A COMPARISON OF THE TOXICITIES OF 4-(ETHOXYCARBOPHENYL) RETINAMIDE AND SOME OTHER RETINOIDS

Since 4-(ethoxycarbophenyl) retinamide (abbr. RI)was shown to possess cancer chernopreventive activity in vivo, a comparative study of the toxicities of RI and some other retinoids was carried out. Acute toxicity tests in mice indicated that retinoic acid (5 mM/kg) may induce CNS toxicity, hair loss and death of part of the animals, but these were not seen with RI (25 mM/kg). Comparison of the subacute toxicity in mice was also studied for 2 weeks with two levels of daily oral dose. Experimental evidences indicated that retinoic acid, Ro 10-9359 and Ro 11-1430 at doses of 0.5 mM/kg caused serious hypervitaminosis A symptoms such as weight loss, hair loss and bone fractures. These toxic effects were not seen for Ro 43780 and 4-(hydroxycarbophenyl) retinamide (abbr. RII) at 1.5 mM/kg, but both inhibiied the increase of body weight. However, RII caused liver damage and a decrease of spermatozoa. Compound RI (2 mM/kg) caused neither hypervitaminosis A nor influence the increase of body weight. The results of subacute toxicity tests of RI and retinoic acid in rats were similar to the results obtained in mice. Chronic toxicity studies of RI and retinoic acid in mice were carried out for 3 months with daily oral administration. Differences were observed in the weight gain between the treated and control mice for RI (300mg/kg) and retinoie acid (60 mg/kg). In chronic toxicity tests of RI in dos at 60 mg/kg×2 months plus 240 mg/kg×1 month, no abnormality was observed beside occasional anorexia. These results indicate that the acute toxicity of compound RI is very low and that the subacute and chronic toxicity of RI in mice and rats are much lower than those of the other retinoids by oral administration.