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:

Skin sensitisation

Ten sensitisation studies were performed. Among these the outcomes of 4 studies were rated as ambiguous. The other 6 were rated as “Not sensitising”. The studies were performed with IQACs based on different fatty acid species. The results rated as ambiguous were derived from 1 study with oleic acid as fatty acid moiety, 2 with palm oil and 1 with tallow fatty acids. One study (with an ambiguous result) was performed with an oleic-acid based IQAC, DMS quaternised (CAS-No. 72749-55-4); the other substances were partially unsaturated IQAC, DMS quaternised (palm oil based; 4 studies: CAS-No. 98219-51-3) or (tallow fatty acids based; 2 studies: CAS-No. 86088-85-9 and 3 studies: CAS-No.68122-86-1).

 

Experimental studies on skin sensitisation; different methods

 

LLNA

MK

Bühler

oleic-acid based IQAC, DMS quaternised

 

1 ambiguous, (2)*

 

partially unsaturated IQAC,DMS quaternised

1 not sensitising (1)

1 ambiguous (1)

1 ambiguous (3)

1 not sensitising (1)

1 not sensitising (2)

1 ambiguous (3)

3 not sensitising (2)

 

*:Klimisch rating

Of the studies rated as ambiguous, 2 were performed with the LLNA and 2 with the Magnuson-Kligman Maximization test. Of the results rated as “Not sensitising” one was obtained with a variant of the LLNA test, including a challenge test, 3 with the Buehler test and 2 with the standard Magnuson-Kligman Maximization test.

The reasons for rating the studies as ambiguous were technical insufficiencies and lack of differentiation between irritation and sensitisation as the test group and the controls showed similar incidences of erythema and squamation (Evonik, 1983). In a second study the concentration of the test substance was too high to clearly differentiate between irritation and allergic response in an LLNA (Evonik, 2008) and the interpretation of the result was further compromised due to the observed inconsistency in the results induced at high levels of irritation which clearly mask the possibility to distinguish between a true immunologically mediated memory response and a non-immunologically mediated irritation effect.

The test was further found to be inconclusive due to the missing measurement of ear thickness on the day of the challenge application.

 

In a dermal sensitisation study (Evonik, 2008) with a partially unsaturated IQAC, DMS quaternised, (palm oil based; CAS-No. 98219-51-3, purity 100%) in methyl ethyl ketone, groups of 5 female CBA/CaOlaHsd mice were tested using the LLNA method according to OECD Guideline 429. Positive control substance was alpha hexyl cinnamic aldehyde, which gave a positive result (STIMULATION INDEX (S.I.) of 3.03) at a concentration of 25 % in acetone: olive oil, 4:1 (w/v).

Stimulation indices of 17.20, 13.34 and 11.72 were determined with the test item at concentrations of 2.5, 5 and 10 % (w/v), respectively.

A test item is regarded as a sensitizer in the LLNA if the exposure to at least one concentration of the test item results in an incorporation of 3HTdR at least 3-fold or greater than that recorded in control mice, as indicated by the stimulation index.

On the basis of the stimulation indices (S.I.) of 17.20, 13.34, and 11.72 determined at concentrations of 2.5, 5, 10 % (w/v), respectively, a sensitising activity of the test item might be supposed. However, the unusual inverse dose-response prompts questions whether the increased incorporation of 3H-TdR seen is really based on a sensitising activity of the test item.

For further evidence regarding the question whether the obtained effect is truly of a sensitising nature an additional LLNA test with challenge was initiated. In this experiment, a sensitising activity of the test item could not be confirmed (Evonik, 2008).

 

In a dermal sensitization study with oleic-acid based IQAC, DMS quaternised (Evonik, 1984), young adult Pirbright white guinea pig (10 female) were tested using the Maximisation Test.

