BAMM Developments

Derivation of No Significant Risk Levels for Three Lower Acrylates: Conclusions and Recommendations from an Expert Panel

A panel of toxicology, mode of action (MOA), and cancer risk assessment experts was engaged to derive no-significant-risk-levels (NSRLs) for three lower acrylates: methyl acrylate (MA), ethyl acrylate (EA), and 2-ethylhexyl acrylate (2EHA) using the best available science, data, and methods. The review was structured as a five-round, modified Delphi format, a systematic process for collecting independent and deliberative input from panel members, and it included several procedural elements to reduce potential sources of bias and groupthink. Input from the panel for key decisions in the dose-response assessments resulted in NSRL values of 530 ug/day (330-800 ug/day), 640 ug/day (280-670 ug/day), and 1700 ug/day (1300-2700 ug/day) for MA, EA, and 2EHA, respectively. Novel to this approach were the use of nonneoplastic lesions reported at point of contact where tumors have been reported in laboratory rodents, along with nonlinear extrapolation to low doses (uncertainty factor approach) based upon panel recommendations. Confidence in these values is considered medium to high for exposures applied to the routes of exposure tested (inhalation for MA and EA, dermal for 2EHA), but confidence is considered lower when applied to other routes of exposure. Publication

Cancer weight of evidence for three lower acrylates: Conclusions and recommendations from an expert panel

An international panel of experts was engaged to assess the cancer weight of evidence (WOE) for three lower acrylates: methyl acrylate, ethyl acrylate, and 2-ethylhexyl acrylate. The review was structured as a three-round, modified Delphi format, a systematic process for collecting independent and deliberative input from panel members, and it included procedural elements to reduce bias and groupthink. Based upon the available science, the panel concluded: (1) The MOA for point of contact tumors observed in rodent cancer bioassays that is best supported by available data involves increased cell replication by cytotoxicity and regenerative proliferation; (2) The WOE supports a cancer classification of “Not likely to be carcinogenic to humans” a conclusion that is more in line with an IARC classification of Group 3 rather than Group 2 B; (3) Quantitative cancer potency values based on rodent tumor data are not required for these chemicals; and (4) Human health risk assessment for these chemicals should instead rely on non-cancer, precursor endpoints observed at the point of contact (e.g., hyperplasia). The degree of consensus (consensus scores of 0.84–0.91 out of a maximum score of 1) and degree of confidence (7.7–8.7 out of a maximum score of 10) in the WOE conclusions is considered high. Publication

Encyclopedia of Toxicology Updates for Methyl Acrylate, Ethyl Acrylate and n-Butyl Acrylate

Encyclopedia of Toxicology has issued updates for Methyl Acrylate, Ethyl Acrylate and n-Butyl Acrylate in its 4th Edition.

  • Murphy Sandra R., and Hunt Elizabeth K. (2024)) Methyl acrylate. In: [Wexler], [Phillip] (ed.) Encyclopedia of Toxicology 4th Edition, Vol. [6], Oxford: Elsevier, pp. 237-244.
  • Murphy Sandra R., and Hunt Elizabeth K. (2024)) Ethyl acrylate. In: [Wexler], [Phillip] (ed.) Encyclopedia of Toxicology 4th Edition, Vol. [4], Oxford: Elsevier, pp. 443-450.
  • Murphy Sandra R., and Hunt Elizabeth K. (2024)) Butyl acrylate. In: [Wexler], [Phillip] (ed.) Encyclopedia of Toxicology 4th Edition, Vol. [2], Oxford: Elsevier, pp. 337-342.

Genotoxicity of methyl acrylate and ethyl acrylate and its relationship with glutathione

Abstract Methyl acrylate (MA) and ethyl acrylate (EA) had previously tested positive for mutagenicity in vitro, but in vivo studies were negative. One of the metabolism pathways of alkyl acrylates is conjugation with glutathione. The glutathione availability is restricted in standard in vitro test systems so that they do not reflect the in vivo metabolism in this respect. We investigated whether the addition of glutathione to the in vitro L5178Y/TK+/− mouse lymphoma mutagenicity test prevents alkyl acrylate’s mutagenicity in vitro. We also investigated whether the quantitative relationships support the notion that the GSH supplemented in vitro systems reflect the true in vivo activity. Indeed, glutathione concentrations as low as 1 mM completely negate the mutagenicity of MA and EA in the L5178Y/TK+/− mouse lymphoma mutagenicity test up to the highest concentrations of the two acrylates tested, 35 µg/ml, a higher concentration than that previously found to be mutagenic in this test (14 µg MA/ml and 20 µg EA/ml). 1 mM Glutathione reduced the residual MA and EA at the end of the exposure period in the mutagenicity tests by 96–97%, but in vivo up to 100 mg/kg body weight MA and EA left the glutathione levels in the mouse liver and forestomach completely intact. It is concluded that the in-situ levels of glutathione, 7.55±0.57 and 2.84±0.22 µmol/g mouse liver and forestomach, respectively, can efficiently protect against MA and EA-induced mutagenicity up to the high concentration of 100 mg MA and EA/kg body weight and that the negative in vivo mutagenicity tests on MA and EA reflect the true in vivo situation. Publication

