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Scheduling delegate's final decisions: ACCS, November 2015

Scheduling medicines and poisons

19 November 2015

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2.9 4-amino-m-cresol (Phenol, 4-amino-3-methyl)

Part A - Final decisions on matters referred to an expert advisory committee

2. Scheduling proposals referred to the August 2015 ACCS meeting

2.9 4-amino-m-cresol (Phenol, 4-amino-3-methyl)

Scheduling proposal

The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):

  • In April 2015 the delegate received a request to consider creating a new entry for 4-amino-m-cresol in Schedule 5 to include use in hair dyes and eyelash colouring products with an appropriate cut-off.
Scheduling application

In February 2015, the National Industrial Chemicals Notification and Assessment Scheme (NICNAS), under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) programme, referred the following proposal to be considered by the delegate for inclusion in the Poisons Standard:

  • A proposal to create a new entry for 4-amino-m-cresol in Schedule 5 to include use in hair dyes and eyelash colouring products with an appropriate cut-off.

The reasons for the request were:

  • the chemical has reported cosmetic use in permanent hair dye preparations in Australia;
  • the chemical is a moderate skin sensitiser;
  • only limited data are available on eye and skin irritation; with a 1.5 % concentration the chemical may have a minimal eye irritation potential;
  • there is a lack of data on acute or repeated dose dermal and inhalation toxicity; and
  • the overseas restrictions for use of this chemical in hair dyes state that the maximum concentration allowed in an oxidative hair dye substance is 1.5 % (after mixing with hydrogen peroxide).

The critical health effect for risk characterisation is skin sensitisation. Given the potential for induction and elicitation of sensitisation even below the overseas restriction cut-off, the risk would be better controlled by inclusion of 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.

Delegate's reasons for referring this to the committee

The toxicological issues in this scheduling proposal are similar to those considered by the ACCS in November 2013 for 2-amino-5-ethyl-phenol and in July 2014 for o-aminophenol and for 5-amino-2-methyl-phenol at this meeting. The delegate's reasons for referring the current proposal for 4-amino-m-cresol are similar, in that it is an ingredient in hair dyes and cosmetic products for dyeing eyebrows and eyelashes and it has the following toxicological issues: acute toxicity and sensitisation potential. The NICNAS recommendation was for scheduling controls to restrict use in hair dye and other cosmetic preparations. Its use in cosmetics is restricted in various overseas regulations. ACCS advice is needed to determine the optimal scheduling actions to achieve the requested controls.

The delegate asked the committee the following questions:

  • Does the ACCS agree that the toxicological profile of 4-amino-m-cresol (acute toxicity, sensitisation potential, negative mutagenicity but limited information on skin-eye irritancy and carcinogenicity) warrants controls over use in cosmetics and consumer products?
  • What weight should be given to the evidence of moderate skin sensitisation potential? Does the data suggest a suitable cut-off for the sensitisation potential?
  • Does the ACCS consider that including 4-amino-m-cresol in Schedule 6 is the best option for controlling its use in consumer products and cosmetics, including hair dyes and eyebrow/eyelash products? Should there be a cut-off to exempt at 1.5%, as suggested in the NICNAS report?
  • If the ACCS recommends listing in Schedule 6, should exemptions apply when the product is labelled with appropriate warning statements, consistent with other oxidative hair dye ingredients with similar toxicological profiles?
  • Which of the names in the NICNAS IMAP report should be used for any schedule entry? e.g. 4-amino-m-cresol, 4-amino-o-cresol or 4-hydroxy-o-toluidine?
  • Is there a need for specific entries in Appendices E & F to manage labelling of scheduled products?
Substance summary

Refer to the NICNAS IMAP report available on the NICNAS website: NICNAS IMAP assessment ID 1040.

Acute toxicity

The acute toxicity end-points for this chemical are listed in the table below.

Toxicity Species Phenol, 5-amino-2-methyl SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 870 mg/kg bw Schedule 6
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 Guinea pig Not irritant at concentrations up to 3 % (limited data) N/A
Eye irritation Guinea pig Minimal irritant potential at 1.5 % Schedule 5
Skin sensitisation

The chemical is a skin sensitiser based on the data from the NICNAS IMAP report.

A local lymph node assay (LLNA) with the chemical was conducted in CBA/J mice (OECD TG 429). The chemical was mixed either with water/acetone (1:1) and olive oil (4:1) or with DMSO and administered at the final concentrations of 0.5, 1.5, 3 or 5 % and 0.5, 1.5, 5 or 10 %, respectively. The estimated concentration required to produce a stimulation index of three (EC3) was 2.15 % when a mix of water/acetone/olive oil was used as a vehicle, and 1.45 % when DMSO was used as a vehicle. The chemical is, therefore considered to be a moderate skin sensitiser.

Repeat dose toxicity

Based on the data available for a sulphate salt of the chemical, 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 reported for all in vitro and in vivo genotoxicity studies, the chemical is not considered to be genotoxic.

