MPA Other Developments
Identification of true chemical respiratory allergens: current status, limitations and recommendations
Asthma in the workplace is an important occupational health issue. It comprises various subtypes: occupational asthma (OA; both allergic asthma and irritant-induced asthma) and work-exacerbated asthma (WEA). Current regulatory paradigms for the management of OA are not fit for purpose. There is therefore an important unmet need, for the purposes of both effective human health protection and appropriate and proportionate regulation, that sub-types of work-related asthma can be accurately identified and classified, and that chemical respiratory allergens that drive allergic asthma can be differentiated according to potency. In this article presently available strategies for the diagnosis and characterisation of asthma in the workplace are described and critically evaluated. These include human health studies, clinical investigations and experimental approaches (structure-activity relationships, assessments of chemical reactivity, experimental animal studies and in vitro methods). Each of these approaches has limitations with respect to providing a clear discrimination between OA and WEA, and between allergen-induced and irritant-induced asthma. Against this background the needs for improved characterisation of work-related asthma, in the context of more appropriate regulation is discussed. Publication
Evidential Requirements for the Regulatory Hazard and Risk Assessment of Respiratory Sensitisers: Methyl Methacrylate as an Example
The European Chemical Industry Council (Cefic) Methacrylates Sector Group (MSG) and the Methacrylate Producers Association, Inc. (MPA) commissioned a workshop in October 2021 during which an independent Expert Panel discussed the hazard assessment of chemicals as respiratory sensitisers illustrated through a case study on Methyl Methacrylate (MMA). The conclusions reached by the Panel and the manuscript that followed solely reflect the discussion, views and conclusions of the panel members. Publication
The Expert Panel recognised the considerable quantity and complexity of the toxicological, clinical and other data available on MMA and felt that in the time available to them that they could not make a final conclusion on whether or not MMA should be classified as a respiratory sensitiser. Nevertheless, the Expert Panel recognised it significant that “ in those sectors in which there are anticipated high exposures to MMA for long periods of time (e.g. cast acrylic sheets industry and floor coating sector; Section 3.2.1), there have been no reports of OA caused by MMA” (OA – Occupational Asthma) and that “information from the published literature indicates that dental technicians and nail beauticians may be exposed to a wide range of dusts and (volatile) chemicals and thus to much lower levels of airborne MMA than workers in the cast acrylic sheets industry or floor coating sector. …These mixed exposures could explain why OA was seen in the dental sector, but not in the other sectors.” The “overall low incidence of OA in populations that may be exposed to MMA (see above) and the evidence that MMA is a weak dermal sensitiser” was considered by the Expert panel as potential justification “that the irritant MoA (mode of action) may be the most important mechanism for the development of respiratory effects caused by MMA”.
In consideration of the complexity of the evidence on MMA, the Expert Panel was motivated to make general recommendations including specifically the “need for a framework to increase the consistency, objectivity and transparency in the regulatory assessment of respiratory sensitisers and associated uncertainties”. In their view, such framework should contain a “formal documentation of the weight-of-evidence for hazard classification both at the level of integration of individual studies within lines of evidence and across a broad range of data streams was agreed to be critical for such a framework”. Also, they propose the integration of all relevant data into a “weight-of-evidence protocol against pre-defined considerations” and the use of modified Bradford Hill considerations to assess causality. Furthermore, that regulatory “conclusions should be based on transparent weighting of relevant data on the observed prevalence of occupational asthma in various studies taking into account all relevant information including the range and nature of workplace exposures to the substance of interest, co-exposure to other chemicals and study quality”. In this regard Cefic MSG and MPA draw a parallel between these recommendations and the existing requirements of the CLP guidance for classification for respiratory sensitisation.
Reflecting upon the data available for MMA, the Expert Panel identified further aspects for such a weight-of-evidence (WoE) assessment that are of specific relevance for MMA:
- The “interpretation of results of human case reports and epidemiological studies for assessment of individual chemicals is often complicated by co-exposures to complex mixtures”, especially when the “specific composition of the applied products [in SIC[1] tests] was not disclosed”.
