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additional toxicological information
Type of information:
other: Expert review
Review of the genotoxicity and related mechanistic data for acrylonitrile with regard to proposing a mechanism of action for carcinogenicity
Adequacy of study:
key study
Study period:
Not applicable
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Expert review

Data source

Reference Type:
review article or handbook

Materials and methods

Type of study / information:
Expert review of exisiting information on the genotoxicity of acrylonitrile, together with relevant metabolic and mechanistic data, in the context of a mode of action for carcinogenicity.
Test guideline
no guideline available
Principles of method if other than guideline:
Expert review
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Specific details on test material used for the study:
Not applicable

Results and discussion

Applicant's summary and conclusion

The genotoxicity of acrylonitrile has been demonstrated in a number of experimental systems; however there is a lack of clarity on the mechanisms underlying the demonstrated genotoxicity. The genotoxicity could be due to direct DNA reactivity or, equally, to indirect effects caused by oxidative damage. Evidence for direct genotoxicity comes from the ability of acrylonitrile to bind to proteins and DNA in vitro and in vivo (acrylonitrile and its reactive metabolite CNEO). Site-specific DNA adducts are seen in vitro and there is evidence for the formation of N7OEG adducts in the liver of rats (although not in the brain) and for the formation of CEVal haemoglobin adducts in exposed humans. Acrylonitrile is therefore clearly DNA-reactive and has the ability to form DNA adductsin vitro. Although only one study has shown the formation of adductsin vivo, there is a lack of studies and none have used modern sensitive methods. In vitrostudies, however, have used massive concentrations of acrylonitrile or CNEO and prolonged exposure times unlikely to be encounteredin vivo. The assessment of DNA bindingin vitroandin vivois problematic due to the issue of protein contamination, even following purification using the most rigorous techniques. Evidence for indirect genotoxicity mediated by oxidative DNA damage comes from the formation of 8oxoG adducts in multiple tissues in ratsin vivoand,in vitro, in rat astrocytes but not in hepatocytes. Effects in the rat are associated with markers of oxidative stress DNA fragmentation in brain tissue is inhibited by antioxidants; UDS in the rat (in vivo) is also associated with markers of oxidative stress DNA fragmentation in brain tissue is inhibited by antioxidants. Cell transformation is associated with the formation of 8oxoG adducts, is inhibited by antioxidants and associated with cyanide administration and ROS production.
Increased levels of 8oxoG adducts have been found in the rat brain in all studies investigating this endpoint and are associated with oxidative stress and cell transformation. In vitro, rat astrocyte exposed to acrylonitrile also show an increase in 8oxoG adducts; similar findings are not seen with the non-genotoxic substance methylacrylonitrile. The administration of acrylonitrile to mice in the drinking water did not induce oxidative damage in the brain. Techniques used to detect 8oxoG adducts may, however, not be specific in all cases, leading to some uncertainty. The majority of studies investigating the genotoxicity of acrylonitrile have assessed endpoints that could equally have resulted from direct or indirect effects. While some studies suggest the effects are attributable to oxidative damage, a firm conclusion for this mechanism over direct mutagenicity cannot be made. The authors conclude, based on the weight of evidence, that it is probably the genotoxicity of acrylonitrile is likely to be mediated by both direct and indirect effects. The current data indicate that,in vivo, the indirect effects may be more important.
Executive summary:

The conclusion on genotoxicity is discussed in terms of the carcinogenicity MoA for acrylonitrile. Data clearly demonstrate that acrylonitrile can induce mutations and oxidative stress. The data indicate that the mutagenic potential of acrylonitrile is weak; most in vitro studies reporting positive results have used comparatively high concentrations and sensitive test systems. The lack of induction of sex-linked recessive lethal mutations in Drosophila is comparable with other weak mutagens where mutagenic effects are inhibited by effective repair. Notably, there is also a remarkable disparity between the potential of acrylonitrile to induce chromosome level mutations in vitro and in vivo, with no evidence being demonstrated in studiesin vivo, even in studies using high dose levels and non-physiological routes of administration. Acrylonitrile does, however, induce gene mutations in vivo in rodents. Furthermore, some molecular epidemiological studies in humans report gene and chromosome level mutations in exposed worker populations; however it is important to note that it impossible to exclude confounder effects in some studies and the use of inappropriate methods in others.  Despite the clear findings of carcinogenicity in rodent species, there is no convincing evidence of human carcinogenicity from epidemiological studies. There is clear evidence from studies performed with radiolabelled acrylonitrile that both acrylonitrile and the active metabolite CNEO are widely distributedin vivoand reach cancer targets. The radioactivity is, however, primarily bound to proteins. Specific DNA adducts (N7OEG) have been demonstrated only in a single study and in a non-target tissue (the liver), indicating that adducts are not efficiently produced and/or are rapidly repaired. The lack of evidence for specific DNA adducts in the target tissue (brain) suggests that direct mutagenicity is not the mode of action. In contrast, there is ample evidence for the induction of 8oxoG adducts in brain tissue at tumorigenic dose levels, implying that if mutation is a critical early event in the production of brain tumours, this is most likely secondary to indirect mutagenicity. Furthermore, several target tissues for acrylonitrile carcinogenicity in the mouse have been evaluated for somatic mutations in mice, and none have been found, arguing against direct mutagenicity. The MOA for rodent carcinogenicity is probably complex and is, in part, mediated through mutagenicity. Mutagenicity, may, however, have two underlying mechanisms - direct and indirect - with current evidence indicating that indirect mutagenicity may be more prominent. Furthermore, both direct and indirect mutagenicity may be influenced by associated tissue effects such as increased cell proliferation and glutathione depletion. Non-genotoxic effects may modulate the rodent carcinogenicity of acrylonitrile in a tissue-specific manner.