Bis(2-ethylhexyl) terephthalate

Endpoint summary

Description of key information

Based on an absence of adverse effects in study, di (2-ethylhexyl) terephthalate is not classified for “Skin Sensitization”.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Remarks:

in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

6 weeks

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods

Remarks:

Reliable without restriction; study was conducted according to acceptable scientific methodology and according to Good Clinical Practices (GCPs). The investigation was reviewed by an Institutional Review Board in accordance with Title 21 of the U.S. Code of Federal Regulations (CFR).

Qualifier:

equivalent or similar to guideline

Guideline:

other: As this was a human clinical study, it was conducted in compliance with Good Clinical Practice Regulations. Prior to its conduct, the protocol for this study was reviewed by an Institutional Review Board in Accordance with CFR, Title 21, Parts 50 and 56.

Version / remarks:

none

Deviations:

no

Remarks:

no

Principles of method if other than guideline:

The test substance was tested for the potential to cause dermal sensitization in a human repeat insult patch test (HRIPT) using a panel of 203 subjects. In the induction phase, a solution of the test substance was applied to the back of the subjects three times a week for three weeks. After 24 hours of exposure to each patch, the subjects removed the patches All sites were then scored for irritation at 48-72 hours after patch application. The induction phase was followed by a 10-17-day rest period. The subjects were subsequently challenged by application of patches at naïve sites on the back and the response was evaluated at 48 and 96 hours after challenge. Potential sensitization to the test substance was determined based on dermal reactions to the challenge patches.

GLP compliance:

yes

Remarks:

As this was a human clinical study, it was conducted in compliance with Good Clinical Practice Regulations. Prior to its conduct, the protocol for this study was reviewed by an Institutional Review Board in Accordance with CFR, Title 21, Parts 50 and 56.

Type of study:

other: HRIPT (modified Draize procedure)

Justification for non-LLNA method:

The test substance was tested for the potential to cause dermal sensitization in a human repeat insult patch test (HRIPT)

Species:

human

Sex:

male/female

Details on test animals and environmental conditions:

Test subjects:
-Sex: male and female
-Number of Subjects: 245 persons were screened for the study; 241 (44 males and 197 females) persons were enrolled and 203 (40 males and 163 females) subjects completed the study.
-Subjects Failing to Complete the Study: A total of thirty-eight subjects failed to complete the study. Nineteen subjects withdrew from the study because they missed two induction applications. Twelve subjects withdrew from the study because they missed the challenge application. Four subjects withdrew from the study following an adverse event. One subject each withdrew from the study because they were inadvertently enrolled while taking an anti-inflammatory drug, they were unable to remove the patches by themselves, or they did not like how the patches felt against their skin.

Study Dates:
-Study Initiation Date: 9 April 2001
-Experimental Completion Date: 29 June 2001

Key result

Reading:

rechallenge

Hours after challenge:

48

Group:

test chemical

Dose level:

0.5%

No. with + reactions:

2

Total no. in group:

203

Clinical observations:

Only slight erythema was observed for one to seven subjects at any given time during the induction phase of the study and for only one subject during the challenge phase of the study

Remarks on result:

no indication of skin sensitisation

Key result

Reading:

rechallenge

Group:

negative control

Dose level:

None

No. with + reactions:

0

Total no. in group:

0

Clinical observations:

none

Remarks on result:

not measured/tested

Key result

Reading:

rechallenge

Group:

positive control

Dose level:

none

No. with + reactions:

0

Total no. in group:

0

Clinical observations:

none

Remarks on result:

not measured/tested

Under the conditions of this study, di (2-ethylhexyl) terephthalate was found to be non-irritating. Only slight erythema was observed for one to seven subjects at any given time during the induction phase of the study and for only one subject during the challenge phase of the study. Di (2-ethylhexyl) terephthalate did not elicit contact dermal sensitization in any individual completing the study. Based on an absence of adverse effects in this study, di (2-ethylhexyl) terephthalate is not classified for “Skin Sensitization” according to GHS.

Interpretation of results:

not sensitising

Conclusions:

Under the conditions of this study, di (2-ethylhexyl) terephthalate was found to be non-irritating. Only slight erythema was observed for one to seven subjects at any given time during the induction phase of the study and for only one subject during the challenge phase of the study. Di (2-ethylhexyl) terephthalate did not elicit contact dermal sensitization in any individual completing the study.

Based on an absence of adverse effects in this study, di (2-ethylhexyl) terephthalate is not classified for “Skin Sensitization” according to GHS.

Executive summary:

Di (2-ethylhexyl) terephthalate (0.5% in acetone) was applied at a dose volume of 0.2 mL to the backs of 203 panelists three times a week for three weeks in a human repeat insult patch test (HRIPT). The application sites were semi-occluded, using a non-woven cotton pad (Webril) held in place on all sides by a strip of hypoallergenic tape (Micropore). Subjects removed the patches after approximately 24 hours. All sites were scored for irritation approximately 48 -72 hours after each patch application. After the three week induction period, the panelists were allowed to rest for up to 17 days and a single open challenge was conducted using naïve sites on the backs of the subjects. The dermal responses in the challenge portion of the study were scored at both 48 and 96 hours after application. Under the study conditions, di (2-ethylhexyl) terephthalate was found to be essentially non-irritating and did not elicit a dermal sensitization reaction.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

The potential for di (2-ethylhexyl) terephthalate to cause dermal sensitization is well understood. In a human repeat insult patch test conducted according to acceptable scientific methodology and Good Clinical Practices, 203 test subjects were induced by application of 0.2 mL of a 0.5% solution of the test material to the back of each test subject three times a week for three weeks. The application sites were semi-occluded and patches were evaluated for signs of irritation at 48-72 hours after application. Only slight erythema was observed for one to seven subjects at any given time during the induction phase. Following a single open challenge application using naïve sites on the back, only one subject exhibited erythema. Under the conditions used in this study, di-(2-ethylhexyl) terephthalate did not elicit dermal sensitization. In a non-guideline supporting study conducted according to an internal Eastman Kodak Company method in which guinea pigs were induced with di (2-ethylhexyl) terephthalate using the footpad technique and challenged seven days later via dermal application, there was no increased incidence of erythema or edema in any animal.

Justification for classification or non-classification

No evidence of a sensitization response was observed when human volunteers were induced with di (2-ethylhexyl) terephthalate by application of 0.2 mL of a 0.5% solution of the test substance to the back three times a week for three weeks under semi-occlusive contact and then challenged at naïve sites on the back following a 10-17 day rest period. In addition, there was no evidence of a sensitization response when guinea pigs were immunized with di (2-ethylhexyl) terephthalate by the footpad technique and challenged via dermal application. Di (2-ethylhexyl) terephthalate was not previously classified under Directive 67/548/EEC, i.e., Annex I of the Dangerous Substances Directive for skin sensitization. Based on a weight-of-the-evidence assessment, di (2-ethylhexyl) terephthalate would not be classified for skin sensitization 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.