- “fundamental knowledge gaps [in the underlying science e.g. in regard to the timing of asthmatic responses] complicate, then, the assessment of whether a substance causes the development of OA as opposed to the aggravation of pre-existing or coincidentally acquired asthma.”
- “human studies may provide some information on respiratory hypersensitivity, [however] the data are frequently limited” (citation of ECHA (2017a) Endpoint-Specific Guidance and referring to SIC tests), as, for example, “it is not known to which specific substances workers were exposed since substance characterisation may be difficult to undertake in the clinical setting” and “SIC tests do not enable decisions to be made on whether a positive response is more likely due to an immune reaction or to irritation”
- “reliable information on the frequency (incidence) of reported effects in exposed populations was an important element for the assessment”
- For “asthmatic responses [that] are observed upon exposure to high levels of a respiratory irritant, it cannot be excluded with confidence that the asthmatic response indicates causation and not merely provocation”.
- “considerations on the concordance of dose-response relationships across different data sources and lines of evidence [and industry sectors] also support the evaluation whether the effects observed in (selected) case reports are causally linked to exposure to the substance of interest.” linked to the ECHA (2017a) guidance statement that “…where there is reliable (e.g. supported by medical surveillance reports) evidence that a large cohort of subjects has had opportunity for regular significant inhalation exposure to a substance for a sustained period of time in the absence of respiratory symptoms, or related health complaints, then this will provide reassurance within a WoE approach regarding the absence of a respiratory sensitisation hazard”.
[1] Specific Inhalation Challenge test
Methyl methacrylate and respiratory sensitisation: a comprehensive review
Methyl methacrylate (MMA) is classified under GHS as a weak skin sensitiser and a skin and respiratory irritant. It has recently been proposed that MMA be classified as a respiratory sensitiser (a designation that in a regulatory context embraces both true respiratory allergens, as well as chemicals that cause asthma through non-immunological mechanisms). This proposal was based primarily upon the interpretation of human data. This review, and a detailed weight of evidence analysis, has led to another interpretation of these data. The conclusion drawn is that persuasive evidence consistent with the designation of MMA as a respiratory sensitiser is lacking. It is suggested that one reason for different interpretations of these data is that occupational asthma poses several challenges with respect to establishing causation. Among these is that it is difficult to distinguish between allergic asthma, non-allergic asthma, and work-related exacerbation of pre-existing asthma. Moreover, there is a lack of methods for the identification of true chemical respiratory allergens. The characterisation and causation of occupational asthma is consequently largely dependent upon interpretation of human data of various types. Recommendations are made that are designed to improve the utility and interpretation of human data for establishing causation in occupational asthma. Publication
Classification of chemicals as respiratory allergens based on human data: Requirements and practical considerations
Occupational asthma is an important health problem that can include exacerbation of existing asthma, or induce new asthma either through allergic sensitisation, or non-immunological mechanisms. While allergic sensitisation of the respiratory tract can be acquired to proteins, or to low molecular weight chemicals (chemical respiratory allergens) this article is on the latter exclusively. Chemical respiratory allergy resulting in occupational asthma is associated with high levels of morbidity and there is a need, therefore, that chemicals which can cause sensitisation of the respiratory tract are identified accurately. However, there are available no validated, or even widely accepted, predictive test methods (in vivo, in vitro or in silico) that have achieved regulatory acceptance for identifying respiratory sensitising hazards. For this reason there is an important reliance on human data for the identification of chemical respiratory allergens, and for distinguishing these from chemicals that cause occupational asthma through non-immunological mechanisms. In this article the reasons why it is important that care is taken in designating chemicals as respiratory allergens are reviewed. The value and limitations of human data that can aid the accurate identification of chemical respiratory allergens are explored, including exposure conditions, response characteristics in specific inhalation challenge tests, and immunological investigations. Publication
