title: 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.
abstract: 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 DEHP.
authors.affiliation: Safety Assessment Department, Chugai Pharmaceutical Co., Ltd., Gotemba, Shizuoka, Japan. takairu@chugai-pharm.co.jp
authors.forename: Ryo
authors.initials: R
authors.lastname: Takai
authors.forename: Shuji
authors.initials: S
authors.lastname: Hayashi
authors.forename: Junpei
authors.initials: J
authors.lastname: Kiyokawa
authors.forename: Yoshika
authors.initials: Y
authors.lastname: Iwata
authors.forename: Saori
authors.initials: S
authors.lastname: Matsuo
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.forename: Keiji
authors.initials: K
authors.lastname: Mizoguchi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Chiba
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Deki
mesh_terms: D000818:Animals; D004051:Diethylhexyl Phthalate / Q000008:administration & dosage / Q000633:toxicity*; D004334:Drug Administration Schedule; D020964:Embryo Loss / Q000139:chemically induced; D004622:Embryo, Mammalian / Q000187:drug effects; D047108:Embryonic Development / Q000187:drug effects; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects*; D007564:Japan; D008297:Male; D006080:Ovarian Follicle / Q000187:drug effects / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000473:pathology; D010968:Plasticizers / Q000008:administration & dosage / Q000633:toxicity*; D011247:Pregnancy; D055818:Public-Private Sector Partnerships; D051381:Rats; D017207:Rats, Sprague-Dawley; D012958:Societies, Scientific; D017154:Stromal Cells / Q000187:drug effects / Q000473:pathology; D018675:Toxicity Tests / Q000379:methods*; D014617:Vacuoles / Q000187:drug effects / Q000473:pathology
chemical_list: D010968:Plasticizers; D004051:Diethylhexyl Phthalate