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Scheduling delegate's final decisions, June 2017

Scheduling medicines and poisons

29 June 2017

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3.3 m-Aminophenol

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

Advisory Committee on Chemicals Scheduling (ACCS #19)

3.3 m-Aminophenol

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 m-aminophenol with an appropriate exemption cut-off for hair dye use.

Current scheduling status and relevant scheduling history

m-Aminophenol is not currently scheduled.

In August 2016, NICNAS, under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) Scheme submitted a proposal to create a new entry for m-aminophenol in Schedule 6 for restriction in cosmetic and domestic products. Prior to this date, m-aminophenol was unscheduled and had not previously been considered for scheduling.

In January 2017, the delegate made a delegate-only final decision to enter m-aminophenol in Schedule 6 and Appendices E and F of the Poisons Standard as follows:

Schedule 6

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 2

m-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 3

m-AMINOPHENOL

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

The implementation date of this decision was 1 February 2017.

Following the release of the final decision on 16 January 2017, feedback from industry indicated that the wording of the Schedule 6 entry may require further amendment.

On 31 January 2017, the Schedule 6 entry for m-aminophenol was removed by amendment from the 1 February 2017 Poisons Standard. This final decision was implemented as Amendment No. 1 of SUSMP 16. m-Aminophenol was subsequently referred to the March 2017 ACCS meeting to enable a consultation process on the proposed scheduling.

An isomer of m-aminophenol, p-aminophenol is in Schedule 6 and Appendices E and F of the Poisons Standard 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 (For advice, contact a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor (at once)), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F, Part 3

p-AMINOPHENOL

Warning Statement: 28 ((Over) (Repeated) exposure may cause sensitisation).

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

Current schedule of related substance 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 (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 3

4-AMINO-m-CRESOL

Warning statement: 28 ((Over) (Repeated) exposure may cause sensitisation).

Current schedule of related substance 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 (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 3

4-AMINO-2-HYDROXYTOLUENE

Warning statement: 28 ((Over) (Repeated) exposure may cause sensitisation).

Index

4-AMINO-2-HYDROXYTOLUENE

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

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

Scheduling application

This was a general application. The applicant'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 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 – New Entry

m-AMINOPHENOL

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

Appendix F, Part 3− New Entry

m-AMINOPHENOL

Warning statement: 28 ((Over) (Repeated) exposure may cause sensitisation).

The applicant's reasons for the request are:

  • Currently, there are no restrictions on introducing or using m-aminophenol 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 m-aminophenol 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 m-aminophenol 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.
Australian regulatory information

m-Aminophenol is listed on the Australian Inventory of Chemical Substances (AICS). Currently there are no restrictions on the use of m-aminophenol in cosmetics or domestic products in Australia. m‑Aminophenol is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2017 and a search of the Australian Register of Therapeutic Goods (ARTG) found it is not an ingredient in any listed products.

International regulations

Use of m-aminophenol 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 m-aminophenol 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 m-aminophenol is present at lower concentrations, sensitisation labelling is required.

Use of m-aminophenol 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 m-aminophenol in hair dyes is restricted to a maximum concentration of 1.2% applied to hair after mixing under oxidative conditions.

Substance summary

m-Aminophenol is used in hair colourants and is an important starting material for dyes, including a variety of latent dyes used in imaging technology, optical bleaches and fluorescent agents, drugs, agricultural chemicals and high performance polymers.[45]

Table 3.3A: Chemical information
Property m-aminophenol
CAS names Phenol, 3-amino
CAS numbers 591-27-5
Chemical structure Chemical structure of m-aminophenol
IUPAC and/or common and/or other names 3-hydroxyaniline
m-aminophenol (INCI)
Molecular formula C6H7NO
Molecular weight 109.13 g/mol

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.

Table 3.3B: Acute toxicity end-points for m-aminophenol
Toxicity Species Result 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 Mouse (LLNA)
Guinea pig (GPMT)

Moderate to strong skin sensitiser (EC3 0.24-3.2%)

Sensitiser. Positive reactions in 100% of animals tested at 5%, following 1% intradermal induction and 10% topical induction.