Carcinogenicity

Based on the available genotoxicity data and information available from Quantitative Structure Activity Relationship (QSAR) modelling, the chemical is not considered to be carcinogenic.

Reproduction and developmental toxicity

Based on a single prenatal developmental toxicity study available, the chemical is not expected to cause reproductive or developmental toxicity at the doses tested. However, the Scientific Committee on Consumer Products (SCCP) opinion stated that this study did not use the dose selection according to the OECD test guidelines and therefore, 'a possible hazard is not adequately identified'.

Public exposure

The chemical is reported to be used in permanent hair dye preparations in Australia. The chemical may also be in products to colour eyelashes.

New Zealand and the European Union have restricted the use of this chemical in cosmetics. The chemical, once mixed under oxidative conditions, should not exceed 1.5 % in hair dyes or eyelash products (CosIng).

If the chemical is included in cosmetic products containing N-nitrosating agents, carcinogenic compounds could be formed.

Currently, there are no restrictions in Australia on using this chemical in hair dyes and eyelash colouring 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 chemical is listed on the following:

  • Association of South East Asian Nations (ASEAN) Cosmetic Directive Annex III Part 2—List of substances provisionally allowed;
  • EU Cosmetics Regulation 1223/2009 Annex III - List of substances which cosmetic products must not contain except subject to the restrictions laid down: '(a) Hair dye substance in oxidative hair dye products; (b) Products intended for colouring eyelashes; For (a) and (b): After mixing under oxidative conditions the maximum concentration applied to hair or eyelashes must not exceed 1.5%; (b) For professional use only'; and
  • New Zealand Cosmetic Products Group Standard - Schedule 5: Components cosmetic products must not contain except subject to the restrictions and conditions laid down.
Scheduling status

4-amino-m-cresol is not specifically scheduled.

Scheduling history

4-amino-m-cresol has not been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

One public submission was received. The submission stated that there were no objections to aligning Australian scheduling with those of the EU.

The public submissions are available at Public submissions on scheduling matters.

Summary of ACCS advice to the delegate

The committee recommended a new Schedule 6 entry be created for 4-amino-m-cresol, except in preparations containing 1.5% or less of the substance after mixing for use when the containers are labelled with the appropriate warning labels.

The committee also recommended appropriate Appendix E and Appendix F statements (provided below) for 4-amino-m-cresol are to be created.

Appendix E, Part 1 - New Entry
Poison Standard Statement
4-AMINO-M-CRESOL

A - For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once).

E1 - If in eyes wash out immediately with water

Appendix F, Part 1 - New Entry
Poison Warning Statement
4-AMINO-M-CRESOL 28 - (Over) (Repeated) exposure may cause sensitisation.

The committee also recommended changing the name from its original reference of phenol, 4-amino-3-methyl is 4-AMINO-M-CRESOL.

The committee recommended an implementation date of 1 February 2016.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (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; and (c) the toxicity of a substance.

The reasons for the recommendations comprised the following:

  • Hair dye, eyelash and eyebrow tinting products
  • Fits the criteria in Schedule 6: skin sensitiser and acute oral toxicity.
Delegate's interim decision

The Committee recommended a new Schedule 6 entry be created for 4-amino-m-cresol with appropriate exempt cut-offs as follows:

Schedule 6 - New Entry

4-AMINO-M-CRESOL in hair dyes and eyebrow/eyelash colouring preparations except:

  1. in hair dye preparations containing 1.5% or less of 4-amino-m-cresol after mixing for use 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.

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

  2. in eyelash and eyebrow tinting products containing 1.5% or less of 4-amino-m-cresol after mixing for use when the immediate container and primary pack are labelled with the following statement:

    WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals, and when used for eyelash or 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 1.5mm in height.

Appendix E, Part 1 - New Entry
Poison Standard Statement
4-AMINO-M-CRESOL

A - For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once).

E1 - If in eyes wash out immediately with water

Appendix F, Part 1 - New Entry
Poison Warning Statement
4-AMINO-M-CRESOL 28 - (Over) (Repeated) exposure may cause sensitisation.

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

The proposed implementation date is 1 June 2016. A later implementation date is proposed to allow for an orderly process of re-labelling of products already on the market.

The reasons for the interim decision comprised the following:

4-amino-m-cresol is an ingredient of oxidative hair dyes. In common with other amine hair dye ingredients, there is a risk of skin/eye irritation and skin sensitisation. This risk has been managed for other oxidative hair dye ingredients by listing in Schedule 6, with ‘reverse scheduling’ provisions that exempt some preparations when labelled with appropriate warning statements. The delegate accepts ACCS advice that 4-amino-m-cresol scheduling should be managed in the same way as previously scheduled hair dye ingredients.

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 factors11;
  • Other relevant information.
Public submissions on the interim decision

One submission was received. The submission supported the delegate’s interim decision.

Edited versions of these submissions are available at Public submissions on scheduling matters.

Delegate's final decision

The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.


Footnotes

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

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