California OEHHA Issues Notice to List Chemicals by the Labor Code Mechanism

On June 11, 2021, California’s Environmental Protection Agency’s Office of Environmental Health Hazard Assessment (OEHHA) published a Notice of Intent to List Chemicals by the Labor Code Mechanism.  OEHHA’s proposed listing includes Methyl Acrylate (MA) and 2-Ethylhexyl Acrylate (2-EHA).  This listing is “ministerial” and is based solely on the IARC Group 2B classifications for these substances.  BAMM strongly believes that the IARC classifications for MA, 2-EHA as well as Ethyl Acrylate are erroneous and misleading, and are based on poor science and a flawed process.  For example, IARC did not take into account the high dosage and associated corrosion effects in certain studies or the genetic deficiencies in the animals used for other studies.  In short, the observed tumors in animal studies are not relevant to humans.  Therefore, BAMM believes an IARC Group 2B listing (and Proposition 65 listing) is inappropriate, unwarranted and misleading. BAMM Comments

Ethyl Acrylate (EA) exposure and thyroid carcinogenicity in rats and mice with relevance to human health

Ethyl acrylate (EA) was classified by IARC as a Group-2B Carcinogen based, in part, on data suggesting increased incidence of thyroid neoplasia in rats and mice exposed chronically to EA vapors. We examined chronic exposure of rats and mice to EA vapors, evaluated the data on the incidence of thyroid follicular neoplasia, and determined the relevance of thyroid tumors to human health risk. The data revealed a small statistically significant increase in thyroid tumors in EA-exposed male rats and mice. The tumor incidences were within the range of historical controls and were not consistently dose-dependent. Most thyroid tumors in exposed animals were benign. Chronic exposure of EA to rats and mice (drinking water or gavage) and dogs (capsules) had no evidence of thyroid neoplasia. Results from chronic studies, in vivo and in vitro data, and ToxCastTM/Tox 21 HTPS did not support genotoxic/mutagenic potential for EA. This suggests that the associations between EA exposure and thyroid neoplasia represent chance or random observations rather than a compound-mediated effect. Due to species-specific physiological differences, the hypothalamic-pituitary-thyroid axis of rodents is more sensitive to endocrine disruptive chemicals than that of humans which further suggests that findings in rodents have questionable relevance to human health. Publication

Comprehensive Analysis of Chronic Rodent Inhalation Toxicity Studies for Methyl Acrylate

Methyl Acrylate is a chemical intermediate, manufactured and processed within closed systems. While so far available subacute to chronic inhalation toxicity studies performed in compliance with OECD TG principles gave no indication of any carcinogenic potential for MA, a recent 2-year inhalation study with F344/DuCrlCrlj rats published in 2017 by the JBRC showed a statistically significant increase of squamous cell carcinoma in the nasal cavity of male rats at the highest tested concentration of 160 ppm. However, the results of the different studies in total indicate that this high concentration exceeded the MTC. As MA has a low potential for genotoxic and mutagenic activity, the increased tumour incidence can be attributed to a non-genotoxic mechanism, namely to a strong inflammatory response observed in this study. Together with mechanistic and epidemiologic data for other compounds related to nasal carcinogenesis via this mode of action, it can be concluded that the relevance of this increased tumour incidence in male rats for humans is questionable. Also, a long-term exposure to higher concentrations of MA is highly unlikely to be reached in the environment or at workplaces. Therefore, a risk for humans including cancer hazard is considered implausible. Publication

Murine Skin Carcinogenesis and the Role of Immune System Dysregulation in the Tumorigenicity of 2-Ethylhexyl Acrylate