Schedule 6
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 m-aminophenol is not irritating to the skin or eyes.

Sensitisation

Based on the available animal and human data, m-aminophenol 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 m-aminophenol 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 m-aminophenol 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 m-aminophenol.
  • In another mouse LLNA study, CBA/Ca mice were administered m-aminophenol 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 m-aminophenol 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 m-aminophenol 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 m-aminophenol 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 m-aminophenol.

Pre-meeting public submissions

One (1) pre-meeting public submission was received with no objections to the proposed scheduling for m-aminophenol. The main points were:

  • The scheduling of m-Aminophenol should align with regulations in other international jurisdictions, such as the EU.
  • m-Aminophenol is used in approximately 85-95% of hair dye products in Australia.

An adequate transition period of at least 12 months is requested to allow for any labelling changes and/or reformulation that may be required where no immediate risk has been identified; and that there is no evidence to suggest immediate action is required for the risk management of this substance.

The public submissions will be made available on the TGA website.

Summary of ACCS advice to the delegate

The committee advised that a new Schedule 6 entry for m-aminophenol be created as follows:

Schedule 6 – New Entry

m-AMINOPHENOL except when used in hair dye and eyebrow/eyelash preparations 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.

The committee recommends Appendix E/F entries be created as follows:

Appendix E, Part 2 – New Entry

m-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)), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F, Part 3 − New Entry

m-AMINOPHENOL

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

Safety directions: 4 (Avoid contact with skin), 8 (Avoid breathing dust (or) vapour (or) spray mist).

The committee also recommended an implementation date of 1 June 2018 to allow for the necessary labelling changes to be implemented by industry.

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:

  • m-Aminophenol is a strong to moderate skin sensitiser.
  • The primary consumer use of m-aminophenol is in hair dye and eyelash dye products, and therefore dermal contact is unavoidable. However, risk can be managed by limiting concentration and applying warning statements.
  • The acute oral toxicity and skin sensitisation of m-aminophenol are consistent with the factors for Schedule 6.
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 m-aminophenol. The proposed Schedule entry is as follows:

Schedule 6 – New Entry

m-AMINOPHENOL except when used in hair dye and eyebrow/eyelash preparations 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 2 – New Entry

m-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)), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F, Part 3 − New Entry

m-AMINOPHENOL

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

Safety directions: 4 (Avoid contact with skin), 8 (Avoid breathing dust (or) vapour (or) spray mist).

The proposed implementation date is 1 June 2018.

The delegate considered the relevant matters under section 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; and (c) the toxicity of a substance.

The reasons for the interim decision are the following:

  • The delegate acknowledges the committee's advice.
  • m-Aminophenol is a strong to moderate skin sensitiser.
  • The primary consumer use of m-aminophenol is in hair dye and eyelash dye products, and therefore dermal contact is unavoidable. However, risk can be managed by limiting concentration and applying warning statements.
  • The acute oral toxicity and skin sensitisation of m-aminophenol are consistent with the factors for Schedule 6.
  • A long implementation date is proposed in order to allow for the necessary labelling changes to be implemented by industry.
Public submissions on the interim decision

One (1) submission was received that supported the delegate's interim decision as it is in line with the EU regulations EC No. 1223/2009. The submitter however, requests that salts and derivatives are exempt from the schedule entry due to difficulty in interpreting which substances are meant to be captured by the Poisons Standard entry (no examples of inappropriately captured substances were given).

Delegate's final decision

The delegate notes the submission however as no new evidence has been received to alter the interim decision, the delegate has confirmed that the final decision and reasons for the final decision are in keeping with those for the interim decision.

The delegate's final decision is to create a new Schedule 6 entry for m-aminophenol. The implementation date is 1 June 2018.


Footnotes

45 Dressler, H. (1994) ‘m-Aminophenol', Resorcinol: Its Uses and Derivatives, Springer US, p 125-134.

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