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Scheduling delegate's final decisions, January 2017

Scheduling medicines and poisons

16 January 2017

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1.1 m-Aminophenol

Final decisions on matters not referred to an expert advisory committee

1. Chemicals not referred to the November 2016 ACCS

1.1. m-Aminophenol

Referred scheduling proposal

An application was submitted to create a new Schedule 6 entry for m-aminophenol and to determine whether an appropriate exemption cut-off is required.

Current scheduling status and relevant scheduling history

m-Aminophenol is not currently scheduled and has not previously been considered for scheduling; therefore, a scheduling history is not available.

Isomers of m-aminophenol, o- and p-aminophenol have been considered for scheduling:

o-Aminophenol

In July 2014, the Advisory Committee on Chemicals Scheduling (ACCS) advised that o-aminophenol does not require scheduling.

p-Aminophenol

In March 2016, the ACCS advised that p-aminophenol be listed in Schedule 6 except when used in hair dye and eyebrow/eyelash colouring products. Effective 1 October 2016 the schedule for p-aminophenol will be as follows:

Schedule 6

p-AMINOPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 1 per cent or less of p-aminophenol 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.

Written in letters not less than 1.5 mm in height.

Appendix E, Part 2 – p-AMINOPHENOL

Standard statements: A, S1.

Appendix F, Part 3 – p-AMINOPHENOL

Warning Statement: 28.

Homologues of m-aminophenol, 4-amino-m-cresol and 4-amino-2-hydroxytoluene, are listed with reference to use in hair dyes with a 1.5 per cent or less cut-off in the SUSMP as follows:

4-Amino-m-cresol

Schedule 6

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

  1. in hair dye preparations containing 1.5 per cent 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 per cent 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 2 – 4-AMINO-m-CRESOL

Standard statements: A, E1.

Appendix F, Part 3 – 4-AMINO-m-CRESOL

Warning statement: 28.

4-Amino-2-hydroxytoluene

Schedule 6

4-AMINO-2-HYDROXYTOLUENE in hair dyes and eyebrow/eyelash colouring products except:

  1. in hair dye preparations containing 1.5 per cent or less of 4-amino-2-hydroxytoluene 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 per cent or less of 4-amino-2-hydroxytoluene 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 2 – 4-AMINO-2-HYDROXYTOLUENE

Standard statements: A, E1.

Appendix F, Part 3 – 4-AMINO-2-HYDROXYTOLUENE

Warning statement: 28.

Index

5-AMINO-o-CRESOL
cross reference: 4-AMINO-2-HYDROXYTOLUENE

Australian regulatory information

New Zealand, ASEAN countries and the EU have restricted the use of m-aminophenol in cosmetics (see International regulations below); however, there are currently no restrictions in Australia on the use of the chemical in cosmetics or domestic products.

Considering the use of this chemical in permanent hair dyes in Australia and other potential domestic uses (based on overseas information), the main routes of public exposure are expected to be through the skin and inhalation from products applied as aerosols.

In the absence of regulatory controls, the characterised critical health effects (acute toxicity and skin sensitisation) have the potential to pose an unreasonable risk under the identified uses. The risk could be mitigated by implementing restrictions for the use of the chemical in hair dyes and other cosmetic products.

International regulations

Use of the chemical in cosmetics in the EU is subject to the restrictions described in EU Cosmetics Regulation 344/2013 (as an amendment to the listing under Annex III of Regulation 1223/2009). The use of the chemical in hair dyes is restricted to a maximum concentration of 1.2% applied to hair after mixing under oxidative conditions (1:1 ratio with hydrogen peroxide). If the chemical is present at lower concentrations, sensitisation labelling is required.

Use of the chemical in cosmetics and domestic products is also restricted in several other countries as follows:

  • ASEAN Cosmetic Directive Annex III Part 1: List of substances which cosmetic products must not contain except subject to restrictions and conditions; and
  • New Zealand Cosmetic Products Group Standard-Schedule 5, Table 1: Components cosmetic products must not contain except subject to restrictions and conditions.

Under the above regulations, the use of the chemical in hair dyes is restricted to a maximum concentration of 1.2% applied to hair after mixing under oxidative conditions.

Scheduling application

General application.

