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© 1994 Oxford University Press

research-article

Developmental Toxicity and Structure-Activity Relationships of Aliphatic Acids, Including Dose-Response Assessment of Valproic Acid in Mice and Rats1,2

MICHAEL G. NAROTSKY*, ELAINE Z. FRANICS{dagger} and ROBERT J. KAVLOCK{ddagger}

*Man Tech Environmental Technology, Inc., Research Triangle Park North Carolina 27709 {dagger}Office of Technology Transfer and Regulatory Support, Office of Research and Development, U.S. Environmental Protection Agency Washington, DC 20460 {ddagger}Developmental Toxicology Division, Health Effects Research Laboratory, US Environmental Protection Agency, Research Triangle Park Washington, DC 20460

Received December 28, 1992; accepted July 15, 1993

The anticonvulsant valproic acid (VPA), or 2-propylpentanoic acid, is a short-chain aliphatic acid that is teratogenic in humans and rodents. VPA and 14 related chemicals were screened for developmental toxicity using the Chernoff/Kavlock assay. Test agents, in corn oil, were administered by gavage to Sprague-Dawley rats once daily during organogenesis. The dams were allowed to deliver and the pups were examined post natally. Segment II studies were also conducted using VPA and pentanoic acid in rats and with VPA in CD-1 mice. In both mice and rats, VPA caused transient maternal ataxia and developmental defects of the digits and, especially, the axial skeleton. Exencephaly, however, was seen only in mice. The screening protocol was effective in prioritizing agents within this class of compounds for more definitive developmental toxicity testing. All congeners tested induced maternal respiratory effects and six compounds caused motor depression. Only 2-ethylhexanoic (2EH) and 2-propylhexanoic (2PH) acid 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. The incorporation of skeletal examinations in the Chernoff/Kavlock assay en abled the detection of the sole developmental effect (increased incidence of lumbar ribs) of 2-butylhexanoic acid. VPA, 2EH, and 2PH were among the compounds that caused maternal motor depression. These data, consistent with previous reports, in dicate a broader specificity for activity in the adult nervous sys tem than that in the developing system and suggest differing mechanisms for the two effects.


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