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Chemicals with limited data availability that may be used in hair dyes overseas: Human health tier II assessment

01 July 2016

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Chemicals in this assessment

Chemical Name in the Inventory CAS Number
Ethanaminium, N-[9-(2-carboxyphenyl)-6-(diethylamino)-3H-xanthen-3-ylidene]-N-ethyl-, chloride 81-88-9
2,3-Naphthalenediol 92-44-4
1,4-Benzenediamine, N,N-diethyl- 93-05-0
1,2-Benzenediamine, 4-chloro- 95-83-0
1,4-Benzenediamine, N,N-dimethyl- 99-98-9
1,3,5-Benzenetriol 108-73-6
Phenol, 4-amino-2-nitro- 119-34-6
1,4-Benzenediamine, N-(4-aminophenyl)- 537-65-5
2-Naphthalenesulfonic acid, 7-(benzoylamino)-4-hydroxy-3-[[4-[(4-sulfophenyl)azo]phenyl]azo]-, disodium salt 2610-11-9
Benzenesulfonic acid, 2,2'-(1,2-ethenediyl)bis[5-[(4-ethoxyphenyl)azo]-, disodium salt 2870-32-8
1,4-Benzenediamine, N4-methyl-2-nitro- 2973-21-9
1,3-Benzenediamine, 4-nitro- 5131-58-8
1,4-Benzenediamine, N,N-diethyl-, sulfate 6065-27-6
1,4-Benzenediamine, N,N-dimethyl-, sulfate 6219-73-4
Ethanol, 2-[methyl[4-(methylamino)-3-nitrophenyl]amino]- 10228-03-2
C.I. Basic Red 46 12221-69-1
1,3-Benzodioxol-5-amine 14268-66-7
Phenol, 2-amino-6-methyl- 17672-22-9
Phenol, 4-amino-2-(methoxymethyl)- 29785-47-5
Cuprate(2-), [.mu.-[[7,7'-iminobis[4-hydroxy-3-[[2-hydroxy-5-[(methylamino)sulfonyl]phenyl]azo]-2-naphthalenesulfonato]](6-)]]di-, disodium 37279-54-2
Ethanol, 2-(4-amino-3-nitrophenoxy)- 50982-74-6
1,3-Propanediol, 2-[(2-amino-4-nitrophenyl)amino]-2-(hydroxymethyl)- 56932-45-7
Ethanol, 2-[(4-methoxy-2-nitrophenyl)amino]- 57524-53-5
1,3-Benzenediamine, 4-ethoxy-, sulfate (1:1) 68015-98-5
Benzenaminium, 3-[[4-[[diamino(phenylazo)phenyl]azo]-1-naphthalenyl]azo]-N,N,N-trimethyl-, chloride 83803-98-9
Benzenaminium, 3-[[4-[[diamino(phenylazo)phenyl]azo]-2-methylphenyl]azo]-N,N,N-trimethyl-, chloride 83803-99-0
1H-1,2,4-Triazolium, 1,2(or 1,4)-dimethyl-3(or 5)-[[4-[methyl(phenylmethyl)amino]phenyl]azo]-, bromide 89959-98-8
1,2-Propanediol, 3-[[4-[(2-hydroxyethyl)methylamino]-2-nitrophenyl]amino]- 102767-27-1
3-Pyridinol, 5-amino-2,6-dimethoxy- 104333-03-1
Ethanol, 2,2'-[(3,5-diamino-2,6-pyridinediyl)bis(oxy)]bis- 117907-42-3
Ethanol, 2-[(4-methoxy-2,6-dinitrophenyl)amino]- 122252-11-3
Phenol, 4-amino-2-(methoxymethyl)-, monohydrochloride 135043-65-1

Preface

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

Disclaimer

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.

Grouping Rationale

The chemicals in this group have reported uses in hair dye preparations overseas. Based on a review of publicly available hazard information in accordance with the IMAP Framework (NICNAS, 2013), limited empirical toxicological data were identified for all of the chemicals in this group.

