Species differences in developmental toxicity of epoxiconazole and its relevance to humans.

Abstract

Epoxiconazole, a triazole-based fungicide, was tested in toxicokinetic, prenatal and pre-postnatal toxicity studies in guinea pigs, following oral (gavage) administration at several dose levels (high dose: 90 mg/kg body weight per day). Maternal toxicity was evidenced by slightly increased abortion rates and by histopathological changes in adrenal glands, suggesting maternal stress. No compound-related increase in the incidence of malformations or variations was observed in the prenatal study. In the pre-postnatal study, epoxiconazole did not adversely affect gestation length, parturition, or postnatal growth and development. Administration of epoxiconazole did not alter circulating estradiol levels. Histopathological examination of the placentas did not reveal compound-related effects. The results in guinea pigs are strikingly different to those observed in pregnant rats, in which maternal estrogen depletion, pathological alteration of placentas, increased gestation length, late fetal death, and dystocia were observed after administration of epoxiconazole. In the studies reported here, analysis of maternal plasma concentrations and metabolism after administration of radiolabeled epoxiconazole demonstrated that the different results in rats and guinea pigs were not due to different exposures of the animals. A comprehensive comparison of hormonal regulation of pregnancy and birth in murid rodents and primates indicates that the effects on pregnancy and parturition observed in rats are not applicable to humans. In contrast, the pregnant guinea pig shares many similarities to pregnant humans regarding hormonal regulation and is therefore considered to be a suitable species for extrapolation of related effects to humans.

• Authors: Steffen Schneider, Thomas Hofmann, Stefan Stinchcombe, Maria Cecilia Rey Moreno, Ivana Fegert, Volker Strauss, Sibylle Gröters, Eric Fabian, Jutta Thiaener, Karma C Fussell, Bennard van Ravenzwaay
• Journal: Birth defects research. Part B, Developmental and reproductive toxicology (Birth Defects Res B Dev Reprod Toxicol) Vol. 98 Issue 3 Pg. 230-46 (Jun 2013) ISSN: 1542-9741 [Electronic] United States
• PMID: 23630118 (Publication Type: Journal Article)
• Copyright: © 2013 Wiley Periodicals, Inc.

Chemical References

• Carbon Radioisotopes
• Epoxy Compounds
• Triazoles
• epoxiconazole

Topics

• Animals
• Carbon Radioisotopes (blood)
• Epoxy Compounds (chemistry, toxicity)
• Female
• Fetus (drug effects, pathology)
• Growth and Development (drug effects)
• Guinea Pigs (blood)
• Humans
• Male
• Metabolic Networks and Pathways (drug effects)
• Organ Size (drug effects)
• Pregnancy
• Prenatal Exposure Delayed Effects (pathology)
• Rats
• Species Specificity
• Triazoles (chemistry, toxicity)