Studies on metabolism and identification of the causative agent in aspirin teratogenesis in rats

Abstract Pregnant Wistar rats treated orally at day 9, 10, or 11 with 250, 500, 750, or 1000 mg/kg aspirin showed a teratogenic dose‐response relation at each treatment time, but a decreased overall embryonic susceptibility as treatment was applied later in gestation. The types of abnormalities produced generally correlated with the state of development at the time of treatment. Treatment of animals at day 9 with 510 mg/kg benzole acid and 2 hours later with 250 or 500 mg/kg aspirin caused a significant increase in percentage of malformations above effects observed after 250 or 500 mg/kg aspirin alone. Determination of free salicylate in embryos and maternal serum after treatment at day 11 with sodium salicylate with or without benzoic acid pretreatment indicated that benzoic acid significantly increased the concentration of salicylate in both embryos and serum 6 and 12 hours after salicylate treatment and throughout the observed period. Thin‐layer chromatography of tissues from these animals revealed only salicylic acid in both embryos and maternal serum, thus implicating salicylic acid as the causative agent in aspirin teratogenesis.