Collaborative work on evaluation of ovarian toxicity. 9) Effects of 2- or 4-week repeated dose studies and fertility study of di(2-ethylhexyl)adipate (DEHA) in female rats.

The present study was designed to confirm whether or not the ovarian toxicity of di(2-ethylhexyl)adipate (DEHA), which is known to have effects on female fertility, could be evaluated by the new method of histopathological examination of the ovaries in repeated dose toxicity. DEHA was orally administered to Crl:CD(SD) female rats at the doses of 0, 200, 1,000 and 2,000 mg/kg for 2 or 4 weeks in repeated dose toxicity study and for 2 weeks before mating, throughout mating and until Gestation Days 7 in female fertility. In the repeated dose toxicity studies, increase in atresia of large follicle, decrease in currently formed corpus luteum and follicular cyst were observed in the 1,000 mg/kg and above groups, suggesting that DEHA disturbed ovulation and large follicle growth. In the fertility study, a significant increase in mean estrus cycle length and post-implantation loss rate were observed in the 1,000 mg/kg and above groups, and a significant decrease in implantation rate and number of live embryos and a significant increase in pre-implantation loss rate were observed in the 2,000 mg/kg group. The histopathological changes of ovary observed in the repeated dose toxicity studies were correlated with the result that DEHA affected the estrus cycle in the female fertility study. In conclusion, a 2-week administration period is sufficient for detection of the ovarian toxicities following treatment with DEHA by new histopathological examination of the ovaries.