Sensitization
Technical Summary:
Short chain alkyl-methacrylate esters (MMA, EMA, nBMA, iBMA and 2-EHMA) are high production volume chemicals and have been reviewed extensively under EU and OECD Existing Chemicals Risk Assessment programs. MMA has been the subject of an EU Risk Assessment (2002) and OECD review (2007). EMA, nBMA, iBMA and 2-EHMA underwent review as a category in the OECD SIAR program (2009). Data on MAA, the common metabolite, has also been reviewed in the EU Risk Assessment (2002).
Drawing from the OECD SIAR (Summary Initial Assessment Report) on short chain alkyl-methacrylate esters and including information on MMA from the EU and OECD reviews we can conclude the following:
All short chain alkyl-methacrylate esters (MMA, EMA, nBMA, iBMA and 2-EHMA) appear to give equivocal results in adjuvant studies in guinea pigs and, on balance, they may be regarded as weak contact sensitizers. Short chain alkyl-methacrylate esters have been reported to cross-react with other methacrylate esters, but not with acrylate esters.
Methacrylate esters are generally regarded by dermatologists as skin sensitizing and consequently EMA and n-BMA are often included in dermatological patch tests when exposure to (meth)acrylates is suspected. Despite this, very few cases of confirmed contact allergy to EMA or BMA esters have been reported in the literature appearing to confirm that the contact sensitizing potential of these esters is low. As in animals, methacrylate esters can cross-react with other methacrylates but not with acrylates in humans.
Considerably more human data are available on the more widely used ester, MMA. The EU and OECD risk assessment on MMA extensively reviewed the available human information and concluded "There have been numerous reports on skin sensitization in certain occupational environments, where frequent and prolonged unprotected skin contact with monomer containing preparations was common practice. In the literature cases of sensitization of patients with implanted acrylic bone cement, of patients with hearing aids and of persons using synthetic fingernails have been reported."
Methacrylic acid, the common hydrolysis product for these methacrylate esters, is not a contact allergen (ECETOC, 1996; OECD 2002).
In 2006, Betts and co-workers published a paper on the potency of MMA to induce contact allergy in the Local Lymph Node Assay (LLNA) and reviewed prevalence data for published clinical studies on contact allergy due to MMA in humans (i.e. Rustemeyer T and Frosch P J, 1996 (also as Peiler et al., 1996); Schnuch and Geier, 1994 and Kiec-Swierczynska, 1996). Based upon the low potency of MMA to induce allergy in the LLNA assay and in observing that there was a positive bias to inclusion of sensitized individuals in the test cohort used in these studies, thereby overstating actual prevalence, Betts concluded that MMA "has only a relatively weak potential to cause the acquisition of skin sensitization" (Betts et al., 2006).
In 2014 Kimber and Pemberton reviewed the available LLNA, guinea pig, in silico in vitro and clinical (human) skin sensitization data on MMA and a series of related lower alkyl methacrylate (LAM) esters including EMA, nBMA, iBMA and 2-EHMA with a view to determining their skin sensitizing potency. They found that MMA and other LAM are contact allergens but had weak skin sensitizing potency. They also found that the clinical prevalence of allergic contact dermatitis (ACD) to these chemicals was low compared with the numbers of individuals exposed and that the greater incidence of ACD in certain industries, like the dental industry, was likely the result of extended and intimate exposure (Kimber and Pemberton, 2014).
As a result of the increased interest in, and requirement for, non-animal assays for skin sensitization, Kimber reviewed the ability of a number of non-animals assays including validated in vitro assays and consideration of quantitative structure-activity relationships (QSAR) to predict the outcome of traditional assays for skin sensitizing potential, including guinea pig maximisation test (GPMT) and mouse local lymph node (LLNA). Kimber found that available data on 11 methacrylate esters (including MMA, EMA, nBMA, iBMA, 2-EHMA and methacrylic acid) supported the conclusion that there is a strong correlation between the results of validated in vitro assays (Direct Peptide Reactivity Assay (DPRA), ARE-Nrf2 luciferase test methods, and – with some chemicals – a dendritic cell activation test, the myeloid U937 Skin Sensitisation test [U-SENS] assay) and traditional animal tests using guinea pigs and mice, but that QSAR approaches (DEREKandTIMES-SS) often over-predicted hazard potential (Kimber, 2019).
References:
Betts C, Dearman RJ, Heylings JR, Kimber I and Basketter DA: Skin sensitization potency of methyl methacrylate in the local lymph node assay: comparisons with guinea-pig data and human experience. Contact Dermatitis Volume 55 Issue 3, Pages 140 - 147.
Kiec-Swierczynska, M.: Occupational allergic contact dermatitis due to acrylates in Lodz. Contact Dermatitis 34(6) 419-422 (1996).
Kimber, I., 2019. The activity of methacrylate esters in skin sensitisation test methods: A review. Regulatory Toxicology and Pharmacology, Volume 104, June 2019, Pages 14-20
Kimber, I., Mark A. Pemberton: Assessment of the skin sensitising potency of the lower alkyl methacrylate esters. Regulatory Toxicology and Pharmacology Volume 70, Issue 1, October 2014, Pages 24-36.
Peiler D, Rustemeyer T, Frosch P J. Dermatitis in dental technicians - irritation and allergy. Gemeinschaftstagung der DKG, des IVDK unde der ABD der DKG, p93 (1996).
Rustemeyer T, Frosch P J. Occupational skin diseases in dental laboratory technicians - 1) clinical picture and causative factors. Contact Dermatitis 34 125-133 (1996).
