Subchronic toxicity of all-trans-retinoic acid and retinylidene dimedone in Sprague-Dawley rats.
Sprague-Dawley rats received daily oral gavage doses of either 2-retinylidene-5,5-dimethyl-1,3-cyclohexanedione (retinylidene dimedone; 14, 50, 150, or 330 mg/kg) or all-trans-retinoic acid (1, 4, 14, or 50 mg/kg) for 13 weeks. Rats given 50 mg/kg of all-trans-retinoic acid developed numerous long-bone fractures and became moribund during the third week of the study. Those receiving lower dosages survived until scheduled termination, but the 14 mg/kg group showed clear signs of retinoid intoxication including growth depression, anemia, serum alkaline phosphatase elevation, bone fracture, and testicular degeneration. Exposure to retinylidene dimedone did not result in any treatment-related deaths, growth depression, or histopathologic lesions, even at the highest dose, 300 mg/kg. Animals given this dosage exhibited mild anemia, equivocal evidence of bone fracture, but no increase in alkaline phosphatase activity. Retinylidene dimedone appears to be considerably less toxic than all-trans-retinoic acid.
D000818:Animals; D001769:Blood / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001847:Bone Diseases / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D005260:Female; D050723:Fractures, Bone / Q000139:chemically induced; D008297:Male; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D012176:Retinoids / Q000633:toxicity*; D014212:Tretinoin / Q000633:toxicity*
D012176:Retinoids; D014212:Tretinoin; C023048:retinylidene dimedone