Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Additional information

The potential for di (2-ethylhexyl) terephthalate to cause target organ toxicity following repeated exposure is well understood. Two key guideline and four lesser non-guideline studies were available for review. The first key study is considered to be a 90-day feeding study in rats conducted according to GLPs and EPA guideline 799.9310. In this repeat-exposure study in which male and female rats were exposed to 0.1, 0.5 or 1.0% of di (2-ethylhexyl) terephthalate in the diet for 90 days, there were no deaths or functional changes in any organ system and no significant adverse effects on food consumption, ophthalmic examination, clinical chemistry parameters, urinalysis, or gross/microscopic pathology. Adverse effects were limited to minor effects in hematology parameters and increases in relative liver weights in both sexes. The latter occurred in the absence of liver dysfunction, gross/microscopic changes, or changes in clinical chemistry parameters that would be suggestive of target organ effects. There was also no indication of an increase in peroxisome proliferation at the highest concentration tested (equivalent to 561 and 617 mg/kg bw/day for male and female rats, respectively). The NOEL for systemic effects was considered to be 277 mg/kg bw/day and 309 mg/kg bw/day for males and females in this study. The second key study is a 2-year carcinogenicity study conducted according to EPA OPPTS Guideline 870.4200 in which male and female rats were exposed to 1500, 6000 or 12000 ppm in the diet for a lifetime. The highest dose level was equivalent of 666 and 901 mg/kg bw/day in males and females, respectively. Like the 13-week study, increases in relative liver weights were observed in high-dose groups of both sexes but this again occurred in the absence of gross/microscopic changes or changes in clinical chemistry parameters. The observed changes were considered an adaptive change rather than an indication of target organ toxicity.

  

In addition, several shorter non-guideline studies conducted by a variety of routes were considered in the overall evaluation. Because the structural analog di-(ethylhexyl) phthalate (DEHP) caused significant peroxisome proliferation in rats following oral administration, groups of male and female rats were exposed to di (2-ethylhexyl) terephthalate in the diet at concentrations of 0.1, 0.5, 1.0, 1.2 and 2.5% for comparison. The latter two concentration levels of DEHP caused moderate to marked peroxisome proliferation in rats exposed via the diet. Following administration of di (2-ethylhexyl) terephthalate ad libitum in the diet at concentration levels up to 2.5% for 21 days, effects on lipid metabolism and slight peroxisome proliferation were observed only in the 2.5% exposure group (equivalent to 2104 and 1900 mg/kg bw/day for male and female rats, respectively). At this dose level, there was a significant decrease in food consumption and body weight gain and a variety of adverse clinical signs. Since fasting alone has been implicated in the formation of hepatic peroxisomes and altered lipid metabolism, it is likely that effects observed in this study were related to feed restriction rather than exposure to di (2-ethylhexyl) terephthalate alone. No treatment-related changes were observed in the kidneys or testes. Based on the study conditions, the NOEL for 21-day exposure via the diet was considered to be 0.5% which corresponded to 505 and 487 mg/kg bw/day for male and female rats, respectively. Minimal effects were observed at 1% (equivalent to 1037 mg/kg bw/day for males and 1052 mg/kg bw/day for females). In a third supporting oral study, there were no adverse effects on survival, clinical observations, body weight, hematology, clinical chemistries, or gross/microscopic examinations in male rats receiving up to 1% di (2-ethylhexyl) terephthalate in the diet for 10 days (equivalent to 885 mg/kg bw/day).

  

In a subacute dermal toxicity study, no deaths, signs of skin absorption or systemic toxicity were evident when guinea pigs were exposed to 0.5 mL of undiluted di (2-ethylhexyl) terephthalate (equating to 813 - 1144 mg/kg bw/day) for 9 exposures over an 11 day period. There were no gross or microscopic examinations conducted in this study. In a subacute inhalation study in which male rats were exposed to a mean concentration of 0.0718 mg/L (highest concentration that could be generated by heating the test material to 95°C) for 6 hours/day, 5 days/week for 2 weeks, no deaths or signs of toxicity were evident during the study.  Hematology and clinical chemistry parameters were within the normal ranges for the control and test group and there were no significant treatment-related gross or microscopic effects observed at necropsy. 

  

Justification for classification or non-classification

No significant target organ effects were observed in male or female rats following ad libitum exposure to up to 1% in the diet for 90 days (resulting in overall mean consumption over the study of 561 and 617 mg/kg bw/day in males and females, respectively). Toxicity related to test substance administration was limited to minor effects on red blood cell formation and enlargement of the liver with no corresponding adverse effect on liver function, clinical chemistries or gross/microscopic pathology. The overall NOEL for the 90-day feeding study was 0.5% in the diet (equivalent to 277 and 309 mg/kg bw/day for males and females, respectively). There was no evidence of peroxisome proliferation in the 90-day study at the highest concentration tested. There were also no significant target organ effects in a 2-year feeding study in which groups of male and female rats were provided ad libitum access to a diet containing up to 12000 ppm of di (2-ethylhexyl) terephthalate. Several lesser oral studies of shorter duration support results observed in the 90-day feeding study. In addition, no signs of absorption or systemic toxicity were observed following administration of 0.5 mL of undiluted di (2-ethylhexyl) terephthalate to the backs of guinea pigs for a total of 9 exposures over an 11 day period (equivalent to 813-1144 mg/kg bw/day). This dose level did cause moderate to strong erythema. There were also no deaths, no adverse clinical signs, no effects on hematology or clinical chemistry, or gross/microscopic changes in rats exposed 6 hours/day, 5 days/week for 2 weeks to the highest vapor concentration that could be generated by heating di (2-ethylhexyl) terephthalate to 95°C. Di (2-ethylhexyl) terephthalate was not previously classified under Directive 67/548/EEC, i.e., Annex I of the Dangerous Substances Directive for target organ toxicity following repeated exposure. Based on a weight-of-the-evidence assessment, di (2-ethylhexyl) terephthalate would not be classified for “Specific Target Organ Toxicity – Repeated Exposure” 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.