Carcinogenicity
AA and the acrylate esters have been assessed for carcinogenicity in a number of studies by various routes of exposure and found in most studies to be not carcinogenic. AA did not cause an increase in tumors in a rat 2-year drinking water study or in chronic mouse skin painting studies. MA, EA, and BA did not cause increases in tumors in rats in 2-year inhalation studies. EA was also negative for carcinogenicity in chronic dermal and drinking water studies. It did cause tumors in the forestomachs of rats and mice given by gavage in doses that caused marked local irritation, a situation that is not considered relevant to humans. 2-EHA caused an increase in skin tumors in some, but not all, chronic dermal studies in mice. 2-EHA induced skin tumors at concentrations that were highly irritating, and this damage was presumed to be the mode of action for tumor formation. These studies illustrate that none of the members tested produced evidence of carcinogenicity of known relevance to humans in chronic/oncogenicity studies.
Excerpt from ARTF Category Justification -Carcinogenicity studies are available for the category members in rats and/or mice for oral, inhalation or dermal routes except for iBA and tBA. Overall, none of the category members is considered to be a carcinogen following systemic exposure. Carcinogenicity studies for some of category members confirmed that tumour formation may be associated with localised irritation at the site of contact for dosing at dose levels in excess of the maximum tolerated dose (MTD). There is no evidence of tumour formation at a site distant from the route of entry for any of the acrylate esters. The forestomach carcinogenicity observed in the gavage studies with EA were concluded to be secondary to a site-specific and concentration-dependent irritating effect of the substance. This was supported by negative data from a transgenic rodent gene mutation assay (OECD TG 488). No EA-induced gene mutations were observed in the stomach, bone marrow or liver of gpt-delta mice exposed via oral gavage. This confirms that the mode of action for EA-induced forestomach tumours is via a secondary, non-DNA-reactive (i.e. non-genotoxic) mechanism. In a 2-year inhalation study in rats with MA, a dose-related degeneration of the olfactory epithelium (primarily the anterior portion) and a subsequent regeneration and replacement with respiratory epithelium was also observed at the highest dose level of 0.519 mg/L. However, no differences in the incidence of preneoplastic or neoplastic lesions were observed in this study. In an inhalation study in the mouse MA did not induce neoplastic lesions at the highest dose tested though the conclusion from this study are considered unreliable due to major methodological deficiencies (JBRC 2017). Furthermore, an OECD 451 inhalation study in the rat 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 MTD (JBRC 2017). In a dermal mouse carcinogenicity study with 2EHA, skin tumours were induced that are considered to be associated with the highly irritative properties of 2EHA at dose levels in excess of the maximum tolerated dose (MTD). At a low concentration of 2.5% (approx. 269 mg/kg bw/day) of 2EHA dermally applied 3 times/week, a transient irritation was observed but this did not develop into any tumour formation. Other long-term studies with different mouse strains did not confirm tumour induction in mouse skin. Since none of the category members are considered to be genotoxic, and since EA has been confirmed not to induce gene mutation in vivo, it is concluded that the observed tumours at the site of contact are due to irritation and not a DNA-reactive mode of action. In conclusion, the available data support a lack of carcinogenicity associated with systemic exposure of the category across the tested species.
For this endpoint, the common primary metabolic pathway of the category members (i.e. common functional groups and rapid metabolism by ester cleavage leading to the common metabolite AA) is considered as the most relevant aspect of the category approach. Qualitatively, this aspect can be categorised as scenario 3 “(Bio) transformation to common compound(s)”, whereas AA is the toxicologically relevant metabolite.
For more information, see Category Justifcation Document for use under EU REACH.