In a small scale pilot study, necrosis occurred after intradermal application of 10, 5, 1, or 0.5 % (v/v) solutions in 2/2 animals each and moderate reddening (score 2) after application of a 0.1 % (v/v) aqueous solution in 2/2 animals. The dermal application of the undiluted test item caused moderate to diffuse erythema (score 2) in 3/3 animals; 50, 25, and 10 % aqueous solutions (v/v) discrete slight erythema (score 1) in 3/3 animals each, and a 5 % (v/v) aqueous solution no skin reactions.

Based on the results of this small scale pilot study, for the intradermal and epicutaneous induction procedure test substance concentrations of 0.1 % and 10 % were used, respectively. The test article concentration for the challenge procedure was 5 %.

After intradermal induction, animals showed discrete slight erythema (score 1) to intense erythema and swelling (score 3). 48 hours after epicutaneous induction, almost all animals showed discrete slight erythema (score 1).

After challenge, 9/10 and 8/10 animals of the test group, exhibited discrete slight erythema (score 1) at the first and the second scoring, respectively. At both scorings all animals showed scaling.

Skin effects were also seen in the negative control after challenge. At the 48 and the 72 hours scoring 1/5 animals showed discrete slight erythema (score 1) and 3/5 and 5/5 showed scaling at these scorings, respectively.

As 90 and 80 % of the test animals showed skin reactions at the first and second scoring after challenge treatment, respectively, the test item has been judged by the study author as strong sensitising agent. However, as seen in the pilot study, the test substance is a strong local irritant/corrosive material especially when applied intradermally.

The reaction after intradermal induction was more intense than mild to moderate (discrete slight erythema (score 1) to intense erythema and swelling (score 3) occurred). Furthermore, in the non-induced negative controls skin reactions in the form of discrete slight erythema (score 1) in 1/5 animals and scaling in 5/5 animals occurred. This result shows that the threshold levels for induction of strong irritation were difficult to reproduce and to control. This prompts question whether the concentrations used for intradermal induction and challenge were appropriate.

In addition, as the intracutaneous pre-treatment with complete adjuvant also increases the sensitivity of the test system for primary skin irritation, it is recommended to verify allergic reactions as such reactions or to separate them from the primary irritating effects by a re-challenge with lower test concentrations. However, such a re-challenge was not included in the test procedure.

Therefore, it cannot be decided whether the reactions seen in this study after challenge treatment are really based on a sensitising activity or rather on the irritating activity of the test item.

 

In the “NATIONAL INDUSTRIAL CHEMICALS NOTIFICATION AND ASSESSMENT SCHEME; FULL PUBLIC REPORT, Varisoft 3690” by the National Occupational Health and Safety Commission of Australia 1999 (NICNAS 1999) an Assessment of the sensitising potential of Varisoft 3690 (CAS-No. 72749-55-4; Oleic-acid based IQAC, DMS quaternised) has been presented. As reference compound Varisoft 475 (CAS-No. 68122-86-1; partially unsaturated IQAC, DMS quaternised (based on tallow fatty acids) was discussed. Three lots of the test substance were studied at 1% concentration in the Buehler test, in which two lots were evaluated as non-sensitising and one lot as sensitising and one test substance tested at 5 % was evaluated as sensitising. While the results on the two lots tested as non-sensitisers were reported in detail, conducted with concomitant controls and containing a challenge experiment, this was not the case with the third lot where the reported data were rather limited and did not include information on control animals. The test performed at 5 % concentration was only submitted as an abstract so that the claim of a sensitising potential cannot be reconstructed.

Further, a Human Repeat Insult Patch Test conducted with apartially unsaturated IQAC, DMS quaternised (based on tallow fatty acids; Test lot with 90 % a.i.) (was submitted as a summary of the test results. NICNAS cites 217 volunteers receiving 9 exposures to an induction concentration of 0.25 % aqueous partially unsaturated IQAC, DMS quaternised (tallow fatty acids, 0.3 mL/occluded patch) applied for a 24 hour period, three times a week during a three week induction period and after two weeks later a challenge dose of 0.25% aqueous solution of the test substance applied in a single 24-hour occluded patch. It is reported that none of the volunteers were sensitised to partially unsaturated IQAC, DMS quaternised (tallow fatty acids; 90 %).

