All
vitamin K antagonist active substances used as
rodenticides were reclassified in 2016 by the European authorities as active substances "toxic for reproduction", using a "read-across" alternative method based on
warfarin, a human
vitamin K antagonist drug. Recent study suggested that all
vitamin K antagonist active substances are not all teratogenic. Using a neonatal exposure protocol,
warfarin evokes skeletal
deformities in rats, while
bromadiolone, a widely used second-generation
anticoagulant rodenticide, failed to cause such effects. Herein, using a rat model we investigated the mechanisms that may explain teratogenicity differences between
warfarin and
bromadiolone, despite their similar
vitamin K antagonist mechanism of action. This study also included
coumatetralyl, a first-generation active substance
rodenticide. Pharmacokinetic studies were conducted in rats to evaluate a potential difference in the transfer of
vitamin K antagonists from mother to fetus. The data clearly demonstrate that
warfarin is highly transferred from the mother to the fetus during gestation or lactation. In contrast,
bromadiolone transfer from dam to the fetus is modest (5% compared to
warfarin). This difference appears to be associated to almost complete uptake of
bromadiolone by mother's liver, resulting in very low exposure in plasma and eventually in other peripheric tissues. This study suggests that the pharmacokinetic properties of
vitamin K antagonists are not identical and could challenge the classification of such active substances as "toxic for reproduction".