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.



    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).


    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).


         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.


    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.


         0-0.08 mg/kg bw.



    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.


         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


         The recommendations made in 1973 are confirmed as being no longer
    temporary and amended as follows:


         Commodity                     Limit

         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.


         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.


    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)