Collaborative work on evaluation of ovarian toxicity. 11) Two- or four-week repeated-dose studies and fertility study of ethylene glycol monomethyl ether in female rats.
The objective of this study was to determine the optimal period of administration for detection of ovarian toxicity in rat repeated-dose toxicity studies. A well-known ovarian toxicant, ethylene glycol monomethyl ether (EGME), was administered to female rats at dose levels of 0, 30, 100, or 300 mg/kg for 2 or 4 weeks (repeated-dose toxicity studies). The same doses were administered to female rats for 2 weeks prior to mating, during mating, and until Day 6 of pregnancy (fertility study). In the repeated-dose toxicity studies, continuous diestrus was observed at > or = 100 mg/kg regardless of period of administration. The alterations of ovarian morphology observed at > or = 100 mg/kg after 2 or 4 weeks of administration were characterized by hypertrophy of the corpora lutea with decreased cellular debris indicating apoptosis, and increased proliferating cell nuclear antigen (PCNA)-negative large atretic follicles. The finding that newly-formed basophilic corpora lutea were scarce in affected animals exhibiting continuous diestrus suggested suppression of ovulation due to hypertrophic corpora lutea. In the fertility study, irregular estrous cycles, prolonged mating periods, lower pregnancy rates and decreased corpora lutea of pregnancy were observed at > or = 100 mg/kg. The irregularities of estrous cycle observed in some animals at 30 mg/kg were minimal. The ovarian histopathological changes in repeated-dose toxicity studies correlated well with impairment of female fertility found in the fertility study. It is concluded that a repeated-dose toxicity study with a treatment period for 2 weeks or longer is sufficient for evaluation of ovarian toxicity induced by EGME.
Dodo
Tetsushi
T
Drug Safety Research Laboratories (Kakamigahara), Eisai Co., Ltd., Kakamigahara-shi, Gifu, Japan. t-dodo@hhc.eisai.co.jp
Taketa
Yoshikazu
Y
Sugiyama
Mayumi
M
Inomata
Akira
A
Sonoda
Jiro
J
Okuda
Yasuyuki
Y
Mineshima
Hiroshi
H
Hosokawa
Satoru
S
Aoki
Toyohiko
T
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D003338:Corpus Luteum / Q000187:drug effects / Q000473:pathology; 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; D005026:Ethylene Glycols / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D005298:Fertility / Q000187:drug effects*; D007564:Japan; D008297:Male; D006080:Ovarian Follicle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010053:Ovary / Q000187:drug effects* / Q000473:pathology; D010060:Ovulation / Q000187:drug effects; D011247:Pregnancy; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D055818:Public-Private Sector Partnerships; D051381:Rats; D017207:Rats, Sprague-Dawley; D012958:Societies, Scientific; D012997:Solvents / Q000008:administration & dosage / Q000633:toxicity*; D018675:Toxicity Tests / Q000379:methods*; D015430:Weight Gain / Q000187:drug effects
D015415:Biomarkers; D005026:Ethylene Glycols; D018809:Proliferating Cell Nuclear Antigen; D012997:Solvents; C005219:methyl cellosolve