NICNAS has evaluated the available information and state that based on these results, a skin sensitisation potential of oleic-acid based IQAC, DMS quaternised (CAS-no. 72749-55-4) cannot be discounted. The difficulties in discerning irritative from truly sensitising effects may not have been considered sufficiently in this context. The proof of evidence for a sensitising potential of this substance class is very limited and contradictory, so that no firm conclusion can be drawn.

In summary it can be concluded that the majority of the studies conducted with different representatives of the IQAC structural family and with due consideration of skin irritation as a potential confounder, have proven that these substances are not to be regarded as skin sensitisers.

No studies have been reported where a clear evidence for a skin sensitising potential could be demonstrated while excluding the confounding effect of significant skin irritation.

The OECD TG 429 refers to confounding factors - like irritation - believed to play a role in an observed increase of false positives in the LLNA when looking at e.g. Surfactants.

 

The majority of the studies were judged to be of good quality and reliability. The animal studies were either in full compliance or partly compliant with OECD guideline 429 (LLNA) or 406 (guinea pig maximization or Buehler test). One Maximisation Test and one LLNA were rated as ‘not reliable due to significant methodological deficiencies’ (Klimisch rating 3). While broadly compliant with the testing guidelines, a high level of irritation was observed in several studies in test and control animals. This could have masked a potential skin sensitisation response or impacted on the overall study outcomes. These studies were dismissed from final evaluation, because no reliable conclusion, with regard to classification and labelling, can be drawn from these studies.

Reliable studies, evaluated on the base of the requirement for classification as skin sensitizer were negative with respect to a skin sensitising potential.

Discussion:

Following the Integrated Testing Strategy (ITS) according to Guidance on information requirements and chemical safety assessment, Endpoint specific guidance, Chapter R. 7.2.6 there is sufficient information available to proceed with classification and labelling using a weight of evidence approach for all IQACs studied.

It is considered suitable to include all IQACs in the weight of evidence approach., the IQACs differing mainly in the fatty acid moiety

In conclusion the weight of the evidence suggests that neither of the IQACs represents a skin sensitisation hazard to humans and hence there is no need to classify according to Directive 67/548/EEC as well as GHS Regulation EC No 1272/2008 and labelling is not required.

Justification for read-across:

The structural similarities between the source and the target substances are the basis for the read-across hypothesis. Adequate, reliable and available scientific information indicates that the source and target substances have similar physicochemical properties and toxicity profiles and thus support the read-across hypothesis.

Acute oral toxicity for source substance (partially unsaturated IQAC, DMS quaternised) and target substance (oleic-acid based IQAC, DMS quaternised) is comparably low. Also the skin irritation and sensitizing potential is similar. There is no potential for point mutations and chromosome aberrations indicated by data from both substances.

Therefore, based on the considerations above, it can be concluded that read-across within this weight of evidence approach is justified without restrictions and Read-across is adequate to fulfil the information requirements of Annex VII 8.3 (sensitisation).

 

A more detailed justification for read-across is outlined in a separate document:

“Justification for read-across - toxicological information”, is attached to the endpoint summary acute toxicity and provided in chapter 13 of Technical dossier.

 


Migrated from Short description of key information:
No skin sensitisation hazard was identified

Justification for selection of skin sensitisation endpoint:
The endpoint was evaluated by a weight of evidence approach; therefore no single study was selected.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available (further information necessary)
Additional information:

Due to the low vapour pressure of the IQACs, the low concentration in aerosols generated in car wash applications and the absence of indications for skin sensitisation, a respiratory sensitisation potential of the test substance can practically be excluded.


Migrated from Short description of key information:
A respiratory sensitisation potential of the test substance can practically be excluded.

Justification for classification or non-classification

Based on the results of the dermal sensitization studies according to OECD guidelines 406 and 429 there is no need for classification of IQACs according to EU criteria and GHS requirements with respect to skin sensitisation. On the basis of absence of skin sensitisation and the very low vapour pressure of the test substance family there is no need to classify the test substance with respect to respiratory sensitisation.