DEVELOPMENTAL TOXICITY AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF ALIPHATIC-ACIDS, INCLUDING DOSE-RESPONSE ASSESSMENT OF VALPROIC ACID IN MICEAND RATS

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 toxicit y using the Chernoff/Kavlock assay. Test agents, in corn oil, were adm inistered by gavage to Sprague-Dawley rats once daily during organogen esis. The dams were allowed to deliver and the pups were examined post natally. Segment II studies were also conducted using VPA and pentanoi c acid in rats and with VPA in CD-1 mice. In both mice and rats, VPA c aused transient maternal ataxia and developmental defects of the digit s and, especially, the axial skeleton. Exencephaly, however, was seen only in mice. The screening protocol was effective in prioritizing age nts within this class of compounds for more definitive developmental t oxicity testing. All congeners tested induced maternal respiratory eff ects 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, fu sed ribs, and delayed parturition), confirming the strict structural r equirements for developmental toxicity previously reported for acute e xposure in mice. The incorporation of skeletal examinations in the Che rnoff/Kavlock assay enabled the detection of the sole developmental ef fect (increased incidence of lumbar ribs) of 2-butylhexanoic acid. VPA , 2EH, and 2PH were among the compounds that caused maternal motor dep ression. These data, consistent: with previous reports, indicate a bro ader specificity for activity in the adult nervous system than that in the developing system and suggest differing mechanisms for the two ef fects. (C) 1994 Society of Toxicology.