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

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概要

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• 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 300mg/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 ≥100mg/kg regardless of period of administration. The alterations of ovarian morphology observed at ≥100mg/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 ≥100mg/kg. The irregularities of estrous cycle observed in some animals at 30mg/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.

著者

• Okuda Yasuyuki

  日本製薬工業協会

• Okuda Yasuyuki

  Drug Safety Research Laboratories Eisai Co. Ltd.

• AOKI Toyohiko

  Drug Safety Research Laboratories, Eisai Co., Ltd.

• Aoki Toyohiko

  Drug Safety Research Laboratories Eisai Co. Ltd

• Inomata Akira

  Drug Safety Research Laboratories Eisai Co. Ltd.

• Okuda Yasuyuki

  Drug Safety & Disposition Research Laboratories Eisai Co. Ltd.

• Dodo Tetsushi

  Drug Safety Research Laboratories Eisai Co. Ltd.

• HOSOKAWA Satoru

  Drug Safety Research Lab., Eisai Co., Ltd.

• Hosokawa Satoru

  Drug Safety And Disposition

• MINESHIMA Hiroshi

  Drug Evaluation Committee, the Japan Pharmaceutical Manufacturers Association (JPMA)

• Taketa Yoshikazu

  Drug Safety Research Laboratories, Eisai Co., Ltd.

• Sugiyama Mayumi

  Drug Safety Research Laboratories, Eisai Co., Ltd.

• Sonoda Jiro

  Drug Safety Research Laboratories, Eisai Co., Ltd.

• Aoki Toyohiko

  Drug Safety Japan Global Drug Safety Biopharmaceutical Assessments Core Function Unit

• Sonoda Jiro

  Drug Safety Research Laboratories Eisai Co. Ltd.

• Sonoda Jiro

  Drug Safety Research Laboratories Eisai Co. Ltb.

• Taketa Yoshikazu

  Drug Safety Research Laboratories Eisai Co. Ltd.

• Sugiyama Mayumi

  Drug Safety Research Laboratories Eisai Co. Ltd.

• Mineshima Hiroshi

  Drug Safety Research Laboratories Eisai Co. Ltd.

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