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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March 2016

Scheduling medicines and poisons

12 May 2016

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1.2 Disperse Yellow 3

Part A - Interim decisions on scheduling proposals referred to an advisory committee (March 2016)

1. Advisory Committee on Chemicals Scheduling (ACCS#16)

1.2 Disperse Yellow 3

Referred scheduling proposal
  • In response to issues raised in a NICNAS IMAP Human Health Tier 2 assessment report on Disperse Yellow 3, the scheduling proposal is to create a new Schedule 6, 7 or 10 entry for Disperse Yellow 3 to regulate its use in hair dyes and other products.
Scheduling application

The reasons for the request are:

  • Although use in cosmetic products in Australia is not known, the chemical has identified use in hair dye products. This use is now prohibited in some countries overseas.
  • Currently, there are no restrictions in Australia on using this chemical in cosmetics. In the absence of any regulatory controls in Australia, the characterised critical health effects, including sensitisation and carcinogenicity, have the potential to pose an unreasonable risk if the chemical is used in hair dye products in Australia.
  • the chemical is a known sensitiser which has elicited positive reactions in patch tests at concentrations of 0.01 %;
  • the chemical is carcinogenic in animals with evidence of a genotoxic mode of action; and
  • The NICNAS IMAP Tier II Human Health Report.
Specific issues/questions raised by the delegate

The reasons for the request were:

Disperse yellow 3 is one of several oxidative hair dye ingredients that have been referred for scheduling in the past three years. Generally, these have been listed in either schedules 5 or 6, with cut-offs to exempt at a relevant concentration that minimises the risks of skin sensitisation and/or irritancy. In some cases, scheduling exemptions have been allowed via ‘reverse scheduling', where products labelled with specified warning statements may be exempted from the generic scheduling controls of Schedule 5 or 6.

Further restrictions may have been applied where products are used in eyebrow/eyelash tints as well as in hair dyes. Additional restrictions (Schedule 10 listing) have been placed where there is a significant risk of genotoxicity and/or carcinogenicity, or where precluded use in products for skin colouration (tattooing) have been required. In some cases where there was no evidence of significant use in Australia, the delegate's decision was not to schedule the substance (e.g. o-aminophenol from the July 2014 meeting).

The Delegate sought advice from the Committee on the following questions:

  • Does the ACCS agree that, despite the paucity of available toxicity studies on the substance itself, the toxicological profile of Disperse Yellow 3 (low acute toxicity, sensitisation potential and genotoxicity) warrants controls over use in cosmetics and consumer products?
  • What weight should be given to the evidence of skin sensitisation potential in both LLNA tests and human exposures experience? Does the data suggest a suitable cut-off for the sensitisation potential?
  • What weight should be given to the evidence of genotoxicity, and potential carcinogenicity, in deciding the most appropriate controls over the use of Disperse Yellow 3?
  • If the ACCS recommends listing in Schedules 6, 7 or 10, should exemptions apply when the product is labelled with appropriate warning statements, consistent with other oxidative hair dye ingredients with similar toxicological profiles?
  • There appear to be non-cosmetic uses that could result in consumer exposure (e.g. dyeing textiles, clothing and carpets). Should a Schedule listing be specific to control use in hair dyes or cosmetic products (as for some other hair dye ingredients), or should the entry be broader in order to capture these other uses (as for the carcinogenic azo dyes included in Schedule 7 as a result of recent scheduling actions)?
  • What name should be used for any schedule entry - Disperse Yellow 3; or 4-(2-hydroxy-5-methylphenylazo)acetanilide?
  • Would this substance be captured by existing schedule entries for phenylenediamines (Schedule 6 and Schedule10), or AZO DYES that are derivatives by diazotisation of any of the following substances (Schedule7); or benzidine-based azo dyes (Schedule 7), or benzidine-congener (3,3' substituted) azo dyes (Schedule 7)?
  • Is there a need for specific entries in Appendices E and F to manage labelling of scheduled products?
Substance summary

Please refer to the NICNAS assessment report for Acetamide, N-[4-[(2-hydroxy-5-methylphenyl)azo]phenyl]-

Figure 2. Structure of Disperse Yellow 3

Figure 2. Structure of Disperse Yellow 3

Acute toxicity
Toxicity Species Disperse Yellow 3 SPF* Classification
Acute oral toxicity LD50 Rat > 5000 mg/kg bw Not classified
Skin sensitisation - LLNA challenge and loose-fit coculture-based sensitisation assay (LCSA)) positive Schedule 6

*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)

Skin sensitisation

This chemical is classified as hazardous with the risk phrase ‘May cause sensitisation by skin contact' (R43) in the Hazardous Substance Information System (HSIS) (Safe Work Australia). The positive results reported in a modified LLNA in mice and skin patch tests in humans (see Observation in humans section) support this classification.

