Azo Dyes that Cleave to Aromatic Amines of Potential Toxicological Concern: Human health tier II assessment
01 July 2016
- Chemicals in this assessment
- Grouping Rationale
- Import, Manufacture and Use
- Existing Worker Health and Safety Controls
- Health Hazard Information
- Risk Characterisation
- NICNAS Recommendation
Chemicals in this assessment
This assessment was carried out by staff of the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) using the Inventory Multi-tiered Assessment and Prioritisation (IMAP) framework.
The IMAP framework addresses the human health and environmental impacts of previously unassessed industrial chemicals listed on the Australian Inventory of Chemical Substances (the Inventory).
The framework was developed with significant input from stakeholders and provides a more rapid, flexible and transparent approach for the assessment of chemicals listed on the Inventory.
Stage One of the implementation of this framework, which lasted four years from 1 July 2012, examined 3000 chemicals meeting characteristics identified by stakeholders as needing priority assessment. This included chemicals for which NICNAS already held exposure information, chemicals identified as a concern or for which regulatory action had been taken overseas, and chemicals detected in international studies analysing chemicals present in babies’ umbilical cord blood.
Stage Two of IMAP began in July 2016. We are continuing to assess chemicals on the Inventory, including chemicals identified as a concern for which action has been taken overseas and chemicals that can be rapidly identified and assessed by using Stage One information. We are also continuing to publish information for chemicals on the Inventory that pose a low risk to human health or the environment or both. This work provides efficiencies and enables us to identify higher risk chemicals requiring assessment.
The IMAP framework is a science and risk-based model designed to align the assessment effort with the human health and environmental impacts of chemicals. It has three tiers of assessment, with the assessment effort increasing with each tier. The Tier I assessment is a high throughput approach using tabulated electronic data. The Tier II assessment is an evaluation of risk on a substance-by-substance or chemical category-by-category basis. Tier III assessments are conducted to address specific concerns that could not be resolved during the Tier II assessment.
These assessments are carried out by staff employed by the Australian Government Department of Health and the Australian Government Department of the Environment and Energy. The human health and environment risk assessments are conducted and published separately, using information available at the time, and may be undertaken at different tiers.This chemical or group of chemicals are being assessed at Tier II because the Tier I assessment indicated that it needed further investigation.
For more detail on this program please visit:www.nicnas.gov.au
NICNAS has made every effort to assure the quality of information available in this report. However, before relying on it for a specific purpose, users should obtain advice relevant to their particular circumstances. This report has been prepared by NICNAS using a range of sources, including information from databases maintained by third parties, which include data supplied by industry. NICNAS has not verified and cannot guarantee the correctness of all information obtained from those databases. Reproduction or further distribution of this information may be subject to copyright protection. Use of this information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner. NICNAS does not take any responsibility whatsoever for any copyright or other infringements that may be caused by using this information.
All the chemicals in this group are azo compounds that share a similar molecular structure (R—N=N—R). The chemicals in this group could contain one or more azo linkages, in which the attached functional groups differ for each chemical.
The significance of azo-reduction in the mutagenicity and carcinogenicity of azo dyes is well established. The chemicals in this group have the potential to undergo reductive cleavage to form one or more of the following aromatic amines, which have been identified as having potential carcinogenic and/or genotoxic concerns based on a recent study by Bruschweiler et al. (2014):
- benzenamine (CAS No. 62-53-3);
- benzenamine, 2,4-dimethyl- (CAS No. 95-68-1);
- benzenamine, 4-nitro- (CAS No. 100-01-6);
- phenol, 4-amino- (CAS No. 123-30-8); and
- 2-benzothiazolamine, 6-nitro- (CAS No. 6285-57-0; not on AICS).
The critical concern for these chemicals relates to potential carcinogenicity. Due to the range of functional groups present in the chemicals being assessed, they are not considered to be toxicologically similar for local toxicity effects, including sensitisation, and there is a lack of data to assess these effects. However, these local effects are not a high priority for assessment compared with the concerns about carcinogenicity, which, if validated, would be expected to determine appropriate risk management measures.
Import, Manufacture and Use
No specific Australian use, import, or manufacturing information has been identified.
