Genotoxicity data on commercial azo dyes and their components remain sparse, despite their widespread use. We have tested the mutagenicity of 2-cyano-4-nitroaniline (CNNA) and 2,6-dicyano-4-nitroaniline (CNCNNA), components of azo dyes such as Disperse Blue 165 and Disperse Red 73, in Ames test strains. Both compounds are extraordinarily potent frameshift mutagens, with much greater activity than structurally similar dihalonitroanilines and halodinitroanilines. Analysis of the responses of strains over-expressing or deficient in bioactivation enzymes shows that bacterial nitroreductase and acetyl CoA: arylamine N-acetyltransferase are important mediators of the mutagenicity of CNNA and CNCNNA. Environ. Mol. Mutagen. 57:10-16, 2016. V C 2015 Wiley Periodicals, Inc.Key words: Ames test; nitroanilines; cyanoaromatics; disperse dyes INTRODUCTIONThe history of the synthetic dye industry is interwoven with the development of organic chemistry, toxicology, and occupational safety. Azo dyes continue to comprise more than half of the worldwide production volume of dyes. Azo compounds are found in many functional classes of dyes, including acid, basic, disperse, reactive, and solvent dyes [Freeman, 2013]. The European Commission has banned the use of any azo dyes which, upon reduction, might liberate any of 22 designated aromatic amines, including benzidine, 4-aminobiphenyl, 2-naphthylamine, and other proven or suspected carcinogens [Ahlstr€ om et al., 2005]. However, absence from this list is not proof of safety. Regulatory agencies have conducted major research studies and risk-assessment reviews of azo dyes and their aromatic amine precursors, notably the "Benzidine Dye Initiative" of the National Toxicology Program, USA [Morgan et al., 1994] and the recent "Aromatic Azo and Benzidinebased Substance Grouping" component of the "Substance Groupings Initiative" conducted by Environment Canada and Health Canada. The chemical structures of many of these dyes include "structural alerts" for mutagenicity, such as nitroaromatic and arylamine functional groups. Nevertheless, there are many knowledge gaps in the toxicology and genotoxicology data for azo dyes and their components. One major reason for this is simply the very large number of synthetic dyes; Weaver states that nearly 100,000 different dyes were produced at the Eastman Kodak Co. alone, through 1986[Weaver, 2003.Besides the possible toxicity of azo dyes per se [Yadav et al., 2013;Fernandes et al., 2015], these dyes can also present hazards mediated by their constituent aromatic Abbreviations: BrBrNA, 2,6-dibromo-4-nitroaniline; BrDNA, 2-bromo-4,6-dinitroaniline; ClBrNA, 2-bromo-6-chloro-4-nitroaniline; ClClNA, 2,6-dichloro-4-nitroaniline; ClDNA, 2-chloro-4,6-dinitroaniline; CNCNNA, 2,6-dicyano-4-nitroaniline; CNCNNB, 1,3-dicyano-5-nitrobenzene; CNCNPPD, 2,6-dicyano-p-phenylenediamine; CNNA, 2-cyano-4-nitroaniline. All authors declare that there are no conflicts of interest. Environmental and Molecular Mutagenesis 57:10^16 (2016) amines. Residues of the amines used i...

2,6-Dicyano-4-nitroaniline and 2-cyano-4-nitroaniline (CNNA; 2-amino-5-nitrobenzonitrile) are potent mutagens in the Ames test, even though unsubstituted nitroanilines (NAs) are no more than weak mutagens. These compounds are putative reduction products of many commercial azo dyes, including Disperse Blue 165, Disperse Blue 337, Disperse Red 73, Disperse Red 82, Disperse Violet 33, and Disperse Violet 63. We have examined the mutagenicity in strains TA98 and YG1024 of a series of commercially-available isomers of CNNA, and some related compounds, to probe the relationship between structure and genotoxic activity in this class of compounds. The potentiating effect of the cyano substituent is seen in many cases; e.g. 2-amino-4-nitrobenzonitrile is a much more potent mutagen than 3-NA. 2,4-Dinitrobenzonitrile is also highly mutagenic. Possible mechanisms for the "cyano effect" are considered, with respect to the likely structures of cyanonitroaniline-DNA adducts and the roles of the enzymes (nitroreductase and acetyl CoA:arylamine N-acetyltransferase) believed to be involved in the activation of nitroaromatic compounds. Environ. Mol. Mutagen. 59:114-122, 2018. © 2017 Wiley Periodicals, Inc.

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