The standard and modified (sensitisation—challenge) LLNA were used to test the sensitising potential of Disperse Yellow 3 and its aromatic amine metabolites, 4-Aminoacetanilide and 2-amino-p-cresol (Stahlmann et al., 2006). In the standard LLNA Disperse Yellow 3 and 4-aminoacetanilide were negative, but 2-amino-p-cresol showed a clear positive reaction. However, when the protocol was modified to a sensitisation—challenge assay, all three chemicals produced sensitisation reactions.

Compared with controls, significant increases in lymph node weights, cellularity and in the number of lymphocytes carrying A1 epitopes were observed in animals exposed to Disperse Yellow 3 (10 % and 30 % concentration) and 4-aminoacetanilide (30 % concentration). These results indicated sensitisation reactions. However, stronger sensitisation was induced by 2-amino-p-cresol.

Genotoxicity

Based on the weight of evidence from the available in vitro and in vivo genotoxicity studies, the chemical is considered to be genotoxic.

A number of in vitro genotoxicity tests gave positive results, and Disperse Yellow 3 also induced DNA damage in vivo. The aromatic amine metabolites are also genotoxic in vivo and/or in vitro.

Carcinogenicity

The chemical is classified as hazardous—Category 3 carcinogenic substance - with the risk phrase ‘Limited evidence of carcinogenic effect' (Xn; R40 in the HSIS (Safe Work Australia)). The available data support this classification.

In long-term feeding studies (103 weeks) exposure to the chemical caused tumours in male Fischer (F344) rats and male and female B6C3F1 mice. The liver was the main target organ of carcinogenicity in male rats. In these animals, dose-dependent significant increases in hepatocellular adenomas and combined hepatocellular adenomas and carcinomas were observed in treated males (dose). In addition, combined rare adenoma, mucinous adenocarcinoma and sarcoma, and combined squamous cell papilloma and fibrosarcoma were also identified in the glandular and non-glandular portions of the stomach of the exposed male rats. No tumours were reported in exposed female rats.

There is a lack of epidemiological data to indicate specific links between occupational exposure to the chemical and tumour development.

The mechanism of action underlying the chemical's carcinogenic potential is not fully understood. However, the available data suggest a genotoxic mode of action.

Reproduction and developmental toxicity

No data are available.

Observation in humans

A number of reports indicate sensitisation potential of the chemical. Allergic, contact-type dermatitis was reported in individuals with exposure to textiles coloured with dyes containing Disperse Yellow 3 (IARC, 1990; HSDB). The chemical has been identified as a disperse dye known to cause occupational contact allergic dermatitis in the textile industry (Office of Environmental Health Hazard Assessments, OEHHA, 2012).

Epicutaneous testing of the chemical (1% in petroleum) was conducted in 12 eczema patients with suspected contact allergy to textile dyes. The result showed that five patients had positive reactions to the chemical (Cosmetic Ingredient Review, CIR, 1996).

In another study, a number of patients who tested positive for Disperse Yellow 3 were also positive for the aromatic amine metabolites 4-aminoacetanilide and 2-amino-p-cresol. In this study, 6/10 patients tested with a dilution series of the chemical showed positive reactions. In addition, four patients showed positive reactions at 0.01 % of the chemical. These patients also showed a positive reaction to 4-aminoacetanilide (3/6) and 2-amino-p-cresol (6/6) (Malinauskiene et al., 2012).

Positive results in a patch test performed with a purified form of the dye indicated that it is the chemical and not the impurities that is responsible for the sensitisation response (CIR, 1996).

In a recent review on contact dermatitis from textiles, Malinauskiene et al. (2013) reported that a considerable number of patients showed positive patch test reactions to Disperse Yellow 3 (1 % in petrolatum). Positive responses were seen in approximately 7 % (averaged over 18 studies) of patients suspected or thought likely to have contact dermatitis caused by disperse dye allergy (aimed patch testing). In routine patch testing that included textile dyes (screening testing), a 0.8 % prevalence rate for Disperse Yellow 3 was reported (averaged over 12 studies). In Italy, Disperse Yellow 3 was also found to be one of the prevalent contact allergens in children (Malinauskiene et al., 2013).

