Collaborative work on evaluation of ovarian toxicity 10) Two- or four-week repeated dose studies and fertility study of di-(2-ethylhexyl) phthalate (DEHP) in female rats

The main purpose of this collaborative work is to determine the optimal administration period required to detect toxic effects in evaluation of ovarian morphological changes in repeated-dose toxicity studies. To assess the morphological and functional changes induced in the ovaries by di-(2-ethylhexyl) phthalate (DEHP), two repeated-dose toxicity studies (repeated dose for 2 or 4 weeks) of DEHP administrated to female rats at dose levels of 0, 300, 1,000 and 3,000 mg/kg were conducted in collaboration with a female fertility study at the same dosages from 2 weeks prior to mating to Day 7 of pregnancy. Histopathology of the ovaries in both repeated-dose toxicity studies showed vacuolation of stromal cells in the groups receiving 300 mg/kg or more and an increase of large atretic follicles in groups at 1,000 mg/kg or more. In the 4-week study, a decrease in new corpora lutea was observed in the 3,000 mg/kg group. In the female fertility study, the 3,000 mg/kg group showed prolongation of the mean estrous cycle and irregular estrous cycles. Cesarean section revealed a decrease of pregnancy rate in the 3,000 mg/kg group. No effects on fertility or early embryonic development were found in groups at 1,000 mg/kg or less. These findings indicate that histopathological changes in the ovary are important endpoints for the evaluation of drugs which induce ovarian damage. In conclusion, for a repeated-dose toxicity study, a 2-week administration period is sufficient to detect ovarian toxicity caused by DEAR