Pharmacokinetic determinants of embryotoxicity in rats associated with organic acids.

Abstract

We have studied four organic acids of similar structure to further understand the basis of their developmental toxicity. Valproic acid (2-propyl pentanoic acid), ethylhexanoic acid, and octanoic acid are isomeric C8 organic acids but their teratologic potency varied widely. Valproic acid induced a moderate to severe teratologic outcome after a single oral administration of 6.25 mmoles/kg on day 12 of rat pregnancy. Twice as much ethylhexanoic acid (12.5 mmoles/kg) induced a less severe response. Octanoic acid was nonteratogenic even at the very high dose of 18.75 mmoles/kg. This latter result is undoubtedly due to poor intestinal absorption of octanoic acid, as the maternal plasma levels never reached half of those measured for valproic acid and ethylhexanoic acid. Moreover, only a tiny fraction of that in maternal plasma was actually transferred into the embryo. On the other hand, the peak concentration and duration of exposure to valproic acid and ethylhexanoic acid were very similar despite a more severe teratologic outcome following valproic acid, which indicated higher intrinsic activity of this latter agent. A fourth agent, methylhexanoic acid, was also studied and had no teratogenic effects when given at 14.1 mmoles/kg. Pharmacokinetic studies of this agent revealed higher peak concentrations in maternal plasma and embryo than valproic acid or ethylhexanoic acid, but the duration of exposure was shorter. We conclude that pharmacokinetic parameters can be important determinants of teratologic outcome and thereby help explain differing potencies of structurally similar chemicals. -Environ Health Perspect 1 02(Suppl 1 1): 97-101 (1994)

Developmental toxicity evaluation of trimethylolpropane caprylate caprate in Sprague‐Dawley rats

“…These likely metabolites have little or no potential to be developmental toxicants. Scott et al (1994) reported that octanoic acid was not teratogenic in the rat even after an oral dosage of 18.75 mmol/kg (approximately 2,700 mg/ kg) on gestation day 12. These authors attributed the lack of toxicity to poor intestinal absorption because plasma levels were lower than similar dosages of branched-chain acids; however, data on absorption of decanoic acid from isolated gut loop preparations indicate that it is very high (Opdyke, 1979).…”

“…It is more likely that the blood levels were low because octanoic acid is a substrate for energy production or triglyceride formation in the liver. Of interest is the observation by Scott et al (1994) that the transfer of octanoic acid from mother to the rat embryo was minimal. Nau and Loscher (1986) reported a similar lack of embryotoxicity in mice after sc injection of sodium octanoate on gestation day 8.…”

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:…”

“…Dev. tox./ day 12 of gestation Rat/F Gavage Offspring < 1800 Maternal toxicity not reported (Scott et al, 1994) 10.…”

Read-across of 90-day rat oral repeated-dose toxicity: A case study for selected 2-alkyl-1-alkanols

“…Valproic acid induces moderate to severe malformations after a single oral administration of 6.25 mmoles/kg on day 12 of rat pregnancy. Twice as much 2-ethyl-1-hexanoic acid (12.5mmoles/kg) induces a less severe response and 1-octanoic acid is non-teratogenic, even at the higher dose of 18.75 mmoles/kg[62]. While 1-octanoic acid exhibits poor intestinal absorption, the peak concentration and duration of exposure to valproic acid and 2-ethyl-1-hexanoic acid were very similar.…”