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Administrative data

Key value for chemical safety assessment

Effects on fertility

Additional information

The potential for di (2-ethylhexyl) terephthalate to cause reproductive toxicity is well understood. In a 13-week oral toxicity study conducted according to US EPA Guideline 799.9310, male and female Sprague-Dawley rats were exposed to 0, 0.1, 0.5 or 1.0% of di (2-ethylhexyl) terephthalate in the diet (equivalent to 561 mg/kg bw/day in males and 617 mg/kg bw/day in females at the 1% dose level). There were no adverse effects on weight of testes or ovaries and gross/microscopic examination of testes, epididymides, male accessory sex glands, ovaries, uterus, vagina, fallopian tubes, and male and female mammary glands revealed no treatment-related effects. In a feeding study of shorter duration, there were no adverse effects on testicular weight or gross/microscopic pathology in male Fischer 344 rats receiving up to 2.5% (equivalent to 2104 mg/kg bw/day) di (2-ethylhexyl) terephthalate in the diet for 21 days. In a 2-year oral study conducted according to EPA OPPTS Guideline 870.4200 in which male and female rats were provided ad libitum access to diets containing up to 12000 ppm (equivalent to 666 and 901 mg/kg bw/day in males and females, respectively) di (2-ethylhexyl) terephthalate, there were no adverse effects on reproductive organs in either sex. In a two-generation reproductive toxicity study conducted in male and female rats according to OECD Guideline 416, there were no adverse effects on sexual function, fertility or reproductive organs in either sex receiving up to 10000 ppm in the diet. All F0 animals were treated for a minimum of 70 days prior to mating until necropsy and F0 offspring chosen for the F1 study received similar treatment. Estrous cyclicity, spermatogenic endpoints (motility, morphology, numbers), and reproductive indices (mating, fertility, copulation and conception) were also unaffected by test substance administration. In a dietary prenatal developmental toxicity study conducted according to OECD Guideline 414, female mice were exposed to test diets containing up to 7000 ppm (equivalent to 1382 mg/kg bw/day) di (2-ethylhexyl) terephthalate during gestation days 0-18. There were no adverse effects on any reproductive parameters including preimplantation loss, number of implantation sites and numbers of corpora lutea. In a similar study in which pregnant Sprague-Dawley rats were exposed to up to 10000 ppm di (2-ethylhexyl) terephthalate in the diet from gestation days 0-20, there were no adverse effects on reproductive organs and no significant differences in numbers of early or late resorptions, corpora lutea, viable fetuses per litter, implantation sites, or pre- or post-implantation loss among any of the groups. Fetal sex ratios were also unaffected. Di (2-ethylhexyl) terephthalate caused no adverse reproductive effects in either sex under conditions used in these studies.

   

Effects on developmental toxicity

Additional information

The potential for di (2-ethylhexyl) terephthalate to cause developmental toxicity is well understood. In a two-generation reproductive toxicity study conducted according to OECD Guideline 416, male and female Sprague-Dawley rats were allowed ad libitum access to diets containing up to 10000 ppm di (2-ethylhexyl) terephthalate. Age of acquisition of balanopreputial separation and vaginal patency were unaffected in the F1 and F2 offspring. Mean live litter sizes, numbers of pups born, percentages of males per litter at birth and postnatal survival were unaffected by parental consumption of the test substance.  Although some developmental toxicity (lower body and organ weights) was observed in the offspring of both generations at 6000 and 10000 ppm, these generally only occurred in the presence of maternal toxicity. In a dietary prenatal developmental toxicity study conducted according to OECD Guideline 414, female mice were exposed to test diets containing up to 7000 ppm (equivalent to 1382 mg/kg bw/day) di (2-ethylhexyl) terephthalate during gestation days 0-18. There was no adverse effect on live litter size, fetal body weight or sex ratio and there was no increase in the incidence of external, skeletal or visceral malformations or variations even at maternally toxic doses. In a similar study in which pregnant Sprague-Dawley rats were exposed to up to 10000 ppm di (2-ethylhexyl) terephthalate in the diet from gestation days 0-20, intrauterine growth and survival and incidences of fetal external, visceral or skeletal malformations were unaffected by test substance administration at any dose level. An increase in the occurrence of rudimentary 14thribs observed in the 10000 ppm exposure group was not considered an adverse effect. In a supporting study in which di (2-ethylhexyl) terephthalate was administered in corn oil via oral gavage to pregnant female Sprague-Dawley rats at a dose level of 0.75 g/kg bw/day from gestation day 14 to postnatal day 3, there were no adverse effects in male offspring on any endpoints specific to androgen disruption including anogenital distance, onset of puberty, serum testosterone levels, retained nipples, cleft phallus, blind vaginal pouch, hypospadias, undescended testes, histopathology of the testes, and sperm analysis. Di (2-ethylhexyl) terephthalate is not a teratogen and is not selectively toxic to the developing fetus. Minor developmental toxicity, such as weight reduction, was observed but only in the presence of maternal toxicity.

   

Justification for classification or non-classification

There were no adverse effects on reproductive organs in either sex of rat exposed ad libitum to 12000 ppm (equivalent to 666 and 901 mg/kg bw/day in males and females, respectively) di (2-ethylhexyl) terephthalate in the diet for up to two years and there were no adverse effects on any reproductive organs or reproductive parameters in a 2-generation reproductive toxicity study in which males and females from both generations were exposed to up to 10000 ppm in the diet for a minimum of 70 days prior to mating until necropsy. Di (2-ethylhexyl) terephthalate was not previously classified under Directive 67/548/EEC, i.e., Annex I of the Dangerous Substances Directive for reproductive toxicity. Based on a weight-of-the-evidence assessment, di (2-ethylhexyl) terephthalate is not classified for “Reproductive Toxicity” according to the UN Globally Harmonized System of Classification and Labeling (GHS) or the EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) no. 1272/2008. 

  

Di (2-ehtylhexyl) terephthalate is not teratogenic. In several guideline studies, there was no increase in external, visceral or skeletal malformations at any dose level tested. While slight fetotoxicity in the form of reductions in body weight was observed, this was generally in the presence of maternal toxicity. Di (2-ethylhexyl) terephthalate was not previously classified under Directive 67/548/EEC, i.e., Annex I of the Dangerous Substances Directive for developmental toxicity. Based on a weight-of-the-evidence assessment, di (2-ethylhexyl) terephthalate is not classified for “Developmental Toxicity” according to the UN Globally Harmonized System of Classification and Labeling (GHS) or the EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) no. 1272/2008.