Assessment of the Developmental Toxicity of 2-Ethylhexanoic Acid in Rats and Rabbits. Hendrickx, A. G., Peterson, P. E., Tyl, R. W., Fisher, L. C., Fosnight, L. J., Kubena, M. F., Vrbanic, M, A., and Katz, G, V, (1993). Fundam. Appl. Toxicol. 20, 199-209. This study was carried out to assess the developmental toxicity of orally administered 2-ethylhexanoic acid (2-EHA) throughout organogenesis in the rat and the rabbit. Treatment of Fischer 344 inbred rats with doses of 100 to 1000 mg 2-EHA/ kg/day on (Gestation Days) (GD) 6-15 in a range-finding and a definitive study resulted in a high level of maternal death at 1000 mg/kg/day. Clinical signs of maternal toxicity, including increased liver weight, as well as increased resorptions, dead fetuses, and growth retardation, but no malformations, were observed at 500 mg/kg/day. Slight developmental toxicity, manifested as a reduction in skeletal ossification, occurred in fetuses exposed to 250 mg/kg/day. No adverse effects of treatment were associated with the lower 2-EHA doses (100 and 125 mg/kg/ day). Maternal toxicity was also observed in range-finding and definitive studies in New Zealand white rabbits exposed to 25 to 1000 mg 2-EHA/kg/day on GD 6-18 with excessive mortality observed at the highest doses (500 and 1000 mg/kg/day). A low incidence of maternal death as well as abortion occurred following treatment with 125 and 250 mg 2-EHA/kg/day. Less severe clinical signs (reduced weight and food consumption and hypoactivity) were also observed in the 250 mg/kg/day group. There were no adverse effects on fetal viability, growth, or morphology at any dose level. Thus, exposure to 2-EHA during the entire period of organogenesis caused developmental toxicity only at maternally toxic doses in the rat or adverse maternal effects in the absence of developmental toxicity in the rabbit. No evidence of teratogenicity was associated with 2-EHA in this classical safety assessment regimen in either species. The no observed adverse effect levels (NOAELs) for maternal and developmental toxicities in rats are 250 and 100 mg/kg/day, respectively; the corresponding NOAELs for rabbits are 25 mg/kg/day (maternal) and ≥250 mg/kg/day (developmental).
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