A DEVELOPMENTAL TOXICITY STUDY OF TRETINOIN ADMINISTERED TOPICALLY AND ORALLY TO PREGNANT WISTAR RATS

Background: Although it is well established that oral tretinoin produc es embryofetal developmental toxicity in various laboratory animals, t he toxic potential of topical tretinoin has not been clearly establish ed. Objective: This study of tretinoin administration to pregnant Wist ar rats was conducted to determine whether topical tretinoin is associ ated with adverse effects on reproductive function or embryofetal grow th and development and to compare outcomes with topical and oral treti noin. Methods: Topical and oral tretinoin (1 to 20 mg/kg and 1 to 10 m g/kg, respectively) or vehicles alone were administered on gestational days 6 through 16 and 15, respectively. Results: Topical tretinoin: A fter topical treatment, darns receiving 10 mg/kg daily or greater had severe local and systemic toxicity prompting discontinuation of tretin oin. At doses of 2.5 mg/kg or greater, dam weight gain and food consum ption were significantly less than those of control dams. Offspring of dams receiving 5 mg/kg weighed significantly less, and offspring of d ams receiving 2.5 mg/kg or greater had a significantly greater occurre nce of supernumerary ribs compared with control offspring. Oral tretin oin: After oral treatment, in the absence of maternal toxicity, signif icantly more offspring of dams receiving 5 mg/kg or greater had supern umerary ribs, and offspring of the 10 mg/kg treatment group had a grea ter incidence of cleft palate than had control offspring. Conclusion: The local and systemic maternal toxicity found in association with sup ernumerary ribs and low weights in the offspring at topical tretinoin doses of 2.5 and 5 mg/kg suggests that these developmental effects may be nonspecific or maternally mediated. Oral tretinoin at doses of 10 mg/kg, however, is clearly associated with embryofetal alterations in the Wistar rat.