Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

The animal studies were either in full or limited compliance with OECD guideline 406 for the guinea pig maximization or Buehler test, with exception of one study. This study is a modified Buehler study (Stepan, 1983), which did not include a negative control. Therefore, the results could not be interpreted sufficiently and the study was rated as ‘not reliable’ (Klimisch 3) i.e. excluded from evaluation. The human volunteer studies were conducted in line with the respective and broadly accepted testing protocol according to the method of Stotts (1980) under the supervision of expert dermatologists.

Three out of the 9 remaining Buehler tests were rated as ‘not reliable’ (Klimisch 3). While compliant with the testing guidelines, a high level of irritation was observed (Kao (1989b), Cognis (1991) and Cognis (1995a)) in test and control animals. Since no re-challenge was conducted in these studies, no clear conclusion can be drawn and therefore a Klimisch code of 3 was assigned.

One out of the three Maximisation studies is also rated as ‘not reliable’ (Klimisch 3) because all control animals showed irritating reactions which were even more severe than those seen in the test animals. Again, due to the potential masking effect of irritation, no clear assessment of the skin sensitising potential can be made from this study (Cognis, 1990a).   

Reliable studies, evaluated according to the requirements for classification & labelling (67/548 and GHS) are summarized in the table below.

One Bühler study (Cognis, 1994d) revealed positive reactions in > 15 % out of 20 animals with a challenge concentration of 10 % test substance. Grades were at the lower end of the scale i.e. grades ≤ 1.

A re-challenge with 3 % test substance revealed slight reactions (≤ grade 1) in only three animals on only one side of their flanks. The negative control groups showed each time no reactions. Since a reaction is only regarded as positive, if they appear on both flanks and since the grade has not increased in severity, this reaction may reflect irritation rather than sensitisation. This also correlates with the reduced challenge concentration.

However, taking the number of animals having reacted positively at 10% challenge into consideration, the classification & labeling cut off level of 15 % was met. Due to the grades being on the lower end of the scale the findings in this study reflect a weak sensitisation.

 

The result of another Buehler study (Cognis, 1994c) was considered ambiguous for the following reasons: A challenge concentration of 3 % resulted in reactions in the test and negative control group on both flanks. This observation was confirmed at re-challenge with the same concentration. A re-challenge with 1 % test substance was evaluated negative, as no effects were observed on the right flank (which one is recommended for treatment by the OECD guideline 406). However, reduced reactions only at one time point and with grade 1 in 3/20 animals were observable only on the left flank. Also, inconsistent pattern and in most cases rapid fading of responses were observed at challenge and re-challenge in test and control animals. These findings may reflect irritation rather than sensitisation.

There were 4 negative Bühler studies and 2 negative Maximisation studies, with proper performed intradermal and dermal induction concentrations, adequate challenge concentration and clean negative controls. There was no evidence for a sensitisation potential from these studies, i.e. the sensitisation rates were 0%.

There was no evidence for a skin sensitisation potential from the two Human Repeated Insult Patch Tests involving a total of 208 volunteers.

 

Table16: Reliable sensitisation studies with different methods

Method

fully

saturated  

TEA-EQ

partially unsaturated TEA-EQ

oleic acid-based 

TEA-EQ

Bühler

2 negative

 

2 negative

1 ambiguous        

1 weak sensitizer

 

 

Maximisation

(Magnussen and Kligman)

 

1 negative

 

1 negative

 

Human HRIPT

2 negative studies

with a total of 208 volunteers

 

 

  

Discussion:

A weight of evidence approach covering all three TEA-Esterquats is used for evaluation. It is considered suitable to include all three TEA-Esterquats, differing mainly in the degree of saturation of fatty acid moiety, in the weight of evidence approach.

There is no indication from available specifications, to link the weak positive findings in theBühler studies to differences in the degree of saturation of the underlying alkyl chain in the partially unsaturatedTEA-Esterquats.Therefore the result of this weight of evidence approach is justified to be valid without restrictions for this whole TEA-Esterquat group.

 

According to “Guidance on information requirements and chemical safety assessment Chapter R.7.3.4.2” reliable and relevant human data should be used for hazard identification and are even preferable to animal data. Adjuvant-type tests are likely to be more accurate in predicting a probable skinsensitizing potential of a substance in humans than those methods not employing Freund’s Complete Adjuvant and are thus the preferred of guinea pig methods (Council Regulation EC No 440/2008).

Under REACH, the LLNA is the preferred method for new developed skin sensitisation studies. Existing data of good quality deriving from guinea pig tests will be acceptable and will, if providing clear results, preclude the need for further in-vivo testing (Guidance on information requirements and chemical safety assessment Chapter R.7.3.3.1). Therefore no LLNA has been conducted with a TEA-Esterquat.

Considering the reliable studies, one study of the Bühler type was evaluated as weak positive and one of them was considered ambiguous because an inconsistent pattern of response was observed as outlined below. Further 4 Bühler studies and 2 guinea pig maximization tests were negative for skin sensitization as defined by Directive 67/548/EEC and GHS.

The interpretation of results for those studies which were evaluated to be positive for skin sensitisation were complicated through the occurrence of a partly inconsistent pattern and in most cases rapid fading of response. Evaluation of response was hampered due to irritation and the absence of a clean negative control. The studies rated with Klimisch 3 were not included in the evaluation,because no clear conclusion with regard to classification and labelling could be drawn. Considering the studies with clean negative controls, proper performed induction with 100 % test substance or mild to moderate irritating concentrations, there was no (0%) evidence for a skin sensitisation potential of the TEA-esterquats.

None of the 2 studies involving exposures of a total of 208 human volunteers to TEA-Esterquats was considered to induce a skin sensitisation response in humans.

The ability of chemicals to penetrate the human skin is a pre-requisite to cause a skin sensitisation response. Due to the relatively high molecular weight and physico-chemical properties the dermal penetration of TEA-Esterquats can be considered to be very low as outlined in chapter 5.1 toxicokinetics.

In conclusion, there was no evidence that the investigated TEA-Esterquats induced and/or elicited skin sensitisation responses in humans or the more accurate predicting adjuvant-type method in animals. Equivocal results were observed in the Bühler studies.Taking all evidence from available human and animal data together and emphasising the results of human data and data from guinea pig maximization test, the weight of evidence suggests, that TEA-Esterquats do not represent a skin sensitisation hazard and therefore none of the registered TEA- Esterquats need to be classified for skin sensitisation according to Directive 67/548/EEC or GHS Regulation EC No 1272/2008.

A comparable conclusion is also drawn in the HERA Risk Assessment Report (RAR), where the TEA-Esterquats as well as two other substance classes of the Esterquat family (HEQ and MDEA-Esterquat) have been evaluated. The whole Esterquat family was judged to be non-sensitizing in the HERA RAR.


Migrated from Short description of key information:
The skin sensitisation potential of TEA-Esterquats has been evaluated on the basis of a total of 13 animal studies (3 Maximisation and 10 Buehler
tests) and 2 human HRIPT studies using a weight of evidence approach.

Respiratory sensitisation

Endpoint conclusion
Additional information:
Migrated from Short description of key information:
No data are available

Justification for classification or non-classification

In conclusion, the weight of evidence approach suggests that based on the available animal- and human-based studies, neither of the TEA-Esterquats represent a skin sensitisation hazard and hence there is no need to classify & label TEA-Esterquats according to Directive 67/548/EEC or GHS Regulation EC No 1272/2008.