This study was conducted to assess the potential for orally administered thiophenol to cause developmental toxicity. Human exposure to THIO occurs in industrial settings in the production of pesticides, polymers, and pharmaceuticals. THIO is approved for use as a food additive. It is also found in the 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 mated CD rats (25/group) on gestation days 6 through 15 at levels of 0, 20, 35, or 50 mg/kg/day. Animals were observed daily for clinical signs of toxicity. Body weight was recorded on the mornings of gd 0, 3, 6 through 15, 18 and 20. Food and water weights were recorded for the animals in each group on gd 0, 3, 6, 9, 12, 15, 18, and 20. All animals in the developmental toxicity study were killed on gd 20 and examined for maternal body and organ weights, implant status, fetal weight, sex, and morphological development.
Four animals in the high dose group died or were sacrificed in extremis. For animals surviving to scheduled necropsy on gd 20, pregnancy rates were 100%, 100%, 96% and 100% in the control through high exposure groups, respectively. Clinical signs consisted primarily of rooting behavior after gavage administration of THIO. The incidence of rooting behavior increased with increasing dose, and also with time across the dosing period. Thus, rooting was first noted on gd 11 (low dose), gd 8 (mid dose) and gd 6 (high dose), reaching a maximum incidence of 0% (control), 28% (low dose), 92% (mid dose) and 100% (high dose) by gd 15. This behavior was not observed after the treatment period was concluded. Maternal body weight was significantly depressed in the high dose group from gd 9 to termination on gd 20. Maternal body weight change was depressed in all treatment groups for the period of gd 6 to 9, and in the high dose group for gd 9 to 12, during the treatment and total gestational periods, and for corrected maternal weight gain. Maternal food consumption (g/kg/day) was decreased in all treated groups for gd 6 to 9, and in the high dose group on gd 9 to 12, and the treatment period (gd 6 to 15). Relative maternal food consumption increased in the high dose group during the post-treatment period (gd 15-18, 18-20, and 15-20). Maternal water consumption (g/kg/day) was higher in the high dose group compared to the control group on gd 6 to 9, 9 to 12, 12 to 15, 15 to 18, 18 to 20, during the treatment period (gd 6 to 15), and the post-treatment period (gd 15 to 20). Necropsy of the maternal animals revealed increased relative (percent body weight) and adjusted (for maternal weight) liver weight in the high dose group, but no change in right kidney weight. Gravid uterine weight was decreased at the high dose. THIO administration during gestation increased postimplantation loss, decreased the live litter size, decreased fetal body weight per litter, and increased the incidence of external malformations in the high dose group.
In summary, maternal toxicity, observed as maternal mortality, a persistent decrease in body weight and weight gain, and decrease in food consumption during the treatment period occurred at the high dose level of 50 mg/kg/day. Rooting behavior was observed in all THIO groups during the dosing period indicating an aversion to the dosing formulation. Rooting behavior showed a dose-related increase and an earlier onset with increasing dose. The lowest observed-adverse-effect-level was 20 mg/kg/day for maternal toxicity based upon minor, transient decreases in maternal weight gain and food consumption on gd 6 to 9. The maternal no observed adverse effect level could not be determined based upon the doses evaluated in this study. Developmental toxicity, observed as increased postimplantation death, decreased litter size, decreased fetal body weight, and an increase in the incidence of external malformations occurred at the high dose. Reduced female fetal body weight was observed at 35 mg/kg/day, suggesting a no observed adverse effect level for developmental toxicity of 20 mg/kg/day.