SP 1 - SP 22 , 2009 SP 1 Coltaborative work on evaluation of ovarian toxicity by repeated - dose and fertility studies in female rats

The National Institute ofHealth Sciences (NIHS) and 18 pharmaceutical companies of the Japan Pharrnaceutical Manufacturers Association (JPMA) have conducted a validation study intended to evaluate whether a 2-week repeated general toxicity period with histopathological examination is suencient to detect ovarian toxicity or not. The current repeated dose general toxicity study is considered to be insuMcjent in terms of evaluatjng female reproductive function due to a lack of evidence indicating that it is adequate, Evaluation ofovarian toxicity by eomprehensive histopathological examination of the female reproductive organs based on the underlying morphology ofa norrna] cycle ofthe reproductive tract including the ovary and additional inirnunohistochemical sta ning with proliferative cell nuclear antigen (PCNA) to identify small fo11icles may be a good tool to assess female reproductive function, ln the co][aborative study, 2or 4-week repeated dose toxicity studies with ovarian histopathological examinations were ¢ onducted. A female fenility study was also conducted to cornpare the results with those of the ovarian histopathological findings. A total of 17 test substances were evaluatcd and categorized into hormone analogues, primordial fo11icle damaging agents, metabolite imbalanee indueers, and endocrine imba]ance inducers. Based on the results, ovarian toxicity could be detected by a carefu1 histopatholgical examination. A 2-weck dosing period may be suencient for the evaluation ofovarian toxicity, except for cytotoxic compounds such as alkylating agents, The pathological findings ofovarian toxicity (decreases in foIlicles, increases in atretic fo1]jcles, increases in currcntly formed corpora lutea, etc) rcfiected thc female fertility parameters (irregular estrous cycle, pre-implantation less),