Registration Dossier

Administrative data

Description of key information

The available GPMT data with LMA are either negative or flawed. The results of the Buehler occluded patch test are not interpretable and provide no evidence for LMA having skin sensitising potential. The negative result of the LLNA with test concentrations of up to 25% of LMA failing to elicit a positive response confirms the opinion that LMA has no evidance to cause skin sensitisation.
These test results were confirmed based upon the available experience of human exposure to lauryl methacrylate (LMA). There is no evidence to suggest that it has the potential to cause skin sensitisation.

Justification for selection of skin sensitisation endpoint:
No single key study has been selected: instead, all available studies have been used in a weight-of-evidence approach.

Key value for chemical safety assessment

Skin sensitisation

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

Data regarding skin sensitization is available for mixtures containing C12 up to C22 MA, and for pure docosyl methacrylate. These data are covering almost the whole category except for C20 MA which was just tested in a mixture containing ~10% and is assessed within this category approach. For sensitization, the relevant molecular inducing event is the electron accepting capacity of the double bond on the methacrylate moiety leading to reaction with proteins. The adverse outcome pathway is Michael addition of the electrophilic ester to macromolecules in the target cells. In RAAF nomenclature, this approach is described in Scenario 6 (i.e., no variation between category members; different compounds which have the same type of effect). For the long chain methacrylates the reactivity is substantially modulated by the substance specific dermal permeability and metabolism rate in the skin layers. The relevant mode of action for sensitization and metabolism of methacrylates to MAA and the corresponding alcohol are well understood, thus there is low bias that influences the prediction since all category members show the same pattern confirming the common underlying mechanism. The decreasing polarity and resulting decreasing skin permeability reduce the amount of long-chain esters that potentially penetrate through the stratum corneum and could form haptene-proteine complexes to a minimum. Following skin penetration, the esters are rapidly hydrolyzed by esterases (proven for esters up to EHMA (C8) and indicated for LMA (C12); for esters with longer chain length of the alcohol moiety experimental prove is technically not feasible). The primary metabolites MAA and the corresponding alcohols are not sensitizing in animal studies, thus ester cleavage has to be considered as a detoxification pathway in terms of sensitization.

Formally, on the first glance there is some bias influencing the prediction since for few esters there have been (false) positive outcome generated. Various studies of the data set which partly stand against the afore described considerations regarding bioavailability and mode of action were additionally assessed by an external, reputable expert. In single cases, the suspicion of being a skin sensitizer couldn´t be averted on the existing data basis and therefore additional studies according to recent guidelines were conducted.

Today the LLNA is often used as a benchmark, however knowing the accuracy of the LLNA is incomplete (Basketter et al., 2009) a Weight of Evidence evaluation for skin sensitization (Ball, 2011) is recommended for some cases (AOP -OECD, 20XX).

On the basis of the whole dataset, the physicochemical properties of the esters in combination with experimentally proven dermal absorption and metabolism in skin and a further assessment by an external expert the read across using a category approach is done with a high level of confidence.

The general conclusions drawn are that there are no compelling animal data to suggest that Lauryl methacrylate (LMA) has a significant potential to cause skin sensitisation. The available GPMT data are either negative or flawed. The results of the Buehler occluded patch test are not interpretable and provide no evidence for LMA having skin sensitising potential. The results of a LLNA-test with methacrylic acid ester 13.0 (CAS: 90551-76-1, 2 -propenoic acid, 2-methyl-, C12-16-alkyl esters) according to OECD 429 was negative. The top concentration of the assay was 25% in acetone:olive oil (4 +1).

There are three GPMT tests conducted independently with lauryl methacrylate:

The first of these was conducted by Safepharm Laboratories Ltd (UK) and reported in 1999. In this investigation the test material was identified as Empicryl 6047, this being methacrylic acid esters of aliphatic alcohols with a chain length C10 to C16 - with the content of C12 (lauryl) being between 64% and 80%. The study was conducted using a conventional design. Induction was with 25% (id) and 50% (topical). Subsequent challenge was performed with 75% of the test material. There was no evidence of any reactivity and the sensitisation rate was recorded as being 0%. On the basis of these data the conclusion is that Empicryl 6047 (LMA) lacks skin sensitisation potential.

 

A second GPMT was commissioned by Norsolor and reported by Consultox Laboratories Ltd (UK) in 1980. This used an unconventional study design; the most important point being that there is no indication that any control (non-sensitised) animals were challenged. Certainly the report contains no control data. 

