Carcinogenicity of azo colorants: influence of solubility and bioavailability

doi:10.1016/j.toxlet.2003.11.016

Toxicology Letters

Volume 151, Issue 1, 15 June 2004, Pages 203-210

Dedicated to the late Christian Hodel

https://doi.org/10.1016/j.toxlet.2003.11.016 Get rights and content

Abstract

In the past, azo colorants based on benzidine, 3,3′-dichlorobenzidine, 3,3′-dimethylbenzidine (o-tolidine), and 3,3′-dimethoxybenzidine (o-dianisidine) have been synthesized in large amounts and numbers. Studies in exposed workers have demonstrated that the azoreduction of benzidine-based dyes occurs in man. The metabolic conversion of benzidine-, 3,3′-dimethylbenzidine- and 3,3′-dimethoxybenzidine-based dyes to their (carcinogenic) amine precursors in vivo is a general phenomenon that must be considered for each member of this class of chemicals. Several epidemiological studies have demonstrated that the use of the benzidine-based dyes has caused bladder cancer in humans. However, in contrast to water-soluble dyes, the question of biological azoreduction of (practically insoluble) pigments has been a matter of discussion. As a majority of azo pigments are based on 3,3′-dichlorobenzidine, much of the available experimental data are focused on this group. Long-term animal carcinogenicity studies performed with pigments based on 3,3′-dichlorobenzidine did not show a carcinogenic effect. The absence of a genotoxic effect has been supported by mutagenicity studies with the 3,3′-dichlorobenzidine-based Pigment Yellow 12. Studies in which azo pigments based on 3,3′-dichlorobenzidine had been orally administered to rats, hamsters, rabbits and monkeys could generally not detect significant amounts of 3,3′-dichlorobenzidine in the urine. It, therefore, appears well established that the aromatic amine components from azo pigments based on 3,3′-dichlorobenzidine are practically not bioavailable. Hence, it is very unlikely that occupational exposure to insoluble azo pigments would be associated with a substantial risk of (bladder) cancer in man. According to current EU regulations, azo dyes based on benzidine, 3,3′-dimethoxybenzidine and 3,3′-dimethylbenzidine have been classified as carcinogens of category 2 as “substances which should be regarded as if they are carcinogenic to man”. This is not the case for 3,3′-dichlorobenzidine-based azo pigments.

Section snippets

Introduction: the problem of carcinogenic azo colorants

Colorants (dyes and pigments) are important industrial chemicals. Following the technological nomenclature, pigments are colorants that are insoluble in the application medium whereas dyes are applied in soluble form. The question of systemic bioavailability, upon inhalation and skin contact, is of particular importance for azo colorants based on carcinogenic aromatic amines (Myslak and Bolt, 1988, Bolt and Golka, 1993).

In the past, azo colorants based on benzidine, 3,3′-dichlorobenzidine,

Metabolism and bioactivation of azo colorants

Azo colorants are biologically active through their metabolites. Azoreduction of these compounds occurs in vivo (Radomski and Mellinger, 1962, Rinde and Troll, 1975, Robens et al., 1980) by an enzyme-mediated reaction. Azoreductases are found in mammalian tissues, particularly in liver (Fouts et al., 1957, Walker, 1970, Martin and Kennelly, 1981, Kennelly et al., 1982), in gut bacteria (Yoshida and Miyakawa, 1973, Chung et al., 1978, Hartman et al., 1978, Cerniglia et al., 1982, Bos et al., 1986

Azo pigments

As azo pigments are per definitionem considered insoluble, the question is of high relevance whether this group of azo colorants is carcinogenic or not, with considerable consequences for labelling and handling of these compounds (Bowman and Nony, 1981, Pylev et al., 1985). As a majority of azo pigments are based on 3,3′-dichlorobenzidine, much of the available experimental data are focused on this group.

The biological activation of 3,3′-dichlorobenzidine is complex (Iba, 1989/1990), but shows

Regulatory consequences

The problem of carcinogenicity of azo colorants was first officially addressed by the German Commission for Investigation of Health Hazards of Chemical Compounds in the Work Area (“MAK-Commission”) which included a new chapter in the MAK-list, since 1988 (DFG, 1988), with the following summary:

Thus, all azo colorants whose metabolism can liberate a carcinogenic aryl amine are suspected of having carcinogenic potential. Due to the large number of such dyes (several hundred) it seems neither

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ReviewCarcinogenicity of azo colorants: influence of solubility and bioavailability

Abstract

Section snippets

Introduction: the problem of carcinogenic azo colorants

Metabolism and bioactivation of azo colorants

Azo pigments

Regulatory consequences

Toxicology

Cancer Lett.

Mutat. Res.

Toxicol. Lett.

Toxicol. Lett.

Toxicol. Appl. Pharmacol.

Mutat. Res.

Toxicol. Appl. Pharmacol.

Food Cosmet. Toxicol.

The investigation on the manufacturing plant of organic pigment

Jikeikai Med. J.

Industrial exposure in patients with carcinoma of the bladder

J. Soc. Occup. Med.

Zur früheren Exposition von Malern gegenüber Azofarbstoffen

Arbeitsmed. Sozialmed. Umweltmed.

Possible carcinogenic metabolites of azo dye and pigment: trace-level determination of benzidine, 3,3′-dichlorobenzidine and their acetylated and conjugated products in human and hamster urine

IARC Sci. Publ.

Metabolism of nine benzidine-congener-based azo dyes in rats based on gas chromatographic assays of the urine for potentially carcinogenic metabolites

J. Anal. Toxicol.

Metabolism of azo dyes derived from benzidine, 3,3′-dimethylbenzidine and 3,3′-dimethoxybenzidine to potentially carcinogenic aromatic amines by intestinal bacteria

Carcinogenesis

Reduction of azo dyes by intestinal anaerobes

Appl. Environ. Microbiol.

Fate of water-insoluble and water-soluble dichlorobenzidine-based pigments in Fisher 344 rats

J. Toxicol. Environ. Health

Cancer risk associated with employment in the leather and leather products industry

Arch. Environ. Health

Benzidine and its acetylated metabolites in the urine of workers exposed to Direct Black 38

Arch. Environ. Health

Enzymatic reduction of prontosil and other azo dyes

J. Pharmacol. Exp. Ther.

Occupational bladder cancer in textile dyeing and printing workers: six cases and their significance for screening programs

J. Occup. Med.

Use of permanent hair dyes and bladder-cancer risk

Int. J. Cancer

Formation of blastomogenic diphenylamino derivatives as a result of the metabolism of direct azo dyes

Vopr. Onkol.

Review
Carcinogenicity of azo colorants: influence of solubility and bioavailability