Epoxiconazole (EPX; CAS-No. 133855-98-8) is a
triazole class-active substance of plant protection products. At a dose level of 50 mg/kg bw/day, it causes a significantly increased incidence of late fetal mortality when administered to pregnant rats throughout gestation (gestation day [
GD] 7-18 or 21), as reported previously (Taxvig et al., 2007, 2008) and confirmed in these studies. Late
fetal resorptions occurred in the presence of significant maternal toxicity such as clear reduction of corrected
body weight gain, signs of
anemia, and, critically, a marked reduction of maternal
estradiol plasma levels. Furthermore,
estradiol supplementation at dose levels of 0.5 or 1.0 μg/animal/day of
estradiol cyclopentylpropionate abolished the EPX-mediated late
fetal resorptions. No increased incidences of external malformations were found in rats cotreated with 50 mg/kg bw/day EPX and
estradiol cyclopentylpropionate, indicating that the occurrence of malformations was not masked by fetal mortality under the study conditions. Overall, the study data indicate that fetal mortality observed in rat studies with EPX is not the result of direct fetal toxicity but occurs indirectly via depletion of maternal
estradiol levels. The clarification of the human relevance of the
estrogen-related mechanism behind EPX-mediated late
fetal resorptions in rats warrants further studies. In particular, this should involve investigation of the placenta (Rey Moreno et al., 2013), since it is the materno-fetal interface and crucial for fetal maintenance. The human relevance is best addressed in a species which is closer to humans with reference to placentation and hormonal regulation of pregnancy, such as the guinea pig (Schneider et al., 2013).