The activity of methacrylate esters in skin sensitization test methods II. A review of complementary and additional analyses
Allergic contact dermatitis is an important occupational health issue, and there is a need to identify accurately those chemicals that have the potential to induce skin sensitisation. Hazard identification was performed initially using animal (guinea pig and mouse) models. More recently, as a result of the drive towards non-animal methods, alternative in vitro and in silico approaches have been developed. Some of these new in vitro methods have been formally validated and have been assigned OECD Test Guideline status. The performance of some of these recently developed in vitro methods, and of 2 quantitative structure-activity relationships (QSAR) approaches, with a series of methacrylate esters has been reviewed and reported previously. In this article that first review has been extended further with additional data and complementary analyses. Results obtained using in vitro methods (Direct Peptide Reactivity Assay, DPRA; ARE-Nrf2 luciferase test methods, KeratinoSens and LuSens; Epidermal Sensitisation Assay, EpiSensA; human Cell Line Activation Test, h-CLAT, and the myeloid U937 Skin Sensitisation test, U-SENS), and 2 QSAR approaches (DEREKTM-nexus and TIMES-SS), with 11 methacrylate esters and methacrylic acid are reported here, and compared with existing data from the guinea pig maximisation test and the local lymph node assay. With this series of chemicals it was found that some in vitro tests (DPRA and ARE-Nrf2 luciferase) performed well in comparison with animal test results and available human skin sensitisation data. Other in vitro tests (EpiSensA and h-CLAT) proved rather more problematic. Results with DEREKTM-nexus and TIMES-SS failed to reflect accurately the skin sensitisation potential of the methacrylate esters. The implications for assessment of skin sensitising activity are discussed. Publication
Methacrylates Use in Nail Enhancements
The Methacrylate Producers Association, Inc. (MPA) and its member companies work jointly to address important health, safety and environmental issues involving the basic methacrylate monomer products. MPA has been aware of the use of liquid methacrylate monomers in nail enhancement products for many years and has a long-standing position of not supporting the use of these chemicals in these applications on grounds that they are skin sensitizers and direct contact between the liquid monomer and the nail or skin cannot be completely avoided. Despite this policy, basic methacrylates continue to be used in these products. Growing concerns over adverse health effects in cosmetologists and consumers, combined with the range and complexity of nail products in the marketplace, encouraged MPA to investigate in greater depth the extent of use of the basic methacrylates in these products. Since neither MPA nor its member companies have any involvement in the manufacture or sale of artificial nail enhancement products, MPA commissioned an independent researcher to summarize the information readily available from the internet, existing reviews and publications. Click here for White Paper.
The activity of methacrylate esters in skin sensitisation test methods: A review
Skin sensitisation associated with allergic contact dermatitis is an important occupational and environmental disease. The identification of skin sensitisation hazards was traditionally performed using animal tests; originally guinea pig assays and subsequently the murine local lymph node assay (LLNA). More recently there has, for a variety of reasons, been an increased interest in, and requirement for, non-animal assays. There are now available both validated in vitro assays and a variety of approaches based on consideration of quantitative structure-activity relationships (QSAR). With the increased availability and use of non-animal alternatives for skin sensitisation testing there is a continuing need to monitor the performance of these approaches using series of chemicals that do not normally form part of validation exercises. Here we report studies conducted with 11 methacrylate esters and methacrylic acid in which results obtained with 3 validated in vitro tests for which there are OECD guidelines (the 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) have been compared with QSAR approaches (DEREK and TIMES-SS), and with LLNA and guinea pig maximisation test (GPMT) data. The conclusions drawn from these data are that – with this series of chemicals at least – there is a strong correlation between the results of animal tests and the in vitro assays considered, but not with either DEREK or TIMES-SS. Click here for publication.
Epidemiologist Concludes that MMA is Not Associated with Cancer Risk
Methyl methacrylate (MMA) is a “monomer” used as a raw material to make various “polymers”, which are plastics and resins used in many important applications. Persons who work in facilities that manufacture MMA or that manufacture polymers with MMA can be exposed to MMA.
