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.
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.
Shin
Jae-Ho
JH
Endocrine Toxicology Division, National Institute of Toxicological Research, Korea Food and Drug Administration, Seoul 122-704, Korea. jaehoshin@hanmir.com
Moon
Hyun Ju
HJ
Kang
Il Hyun
IH
Kim
Tae Sung
TS
Kim
In Young
IY
Park
In Sook
IS
Kim
Hyung Sik
HS
Jeung
Eui Bae
EB
Han
Soon-Young
SY
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*
D000935:Antifungal Agents; D052244:Endocrine Disruptors; D013963:Thyroid Hormones; D013739:Testosterone; D004958:Estradiol; D007986:Luteinizing Hormone; D005640:Follicle Stimulating Hormone; D007654:Ketoconazole