A developmental toxicity study of tretinoin administered topically and orally to pregnant Wistar rats

Background: Although it is well established that oral tretinoin produces embryofetal developmental toxicity in various laboratory animals, the toxic potential of topical tretinoin has not been clearly established. Objective: This study of tretinoin administration to pregnant Wistar rats was conducted to determine whether topical tretinoin is associated with adverse effects on reproductive function or embryofetal growth and development and to compare outcomes with topical and oral tretinoin. Methods: Topical and oral tretinoin (1 to 20 mg/kg and 1 to 10 mg/kg, respectively) or vehicles alone were administered on gestational days 6 through 16 and 15, respectively. Results: Topical tretinoin: After topical treatment, darns receiving 10 mg/kg daily or greater had severe local and systemic toxicity prompting discontinuation of tretinoin. At doses of 2.5 mg/kg or greater, dam weight gain and food consumption were significantly less than those of control dams. Offspring of dams receiving 5 mg/kg weighed significantly less, and offspring of dams receiving 2.5 mg/kg or greater had a significantly greater occurrence of supernumerary ribs compared with control offspring. Oral tretinoin: After oral treatment, in the absence of maternal toxicity, significantly more offspring of dams receiving 5 mg/kg or greater had supernumerary ribs, and offspring of the 10 mg/kg treatment group had a greater incidence of cleft palate than had control offspring. Conclusion: The local and systemic maternal toxicity found in association with supernumerary 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.