THIODICARB

    EXPLANATION

         Thiodicarb was evaluated for acceptable daily intake by the 1985
    Joint Meeting (Annex 1, FAO/WHO, 1986a), at which time a temporary ADI
    of 0 - 0.01 mg/kg b.w. was established. A toxicology monograph was
    published (Annex 1, FAO/WHO, 1986c). Data designed to satisfy the
    requirements of the 1985 Joint Meeting were submitted for
    consideration by the present Meeting, and these data are summarized in
    this monograph addendum.

    EVALUATION FOR ACCEPTABLE INTAKE

    BIOLOGICAL DATA

    Toxicological studies

    Special study on teratogenicity

    Rabbits

         Thiodicarb was administered orally in 0.5% carboxymethylcellulose
    to 4 groups of 22 artificially-inseminated New Zealand white rabbits
    once daily on gestation days 6 through 19, inclusive. Dosage levels
    were 0, 5, 20, and 40 mg/kg b.w./day. Throughout gestation, all
    females were observed twice daily for toxicity, and body weights and
    food consumption were recorded at appropriate intervals. On gestation
    day 29, all surviving females were sacrificed for the scheduled
    caesarean sections. All fetuses were weighed, sexed, and examined for
    external, skeletal, and soft-tissue anomalies and developmental
    variations.

         Body-weight gain and food consumption were inhibited during the
    treatment and post-treatment periods in the 40 mg/kg b.w./day dose
    group, primarily during the initial 6 days of compound administration.
    No clinical signs of maternal toxicity or embryo-/fetotoxicity were
    observed at any dose levels. Maternal body-weight gain and food
    consumption were not adversely affected at dose levels of 5 or
    20 mg/kg b.w./day. An evaluation of the types and frequency of fetal
    anomalies and developmental variations did not indicate a teratogenic
    response in this study (Rodwell, 1986).

    Short-term study

    Dogs

         Four groups of 6 beagle dogs/sex/dose level were administered
    thiodicarb in the diet at levels of 0, 164, 487, or 1510 ppm (equal to
    4.4 and 4.5, 12.8 and 13.8, and 38.3 and 39.5 mg/kg b.w./day for males
    and females, respectively) for 1 year. Criteria evaluated for compound
    effects included mortality, body-weight gain, appearance and
    behaviour, and food and compound consumption. Clinical laboratory
    studies, ophthalmologic examinations, gross necropsy findings,
    organ-weight data, and histopathology were performed.

         No effects were observed on mortality, clinical signs,
    body-weight gain, or food or water consumption. Slight decreases in
    erythrocyte count, haematocrit, and haemoglobin were noted in the
    high-dose males and females at all 3 observation intervals in the
    study. Erythrocyte counts and haemoglobin values in males were
    slightly lower than control values at weeks 13 and 26.

         Significant plasma, red blood cell, and brain cholinesterase
    activity inhibition (> 25%) occurred in the high-dose animals during
    the course of the study. Red blood cell cholinesterase activity
    inhibition exceeding 25% also occurred in the mid-dose males (27%) and
    females (28%) at week 13. No other changes were noted that would
    suggest a compound-related effect on any other measured clinical
    pathology parameter.

         Liver and spleen weights of the treated females were increased in
    a dose-related manner when compared to the controls. These increases
    were noted also in the organ/body- and organ/brain-weight ratios in
    females, where statistical significance, compared to controls, was
    noted at the high dose only. These changes were not seen in the males.
    No other changes were notes that would suggest a compound-related
    effect in the other organ weight data, or in the ophthalmology, gross
    pathology, or histopathology data.

         Based on these observations, the NOEL of thiodicarb in beagle
    dogs in this study was 487 ppm, equal to an intake of 12.8 mg/kg
    b.w./day for males and 13.8 mg/kg b.w./day for females (Hamada, 1986).

    COMMENTS

         The 1-year dog study requested by the 1985 Joint Meeting has been
    received and reviewed. A NOEL of 487 ppm was established. The previous
    Meeting had also requested information on a possible effect on
    body-weight gain noted in a rat teratology study. A study in rabbits
    was submitted to the present Meeting, which failed to confirm the
    observations in rats. The Meeting therefore concluded that the
    available data permitted the allocation of a full ADI.

    LEVEL CAUSING NO TOXICOLOGICAL EFFECT

         Rat:      60 ppm in the diet, equivalent to 3 mg/kg b.w./day.
         Dog:      487 ppm in the diet, equal to 12.8 mg/kg b.w./day in
                   males. and 13.8 mg/kg b.w./day in females.

    ESTIMATE OF ACCEPTABLE DAILY INTAKE FOR MAN

         0 - 0.03 mg/kg b.w.

    STUDIES WHICH WILL PROVIDE INFORMATION VALUABLE FOR THE CONTINUED
    EVALUATION OF THE COMPOUND

         Observations in humans.

    REFERENCES

    Hamada, N. One-year feeding study in dogs with thiodicarb technical.
    1986      Project No. 21100-126. Unpublished report from Hazleton
              Laboratories, Inc., Falls Church, VA, USA. Submitted to WHO
              by Union Carbide Agricultural Products Company, Inc.,
              Research Triangle Park, NC, USA.

    Rodwell, D.E. A teratology study in rabbits with thiodicarb, Project
    1986      No. WIL-95002. Unpublished report from WIL Research
              Laboratories, Inc. Submitted to WHO by Union Carbide
              Agricultural Products Company, Inc., Research Triangle Park,
              NC, USA.
    

    See Also:
       Toxicological Abbreviations
       Thiodicarb (Pesticide residues in food: 1985 evaluations Part II Toxicology)
       Thiodicarb (JMPR Evaluations 2000 Part II Toxicological)