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

Scheduling medicines and poisons

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2 February 2017

1.6 HC Violet 1 (2-[(4-amino-2-methyl-5-nitrophenyl)amino]-ethanol)

Part A - Interim decisions on matters referred to an expert advisory committee (November 2016)

Advisory Committee on Chemicals Scheduling (ACCS #18)

1.6 HC Violet 1, (2-[(4-amino-2-methyl-5-nitrophenyl)amino]-ethanol)

Referred scheduling proposal

An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new Schedule 6 entry for 2-[(4-amino-2-methyl-5-nitrophenyl)amino]-ethanol in hair dyes and eyebrow/eyelash colouring products and to determine whether an appropriate exemption cut-off is required.

Scheduling application

General application.

The applicant's proposed amendments to the Poisons Standard are as follows:

Schedule 6 - New Entry

2-[(4-AMINO-2-METHYL-5-NITROPHENYL)AMINO]ETHANOL except when used in hair dye preparations containing 0.25 per cent or less of 2-[(4-amino-2-methyl-5-nitrophenyl)amino]ethanol under oxidative conditions (after mixing with hydrogen peroxide), or 0.28 per cent or less of 2-[(4-amino-2-methyl-5-nitrophenyl)amino]ethanol under non-oxidative conditions, and 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 sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use.

Written in letters not less than 1.5mm in height

Appendix E, Part 2 - New Entry

2-[(4-AMINO-2-METHYL-5-NITROPHENYL)AMINO]ETHANOL

Standard statements: E1 (if in eyes wash out immediately with water).

Appendix F, Part 3 - New Entry

2-[(4-AMINO-2-METHYL-5-NITROPHENYL)AMINO]ETHANOL

Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).

The applicant's reasons for the request are:

  • 2-[(4-Amino-2-methyl-5-nitrophenyl)amino]-ethanol (HC Violet 1) has reported cosmetic use in semi-permanent hair dye preparations in Australia.
  • HC Violet 1is a strong skin sensitiser.
  • The overseas restrictions for HC Violet 1 in hair dyes state that the maximum concentration allowed in the finished cosmetic product in hair dye products is 0.28% and the maximum use concentration upon application is 0.25% (after mixing under oxidative conditions).
  • The risk could be controlled by including warning statements on the label of hair dye formulations containing HC Violet 1 at any concentration.
  • As a strong sensitiser, HC Violet 1 presents a serious risk of sensitisation even below the maximum concentration of 0.28% permitted under the EU Cosmetic Regulation. Given the potential for induction and elicitation of sensitisation below the EU cut-off, the risk would be better controlled by inclusion of appropriate cut-offs and warning statements on the label of preparations containing the chemical below the cut-off. This is consistent with Schedule 6 entries for some other hair dye ingredients.
Current scheduling status and relevant scheduling history

2-[(4-amino-2-methyl-5-nitrophenyl) amino]-ethanol (HC Violet 1) is not currently scheduled and has not been previously considered for scheduling; therefore, a scheduling history is not available.

Australian regulatory information

The chemical is reported to be used in semi-permanent hair dye preparations in Australia (NICNAS, 2007). Currently, there are no restrictions in Australia on using this chemical in cosmetic products. In the absence of any regulatory controls, the characterised critical health effects (skin sensitisation) have the potential to pose an unreasonable risk to public under the uses identified.

International regulations

The European Union (EU), New Zealand and the Association of South East Asian Nations (ASEAN) have restricted the use of the chemical in cosmetics: '(a) the maximum authorised concentration in the finished cosmetic products as hair dye substances in non-oxidative hair dye products is 0.28 %; and (b) after mixing with hydrogen peroxide under oxidative conditions the maximum concentration applied to hair must not exceed 0.25 %'. The EU Cosmetics Regulation No. 344/2013 Annex III, Part 1 also mandates label warning statements relating to the sensitisation potential of the chemical at lower concentrations.

Substance summary

Structure of 2-[(4-amino-2-methyl-5-nitrophenyl) amino]-ethanol (HC Violet 1)

Figure 1.6: Structure of 2-[(4-amino-2-methyl-5-nitrophenyl) amino]-ethanol (HC Violet 1)

Table 1.6A: Chemical information
Property 2-[(4-amino-2-methyl-5-nitrophenyl)amino]-ethanol
CAS name ethanol, 2-[(4-amino-2-methyl-5-nitrophenyl)amino]-
CAS number 82576-75-8
IUPAC and/or common and/or other names HC Violet 1(INCI); Imexine FAA; 1-amino-3-methyl-4-(2-hydroxyethyl)amino-6-nitrobenzene

The following information was extracted from the NICNAS IMAP Human Health Tier II assessment report for Ethanol, 2-[(4-amino-2-methyl-5-nitrophenyl)amino]-.

