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.