Teratogenicity of di(2‐ethylhexyl) phthalate, 2‐ethylhexanol, 2‐ethylhexanoic acid, and valproic acid, and potentiation by caffeine

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Abstract
It is hypothesized that the teratogen di(2‐ethylhexyl) phthalate (DEHP) acts by in vivo hydrolysis to 2‐ethylhexanol (2‐EHXO), which in turn is metabolized to 2‐ethylhexanoic acid (2‐EHXA), the proximate teratogen. Teratological studies were conducted with Wistar rats, with administration of these agents on day 12 of gestation. On an equimolar basis DEHP was least potent, 2‐EHXO was intermediate, and 2‐EXHA was the most potent of the three agents, which is consistent with the hypothesis. Similarity in the types of defects found with these agents also suggests a common mechanism, with 2‐EHXA as the proximate teratogen. All three agents were potentiated by caffeine. Valproic acid, which is an isomer of 2‐EXHA, also produced similar defects, and was approximately twice as potent as 2‐EHXA.