Comparative subacute toxicity of all-trans- and 13-cis-retinoic acid in Swiss mice

Swiss mice were treated once a day for 21 days with all-trans- or 13-cis-retinoic acid administered ip or po. The LD50 of all-trans-retinoic acid was 31 mg/kg ip and 1100 mg/kg po; the LD50 of 13-cis-retinoic acid was 140 mg/kg ip and 26,000 mg/kg po. However, after 21 consecutive days of treatment, fractured bones were observed in treated animals at all tested doses of 13-cis-retinoic acid and at doses of all-trans-retinoic acid higher than 3 mg/kg ip or 10 mg/kg po. By either route of administration, 13-cis-retinoic acid produced the same number and incidence of fractures at doses three to five times that of all-trans-retinoic acid administered by the same route. Treatment with 13-cis-retinoic acid ip resulted in a dose-related decrease in the red blood cell count, but ip administration of all-trans-retinoic acid did not. The concentration of albumin, the serum transport protein for these compounds, was changed only after low oral doses of all-trans-retinoic acid. The appearance of fractured bones was not always associated with elevated plasma alkaline phosphatase concentrations. Based on these parameters of toxicity, 13-cis-retinoic acid was less toxic than all-trans-retinoic acid.