Two‐generation reproduction study of di‐2‐ethylhexyl terephthalate in Crl:CD rats
Authors: Faber Willem D. , Deyo James A. , Stump Donald G. , Ruble Karen 
Published: March 2007

BACKGROUND: This study was conducted to evaluate the potential adverse effects of di‐2‐ethylhexyl terephthalate (DEHT) on reproductive capability from exposure of F0 and F1 parental animals. METHODS: Four groups of male and female Crl:CD (SD)IGS BR rats (30/gender/group) were exposed to 0, 0.3%, 0.6%, and 1.0% DEHT in the feed for at least 70 consecutive days before mating for the F0 and F1 generations. Exposure for the F0 and F1 males continued throughout the mating period until euthanasia. Exposure for the F0 and F1 females continued throughout mating, gestation, and lactation. The F1 and F2 pups were weaned on postnatal day (PND) 21. Assessments included gonadal function, estrous cyclicity, mating behavior, conception rate, gestation, parturition, lactation, and weaning in the F0 and F1 generations, and F1 generation offspring growth and development. RESULTS: DEHT exposure did not affect clinical observations. However, lethality was observed in F0 and F1 dams consuming the 1.0% diet during the post‐weaning period. No treatment‐related mortality occurred in any of the male groups exposed to DEHT or in the female groups exposed to 0.3% or 0.6% DEHT. Male rats consuming the 1.0% diet in both parental generations gained weight more slowly than the controls. There were no indications of adverse effects on reproductive performance in either the F0 or F1 generation. Male and female mating and fertility indices, pre‐coital intervals, spermatogenic endpoints, reproductive organ weights, lengths of estrous cycle and gestation, live litter size, developmental landmarks, and postnatal survival were similar in all exposure groups. Additionally, ovarian follicle counts for the F1 females in the high‐exposure group were similar to the control values. No adverse exposure‐related macroscopic pathology was noted at any exposure level in the F0 and F1 generations. CONCLUSIONS: Increases in liver weights were found in the male and female animals exposed to 0.6% or 1.0% DEHT in the diet. Because there were no accompanying histopathologic changes, this effect was not considered adverse. Significant decreases in feed consumption in the female animals from the groups consuming 1.0% DEHT in the diet during lactation accompanied reduced postnatal pup body weights and rate of weight gain. Reductions in pup body weights later in lactation may also have been due to direct consumption of the treated feed by the pups or taste aversion to the same. Reduced relative spleen weight was found in male weanling pups from the 1.0% group in both generations and reduced relative spleen and thymus weights were found in female pups from the 1.0% group in the F2 generation at necropsy on PND 21. Therefore, for parental and pup systemic toxicity, 0.3% DEHT in the diet (182 mg/kg/day) was considered no‐observed‐effect level (NOEL). The 1.0% DEHT (614 mg/kg/day) in the diet exposure concentration was considered a NOEL for F0 and F1 reproductive toxicity endpoints. Birth Defects Res (Part B), 2007. © 2007 Wiley‐Liss, Inc.