3-(2,2-dimethyl-3-hydroxypropyl)toluene

Endpoint summary

Description of key information

Based on a weight of evidence evaluation of all available data the test item is not considered to be a skin sensitiser.

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

There are comprehensive data available on skin sensitising potential of the test item:

 

Local Lymph Node Assays:

 

Report number 2008088, 2008

A study was performed to assess the skin sensitisation potential of the test material in the CBA/Ca strain mouse following topical application to the dorsal surface of the ear. The method was designed to meet the requirements of the OECD Guideline for the Testing of Chemicals No. 429 "Skin Sensitisation: Local Lymph Node Assay" (adopted 24 April 2002) and Method B42 Skin Sensitisation (Local Lymph Node Assay) of Commission Directive 2004/73/EC. Following a preliminary screening test in which no clinical signs of toxicity were noted at a concentration of 100 % v/v, this concentration was selected as the highest dose investigated in the main test of the Local Lymph Node Assay. Three groups, each of four animals, were treated with 50 µl (25 µl per ear) of the undiluted test material or the test material as a solution in acetone/olive oil 4:1 at concentrations of 50 % or 25 % v/v. A further group of four animals was treated with acetone/olive oil 4:1 alone. The Stimulation Index expressed as the mean radioactive incorporation for each treatment group divided by the mean radioactive incorporation of the vehicle control group are as follows:

 

Concentration (% v/v in acetone/olive oil 4:1	Stimulation Index	Result
Vehicle	na	na
25	1.76	Negative
50	1.47	Negative
100	2.20	Negative

 

The test material was considered to be a non-sensitiser under the conditions of the test.

 

 

Report number 2008087, 2008

A study was performed to assess the skin sensitisation potential of the test material in the CBA/Ca strain mouse following topical application to the dorsal surface of the ear. The method was designed to meet the requirements of the OECD Guideline for the Testing of Chemicals No. 429 "Skin Sensitisation: Local Lymph Node Assay" (adopted 24 April 2002) and Method B42 Skin Sensitisation (Local Lymph Node Assay) of Commission Directive 2004/73/EC. Following a preliminary screening test in which no clinical signs of toxicity were noted at a concentration of 100 % v/v, this concentration was selected as the highest dose investigated in the main test of the Local Lymph Node Assay. Three groups, each of four animals, were treated with 50 µl (25 µl per ear) of the undiluted test material or the test material as a solution in acetone/olive oil 4:1 at concentrations of 50 % or 25 % v/v. A further group of four animals was treated with acetone/olive oil 4:1 alone. The Stimulation Index expressed as the mean radioactive incorporation for each treatment group divided by the mean radioactive incorporation of the vehicle control group are as follows:

 

Concentration (% v/v in acetone/olive oil 4:1	Stimulation Index	Result
Vehicle	na	na
25	1.19	Negative
50	1.38	Negative
100	1.44	Negative

 

The test material was considered to be a non-sensitiser under the conditions of the test.

 

Report number 2002073, 2002

A test item was assessed for its skin sensitisation potential using the mouse Local Lymph Node Assay. The assay determines the level of T lymphocyte proliferation in the lymph nodes draining the site of chemical application, by measuring the amount of radiolabelled thymidine incorporated into the dividing cells. The test substance was applied as 3%, 10% or 30% w/v preparations in acetone in olive oil (4:1). The test substance did not have the capacity to cause skin sensitisation when applied as 3%, 10% or 30% w/v preparations in acetone in olive oil. In a positive control study, hexylcinnamaldehyde was shown to have the capacity to cause skin sensitisation when applied as 3% or 10% w/v preparations in acetone, confirming the validity of the protocol used for this study. In conclusion, the test item is unlikely to be a skin sensitiser under the conditions of the test.

 

 

Report number 2002072, 2002

The test item was assessed for its skin sensitisation potential using the mouse Local Lymph Node Assay. The assay determines the level of T lymphocyte proliferation in the lymph nodes draining the site of chemical application, by measuring the amount of radiolabelled thymidine incorporated into the dividing cells. The test substance was applied as 3%, 10% or 30% w/v preparations in acetone in olive oil (4:1). The test substance was shown to have the capacity to cause skin sensitisation when applied as a 30% w/v preparation in acetone in olive oil. In a positive control study, hexylcinnamaldehyde was shown to have the capacity to cause skin sensitisation when applied as 3% or 10% w/v preparations in acetone, confirming the validity of the protocol used for this study. The test item indicates a skin sensitising potential under the conditions of the test.

