title: Repeated 28-day oral toxicity study of ketoconazole in rats based on the draft protocol for the "Enhanced OECD Test Guideline No. 407" to detect endocrine effects.
abstract: We performed a 28-day repeated-dose toxicity study of ketoconazole, a widely used an antimycotic drug, based on the draft protocol of the "Enhanced OECD Test Guideline 407" (Enhanced TG407) to investigate whether ketoconazole has endocrine-mediated properties according to this assay. Seven-week-old SD rats were administered with ketoconazole daily by oral gavage at doses of 0, 6.25, 25 or 100 mg kg(-1) day(-1) for at least 28 days. The ketoconazole-treated male rats showed reduction of epididymis and accessory sex organ weights, spermatid retention in the seminiferous tubules, decrease of testosterone and increases of estradiol, luteinizing hormone (LH) and follicular stimulating hormone (FSH). A prolongation of the estrous cycle and increases of estradiol, LH and FSH were observed in the treated female rats. Thyroxin and triiodothyronine were decreased and thyroid-stimulating hormone was increased in both sexes; however, there were no compound-related microscopic lesions in the thyroid gland or changes in the thyroid weight. The endocrine-related effects of ketoconazole could be detected by the parameters examined in the present study based on the Organization for Economic Cooperation and Development (OECD) protocol, suggesting that the Enhanced TG407 protocol should be a suitable screening test for detection of endocrine-mediated effects of chemicals.
authors.affiliation: Endocrine Toxicology Division, National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul 122-704, Korea. jaehoshin@hanmir.com
authors.forename: Jae-Ho
authors.initials: JH
authors.lastname: Shin
authors.forename: Hyun Ju
authors.initials: HJ
authors.lastname: Moon
authors.forename: Il Hyun
authors.initials: IH
authors.lastname: Kang
authors.forename: Tae Sung
authors.initials: TS
authors.lastname: Kim
authors.forename: In Young
authors.initials: IY
authors.lastname: Kim
authors.forename: In Sook
authors.initials: IS
authors.lastname: Park
authors.forename: Hyung Sik
authors.initials: HS
authors.lastname: Kim
authors.forename: Eui Bae
authors.initials: EB
authors.lastname: Jeung
authors.forename: Soon-Young
authors.initials: SY
authors.lastname: Han
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D052244:Endocrine Disruptors / Q000008:administration & dosage / Q000633:toxicity*; D004703:Endocrine System / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004822:Epididymis / Q000187:drug effects / Q000473:pathology; D004958:Estradiol / Q000097:blood; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D017408:Guidelines as Topic; D007654:Ketoconazole / Q000008:administration & dosage / Q000633:toxicity*; D007986:Luteinizing Hormone / Q000097:blood; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D012671:Seminiferous Tubules / Q000187:drug effects / Q000473:pathology; D013091:Spermatogenesis / Q000187:drug effects; D013739:Testosterone / Q000097:blood; D013963:Thyroid Hormones / Q000097:blood; D013997:Time Factors; D018675:Toxicity Tests / Q000592:standards*
chemical_list: D000935:Antifungal Agents; D052244:Endocrine Disruptors; D013963:Thyroid Hormones; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D007654:Ketoconazole