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

Schedule 6 – New Entry

m-AMINOPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 1.2 per cent or less of m-aminophenol 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.

Written in letters not less than 1.5 mm in height.

Appendix E, Part 2m-AMINOPHENOL

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

Appendix F, Part 3m-AMINOPHENOL

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

The applicant's reasons for the request are:

  • Currently, there are no restrictions on introducing or using this chemical in Australia. In the absence of any regulatory controls, the characterised critical health effects (particularly skin sensitisation) have the potential to pose an unreasonable risk if m-aminophenol is used in cosmetic products without an appropriate concentration cut-off (exemption) for hair dye use. Whilst domestic use of the chemicals will result in lower levels of exposure, there is sufficient uncertainty regarding the safety of such products to warrant some restriction;
  • m-Aminophenol was reported to be used in permanent hair dye preparations in Australia, and overseas hair products and other personal care products;
  • m-Aminophenol is a contact allergen in humans;
  • m-Aminophenol is a strong skin sensitiser in animals, based on a local lymph node assay (LLNA)-derived EC3 (estimated concentration to produce a three-fold increase in lymphocyte proliferation) value of 0.24-3.2%;
  • The existing overseas restrictions (Association of Southeast Asian Nations (ASEAN), New Zealand, European Union (EU)) on the use of the chemical in cosmetic products, where the use of m-aminophenol in hair dyes is restricted to a maximum concentration of 1.2% applied to hair after mixing under oxidative conditions (a 1:1 mixture of 2.4% 3-aminophenol with hydrogen peroxide); and
  • When m-aminophenol is used as a hair dye, there is a potential risk of for skin sensitisation, which may be controlled through concentration restrictions and warning labels, as have previously been applied to other sensitising hair dyes considered for inclusion in the SUSMP.
Substance summary

The following toxicology information was extracted from the NICNAS IMAP Human Health Tier II assessment report for 3-aminophenol. Further information can also be found in the SCCP report for m-aminophenol.

Figure 1.1: Chemical structure of m-aminophenol
Figure 1.1: Chemical structure of m-aminophenol

Table 1.1A: Chemical properties and identifiers of m-aminophenol
Property/identifier m-Aminophenol
Molecular formula C6H4
Molecular weight 109.13 g/mol
CAS name Phenol, 3-amino-
CAS number 591-27-5
IUPAC and/or common and/or other names 3-hydroxyaniline (IUPAC); m-aminophenol (INCI)
SUSMP name Not listed in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP). Based on previously considered isomers, p-aminophenol (March 2016 ACCS meeting cycle) and o-aminophenol (July 2014 ACCS meeting cycle), the recommended SUSMP name is m-aminophenol.
Table 1.1B: Acute toxicity end-points for m-aminophenol
Toxicity Species m-Aminophenol SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bodyweight (bw)) Rat 812-1000 Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) N/A No data N/A
Acute inhalational toxicity LC50 (mg/m3/4h) Rat 1162 Schedule 6
Skin irritation Rabbit No irritation (2% m-aminophenol in a suspension of 0.5% methylcellulose in purified water) N/A
Eye irritation Rabbit Mild irritation (2% m-aminophenol in a suspension of 0.5% methylcellulose in purified water) N/A
Skin sensitisation (LLNA) Mouse Moderate to strong skin sensitiser (EC3 0.24-3.2%) Schedule 6
Skin sensitisation (Guinea pig maximisation test (GPMT)) Guinea pig Sensitiser. Positive reactions in 100% of animals tested at 5%, following 1% intradermal induction and 1% topical induction.
Acute toxicity

m-Aminophenol has moderate acute oral and inhalation toxicity, warranting hazard classification. No data were available for acute dermal toxicity.

Irritation

The available data from animal and human studies indicate that the chemical is not irritating to the skin or eyes.

Sensitisation

Based on the available animal and human data, the chemical is considered to be a moderate to strong skin sensitiser and is recommended for classification.