For chemicals with limited data, NICNAS commonly uses the principles of 'read across' in accordance with the Organisation for Economic Co-operation and Development (OECD) Guidance on grouping of chemicals (OECD, 2014) based on the known properties of similar chemicals (analogues). The quality of the data used is dependent on the similarity of the analogues to the chemicals themselves. However, the relevant analogues identified for the chemicals in this group also have limited toxicological information for which to characterise the hazards and, therefore, are not considered suitable. Therefore, other approaches such as the analysis of Quantitative Structure-Activity Relationship (QSAR) modelling information is required to characterise the hazards of the chemicals.

The critical concern for hair dye chemicals relates to their potential skin sensitisation, mutagenicity and carcinogenicity. As such, these health hazards will be the focus of this assessment, with other hazards not considered.

Australian

No specific Australian use, import, or manufacturing information has been identified for all of the chemicals in this group.

International

The following international uses have been identified through:

  • Galleria Chemica;
  • the Substances and Preparations in 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 Compilation of Ingredients Used in Cosmetics in the US (CIUCUS) (Personal Care Products Council, 2011);
  • the US Environmental Protection Agency's Aggregated Computer Toxicology Resource (ACToR); and
  • the US National Library of Medicine's Hazardous Substances Data Bank (HSDB).

All of the chemicals have reported cosmetic use as hair dyes. Basic Violet 10 has reported use in tattoo inks (Hauri, 2011).

Some of the chemicals have reported site-limited use including as:

  • a biological stain and laser dye (Rhodamine B, CAS No. 81-88-9);
  • a complexing reagent (2,3-dihydroxynaphthalene, CAS No. 92-44-4);
  • a laboratory reagent (N,N-diethyl-p-phenylenediamine, CAS No. 93-05-0; 4-chloro-o-phenylenediamine, CAS No. 95-83-0; 4-amino-N,N-dimethylaniline sulfate, CAS No. 6219-73-4); and
  • an intermediate (Rhodamine B, CAS No. 81-88-9; 4-amino-2-nitrophenol, CAS No. 119-34-6; 4-nitro-1,3-benzenediamine, CAS No. 5131-58-8; methylenedioxyaniline, CAS No. 14268-66-7).

Australian

The chemicals N,N-diethyl-p-phenylenediamine (CAS No. 93-05-0), 4-chloro-o-phenylenediamine (CAS No. 95-83-0), N,N-diethyl-p-phenylenediamine (CAS No. 99-98-9), N-methyl-2-nitrobenzene-1,4-diamine (CAS No. 2973-21-9), and 4-nitro-1,3-benzenediamine (CAS No. 5131-58-8) come under the Poisons Standard—the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) entries in Schedule 6 and Appendix C (SUSMP, 2014).

Schedule 6:

'PHENYLENEDIAMINES and alkylated phenylenediamines not elsewhere specified in these Schedules:

(a) in preparations packed and labelled for photographic purposes;

(b) in preparations packed and labelled for testing water except tablets containing 10 mg or less of diethylpara-phenylenediamine or dimethyl-para-phenylenediamine in opaque strip packaging provided the directions for use include the statement, "Do not discard testing solutions into the pool";

(c) in hair dye preparations except when the immediate container and primary pack are labelled with the following statements: KEEP OUT OF REACH OF CHILDREN, and WARNING - This product contains ingredients which may cause skin irritation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye. Written in letters not less than 1.5 mm in height; or

(d) in eyelash and eyebrow tinting products when the immediate container and primary pack are labelled with the following statement: WARNING - This product contains ingredients which may cause skin irritation to certain individuals, and when used for eyelash and eyebrow tinting may cause injury to the eye. A preliminary test according to the accompanying directions should be made before use. Written in letters not less than 1.5 mm in height.'

