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

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.

Pharmacokinetic determinants of embryotoxicity in rats associated with organic acids.

“…In the present study utilizing and severity of embryotoxic effect, were greatly reduced in litters exposed to EHXA. This same interlitter variability was evident in the previous study in Wistar rats (2).…”

“…In our present work, we have examined the teratogenic activity and transplacental distribution of three isomeric C8 organic acids, valproic acid (VPA, 2-propyl pentanoic acid), 2-ethyl hexanoic acid (EHXA), and octanoic acid (OA). The choice of these agents came from Ritter et al's study (2) showing that VPA was about twice as potent as EHXA in regard to developmental toxicity under identical dosage conditions in pregnant rats.…”

“…Because the Wistar strain of rat used by Ritter et al (2) could no longer be obtained, the present study used SpragueDawley rats, and a new teratology study was conducted to verify the different teratogenic potency of EHXA versus VPA in this rat stock. The straight chain C8 isomer, octanoic acid, was included in the study because other reports indicate a limited embryotoxicity associated with this agent in vivo (3) or in vitro (4).…”

Flavouring Group Evaluation 04 −2-Ethylhexyl derivatives from chemical group 2 - Scientific Opinion of the Panel on Food Additives, Flavourings, Processing Aids and Materials in contact with Food (AFC)

“….078] has been studied extensively to evaluate its potential to cause developmental effects. Several of these studies were conducted only at high doses and not according to regulatory guidelines resulting in strong maternal toxicity (Ritter et al, 1985;Ritter et al, 1987;Narotsky et al, 1989;Hauck et al, 1990;Narotsky et al, 1991;Scott et al, 1994), which limit their utility for hazard assessment and risk characterisation. The most appropriate studies for this evaluation are the rat and rabbit oral gavage developmental toxicity studies described below:…”

HETA 90-0360-2504, CIBA-GEIGY, McIntosh, Alabama.

“…In humans and rodents, the primary metabolic products of DEHP are mono-2-ethyl-hexyl phthalate (MEHP) and 2EH. 2EH is metabolized further to 2-ethylhexanoic acid, which appears to be an active teratogen (Ritter et al, 1987). No information is available concerning the effects of 2EH or 2-ethylhexanoic acid on human male hormones, potency, or libido.…”