Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

Skin irritation

  

The potential for di (2-ethylhexyl) terephthalate to cause skin corrosion/irritation is well understood. Two key dermal irritation studies and a supporting dermal toxicity study were available for review. In a primary dermal irritation/corrosion study conducted according to OECD Guideline 404, no erythema or edema was observed in three New Zealand White Rabbits (2 males, 1 female) at any time during the study when 0.5 mL of the undiluted test material was applied to intact clipped skin under semi-occlusive patch for 4 hours. There were also no signs of gross toxicity or abnormal behavior during the study. In a dermal irritation study conducted according to acceptable scientific methodology and according to Good Clinical Practices, irritation was minimal when 0.2 mL of 0.01, 0.05, 0.1, 0.2 and 0.5% di (2-ethylhexyl) terephthalate in acetone was repeatedly applied to a series of skin sites on the backs of 18 human subjects (9/sex). Application sites were semi-occluded and each application of test material was held in place for approximately 24 hours. Applications were made on Days 1, 3 and 5 and scoring was done on Days 3, 5 and 8. The maximum irritation score noted was 1 on a scale of 1-3. Because irritation was seen irregularly and only at a small proportion of the application sites and was not observed in a concentration-dependent manner, it was not considered to be related to test substance exposure. These effects are consistent with those observed in the rabbit study. In a non-guideline dermal toxicity study in which guinea pigs were exposed to 4920, 9840 or 19,680 mg/kg bw of undiluted di (2-ethylehxyl) terephthalate under occlusive wrap for 24-hours, no erythema was observed. However, the three test animals did exhibit reversible moderate to severe edema. In this study, exposure was for 24 hours under occlusive contact, conditions much more stringent than those used in current skin irritation testing protocols. In addition, the dose volumes used, i.e., ~ 5-20 g/kg bw were significantly greater than the 0.5 g/site currently used. Based on the observations made in two guideline skin irritation studies conducted in humans and rabbits, di (2-ethylhexyl) terephthalate is not classified as a primary skin irritant. Based on edema observed in guinea pigs exposed to extremely high dose volumes for prolonged periods of time under occlusive contact, exposure to di (2-ethylhexyl) terephthalate may cause slight reversible irritation.

  

Eye irritation

  

The potential for di (2-ethylhexyl) terephthalate to cause eye burns/irritation is well understood. In an eye irritation study conducted according to OECD Guideline 405, there was no evidence of corneal opacity or iritis in three test rabbits at any time during the study following installation of 0.1 mL of test material into the conjunctival sac. Conjunctival redness was observed in all animals at 1, 24 and 48 hours after test substance administration but all animals were normal at the 72-hour observation period and the calculated mean score following grading at 24, 48 and 72 hours after installation of the test material was <2. Conjunctival chemosis (grade 1) was also observed in all animals at the 1-hour observation period but all animals were normal at the 24-hour observation period. There was no staining in the eyes when tested with fluorescein dye 24 hours after test substance administration and there were no abnormal systemic signs noted during the 72-hour observation period. In a pre-GLP supporting study conducted by a method similar to OECD Guideline 405, adverse effects were limited to slight erythema on the palpebral conjunctiva and nictitating membranes of all animals at the 1-hour post-dose examination. All animals appeared clinically normal from 24 hours onward.  

  

Respiratory irritation

  

The potential for di (2-ethylhexyl) terephthalate to cause respiratory tract irritation is well understood. In a sub-acute non-guideline inhalation study conducted by a credible testing laboratory according to acceptable scientific methods of the time, groups of 5 male rats were exposed to 0.0718 mg/L of di (2-ethylhexyl) terephthalate by whole body inhalation 5 days/week, 6 hours/day for 10 days over a 14-day period. There were no clinical signs to suggest an adverse effect on respiration and there where no treatment-related gross or microscopic effects observed at necropsy. The exposure concentration used in the study could only be generated by passing an airflow of 6.0 L/min through a gas washing bottle containing undiluted di (2-ethylhexyl) terephthalate that was heated on a water bath at 95°C. 

  

Justification for classification or non-classification

No erythema or edema was observed in a primary dermal irritation/corrosion study conducted in rabbits according to OECD Guideline 404. In a dermal irritation study conducted according to acceptable scientific methodology and Good Clinical Practices, irritation was minimal when 0.2 mL of test material at concentrations ranging from 0.01 to 0.5% di (2-ethylhexyl) terephthalate in acetone was repeatedly applied to a series of skin sites on the backs of 18 human subjects. Because irritation was seen irregularly and only at a small proportion of the application sites and was not observed in a concentration-dependent manner, it was not considered to be related to test substance exposure. Although moderate to severe edema but no erythema was observed in a dermal toxicity study conducted in guinea pigs, the doses, i.e., ~5000 – 20,000 mg/kg and the exposure conditions, i.e., 24-hour occluded contact were much more severe than those currently used in skin irritation testing protocols. Di (2-ethylhexyl) terephthalate was not previously classified under Directive 67/548/EEC, i.e., Annex I of the Dangerous Substances Directive for skin irritation. Based on a weight-of-the-evidence assessment, exposure to large volumes of di (2-ethylhexyl) terephthalate under occluded contact for prolonged periods of time may cause transient skin irritation but di (2-ethylhexyl) terephthalate would not be classified for skin irritation 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. 

  

In the key guideline study, there was no evidence of corneal opacity or iritis in rabbit eyes following instillation of 0.1 mL of di (2-ethylhexyl) terephthalate into the conjunctival sac of the eye. Conjunctival chemosis (grade 1) was observed in all treated eyes but only at the 1-hour examination. Conjunctival redness was observed in all treated eyes at 1, 24 and 48 hours after test substance administration but all animals were normal at the 72-hr examination and the calculated mean score following grading at 24, 48 and 72 hours was <2. A pre-GLP non-guideline study reported similar results. In addition, undiluted di-(2-ethylhexyl) terephthalate was not classified under GHS for either skin corrosivity or irritation following 4-hour semi-occluded contact with intact rabbit skin.  Di (2-ethylhexyl) terephthalate was not previously classified under Directive 67/548/EEC, i.e., Annex I of the Dangerous Substances Directive for eye irritation. Based on a weight-of-the-evidence assessment, di (2-ethylhexyl) terephthalate would not be classified for eye irritation 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. 

  

There were no clinical signs indicative of respiratory tract irritation in rats following repeated exposures to the highest airborne concentrations of di (2-ethylhexyl) terephthalate that could be generated by heating the test material to 95°C. Following exposure for 5 days/week, 6 hours/day for 10 days over a 14-day period, there was no gross or microscopic evidence of irritation in the lungs or trachea. In addition, di (2-ethylhexyl) terephthalate is not classified as an eye or skin irritant according to GHS. Di (2-ethylhexyl) terephthalate was not previously classified under Directive 67/548/EEC, i.e., Annex I of the Dangerous Substances Directive for respiratory tract irritation. Based on a weight-of-the-evidence assessment, di (2-ethylhexyl) terephthalate would not be classified for respiratory tract irritation 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.