Appendix C:

'PHENYLENEDIAMINES in preparations for skin colouration and dyeing of eyelashes or eyebrows except when included in Schedule 6.'

Schedule 6 chemicals are described as 'Substances with a moderate potential for causing harm, the extent of which can be reduced through the use of distinctive packaging with strong warnings and safety directions on the label'. Schedule 6 chemicals are labelled with 'Poison' (SUSMP, 2014).

Appendix C chemicals are substances of such danger to health as to warrant prohibition of sale, supply and use.

International

All of the chemicals in this group are listed in the European Union (EU) Cosmetics Regulation 1223/2009 Annex II—List of substances prohibited in cosmetic products (Galleria Chemica).

Additionally, Rhodamine B (CAS No. 81-88-9), 2,3-dihydroxynaphthalene (CAS No. 92-44-4), N,N-diethyl-p-phenylenediamine (CAS No. 93-05-0), 4-chloro-o-phenylenediamine (CAS No. 95-83-0), N,N-dimethyl-p-phenylenediamine (CAS No. 99-98-9), 4-amino-2-nitrophenol (CAS No. 119-34-6), 2-(methoxymethyl)-4-aminophenol (CAS No. 29785-47-5), HC Yellow No. 3 (CAS No. 56932-45-7), 4-ethoxybenzene-1,3-diammonium sulfate (CAS No. 68015-98-5), and pyridine, 3,5-diamino-2,6-bis(2-hydroxyethoxy)- (CAS No. 117907-42-3) are present in 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;
  • Health Canada List of prohibited and restricted cosmetic ingredients (The Cosmetic Ingredient ‘Hotlist’); and
  • New Zealand Cosmetic Products Group Standard—Schedule 4: Components cosmetic products must not contain.

Existing Worker Health and Safety Controls

Hazard Classification

Two of the chemicals in this group are classified as hazardous, with the following risk phrases for human health in the Hazardous Substances Information System (HSIS) (Safe Work Australia):

N,N-diethyl-p-phenylenediamine (CAS No. 93-05-0):

  • T; R25 (acute toxicity); and
  • C: R34 (corrosivity).

N,N-dimethyl-p-phenylenediamine (CAS No. 99-98-9):

  • T: R23/24/25 (acute toxicity).

The rest of the chemicals are not listed on the HSIS (Safework Australia).

Australian

No specific exposure standards are available.

International

No specific exposure standards are available.

Limited or no toxicological data are available for the chemicals in this group.

The European Commission's (EC) Scientific Committee on Consumer Safety (SCCS), formerly known as the Scientific Committee on Cosmetic Products and Non-Food Products intended for Consumers (SCCNFP) and the Scientific Committee on Consumer Products (SCCP), provided scientific opinions on hair dye use and bladder cancer (SCCNFP, 2001; SCCNFP, 2004) and personal use of hair dyes and cancer risk (SCCP, 2005) based on epidemiological studies in Europe, the United States of America (USA), and Japan. The evaluations indicated a causal link between personal and occupational hair dye use and cancer.

The chemical 4-chloro-o-phenylenediamine (CAS No. 95-83-0) was classified by the International Agency for Research on Cancer (IARC) as a Group 2B carcinogen (Possibly carcinogenic to humans) (IARC, 1982). Rhodamine B (CAS No. 81-88-9) and 4-amino-2-nitrophenol (CAS No. 119-34-6) were classified by IARC as Group 3 carcinogens (Not classifiable as to their carcinogenicity in humans) (IARC, 1978).

The United States National Toxicology Program (US NTP) has available genotoxicity tests for N,N-diethyl-p-phenylenediamine (CAS No. 93-05-0), N,N-dimethyl-p-phenylenediamine (CAS No. 99-98-9), and 4-nitro-1,3-benzenediamine (CAS No. 5131-58-8), which showed that all chemicals were positive for mutagenicity in Salmonella typhimurium (Ames tests), sister chromatid exchange, and chromosomal aberration assays (US NTP).

