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DEVELOPMENTAL TOXICITY AND STRUCTURE-ACTIVITY RELATIONSHIPS OF ALIPHATIC ACIDS, INCLUDING DOSE-RESPONSE ASSESSMENT OF VALPROIC ACID IN MICE AND RATS
Citation:
Narotsky, M., E. Francis, AND R. Kavlock. DEVELOPMENTAL TOXICITY AND STRUCTURE-ACTIVITY RELATIONSHIPS OF ALIPHATIC ACIDS, INCLUDING DOSE-RESPONSE ASSESSMENT OF VALPROIC ACID IN MICE AND RATS. U.S. Environmental Protection Agency, Washington, D.C., EPA/600/J-94/328 (NTIS PB94197084), 1994.
Description:
The anticonvulsant valproic acid (VPA), or 2-propylpentanoic acid, is a short-chain aliphatic acid that is teratogenic in humans and rodents. PA and 14 related using the Chernoff/Kavlock assay Sprague-Dawley rats were gavaged with the test agent in corn oil once daily organogenesis. he dams were allowed to deliver and the pups were examined postnatally. egment II studies were also conducted using VPA and pentanoic acid in rats, and with VPA in CD-1 mice. or both species, VPA caused transient maternal ataxia and developmental defects of the digits and, especially, the axial skeleton. xencephaly, however, was seen only in mice. ll congeners tested induced maternal respiratory effects and six compounds caused motor depression. nly 2-ethylhexanoic (2EH) and 2-propylhexanoic (2PH) acids caused dramatic VPA-like effects on rat development (including mortality, extra presacral vertebrae, fused ribs, and delayed parturition), confirming the strict structural requirements for developmental toxicity previously reported for acute exposure in mice. he incorporation of skeletal examinations in the Chernoff/Kavlock assay enabled the detection of the sole developmental effect (lumbar ribs) of 2-butylhexanoic acid. hese data indicate a broader specificity for activity in the maternal system than in the embryo and suggest differing mechanisms for the two effects.