The following international uses have been identified through: Galleria Chemica; the Substances and Preparations in the Nordic countries (SPIN) database; the European Commission Cosmetic Ingredients and Substances (CosIng) database; the United States (US) Personal Care Product Council International Nomenclature of Cosmetic Ingredients (INCI) Dictionary; the US Environmental Protection Agency's Aggregated Computer Toxicology Resource (ACToR); and the Canadian assessments of aromatic azo and benzidine based dyes (Government of Canada, 2013a; Government of Canada, 2013b; Government of Canada, 2014).
Some of the chemicals are listed in the US Personal Care Product Council INCI dictionary with the following identified functions:
- as colourant (CAS Nos. 1320-07-6, 3118-97-6, 3761-53-3, and 6407-78-9); and
- as hair colourant (CAS Nos. 730-40-5, 1320-07-6, 3441-14-3, and 4438-16-8).
All of the chemicals in this group have reported commercial use as synthetic dyes in textiles, although the introduction of these dyes for domestic dyeing use cannot be excluded.
Resorcinol, bis(xylylazo)- also has reported non-industrial use as a pesticide (US EPA, 2011).
The majority of the chemicals in this group have been pre-registered, but have not undergone the full registration process, specified under the European Union (EU) Registration, Evaluation and Authorisation of Chemicals (REACH) legislation (European Chemicals Agency).
No known restrictions have been identified.
The chemicals identified by the CAS Nos. 730-40-5, 842-07-9, 1320-07-6, 3118-97-6, 3441-14-3, and 4438-16-8 are listed on one or more of the following lists (Galleria Chemica):
- Association of South East Asian Nations (ASEAN) Cosmetic Directive Annex II Part 1: List of substances which must not form part of the composition of cosmetic products;
- EU Cosmetics Regulation 1223/2009 Annex II—List of substances prohibited in cosmetic products;
- New Zealand Cosmetic Products Group Standard—Schedule 4: Components cosmetic products must not contain; and
- Health Canada List of prohibited and restricted cosmetic ingredients (The Cosmetic Ingredient ‘Hotlist’).
Existing Worker Health and Safety Controls
The chemical 2-naphthalenol, 1-(phenylazo)- (CAS No. 842-07-9) is classified as hazardous, with the following risk phrases for human health in the Hazardous Substances Information System (HSIS) (Safe Work Australia):
- Xi; R43 (sensitisation);
- R68 Mut. Cat 3 (mutagenicity); and
- R40 Carc. Cat 3 (carcinogenicity).
All the other chemicals are not listed on HSIS (Safe Work Australia).
No specific exposure standards are available for the chemicals.
No specific exposure standards are available for the chemicals.
Health Hazard Information
Based on a review of publicly available hazard information in accordance with the IMAP Framework (NICNAS, 2013), limited toxicological data were identified for the majority of the chemicals in this group.
The toxicokinetics of this group is expected to be influenced by varying molecular weight and polarity (Bafana et al., 2011; Government of Canada, 2014). The chemicals in this group belong to one the following types of dyes: disperse, direct, reactive, solvent, basic and acidic dyes. Whilst the reported levels of solubility and bioavailability of the dye molecules appear to vary, available data on similar chemicals and empirical data suggest a potential for azo reduction to bioavailable amines (SCCNFP, 2002; SCCP, 2005; SCCS, 2011; Government of Canada, 2011; Government of Canada, 2013a; Government of Canada, 2013b; Government of Canada, 2014).
Azo bond reduction and cleavage occurs by an enzyme-mediated metabolism in the liver, skin and intestines. In the liver, metabolism is facilitated by cytosolic and microsomal enzymes (Platzek et al., 1999), including NADH cytochrome P450 reductase, NAD(P)H quinone oxidoreductase, and cytochrome P450s (OEHHA, 2012). Bacterial strains in human faeces have been shown to cleave azo dyes, suggesting an important role of intestinal microflora in azo reduction (Platzek et al., 1999).
Although azo reduction occurs favourably in anaerobic conditions, several in vitro and in vivo studies indicated that this process could also occur aerobically when azo dyes are applied to the skin (SCCP, 2005). In vitro, the skin microflora of mice, guinea pigs and humans caused reductive cleavage of the azo dyes, followed by percutaneous absorption of the resulting amines (SCCNFP, 2002). In addition, non-biological processes, such as thermal and photochemical degradation, have also been reported to break azo linkages (Engel et al., 2009).
