Trifluoroacetic acid and ocular malformations in rabbits: Proposed mechanisms of action

Administration of high oral doses of sodium trifluoroacetate (NaTFA) to rabbits during pregnancy led to excessively high trifluoroacetic acid (TFAA) body burden after repeated gavage application. This resulted in rare but apparently reproducible fetal ocular malformations, which were dose-related and exceed the available range of historical control data (HCD). We propose that these ocular malformations (absent aqueous and vitreous humour with secondary, multiple, retinal folding, likely caused by an insufficient expansion of the ocular globe) are a result of peak TFAA concentrations that have reached levels high enough to trigger (a) chaotropic reactions and (b) competitive monocarboxylate transporter (MCT) inhibition in ocular tissues. Rabbit-specific characteristics in the excretion and clearance of trifluoroacetate (TFA) resulted in higher systemic exposure than other species, making rabbits more susceptible to these effects on ocular development. Whilst still potentially relevant, the risk to human development is considered to be low given expected exposure levels.