Collaborative work on evaluation of ovarian toxicity. 16) Effects of 2 or 4 weeks repeated dose studies and fertility study of Chlorpromazine hydrochloride in rats.
In order to examine potential ovarian toxicity in 2 weeks or 4 weeks repeated-dose studies and a fertility study, chlorpromazine hydrochloride (CPZ) was administered orally to Crl:CD(SD) female rats at dosage levels of 0, 3, 10 and 30 mg/kg/day. In the repeated-dose studies, ovarian weights were decreased at > or = 10 mg/kg in the 4 weeks study and an increase in large atretic follicles was observed histopathologically at > or = 3 mg/kg and > or = 10 mg/kg in the 2 and 4 weeks studies, respectively. In addition, decreased uterine weights and/or atrophic findings in the uterus and vagina at 30 mg/kg and > or = 10 mg/kg, mucification in the vaginal epithelium and alveolar hyperplasia in the mammary gland at > or = 3 mg/kg and > or = 10 mg/kg were seen in the 2 and 4 weeks studies, respectively. Irregular estrous cycles were seen at > or = 3 mg/kg and > or = 10 mg/kg in the 2 and 4 weeks studies. The no-observed-adverse-effect level (NOAEL) for the 2 and 4 weeks studies was considered to be less than 3 mg/kg and 3 mg/kg, respectively. The fertility study with dosing from 2 weeks before mating to day 6 of gestation showed irregular estrous cycles at > or = 10 mg/kg and prolonged copulatory intervals and a reduced fertility index at 30 mg/kg; the NOAEL was therefore considered to be 3 mg/kg, which was higher than that in the 2 weeks study. These results showed that oral CPZ treatment induced ovarian toxicity with 2 weeks or longer treatment and changed the fertility parameters and was therefore concluded that a 2 weeks administration period is adequate to detect the ovarian toxicity of CPZ.
Izumi
Yuko
Y
Development Research Center, Takeda Pharmaceutical Company Limited, Yodogawa-ku, Osaka, Japan. Izumi_Yuuko@takeda.co.jp
Watanabe
Takeshi
T
Awasaki
Naoko
N
Hikawa
Kenji
K
Minagi
Takashi
T
Chatani
Fumio
F
D000284:Administration, Oral; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001763:Blepharoptosis / Q000139:chemically induced / Q000473:pathology; D002746:Chlorpromazine / Q000008:administration & dosage / Q000633:toxicity*; D004334:Drug Administration Schedule; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005298:Fertility / Q000187:drug effects*; D007564:Japan; D008297:Male; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000473:pathology; D009043:Motor Activity / Q000187:drug effects; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D006080:Ovarian Follicle / Q000187:drug effects / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000473:pathology; D011247:Pregnancy; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D055818:Public-Private Sector Partnerships; D051381:Rats; D017207:Rats, Sprague-Dawley; D012958:Societies, Scientific; D018675:Toxicity Tests / Q000379:methods*; D014599:Uterus / Q000187:drug effects / Q000473:pathology; D014621:Vagina / Q000187:drug effects / Q000473:pathology; D015430:Weight Gain / Q000187:drug effects
D014150:Antipsychotic Agents; D018809:Proliferating Cell Nuclear Antigen; D002746:Chlorpromazine