The critical concern for this group of chemicals relates to potential carcinogenic effects following exposure. Sudan I (CAS No. 842-07-9) and Sudan II (CAS No. 3118-97-6) are considered to have genotoxic and carcinogenic potential (Government of Canada, 2013a). Ponceau MX (CAS No. 3761-53-3) and Sudan I (CAS No. 842-07-9) have been evaluated by the International Agency for Research on Cancer (IARC) and classified the chemicals as Group 2B (possibly carcinogenic to humans) and 3 (not classifiable as to its carcinogenicity to humans), respectively (IARC, 1975).
The chemicals in this group have the potential to undergo reductive cleavage of the azo linkage that would likely result in the formation of potential carcinogenic and/or genotoxic aromatic amines (see Grouping Rationale). The carcinogenicity and/or genotoxicity of three of these amines have been assessed by NICNAS for the following chemicals:
- benzenamine, 2,4-dimethyl- (CAS No. 95-68-1) (NICNASb);
- benzenamine (CAS No. 62-53-3) (NICNASa); and
- phenol, 4-amino- (CAS No. 123-30-8) (NICNASc).
These aromatic amine cleavage products are expected to have greater absorption than the dye from which they are derived (Platzek et al., 1999).
Corrosion / Irritation
Repeated Dose Toxicity
Reproductive and Developmental Toxicity
Other Health Effects
Critical Health Effects
The critical health effects for risk characterisation of these chemicals are genotoxicity and carcinogenicity following breakdown of these chemicals to genotoxic and/or carcinogenic aromatic amines.
Public Risk Characterisation
Cosmetic and domestic
The chemicals identified by the CAS Nos. 730-40-5, 1320-07-6, 3118-97-6, 3441-14-3, 3761-53-3, 4438-16-8, and 6407-78-9 have been identified as having potential cosmetic use. Several of the chemicals are banned or restricted internationally, particularly for use in cosmetics (see Restrictions: International). The Scientific Committee on Cosmetic Products and Non-Food Products intended for Consumers (SCCNFP) (2002) concluded that 'azo dyes which may release one or more carcinogenic aromatic amines, poses a risk to the health of the consumer'.
All of the chemicals have potential use as synthetic dyes. Based on the available data, widespread domestic use is not expected; however, the introduction of these dyes for home use cannot be excluded. The margins between the upper-bounding estimates of exposure of the chemicals identified by the CAS Nos. 842-07-9 and 6407-78-9 from their use in consumer products and their critical health effect levels were estimated by the Government of Canada (2013a). Whilst quantitative risk calculations for these chemicals were considered adequate, in the absence of Australian specific use data, it is not possible to extrapolate this finding for Australia.
Overall, there is sufficient uncertainty regarding the safety of these chemicals in cosmetic and domestic products and therefore, a Tier III assessment is required (see NICNAS Recommendation).
Dyed textiles and leather
The public could also be exposed to potential carcinogenic aromatic amines as impurities, or through the release of these aromatic amines derived from the chemicals in this group through:
- prolonged exposure to articles of clothing and leathergoods containing the dyes; and
- young children exposed by sucking the materials containing the dye.
The Australian Competition and Consumer Commission (ACCC) has published guidance on the safe concentrations of particular chemicals in consumer goods (ACCC, 2014b). The guidance prescribes concentrations of chemicals in clothing, textiles and leather articles in direct and prolonged contact with the human skin or oral cavity, below which a safety concern does not exist. It also includes a list of hazardous aromatic amines classified as carcinogens in the EU and identified in the REACH list of 22 aromatic amines in Annex XVII Appendix 8 (European Commission, 2006).