  • In an in vivo mouse LLNA conducted in accordance with OECD Test Guideline (TG) 429, 28 female CBA/J mice (four animals/group) were administered the chemical at concentrations of 0, 1, 2.5, 5, 10 or 25% (w/v) in dimethylformamide. Stimulation indices (SI) of 0, 7.6, 12.6, 10.4, 7.2 and 6.0 were reported, respectively. In a second experiment, concentrations of 0, 0.05, 0.1, 0.5, 1.0 and 2.5% of the chemical in the same vehicle were administered to the animals. SIs of 1.0, 1.4, 5.9, 9.0 and 11.0 were reported, respectively. The calculated EC3 value (0.24%) indicated strong sensitisation potential for the chemical.
  • In another mouse LLNA study, CBA/Ca mice were administered the chemical at concentrations of 0, 2.5, 5 or 10% (w/v) in acetone/olive oil (ratio of 4:1). SIs of 0, 2.8, 3.5 and 5.7 were reported, respectively. The EC3 value was reported to be 3.2%.
  • In a non-guideline GPMT, guinea pigs were administered the chemical at a concentration of 1.0% (v/v) in acetone/olive oil (ratio of 4:1) by intradermal injection, followed by topical induction with a 10% solution of the chemical one week later. After two weeks, a topical challenge dose of 5% resulted in positive reactions observed in all animals tested.
Repeat-dose toxicity

Based on the available information, m-aminophenol is not considered to cause serious damage to health through repeated oral exposure at low doses. Systemic toxicity has not been demonstrated via the dermal route. No information was available for repeated dose toxicity by inhalation.

Genotoxicity

Based on the weight of evidence from the available in vitro and in vivo genotoxicity studies, m-aminophenol is not considered to be genotoxic.

Carcinogenicity

Based on the available data and the lack of genotoxicity, m-aminophenol is not expected to be carcinogenic.

Reproduction and developmental toxicity

Based on the available information, m-aminophenol is not expected to be a reproductive or developmental toxin.

Observation in humans
Sensitisation:

Sensitisation in humans exposed to the chemical has been observed both in repeat insult patch tests and during diagnostic patch testing.

In two semi-occlusive repeat insult patch tests, 0.1 mL doses of m-aminophenol (3% solution in Schultz vehicle II or similar) were applied to the backs of 98 and 99 test subjects over a six week period. There were 10 consecutive induction patch applications at 48–72 hours, followed by one day of no application. Challenge patch applications on previously unexposed skin on backs of humans were conducted 48 hours following the rest period. In both studies, irritant effects (erythema) were observed in several subjects during the induction phase. In the first study (98 subjects), no reactions to the challenge patches were observed. In the second study (99 subjects), two subjects showed reactions following application of the challenge patches, as well as following application of additional rechallenge patches on different parts of the body.

In an Australian case study, 164 hairdressers and hairdressing apprentices who presented with allergic contact dermatitis at a dermatology clinic were patch-tested against 36 chemicals used in hair salons. Four subjects, previously exposed to m-aminophenol in the workplace, had positive reactions when patch tested with the chemical.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal
  • NICNAS IMAP Tier II Report
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling Policy Framework (SPF 2015) criteria
  • Other relevant information.
Delegate's final decision

The final decision is to create a new Schedule 6 entry for m-aminophenol with a 1.2 per cent exemption cut-off in hair dye preparations as follows:

Schedule 6 − New Entry

m-AMINOPHENOL except when in hair dye preparations containing 1.2 per cent or less of m-aminophenol 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, 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 1.5 mm in height.

Appendix E, Part 2m-AMINOPHENOL

Standard statements: 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 3m-AMINOPHENOL

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

The delegate notes that oxidative hair dyes of the aminophenolic class have common toxicological properties that warrant controls over scheduling. Exposure to m-aminophenol exposure may occur dermally or through inhalation from aerosol products. The acute oral and inhalational toxicity and skin sensitisation of m-aminophenol are consistent with SFP criteria for Schedule 6. Recent decisions for previously considered similar sensitising hair dyes have allowed for some products to be exempted where there are label statements warning of the potential for skin sensitisation, and recommending testing for individual susceptibility before use. This scheduling decision is in alignment with international regulations for m-aminophenol and is consistent with recent decisions agreed on previously considered similar sensitising hair dyes.

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 the substance; (b) the purposes for which the substance is to be used and (c) the toxicity of the substance.

The implementation date is 1 February 2017.

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