Epidemiology studies are used to investigate the relationship between, for example, exposure to a chemical in the workplace and the occurrence of diseases, such as a specific type of cancer. A cancer mortality study compares the observed rate of cancer mortality in the group of individuals being studied with the rate of cancer mortality in the general population with the same age, sex distribution and, if possible, life-style habits, etc. Since there are many risk factors for developing cancer, including, age, genes, immunity, viruses and life styles (smoking, drinking, sunbathing and diet), the design, conduct and interpretation of epidemiology studies is complex.
To date six epidemiology studies have been conducted on occupational (worker) populations with exposure to MMA and reported in the open, scientific literature. Four studies were commissioned by industry on workers in the MMA-monomer production and/or PMMA sheet production industry (polymerized MMA). Two studies were made on orthopedic surgeons, some of which implant medical devices based upon MMA and PMMA (i.e., bone cements).
Collectively, no consistent elevations of specific cancer types were reported across the available studies. The production industry investigations found an increase in colorectal cancer in early studies, but this was not confirmed in follow-up or more extensive studies. In the studies on orthopedic surgeons, an increased cancer rate for esophagus and myeloproliferative cancers was reported in one study and increased breast cancer in another. Overall the epidemiology studies do not support a causal link between these cancers and MMA exposure. First, these cancer types were not elevated in the larger studies conducted by industry as would be expected if there was a causal relationship between MMA and cancer in humans. Second, independent review of these studies by a recognized epidemiologist, Dr. G. Swaen, identified limitations in the methodology used in the orthopedic surgeon studies that make a conclusion of a causal relationship between MMA exposure and cancer unreliable (Swaen, 2019).
With this recent opinion, Dr. Swaen confirmed the conclusion of Dr. J. Tomenson and coworkers in 2005. They concluded that the available human data are not in support of an increased cancer risk from occupational exposure to MMA, based on an exhaustive review of the then available epidemiologic literature. Dr. Swaen goes on to highlight that in his opinion the industry studies conducted in the United States and Great Britain were of sufficient size, statistical power and design, that they still represent the most comprehensive information available on the occurrence of cancer in humans exposed to high concentrations of MMA, and that they demonstrate that exposure to MMA, even at relatively high concentrations, is not associated with cancer risk.
Canadian Government Finds Methacrylic Acid and n-butyl methacrylate Pose Low Risks to Human Health and the Environment
In October 2018, Health Canada (HC) and Environmental and Climate Change Canada (ECCC) released the results of their screening assessment of “the acrylates and methacrylates group.”[1] That group comprised six substances, including methacrylic acid (MAA) and n-butyl methacrylate (n-BMA). HC and ECCC concluded that the six substances, including MAA and n-BMA, “are not entering the environment in a quantity or concentration or under conditions that have or may have an immediate or long-term harmful effect on the environment or its biological diversity or that constitute or may constitute a danger to the environment on which life depends.”[2] They also concluded these substances “are not entering the environment in a quantity or concentration or under conditions that constitute or may constitute a danger in Canada to human life or health.” [3]
The Methacrylate Producers Association (MPA) concurs with these conclusions. MAA and n-BMA are used as building blocks for polymers and are used up in the production of the polymers. The general public would have exposure to very few, if any, products containing MAA or n-BMA themselves, except for very low residual levels in polymers. Thus, a statement that a given final product (e.g., a plastic, coating or lubricant) contains MAA or n-BMA may mean that these monomers are used to produce polymers that in turn are used to make the final product. Readers are urged to evaluate statements about MAA and n-BMA use accordingly.
Regarding the use of liquid, unreacted methacrylate monomers in cosmetics, see MPA’s statement.
[1] Environmental and Climate Change Canada and Health Canada. Screening assessment acrylates and methacrylates group (October 2018), https://www.canada.ca/en/environment-climate-change/services/evaluating-existing-substances/screening-assessment-acrylates-methacrylates-group.html.
[2] Id., synopsis.
[3] Id.