In considering the NICNAS recommendation for previously assessed azo dyes, the ACCC conducted a market survey to determine if any dyes of concern had been used in manufacturing consumer goods supplied in Australia. The ACCC has negotiated several recalls of products based on the results of the surveys (ACCC, 2014a). The ACCC is considering mechanisms to restrict the supply of textiles and leather articles that could come into direct and prolonged contact with the human skin that might plausibly result in human exposure to certain aromatic amines at unacceptable levels. Although the ACCC is only considering restriction mechanisms for azo dyes that cleave to the 22 carcinogenic aromatic amines (European Commission, 2006), the options identified may also be relevant for the chemicals in this group.
Further assessment at Tier III is required to determine whether there are similar concerns to those associated with the 22 carcinogenic aromatic amines (see NICNAS Recommendation).
Occupational Risk Characterisation
During product formulation, oral, dermal, ocular and inhalation exposure of workers to the chemical may occur, particularly where manual or open processes are used. These may include transfer and blending activities, quality control analysis, and cleaning and maintaining equipment. Worker exposure to the chemical at lower concentrations may also occur while using formulated products containing the chemical. The level and route of exposure will vary depending on the method of application and work practices employed.
Overall, there is sufficient uncertainty regarding the hazards of these chemicals in the workplace, and therefore, a Tier III assessment is required (see NICNAS Recommendation) to determine the appropriate occupational controls.
The chemicals in this group and their potentially genotoxic and/or carcinogenic amine cleavage products are recommended for Tier III assessment to determine whether:
- risk management controls for domestic and cosmetic use are required;
- similar concerns to those associated with the 22 amines subject to restrictions in textiles in Europe exist; and
- there are additional azo dye chemicals in the Australian Inventory of Chemical Substances (AICS) which may break down to aromatic amines identified as potentially carcinogenic and/or genotoxic by Bruschweiler et al. (2014) that may require further assessment.
ACCC 2014a. Product Safety Recall on ‘Pillow Talk Pty Ltd—Pillow Talk 50/50 Poly/Cotton 225 Thread Count Plain Dye Range - Red Only’. Accessed February 2015 at http://www.recalls.gov.au/content/index.phtml/itemId/1056169
ACCC 2014b. Safety guidance on concentrations of particular chemicals in certain consumer goods. Accessed February 2015 at http://www.productsafety.gov.au/content/index.phtml/itemId/1009938
Bafana, A., Devi, S. S.,& Chakrabarti, T. (2011). Azo dyes: past, present and the future. Environmental Reviews, 19(NA), 350-371.
Bruschweiler BJ, Kung S, Burgi D, Muralt L, Nyfeler E (2014) Identification of non-regulated aromatic amines of toxicological concern which can be cleaved from azo dyes used in clothing textiles. Regulatory Toxicology and Pharmacology 69 pp. 263-272.
CosIng. Cosmetic Ingredients and Substances. Accessed February 2015 at http://ec.europa.eu/consumers/cosmetics/cosing/
Engel E, Vasold R, Santarelli F, Maisch T, Gopee N, Howard P, Landthaler M, Baumler W (2009) Tattooing of skin results in transportation and light-induced decomposition of tattoo pigments – a first quantification in vivo using a mouse model. Experimental Dermatology 19 pp. 54-60.
