting recommended that the
    temporary ADIs should be withdrawn if required data are not
    forthcoming.

    RESIDUES IN FOOD AND THEIR EVALUATION

         The Meeting examined available information on various
    ethylenebisdithiocarbamate fungicides but data on compounds other than
    mancozeb were lacking. Results of numerous studies on mancozeb were
    evaluated and a separate monograph was prepared.

         Methods of analysis are available which determine total
    ethylenebisdithiocarbamates (EBDTCs) but do not distinguish between
    them. Methods which determine the ethylenediamine moiety are preferred
    since these distinguish EBDTC residues from dimethyldithiocarbamate
    (DMDTC) residues. A separate determination of the metabolite
    ethylenethiourea (ETU) is necessary. The suitability of available
    methods is discussed in detail in the monograph on mancozeb.

         Residue limits were recommended for mancozeb on a number of raw
    agricultural commodities. In the absence of the necessary information
    on the level and nature of residues resulting from approved uses of
    maneb, zineb, metiram etc. however, the Meeting was unable to
    recommend residue limits for these pesticides. Further information on
    these compounds is required.

    FURTHER WORK OR INFORMATION

    REQUIRED (by 1977)

    1.   Residue studies in which both the ethylenediamine moiety and
         ethylenethiourea (ETU) are separately determined.

    2.   Further studies on the fate of residues during the preparation
         and processing of foods with particular reference to their
         conversion to ETU.

    REFERENCES

    Antonovic, E.A. et al. (1971) [Toxicity of dithiocarbamates and their  
    fate in warm-blooded animals.] In: Proceedings on Toxicology and
    Analytical Chemistry of Dithiocarbamates, Dubrovnik, p. 1-143.

    FAO/WHO.  (1965) Evaluation of the toxicity of pesticide residues in
    food. FAO Meeting Report No. PL/1965/10/1; WHO/Food Add./27.65.

    FAO/WHO. (1968) 1967 Evaluations of some pesticide residues in food.
    FAO/PL/1967/M/11/1; WHO/Food Add./68.30.

    FAO/WHO. (1971) 1970 Evaluations of some pesticide residues in food.
    AGP/1970/M/12/1; WHO/Food Add./71.42.

    IARC. (1974) IARC monographs on the evaluation of carcinogenic risk of
    chemicals to man. Vol. 7, Some anti-thyroid and related substances,
    nitrofurans and industrial chemicals.

    Petrova-Vergieva, T. and Ivanova-Chemishanska, L. (1973) Assessment of
    the teratogenic activity of dithiocarbamate fungicides. Food Cosmet.
    Toxicol., 11:239-244.

    Truhaut, R. et al. (1973) C.R. Acad. Sci. (Paris), CD1276, 229. 

    Graham, S.L., Hansen, W.H., Davis, K.J. and Carleene, H.P. (1973)
    Effects of one-year administration of ethylenethiourea upon the
    thyroid of the rat. J. agr. Food Chem., 21:324-329.

    Sram, R.J. and Benes, V. (1974) Observations. (Unpublished).
    

    See Also:
       Toxicological Abbreviations
       Dithiocarbamates (Pesticide residues in food: 1980 evaluations)
       Dithiocarbamates (Pesticide residues in food: 1983 evaluations)