 

 

Overall, the available LLNA studies with the test item indicate that it does not induce skin sensitisation in mice. All studies are considered valid based on results obtained with the concurrent vehicle and positive controls, respectively. Three out of four tests revealed a negative outcome for skin sensitisation with the test item. One study (Report number 2002072, 2002) indicated a positive result. In this study, the positive response observed was very weak and is rather considered a borderline case (SI = 3.07 at 30 % being the highest concentration tested in this study). Taking into account the three valid LLNA studies indicating a clear negative result, the biological relevance of this solely positive finding is rather questionable. Moreover, the undiluted test item, i. e. 100 %, has been assessed in two independend studies (study 2008087 (2008) and study 2008088 (2008)) and was found negative in both cases. Thus, the existence of a dose response relationship can hardly be anticipated with the test item. The SI of 3.07 in study 2002072 should be thus be considered an outlier.

In conclusion, the LLNA data with the test item provide profound evidence that the test item does not induce skin sensitisation in mice.

 

Guinea Pig Maximisation Tests

There are two guinea pig maximization tests available with the test item, both indicating a negative result. Both studies were performed according to the method of B. Magnusson and A. M. Kligman (OECD-guidelines). To test the sensitizing properties of the test item, 20 test- and 20 control-animals were treated. Any signs of erythema and edema were recorded 24 h and 48 h after the challenge. According to the method of B. Magnusson and A. M. Kligman (OECD-guidelines), the test item was found to not cause hypersensitivity in guinea-pigs in both studies.

However, both GPMT studies are considered to be not reliable (RL 3) for assessment of skin sensitising properties due to methodological limitations in the study design. Diluted material was used (1985162) and the intradermal concentration was higher than the topically applied concentration (1985139). Therefore, in both cases the correct protocol was not followed and only little conclusion can be drawn from the results of these studies.

 

Human Repeat Insult Patch Tests

Two valid and reliable HRIP tests are available (2005048 and 2007018) assessing the skin sensitising potential of the test item in humans. Both studies were conducted according to good clinical practice and are thus attributed to a reliability score 1. The studies were performed with 98 and 103 volunteers, respectively. Results of both studies demonstrated that the test item does not induce skin sensitisation in humans. It is thus concluded that there is no concern in regards to skin sensitisation with the test item.

 

There is also additional clinical literature and associated information available on skin sensitising potential of the test item in humans. Publications reporting the test item as a cause of allergic contact dermatitis (ACD) (please refer to IUCLID Section 7.10.4). Overall, all these published data lack essential criteria that would qualify them as being reliable for classification purposes under CLP. The studies were not conducted under good clinical practice. A definition of the critieria for a positive finding is not provided so that results can hardly be applied for a further assessment. Moreover, there were also individual findings of pre-existing skin sensitisation reported in the HRIP tests, indicating that a cross-sensitivity in humans cannot be completely ruled out. Therefore, it was not conclusively be demonstrated that the positive findings reported in the literature are caused by the test item itself.

Due to these methodological limitations, this data cannot be taken into account for final assessment of skin sensitising properties of the test item.

 

 

Conclusion

Animal studies as well as human exposure studies are availble with the test item assessing its skin sensitising potential. The CLP Regulation statest that:

" Evidence from animal studies is usually much more reliable than evidence from human exposure. However, in cases where evidence is available from both sources, and there is conflict between the results, the quality and reliability of the evidence from both sources must be assessed in order to resolve the question of classification on a case-by-case basis. Normally, human data are not generated in controlled experiments with volunteers for the purpose of hazard classification but rather as part of risk assessment to confirm lack of effects seen in animal tests. Consequently, positive human data on skin sensitisation are usually derived from case-control or other, less defined studies. Evaluation of human data must therefore be carried out with caution as the frequency of cases reflect, in addition to the inherent properties of the substances, factors such as the exposure situation, bioavailability, individual predisposition and preventive measures taken." (Regulation (EC) No 1272/2008 Section 3.4.2.2.4.2.).

As discussed above, the literature data on a skin sensitising potential in humans is not sufficient for classification purposes under CLP due to methodological limitations and is thus disregarded. In contrast, two valid and reliable HRIP tests demonstrate that the test item does not induce skin sensitisaion in humans. This is supported by in vivo animal studies, demonstrating in their majority that the test item does not induce skin sensitisation in mammals.

Therefore, and based on the weight of evidence evaluation of all available data, the test item is concluded to have no skin sensitising potential.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on a Weight of Evidence evaluation of the available data and as discussed above the test item does not require classification as skin sensitiser according to Regulation (EC) No 1272/2008 (CLP), as amended for seventeenth time in Regulation (EU) No 2021/849.