Animals were sensitised with the test material using 2% (id), and with an unknown concentration by topical application. Subsequently test animals were challenged with a 10% dispersion of the test material. At 48 hours following challenge 2 of 11 test animals had scores of 1 (scattered mild erythema), and another 2 animals displayed grade 2 reactions (moderate diffuse erythema). This gives an overall sensitisation score of 4/11 (36%). These data should be discounted for two main reasons. First because no control animals were used, and in the absence of such controls it is not possible to conclude that challenge would not have resulted in an equivalent frequency of grade 1 and 2 erythema in naive recipients. This is very poor practice and a lack of appropriate controls is sufficient to invalidate this test. 

However, there is a second issue and this relates to the fact the reactions displayed by 4 of the 11 test animals following challenge were detectable only after 48 hours and had disappeared by 72 hours. A pattern such as this is suggestive of irritation rather than allergic contact dermatitis.

 

Finally, there is a report in the scientific literature of an unconventional GPMT reported by Kanazawa et al (Contact Dermatitis 40: 19-23, 1999). In these studies groups of 5 to 10 guinea pigs were exposed to LMA over a concentration range of 4 orders of magnitude (from approximately 25ppm to 0.0003ppm). The lowest concentration found to induce a positive response (in 3 of 10 guinea pigs) was equivalent to 0.025ppm. These data are rather strange insofar as they would serve to indicate a very extreme potency that is out of keeping with all other available data and human experience. Against that background, and in view of the fact that: (a) no control animals appear to have been used (very poor practice as indicated above), and (b) no details are supplied of how dermal reactions were assessed, it is reasonable to discount these data as being unreliable.

 

 

Occluded Patch Test of Buehler

 

There is one (modified) Buehler test of LMA available for inspection. This was conducted DuPont Haskell Laboratory (USA) and reported in 1993. This is a largely conventional Buehler study employing 20 test animals and 10 controls. The induction was conducted with undiluted test material, and 75% in mineral oil used for challenge. The study proved difficult to interpret because following first challenge reactions ranging from slight patchy redness (+) to moderate redness (2) were observed in both test and control animals (indicative of primary irritation caused by challenge). In the test group 14 of 20 guinea pigs displayed some grade of reaction at 24 and/or 48 hours, and in the control group each of 10 animals displayed some reaction at one or both time points. It is standard practice in such situations to perform a subsequent re-challenge of both groups of animals, and this was requested by the sponsor. For this purpose a concentration of 50% was used and animals were re-challenged 9 days following the primary challenge. Again there were no differences between the test animals and controls. Thus, 16 of 20 test animals displayed reactions at one or more time points examined (24, 48 and 72 hours) and some of these were sporadic and of low grade intensity. Only 5 control animals were re-challenged and of these 4 of 5 displayed reactions at one or more time points. On the basis of the challenge and re-challenge test data there is no evidence that the test material (LMA) was able to cause skin sensitisation. Although the report attempts to make a case - based on small differences in the observed grades of reaction - that there was some net response in test animals compared with controls, this is not sustainable. The conclusion drawn in the report that "the test article may possibly be a dermal sensitiser in this study" is unjustified.

Local Lymph Node Assays

 

A LLNA was conducted using a conventional protocol (conforming with OECD TG 429) by Harlan GmbH, and reported in 2009. The test article was delivered in a 4:1 mixture of acetone and olive oil (AOO) with the selected test concentrations being (w/v) 5%, 10% and 25%. At none of these test concentrations was an SI of 3 or greater achieved relative to concurrent vehicle control values (5% = SI of 0.99; 10% = SI of 2.11; 25% = 2.66). On this basis the clear interpretation is that the test article lacks the potential to cause skin sensitisation.

 

 

Conclusions

 

The general conclusion drawn from these data is that there is no evidence to suggest that LMA has a significant potential to cause skin sensitisation.


Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:

Respiratory tract sensitisation

Due to the very low vapour pressure of the substances and the resulting lack of significant exposure, respiratory tract sensitisation is not considered as relevant.


Justification for classification or non-classification

The general conclusion drawn from the available data is that there is no evidence to suggest that dodecyl methacrylate (lauryl methacrylate, LMA) has a significant potential to cause skin sensitisation.

 

The available GPMT data are either negative or flawed. The results of the Buehler occluded patch test are not interpretable and provide no evidence for LMA having skin sensitising potential. The negative result of the LLNA with test concentrations of up to 25% of LMA failing to elicit a positive response confirms the opinion that LMA has no evidence to cause skin sensitisation.