Carcinogenicity

Technical Summary:

Short chain alkyl-methacrylate esters (MMA, EMA, nBMA, iBMA and 2-EHMA) are high production volume chemicals and have been reviewed extensively by government regulatory agencies. None of these reviews have identified these materials as carcinogens. Reviews were completed by European Union 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 CICAD program (2009). Data on MAA, a metabolite common to all of the methacrylate esters, has also been reviewed in the EU Risk Assessment (2002).

Methacrylate esters and methacrylic acid are not active in genotoxicity tests in bacterial and mammalian cells in culture or in studies in experimental animals indicating a low potential to damage DNA and cause cancer.

An early 2-year chronic study on dogs and rats treated orally with MMA revealed no adverse effect other than a lower body weight gain in high-dose dogs and elevated kidney weights in high-dose female rats (Borzelleca et al., 1964). In this study dogs received gelatin capsules with 10, 100 and 1500 ppm MMA dissolved in corn oil. Rats were administered 7, 70 and 2000 ppm MMA in the drinking water. NTP (1986) conducted a carcinogenicity study that showed no treatment-related tumors in male and female F344/N rats and male and female B6C3F1 mice following inhalation exposure to 500 or 1000 ppm MMA for 102 weeks (6 h/d, 5 d/wk). Lomax et al. (1997) reported no treatment-related increases of cancer in rats exposed to 100, or 400 ppm MMA vapors 2 years (6 h/d, 5 d/wk).

Epidemiology studies (retrospective mortality) have been conducted among workers in US and European plants exposed to MMA vapors. Tomenson et al (2005) reviewed epidemiology studies available for MMA and concluded "Excesses of respiratory, stomach and colorectal cancers were observed in some cohorts of workers exposed to MMA. There was little to suggest that MMA exposure was responsible for the excesses of respiratory and stomach cancer and it is more likely that they resulted from unexplained contributions of lifestyle exposures such as cigarette smoking and diet. An excess of colorectal cancer in one group of workers exposed to high levels of MMA and EA during the 1930s and 1940s remains unexplained. However, the lack of consistency in the results of various studies, the absence of dose response and the lack of support from animal toxicology do not provide persuasive evidence that exposure to MMA is a human carcinogen." This confirmed the earlier findings of the International Agency for Research on Cancer (IARC) who concluded that there is evidence suggesting the lack of carcinogenicity of MMA in experimental animals but inadequate evidence in humans (IARC, 1994).

Contrary to this, IARC classified n-butyl methacrylate (n-BMA) as a Group 2B carcinogen (“possibly carcinogenic to humans”) at its monograph #133 meeting in March 2023. IARC acknowledged that there is a lack of an indication for carcinogenicity of n-BMA in humans and no mechanistic evidence underlying potential carcinogenicity was available. However, IARC interpreted Japanese carcinogenicity studies in a way that in B6D2F1/Crl mice, inhalation of n-BMA caused hepatocellular adenoma or carcinoma (combined) and histiocytic sarcoma of all sites in males, and haemangiosarcoma of all sites in females. Furthermore, IARC interpreted that in F344/DuCrlCrlj rats, n-BMA inhalation caused mononuclear cell leukemia of the spleen in males, and C-cell adenoma or carcinoma (combined) of the thyroid gland in females. The observed tumor findings appear however to be incidental and to not provide reliable and relevant evidence for a carcinogenic potential of n-BMA in humans. As recently published, after thorough review of these bioassays, there is no convincing evidence of carcinogenicity for n-BMA, contrary to the conclusion of the JBRC and the decision by the IARC, based on flaws in the interpretation and conclusions of the studies (include citation for publication).

For the category of lower alkyl methacrylate esters, the 2009 OECD review concluded that: 'Although there are no carcinogenicity studies available for any member of the category [EMA, nBMA (at the time), iBMA and 2-EHMA] there is no relevant concern on carcinogenicity for MMA in humans and animals. Epidemiology data on increased tumour rates in MMA exposed cohorts are of limited reliability and cannot be related to MMA as the solely causal agent. On the basis of the analogy with MMA and the common, rapid metabolism and clearance of these esters from the body it is unlikely that they will represent a carcinogenic risk.'

References:

Borzelleca JF, Larson, PS, Hennigar GR, Huf, EG, Crawford, EM and Smith, RB. Studies on the Chronic Oral Toxicity of Monomeric Ethyl Acrylate and Methyl Methacrylate. Toxicology and Applied Pharmacology 8, 29-36 (1964).

IARC. Methyl Methacrylate (Group 3). International Agency for Research on Cancer (IARC) — Summaries & Evaluations. Vol 60, p445 (1994).

Lomax LG, Krivanek, ND and Frame SR. Chronic Inhalation Toxicity and Oncogenicity of Methyl Methacrylate in Rats and Hamsters. Food and Chemical Toxicology 35, 393-407 (1997).

NTP. Toxicology and Carcinogenesis Studies of Methyl Methacrylate (CAS No. 80-62-6) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). National Toxicology Program Technical Report Series, No 314 (1986).

Tomenson JA, Carpenter AV and Pemberton MA. Critical review of the epidemiology literature on the potential cancer risks of methyl methacrylate. Int Arch Occup Environ Health 78: 603-612 (2005).

Elmore SA, Haseman JK, Pemberton M, Gollapudi BB, and Cohen, SM. A critical evaluation of rodent carcinogenicity studies on butyl methacrylate demonstrates a lack of carcinogenic potential. Critical Reviews in Toxicology, DOI: 10.1080/10408444.2025.2451885.

 Epidemiologist Concludes that MMA is Not Associated with Cancer Risk