A DEVELOPMENTAL TOXICITY STUDY OF TRETINOIN EMOLLIENT CREAM (RENOVA) APPLIED TOPICALLY TO NEW-ZEALAND WHITE-RABBITS

Background: Embryofetal developmental toxicity associated with oral ad ministration of vitamin A analogs has led to concern about risks from topical application. Objective: This study was conducted to evaluate t he potential developmental toxicity of tretinoin emollient cream when applied to the skin of pregnant New Zealand white rabbits during organ ogenesis (gestational days 7 through 19). Methods: Twenty rabbits each were randomly assigned to a control group (group I) or to receive veh icle (group II) or tretinoin emollient cream topically at dosages of 1 0 (0.05 mg/kg, group III) or 100 (0.5 mg/kg*, group IV) times that us ed clinically in humans. Does and fetuses were examined for tretinoin- induced toxic effects, and maternal plasma tretinoin and metabolite le vels were measured. Results: The rate of abortion was increased signif icantly in does in group IV (p less than or equal to 0.01) compared wi th the control group. Dosage-dependent increases in incidence and seve rity of skin reactions occurred in groups administered the vehicle and the two dosages of tretinoin. Does in groups III and IV had clinical and necropsy observations that were considered direct or indirect effe cts of tretinoin administration, persistent weight loss, and reduced f eed consumption. Maternal endogenous plasma tretinoin levels were belo w the lower Limit of quantitation of 5 ng/ml and were not significantl y altered with treatment. Group IV had significantly reduced mean feta l body weight (p less than or equal to 0.01) and a greater frequency o f resorptions compared with group I. Although external, visceral, or s keletal alterations occurred at significantly greater levels in group III, they were unrelated to tretinoin administration because the fetal incidences were not dosage dependent, and the litter incidence did no t significantly differ from the control group values. Conclusion: Mate rnally toxic dosages of tretinoin were associated with an increased in cidence of abortions and resorptions and reduced fetal body weight, tw o end points of developmental toxicity. Consistent with the absence of detectable tretinoin plasma levels, however, no changes in fetal morp hology were attributable to tretinoin administration. The milligrams per kilogram dosage refers to the amount of active ingredient (tretino in). The 0.05 mg/kg and 0.5 mg/kg groups were treated with 0.005% and 0.05% wt/wt tretinoin emollient cream formulation. The 0.05% tretinoin emollient cream is the Renova clinical formulation. The 10 and 100 ti mes clinical multiples refer to Renova clinical multiples and are base d on a 50 kg adult patient's applying 500 mg of 0.05% tretinoin emolli ent cream formulation daily to yield a clinical dosage of 0.005 mg/kg.