Table 1.6B: Acute toxicity end-points for 2-[(4-amino-2-methyl-5-nitrophenyl) amino]-ethanol (HC Violet 1)
Toxicity Species HC Violet 1 SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat >2000 Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) N/A No data N/A
Acute inhalational toxicity LC50 (mg/m3/4h) N/A No data N/A
Skin irritation Rabbit Slight irritant N/A
Eye irritation Rabbit Slight irritant N/A
Skin sensitisation (local lymph node assay, LLNA) Mouse Strong sensitiser Schedule 6
Sensitisation

Based on the available data, the chemical is considered to be a strong skin sensitiser:

  • One LLNA (OECD TG 429) was conducted in female CBA/J mice (n = 5/concentration), using the chemical in dimethyl formamide (DMF) vehicle. All test concentrations of 1, 2.5, 5, 10 and 25% produced a stimulation index (SI) over three (4.08, 6.11, 9.11, 5.64 and 9.79, respectively). The effective concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3), which was calculated to less than 1%, indicated a strong sensitising potential.
  • In another LLNA (OECD TG 429), in female CBA/J mice (n = 5/concentration), using the chemical in DMF vehicle also, test concentrations of 0.1, 0.25, 0.5, 1 and 2.5% produced an SI of 1.20, 1.67, 1.30, 3.40, 3.83 and 11.05, respectively. The EC3 value, which was calculated to be 0.9%, indicated a strong sensitising potential.
Repeat-dose toxicity

Based on the available data, the chemical is not expected to cause serious damage to health from repeated oral exposure. No information was available for repeated dose toxicity by dermal and inhalation routes.

Genotoxicity

Based on the negative results observed in several in vitro and in vivo genotoxicity studies, the chemical is not expected to be genotoxic.

Carcinogenicity

No data are available for carcinogenicity. However, the lack of genotoxicity in vivo and negative bacterial reverse mutation assay results indicates that the likelihood of carcinogenic effects is low.

Reproduction and developmental toxicity

Based on the limited available data, the chemical is not expected to have reproductive and developmental toxicity.

Pre-meeting public submissions

One (1) pre-meeting submission was received in support. The main points were that the new schedule entry would be in alignment with international regulators in the EU, ASEAN and NZ.

Summary of ACCS advice to the delegate

The committee advised that a new Schedule 6 entry for 2-[(4-amino-2-methyl-5-nitrophenyl)amino]-ethanol be created under the INCI name of HC Violet 1 with exemption cut-off concentrations as follows:

Schedule 6 - New Entry

HC VIOLET 1 except:

  1. in non-oxidative hair dye preparations containing 0.28 per cent or less of HC Violet 1 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 sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use, and

    Written in letters not less than 1.5 mm in height; or

  2. in oxidative hair dye preparations containing 0.25 per cent or less of HC Violet 1 after mixing under oxidative conditions 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 sensitisation 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, and

    Written in letters not less than 1.5 mm in height.

The committee also advised that appendix and index entries be created as follows:

Appendix E, Part 2 - New Entry

HC VIOLET 1

Standard statements: E1 (if in eyes wash out immediately with water).

Appendix F, Part 3 - New Entry

HC VIOLET 1

Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).

Index - New Entry

HC VIOLET 1
cross reference: 2-[(4-AMINO-2-METHYL-5-NITROPHENYL)AMINO]-ETHANOL

Schedule 6
Appendix E, Part 2
Appendix F, Part 3

The committee recommended an implementation date of 1 June 2017.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (b) the purpose for which a substance is to be used and the and extent of use; and (c) the toxicity of a substance.

The reasons for the advice comprised the following:

  • HC Violet 1 is used in hair dyes, and dermal contact is unavoidable.
  • HC Violet 1 has demonstrated strong skin sensitisation potential consistent with Schedule 6 factors.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal
  • ACCS advice
  • Public Submissions received
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is to create a new Schedule 6 entry for 2-[(4-amino-2-methyl-5-nitrophenyl)amino]-ethanol under the INCI name of HC Violet 1 with exemption cut-off concentrations.

The proposed Schedule entry is as follows:

Schedule 6 - New Entry

HC VIOLET 1 except:

  1. in non-oxidative hair dye preparations containing 0.28 per cent or less of HC Violet 1 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 sensitisation to certain individuals. A preliminary test according to the accompanying directions should be made before use, and

    Written in letters not less than 1.5 mm in height; or

  2. in oxidative hair dye preparations containing 0.25 per cent or less of HC Violet 1 after mixing under oxidative conditions 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 sensitisation 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, and

    Written in letters not less than 1.5 mm in height.

Appendix E, Part 2 - New Entry

HC VIOLET 1

Standard statements: E1 (if in eyes wash out immediately with water).

Appendix F, Part 3 - New Entry

HC VIOLET 1

Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).

Index - New Entry

HC VIOLET 1
cross reference: 2-[(4-AMINO-2-METHYL-5-NITROPHENYL)AMINO]-ETHANOL

Schedule 6
Appendix E, Part 2
Appendix F, Part 3

The proposed implementation date is 1 June 2017.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: b) the purposes for which a substance is to be used and the extent of use of a substance; and c) the toxicity of the substance.

The reasons for the recommendation comprised the following:

  • The delegate acknowledges the committee's advice.
  • HC Violet 1 is used in hair dyes, and dermal contact is unavoidable.
  • HC Violet 1 has demonstrated strong skin sensitisation potential consistent with Schedule 6 factors.
  • Earliest possible implementation date.

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