Toxicological Assessment of Lower Alkyl Methacrylate Esters by a Category Approach
The health effects of lower alkyl methacrylate esters (methyl, ethyl, n-butyl, iso-butyl and 2-ethylhexyl) are well understood. MMA has the most comprehensive data set and although the data on the other esters is more limited their close structural similarity to MMA enables prediction of their hazard properties without the need to conduct unnecessary testing in animals. This is commonly referred to as the “reading across” of data between a group of structurally related chemicals or “category”. In an attempt to promote the use and consistency of Read Across within the EU REACH[1] process the EU Regulatory Agency has issued an Assessment Framework, referred to as the RAAF (ECHA, 2017[2]). In response MPA sponsored a study of the health effects data on lower alkyl methacrylate esters (C1-C8) and an assessment of how well the RAAF criteria could be satisfied. This study was published in a peer reviewed journal and is available under open access for download at https://doi.org/10.1016/j.yrtph.2017.11.013.
The study confirmed that these chemicals have similar structures, chemical reactivity and fate within the body and consequently Read Across could be used to fill in data gaps for health effects with high confidence. By developing Read Across for these chemicals MPA member companies have gained a far deeper insight into the health effects of lower alkyl methacrylate esters that can be used to better promote their safe handling and use.
[1] https://echa.europa.eu/regulations/reach/legislation
[2] European Chemicals Agency, 2017. Read-Across Assessment Framework (RAAF). https://echa.europa.eu/documents/10162/13628/raaf_en.pdf
Lower alkyl methacrylate esters are shown not to be of concern for cancer
Lower alkyl methacrylate esters1 are chemically-reactive molecules that are used to produce methacrylate-based plastics and resins. Their chemical reactivity (Michael reactivity) results in them combining with proteins such that they can be skin sensitizers in humans. This chemical reactivity also means that they can potentially react with other macromolecules such as DNA; raising the question of whether they might cause genetic damage; and therefore, be of concern for cancer.
To investigate this question, MPA sponsored Dr. Richard Albertini, an independent and eminent genotoxicity expert at the University of Vermont, to review the extensive studies on the lower alkyl methacrylates and publish his findings in a peer-reviewed journal. Dr. Albertini found that in studies in bacteria, which are often used to identify chemicals that might cause cancer in humans, the lower alkyl methacrylates did not cause permanent alterations in DNA. In tests using animal cells in glassware (in vitro) with very high concentrations of the methacrylates, there was disruption or breakages of chromosomes, but Dr. Albertini concluded there was no convincing evidence that the lower alkyl methacrylates cause this type of damage in live animals. This is consistent with the lack of carcinogenicity of methyl methacrylate observed in studies of both animals and humans. Dr. Albertini explained the observation in glassware as likely being due to the high concentrations and to generation of metabolites under these artificial conditions – metabolites that do not occur in animals and humans when exposed to these chemicals. Overall, Dr. Albertini concluded that lower alkyl methacrylate esters are not of concern for cancer.
1The lower alkyl methacrylates are methyl methacrylate (MMA), the largest volume monomer, as well as ethyl methacrylate (EMA), hydroxyethyl methacrylate (HEMA), n-, i- and t-butyl methacrylate (BMA) and 2 ethyl hexyl methacrylate (2-EHMA), as well as methacrylic acid (MAA).
Statement Regarding AOEC Classification of Methyl Methacrylate
In its online Exposure Code database, the Association of Occupational and Environmental Clinics (AOEC) codes methyl methacrylate (MMA) as an asthmagen and respiratory sensitizer. A number of thorough and careful evaluations of MMA have concluded it cannot be classified as an asthmagen or respiratory sensitizer.
The AOEC exposure codes, which were assigned by a single reviewer, do not comport with the findings of other scientific bodies. The Methacrylate Producers Association believes that the science does not support a finding that MMA is an asthmagen or a respiratory sensitizer. For more information, see MPA's position paper.
