Species Differences in Developmental Toxicity of Epoxiconazole and Its Relevance to Humans

• Published in: Birth defects research. Part B. Developmental and reproductive toxicology 2013-06, Vol.98 (3), p.230-246
• Main Authors: Schneider, Steffen, Hofmann, Thomas, Stinchcombe, Stefan, Moreno, Maria Cecilia Rey, Fegert, Ivana, Strauss, Volker, Gröters, Sibylle, Fabian, Eric, Thiaener, Jutta, Fussell, Karma C., van Ravenzwaay, Bennard
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Carbon Radioisotopes - blood; developmental toxicity; Embryology: invertebrates and vertebrates. Teratology; Epoxiconazole; Epoxy Compounds - chemistry; Epoxy Compounds - toxicity; Female; Fetus - drug effects; Fetus - pathology; Fundamental and applied biological sciences. Psychology; Growth and Development - drug effects; guinea pig; Guinea Pigs - blood; Humans; Male; Medical sciences; Metabolic Networks and Pathways - drug effects; Organ Size - drug effects; Pesticides, fertilizers and other agrochemicals toxicology; postnatal toxicity; Pregnancy; Prenatal Exposure Delayed Effects - pathology; prenatal toxicity; rat; Rats; species differences; Species Specificity; Teratology. Teratogens; Toxicology; Triazoles - chemistry; Triazoles - toxicity
• ISSN: 1542-9733; 1542-9741
• DOI: 10.1002/bdrb.21058

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. Birth Defects Res (Part B) 98:230–246, 2013. © 2013 Wiley Periodicals, Inc.