Some chemicals act as human carcinogens in various organ systems including the skin. Mice have been an ideal model to study a wide variety of chemical carcinogens because the pathogenesis in that species often mirrors that in humans. However, different mouse strains vary in their susceptibility to these agents. Thus, reliance on a single strain may lead to inaccurate findings. 2-Ethylhexyl acrylate (2-EHA) is an acrylate used as a co-monomer in the production of polymer resins for adhesives, latex paints, cross-linking agents, finishes for textiles and leather, and paper coatings. Monomer exposure may occur in occupational settings where it is produced or used; the only exposure that may occur to consumers or construction personnel is trace amounts in the final polymer product. There are no reports of cancer in humans caused by exposure to 2-EHA. However, 2-EHA has been reported to cause cancer in one strain of mice. This is an important issue since recommendations about its safety in humans depend, in part, on information derived from animal studies. We reviewed the literature on the preclinical effects of acrylates on skin carcinogenesis in C3H/HeJ mice, which can be criticized because of peculiarities in the immunological composition of that strain, the lack of rigorous histopathologic characterization of tumors that developed, the high doses of 2-EHA that were used for evaluation, and the lack of reproducibility in a second strain of mice. The C3H/HeJ mouse model is not ideal as it has a mutation in Toll-like receptor 4 (TLR4) that impairs its innate and adaptive immune responses. Inconsistencies in the histological evaluation of tumors induced in C3H/HeJ mice provide further evidence that the tumorigenic effect of 2-EHA was strain specific, a result of chronic inflammation during the promotion stage and/or a skewed immune response caused by the TLR4 mutation. In conclusion, 2-EHA has not convincingly been demonstrated to have skin carcinogenic activity to date. More relevant mouse models that mimic human squamous cell carcinoma, basal cell carcinoma, and melanoma with amounts that do not exceed a maximum tolerated dose are needed to assess the carcinogenic effects of 2-EHA. Publication

BAMM Statement Regarding the Recent IARC Cancer Classifications for Three Acrylates (July 9, 2018)

The International Agency for Research on Cancer (IARC) has announced the cancer classifications made at its June 5-12, 2018 meeting. This includes classifications for three acrylates represented by BAMM. Ethyl acrylate (EA) remains in Group 2B (“possibly carcinogenic to humans”). Methyl acrylate (MA) and 2-ethylhexyl acrylate (2EHA) also have been classified as Group 2B.

BAMM strongly believes that the Group 2B classifications for MA, EA, and 2EHA are erroneous and misleading, based on poor science and a flawed, non-transparent process. All these substances are well studied and the evidence strongly shows they are highly unlikely to cause cancer in humans. BAMM member companies stand behind the safety of their acrylates for their intended uses. Acrylates are building blocks for polymers used to produce goods that for decades have provided added benefits and convenience to consumers and manufacturers worldwide, such as acrylic paints and textiles, water purification substances, and self-adhesive bandages. Click here for full statement.

Also see the following publications:

BAMM's Position on Use of Acrylates in Artificial Nail Products

The Basic Acrylic Monomer Manufacturers, Inc. (BAMM) represents U.S. manufacturers1 of acrylic acid (AA) and its esters (including ethyl acrylate (EA), methyl acrylate (MA), n-butyl acrylate (n-BA), iso-butyl acrylate (i-BA), and 2-ethylhexyl acrylate (2EHA)). 

To our knowledge, these substances are not monomer ingredients in nail products.  BAMM’s members believe that the use of these substances, in unreacted monomeric liquid form, would not be appropriate for use in artificial nail products--the corrosive properties of the acid and skin sensitization properties of the esters contraindicate their use in such products.  See BAMM's position paper.

IARC Advisory Group Prioritizes Ethyl Acrylate for Review

During its April 2014 meeting, the IARC Advisory Group recommended priorities for IARC Monographs during 2015-2019. Ethyl Acrylate is included as a “High priority” chemical.   As stated on page 22 of the IARC report:

Ethyl acrylate is an industrial chemical and synthesis intermediate for many consumer products. It was evaluated by IARC in 1986 and again in 1999 (Volumes 39 and 71) and listed in Group 2B (possibly carcinogenic to humans). Ethyl acrylate was also listed as a carcinogen in experimental animals for many years by the NTP Report on Carcinogens, based on the occurrence of forestomach tumours in rats and mice in conjunction with significant toxicity in studies where the chemical was administered by gavage. Cancer studies using other routes of exposure gave negative results. There have been many mechanistic studies carried out over the years suggesting that the forestomach-tumour response may be related to irritation and the proliferative cellular response to deposition of the material in the stomach, calling into question the relevance of this finding to human health hazards.

Recommendation:  High priority

See below for more information about IARC's classification of Ethyl Acrylate:

REACH

REACH is the European Union (EU) regulation for Registration, Evaluation, Authorisation and Restriction of Chemicals. It entered into force on June 1, 2007 with the objective to protect human health and the environment from the risks that can be posed by chemicals.

The Acrylate REACH Task Force, comprised of BAMM member companies along with other manufacturers in the EU and Japan, completed the registration of the lower acrylates (AA, n-BA, i-BA, t-BA, EA, MA) and 2-EHA as a group of related esters (category) in 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.