Department of Transportation and Congress Set New Rail Transportation Rules Applicable to Methyl Methacrylate
With a final rulemaking by the Department of Transportation (DOT) in May 2015, which was modified by a subsequent Act of Congress in December 2015, the Department and Congress set new safety rules for rail transportation of flammable liquids. Although primarily targeting crude oil and ethanol shipments, the rule applies to shipment of all Class 3 flammable liquids and thus to methyl methacrylate (MMA). MPA had commented on the Department’s proposed rules, expressing concern about the need for such rules given the methacrylate industry’s voluntary adoption of higher-safety tank cars, as well as the foreshortened and likely unrealistic timeline proposed for implementing required retrofits (or obtaining new tank cars built to the new DOT-117 specifications). DOT’s final rule was not adequately responsive to such concerns. Congress stepped in with provisions in the” Fixing America’s Surface Transportation Act” (FAST Act) which modified the DOT rule. For Packing Group II substances such as MMA, improved tank cars must be used for transport after May 1, 2029, consistent with MPA’s comments requesting an extended period for implementation of the new rules. DOT can extend this deadline by two years if it determines there is insufficient shop capacity to meet the 2029 deadline. Further, in lieu of meeting the full DOT-117 standards, retrofitted tanks cars may comply with DOT-117R standards, which many tanks cars in MMA service already meet. The voluntary adoption of tank car enhancements by MMA members has contributed to an outstanding safety record for rail transportation of MMA.
ACGIH® Recommended TLVs for Methyl Methacrylate
In response to recent announcements by American Conference of Governmental Industrial Hygienists (ACGIH), MPA comments to ACGIH supporting the recommended Threshold Limit Values (TLVs) for Methyl Methacrylate (MMA). These limits are consistent with occupational exposure limits set by the European Union SCOEL (Scientific Committee on Occupational Exposure Limits). However, two statements concerning potential respiratory and skin sensitization have been included that are not supported by a wider evaluation of the literature, and could lead to misunderstanding by ACGIH’s intended audiences.
Health Review on Asthma
The health effects of MMA are well understood. MMA liquid is recognized as being irritating to the eyes and is a weak skin-sensitizer that may cause skin allergy (allergic contact dermatitis) following skin contact. High concentrations of the vapor are also irritating to the respiratory system. As irritant vapors (cold air, smoke etc.) may worsen the symptoms in individuals that have sensitive airways, such as asthmatics it is not surprising that there has been much debate and confusion about whether or not MMA exposure can also cause respiratory sensitization (occupational asthma). Dr. Jonathan Borak, MD, DABT (Departments of Epidemiology and Public Health and Medicine, Yale University) conducted a critical review all the available information and the results are included in a publication in Critical Reviews in Toxicology in which he concludes that the "weight of evidence" supports the conclusion that "MMA is not a respiratory sensitizer". For for information, see Methacrylates and Asthma.
REACH
REACH is the European Union (EU) regulation for Registration, Evaluation, Authorisation and Restriction of Chemicals. It entered into force on 1st June 2007 with the objective to protect human health and the environment from the risks that can be posed by chemicals.
The Methacrylates REACH Task Force, comprised of MPA’s member companies along with other manufacturers in the EU and Japan, successfully completed the registration of the lower methacrylates (MAA, MMA, EMA, nBMA, iBMA and 2-EHMA) as a group of related esters (or category) in October 2010, before the December 1st deadline for high production volume chemicals (>1000 tpa). The registrations included the conduct of several studies to meet data requirements for compounds in the highest tonnage band, a comprehensive hazard assessment for each compound, as well as an assessment of safe handling conditions for identified uses of each compound.
Assessment of the Skin Sensitizing Potency of the Lower Alkyl Methacrylate Esters
A 2014 publication in Regulatory Toxicology and Pharmacology, "Assessment of the skin sensitising potency of the lower alkyl methacrylate esters" reports that Methyl Methacrylate and other lower alkyl methacrylates had weak skin sensitizing potency.
Methacrylate Polymers Do Not Cause Skin Sensitization When Handled
A 2014 publication in Regulatory Toxicology and Pharmacology, "Risk Assessment of residual monomer migrating from acrylic polymers and causing allergic contact dermatitis during normal handling and use" reports that methacrylate polymers do not cause skin sensitization when handled.
For more information, see MPA Archived Developments.