European Chemicals Agency. Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) legislation. Accessed February 2015 at http://echa.europa.eu/regulations/reach/legislation
European Commission 2006. Regulation (EC) No 1907/2006 of the European Parliament and of the Council (REACH). Accessed February 2015 at http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=CONSLEG:2006R1907:20090627:EN:PDF
Galleria Chemica. Accessed January 2015 at http://jr.chemwatch.net/galleria/
Government of Canada (2011) Screening assessment for the challenge: 2-naphthalenol, 1-[[4-(phenylazo)phenyl]azo]- Solvent Red 23 CAS No. 85-86-9. Accessed February 2015 at http://www.ec.gc.ca/eseees/5B828E08-3266-4189-B32B-39B5D773040A/Batch%206_85-86-9_EN.pdf
Government of Canada (2013a). Draft Screening Assessment of Aromatic Azo and Benzidine-based Substance Grouping. Certain Azo Disperse Dyes. Accessed February 2015 at http://www.ec.gc.ca/ese-ees/default.asp?lang=En&n=E86C5AFA-1
Government of Canada (2013b) Draft Screening Assessement Aromatic Azo and Benzidine-based SubstanceGrouping Certain Azo Disperse Dyes. Accessed February 2015 at http://www.ec.gc.ca/ese-ees/default.asp?lang=En&n=E86C5AFA-1
Government of Canada (2014) Draft Screening Assessement Aromatic Azo and Benzidine-based SubstanceGrouping Certain Azo Direct Dyes and Azo Reactive Dyes. Accessed February 2015 at http://www.ec.gc.ca/eseees/default.asp?lang=En&n=899CF15C-1
International Agency for Research on Cancer (IARC) (1975) Some Aromatic and Azo Compounds. IARC Monographs Volume 8. Accessed February 2015 at http://monographs.iarc.fr/ENG/Monographs/vol1-42/mono8.pdf
National Industrial Chemicals Notification and Assessment Scheme (NICNASa). Tier II human health assessment for benzenamine (CAS No. 62-53-3). Australian Government Department of Health. Accessed February 2015 at http://www.nicnas.gov.au
National Industrial Chemicals Notification and Assessment Scheme (NICNASb). Tier II human health assessment for benzenamine, 2,4-dimethyl- (CAS No. 95-68-1). Australian Government Department of Health. Accessed February 2015 at http://www.nicnas.gov.au
National Industrial Chemicals Notification and Assessment Scheme (NICNASc). Tier II human health assessment for phenol, 4-amino- (CAS No. 123-30-8). Australian Government Department of Health. Accessed February 2015 at http://www.nicnas.gov.au
Office of Environmental Health Hazard Assessment (OEHHA) 2012. Evidence on the carcinogenicity of C.I. Disperse Yellow 3. Accessed January 2015 at http://www.oehha.ca.gov/Prop65/hazard_ident/pdf_zip/081012CIYHID.pdf
Platzek T, Lang C, Grohmann G, Gi US, Baltes W. (1999) Formation of a carcinogenic aromatic amine from an azo dye by human skin bacteria in vitro. Human and Experimental Toxicology 18 pp. 552-559.
REACH Dossiers. Accessed January 2015 at http://echa.europa.eu/web/guest/information-on-chemicals/registered-substances
Safe Work Australia (SWA). Hazardous Substances Information System (HSIS). Accessed January 2015 at http://hsis.safeworkaustralia.gov.au/HazardousSubstance
Scientific Committee on Consumer Products (SCCP) (2005) Opinion on the use of CI 26100 (CI Solvent Red 23) as a colorant in cosmetic products. Adopted by the SCCP during the 4th plenary of 21 June 2005. Accessed February 2015 at http://ec.europa.eu/health/ph_risk/committees/04_sccp/docs/sccp_o_013.pdf
Scientific Committee on Consumer Safety (SCCS) (2011) Opinion on Basic Red 76. COLIPA No. C8. Accessed February 2015 at http://ec.europa.eu/health/scientific_committees/consumer_safety/docs/sccs_o_051.pdf
Substances in Preparations in Nordic Countries (SPIN). Accessed Feburary 2015 at http://184.108.40.206/dotnetnuke/Home/tabid/58/Default.aspx
The Scientific Committee on Cosmetic Products and Non-Food Products intended for Consumers (SCCNFP) (2002) Opinion on the Safety Review of the Use of Certain Azo-Dyes in Cosmetics Products. SCCNFP/0495/01, final. Accessed February 2015 at http://ec.europa.eu/health/archive/ph_risk/committees/sccp/documents/out155_en.pdf
United States (US) Personal Care Product Council International Nomenclature of Cosmetic Ingredients (INCI) dictionary. Accessed February 2015 at http://gov.personalcarecouncil.org/jsp/gov/GovHomePage.jsp
US Environmental Protection Agency's Aggregated Computational Toxicology Resource (ACToR). Accessed January 2015 at http://actor.epa.gov/actor/faces/ACToRHome.jsp
US EPA (2011) Inert ingredients permitted for use in nonfood use pesticide products. Accessed June 2016 from http://www.agriculturedefensecoalition.org/sites/default/files/file/toxic_toys_148/148E_2011_U.S._EPA_Inert_Ingredients_Permiteed_for_Use_in_NonFood_Use_Pesticide_Products_Updated_April_2011_Sodium_Polyacrylate_Listed.pdf