Public exposure

No specific Australian use, import or manufacturing information has been identified.

The chemical has reported cosmetic use in oxidative hair dyes. No information is available on the concentrations used. Use of the chemical in cosmetics in the United States of America (USA) was reported in 1992, but there was no documented use in 2011 (Personal Care Product Council, 2011).

International regulations

The chemical is listed on the following (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; and
  • New Zealand Cosmetic Products Group Standard—Schedule 4: Components cosmetic products must not contain.

The chemical is also in the EU's list of 179 substances banned for use in hair dye products (European Commission, 2010).

Current scheduling status

Disperse Yellow 3 is not specifically scheduled.

Relevant scheduling history

Disperse Yellow 3 has not been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

One public submission was received. The submission did not object to aligning the scheduling controls for this substance with the EU. They noted Disperse Yellow 3 is listed in Annex II of the EU Cosmetics Regulations and cannot be used in cosmetics in the EU.

The public submission is available at: Public submissions on scheduling matters.

ACCS advice to the delegate

In relation to the Delegate's questions the committee agreed that the sensitisation and carcinogenic potential warrants control in cosmetic and consumer products and should not be used in hair dyes. The committee agreed it was appropriate to have both a Schedule 6 entry for disperse yellow 3 for general use and a Schedule 10 entry to specifically prohibit use in hair dyes, noting the schedule 6 entry effectively prohibits use in cosmetics. Members further agreed that appropriate warning statements for general use to advise of the skin sensitization potential was warranted. The committee advised that the name Disperse Yellow 3 be used in any Schedule entry with a cross-reference to the chemical name 4-(2-hydroxy-5-methylphenylazo)acetanilide in the index. Members agreed that the substance is not captured by the existing benzidine azo dye entries or azo dyes derivatised by diazotisation and therefore should be listed separately in the Standard.

The committee agreed on the following amendments to the Poisons Standard:

Schedule 10 - New entry

DISPERSE YELLOW 3 - for use in hair dyes

Schedule 6 - New entry

DISPERSE YELLOW 3- except when in Schedule 10

Appendix E, Part 2 - new entry

DISPERSE YELLOW 3

Standard statements: A, S1

Appendix F, Part 3 - new entry

DISPERSE YELLOW 3

Warning Statement: 28

Safety direction: 4

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: b) to prevent its use in hair dyes but allow use in other dye situations (e.g. fabrics); and c) toxicity - skin sensitization consistent with Schedule 6 listing.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors2;
  • Other relevant information.
Delegate's interim decision

The delegate notes, and accepts, the advice of the ACCS to create new listings for Disperse Yellow 3 in Schedules 6 and 10, and in Appendices E and F. The listings are to be made under the name Disperse Yellow 3, with the chemical name 4-(2-hydroxy-5-methylphenylazo)acetanilide, cross-referenced in the index. The delegate notes that this substance would not be captured under any existing Schedule entries for phenylenediamines or azo dyes.

The purpose of the Schedule 10 entry is to restrict use in hair dyes preparations, in alignment with similar restrictions in international cosmetics regulations (EU, NZ and ASEAN). The toxicological basis for this restriction is the acute toxicity profile, including skin sensitisation potential shown in both toxicological testing and in human studies. For use in products other than hair dyes, the listings in Schedule 6 and Appendices E and F should provide suitable warnings to product users, including the requirement for the signal heading POISON on product labels. There was insufficient information, and no recommendation from the ACCS, for the delegate to consider any low concentration exemptions from the proposed entries.

The proposed implementation date is 1 October 2016. An early implementation date is proposed in order to bring the regulation of this oxidative hair dye ingredient in products sold in Australia into alignment with international regulations.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (a) the risks and benefits of the use of a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

Schedule 10 - New entry

DISPERSE YELLOW 3 - for use in hair dyes

Schedule 6 - New entry

DISPERSE YELLOW 3- except when in Schedule 10

Appendix E, Part 2 - new entry

DISPERSE YELLOW 3

Standard statements: A, S1

Appendix F, Part 3 - new entry

DISPERSE YELLOW 3

Warning Statement: 28

Safety direction: 4


Footnotes

  1. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)

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