The following tools were used to ascertain the mutagenicity and carcinogenicity potential of the chemicals:

  • OECD QSAR Toolbox v3.2 profiling functionalities; and
  • Optimized Approach based on Structural Indices Set–TIssue MEtabolism Simulator (OASIS–TIMES) v2.27.14 QSAR modelling for which predictions were obtained from the following models: in vitro Ames, in vitro chromosomal aberration, in vivo micronucleus test, and in vivo liver genotoxicity.

All the chemicals in this group either have functional groups that present alerts for mutagenicity and carcinogenicity potential based on their molecular structures as profiled by the OECD QSAR Toolbox, or were predicted to be positive for mutagenicity in one or more of the OASIS–TIMES genotoxicity models.

Another critical health concern for hair dyes is their potential for skin sensitisation. Skin sensitisation predictions using OASIS–TIMES were negative for all the chemicals. However, the possible metabolites of the majority of chemicals in this group, based on the metabolism simulators of OASIS–TIMES, were predicted to be strong skin sensitisers. The chemicals identified as CI Basic Red 46 (CAS No. 12221-69-1) and Basic Red 46 (CAS No. 89959-98-8) have been classified as skin sensitisers by NICNAS (NICNAS, 2005).

Some of the predictions were out of the applicability domain of the OASIS–TIMES models for skin sensitisation and genotoxicity, which indicates greater uncertainty about the reliability of the models since the performance statistics from the training set may not be applicable to the chemicals in this group. However, in the absence of any other information, the results from the QSAR model predictions will be considered in the weight of evidence analysis of the health effects of the chemicals.

Critical Health Effects

Based on the limited data available, the chemicals have been identified as having the potential to cause systemic long-term effects (genotoxicity and carcinogenicity). Some of the chemicals in this group also have been identified as having the potential to cause skin sensitisation. Other health hazards have not been considered.

Public Risk Characterisation

The public could be exposed to the chemicals in this group if they are used in hair dye preparations or other cosmetic products in Australia. The extent of current usage is unknown, as the chemicals in this group were not notified as being used in hair dye preparations in Australia.

The directions for use in hair dye preparations normally include instructions for pre-testing for skin sensitisation. Therefore, the local effects, including skin sensitisation, are not a high priority for assessment compared with the concerns about genotoxicity and carcinogenicity which, if validated, would be expected to be the dominant driver for appropriate risk management measures.

Several of the chemicals are prohibited or restricted internationally, particularly for use in cosmetics (see Restrictions: International).

Overall, there is sufficient uncertainty regarding the safety of these chemicals in cosmetic products to warrant a Tier III assessment, including consultation with industry to determine the extent of use and the availability of further genotoxicity and carcinogenicity data (see Recommendation).

Occupational Risk Characterisation

During product formulation, oral, dermal, ocular and/or 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.

The occupations of hairdresser and barber has been classified by the IARC as a Group 2A (Probably carcinogenic to humans) carcinogen (IARC, 2012).

Overall, there is sufficient uncertainty regarding the hazards of these chemicals in the workplace to justify a Tier III assessment, depending on the outcomes of industry consultations (see Recommendation), to determine the appropriate occupational controls.

NICNAS Recommendation

The chemicals in this group are recommended for Tier III assessment to determine:

  • whether the chemicals are being used in hair dye preparations in Australia;
  • any other uses of the chemicals in Australia;
  • the availability of toxicological information that is not accessible in the publicly-available literature to better characterise the hazards of the chemicals; and
  • whether risk management controls are required.

References

CosIng. Cosmetic Ingredients and Substances. Accessed March 2015 at http://ec.europa.eu/consumers/cosmetics/cosing/

Galleria Chemica. Accessed March 2015 at http://jr.chemwatch.net/galeria/

Hauri U. 2011. Inks for tattoos and PMU (permanent make-up)/organic pigments, preservatives and impurities such as primary aromatic and nitrosamines. State Laboratory of the Canton Basel City. Accessed at http://www.kantonslabor-bs.ch/files/berichte/6729_111012_JB_Tattoo_PMU_2011_EN.pdf

Hazardous Substances Data Bank (HSDB). National Library of Medicine. Accessed March 2015 at http://toxnet.nlm.nih.gov.

