This study was conducted to assess the potential for orally administered thiophenol to cause developmental toxicity. Human exposure to THIO has the potential to occur in industrial settings in the production of pesticides, polymers, and pharmaceuticals. Furthermore, THIO is approved for use as a food additive, and has been found in effluents from the petroleum refining and pulp and paper industries. The lack of pertinent developmental toxicity data for THIO in the published literature prompted the initiation of this study. THIO (CAS No. 108-98-5) was administered by gavage in corn oil to artificially inseminated New Zealand White rabbits on gestation days 6 through 19 at levels of 0, 10, 30, or 40 mg/kg/day during the period of major organogenesis. A slightly higher dose (50 mg/kg/day) was excluded from the final study design due to excessive maternal toxicity. Maternal clinical signs, body weight, and food consumption were monitored at regular intervals from gd 0 to 30. On gd 30, fetuses were removed from the does and examined for evidence of THIO-induced developmental toxicity.
Two does died during the study, one each in the 10 and 30 mg/kg/day groups. No consistent clinical signs were observed during the course of the study. Maternal relative food consumption during the end of the dosing period tended to be lower in the 30 and 40 mg/kg/day groups, but overall food consumption during and after the dosing period was comparable to controls in all THIO groups. Maternal body weight gain displayed transient decreases which were confined to gd 12 to 15 within the dosing period and limited to the 30 and 40 mg/kg/day groups. Overall maternal body weight gain during the dosing period (gd 6 to 19) tended to be lower in the THIO-treated does, but maternal body weights in the THIO groups were comparable to control values at all gestational ages.
Necropsy of the maternal animals on GID 30 indicated no THIO-related effects on gravid uterine weight or absolute or relative (percent body weight) liver or right kidney weights. The number of implantation sites/litter and the percent preimplantation loss/litter was comparable in all groups. THIO administration did not adversely affect average live litter size, sex ratio, or average fetal body weight/litter. Morphological evaluation of the fetuses showed no THIO-related increases in the incidence of malformations (external, visceral, or skeletal) or variations.
In summary, 40 mg/kg/day THIO did not adversely affect the growth, viability, or morphological development of the offspring. Thus, the no observed adverse effect level for developmental toxicity in this study was greater than or equal to 40 mg/kg/day; the lowest observed adverse effect level could not be determined at the doses evaluated in this study. The NOAEL for maternal toxicity was 10 mg/kg/day. Toxic effects at 30 and 40 mg/kg/day were minor and transient so that the evidence of toxicity was equivocal. However, a slightly higher dose (50 mg/kg/day) was found to be excessively toxic resulting in maternal morbidity and mortality. Thus, the dose-range evaluated in this study was appropriately selected, and evaluation of developmental toxicity at doses above 40 mg/kg/day was precluded by excessive maternal toxicity.