International Agency for Research on Cancer (IARC) 1978. IARC monographs on the evaluation of carcinogenic risks to humans, Volume 16. Some aromatic amines and related nitro compounds - hair dyes, colouring agents and miscellaneous industrial chemicals. Accessed March 2015 at http://monographs.iarc.fr/ENG/Monographs/vol1-42/mono16.pdf

International Agency for Research on Cancer (IARC) 1978. IARC monographs on the evaluation of carcinogenic risks to humans, Volume 27. Some aromatic amines, anthraquinones and nitroso compounds, and inorganic fluorides used in drinking water and dental preparations. Accessed March 2015 at http://monographs.iarc.fr/ENG/Monographs/vol1-42/mono27.pdf

International Agency for Research on Cancer (IARC) 2012. IARC monographs on the evaluation of carcinogenic risks to humans, Volume 99. Occupational exposures of hairdressers and barbers and personal use of hair colourants. Accessed March 2015 at http://monographs.iarc.fr/ENG/Monographs/vol99/mono99-17.pdf

National Industrial Chemicals Notification and Assessment Scheme (NICNAS), 2005. Final Report on Hazard Classification of Common Skin Sensitisers. January 2005. Accessed at http://www.nicnas.gov.au/__data/assets/pdf_file/0003/4926/Hazard_Classifications_Sensitisers_S2_PDF.pdf

NICNAS 2013. Inventory Multi-tiered Assessment and Priorisation (IMAP) Factsheet 4: Leveraging international information. Accessed March 2015 at http://www.nicnas.gov.au/chemical-information/imap-assessments/imap-factsheets

OECD 2014. Guidance on Grouping of Chemicals, Second Edition. Environment Directorate. Joint meeting of the Chemicals Committee and the Working party on Chemicals, Pesticides and Biotechnology. Series on Testing&Assessment No. 194. Accessed March 2015 at http://search.oecd.org/officialdocuments/displaydocumentpdf/?cote=env/jm/mono(2014)4&doclanguage=en

Personal Care Products Council 2011. Compilation of Ingredients Used in Cosmetics in the United States (CIUCUS), 1st Edition.

Scientific Committee on Consumer Products (SCCP) (2005) Opinion on Personal Use of Hair Dyes and Cancer Risk. Accessed March 2015 at http://ec.europa.eu/health/ph_risk/committees/04_sccp/docs/sccp_o_00l.pdf

Substances in Preparations in Nordic Countries (SPIN). Accessed March 2015 at http://188.183.47.4/dotnetnuke/Home/tabid/58/Default.aspx

SUSMP (2014) The Standard for the Uniform Scheduling of Medicines and Poisons at http://www.comlaw.gov.au/Details/F2012L01200/Download

The Scientific Committee on Cosmetic Products and Non-Food Products intended for consumers (SCCNFP). 2001. Opinionon the Use of Permanent Hair Dyes and Bladder Cancer Risk adopted by the SCCNFP during the 17th Plenary Meeting of 12 June 2001. Accessed March 2015 at http://ec.europa.eu/health/scientific_committees/consumer_safety/opinions/sccnfp_opinions_97_04/sccp_out143_en.htm

The Scientific Committee on Cosmetic Products and Non-Food Products intended for consumers (SCCNFP). 2004. Opinion concerning Use of Permanent Hair Dyes and Bladder Cancer. Accessed March 2015 at http://ec.europa.eu/health/ph_risk/committees/sccp/documents/out272_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 March 2015 at http://actor.epa.gov/actor/faces/ACToRHome.jsp

Last Update 01 July 2016