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Scheduling delegate's final decisions, March 2016

Scheduling medicines and poisons

17 March 2016

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1.13 p-Methylaminophenol

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

1. Scheduling proposals referred to the November 2015 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#15)

1.13 p-Methylaminophenol

Scheduling proposal

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

  • A proposal to create a new entry for p-methylaminophenol and its sulfate salt in Schedule 6 to include use in hair dyes and eyelash colouring products with an appropriate cut-off.
Scheduling application

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

The reasons for the request are:

  • p-methylaminophenol sulfate has reported cosmetic use in permanent hair dye preparations in Australia;
  • the chemicals are moderate to severe skin sensitisers;
  • only limited data are available on eye and skin irritation; a 3 % concentration of the chemicals may have slight eye and skin irritation potential;
  • the chemicals are expected to cause serious health effects following repeated oral exposure;
  • international restrictions for use of the chemicals in hair dyes (European Union - the maximum concentration allowed is 0.68 % after mixing under oxidative conditions).

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 concentration cut-off. These chemicals have similar use and hazard profiles to a number of chemicals which have been listed in Schedule 6 with reverse scheduling requirements.

Specific issues/questions raised by the delegate

The delegate asked the committee the following questions:

  • Does the ACCS agree that the toxicological profile of p-methylaminophenol (acute toxicity, equivocal mutagenicity, skin-eye irritancy and moderate-severe sensitisation potential) warrants controls over use in cosmetics and consumer products?
  • What weight should be given to the evidence of moderate-severe skin sensitisation potential? Does the data suggest a suitable cut-off for the sensitisation potential?
  • Does the ACCS consider that including p-methylaminophenol in Schedules 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 0.68% (EU regulation) or 1% (rounded)? Should there be no cut-off, based on the sensitisation potential?
  • 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?
  • Although there are no notified commercial uses other than in cosmetics, should a Schedule 6 listing be specific for use in hair dyes or cosmetic products (as for some other hair dye ingredients)?
  • What name should be used for any schedule entry - p-methylaminophenol; methyl-p-aminophenol; 4-(methylamino) phenol; N-methyl-4-aminophenol or metol?
  • Is there a need for specific entries in Appendices E & F to manage labelling of scheduled products?
Substance summary

This report, containing more detailed information about the substance, is publicly available on the NICNAS website.

Chemical structure of p-methylaminophenol

Figure 10. Chemical structure of p-methylaminophenol

Acute toxicity

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

Toxicity Species p-methylaminophenol and its sulfate salt SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Mouse 380 Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) N/A No data -
Acute inhalational toxicity LC50 (mg/m3/4h) N/A No data -
Skin irritation Rabbit Slight irritant at 3 % (limited data) -
Eye irritation Rabbit Slight irritant at 3 % (limited data) -
Skin sensitisation (LLNA) Mouse Moderate to severe skin sensitiser (EC3 = 2.2%) Schedule 6

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

Skin sensitisation

The chemicals are considered to be moderate to severe skin sensitisers according to the SPF classification.

The skin sensitising potential of p-methylaminophenol sulfate was investigated in a local lymph node assay (LLNA). A solution containing the chemical at 0.25, 0.5, 1, 2.5 or 5 % was applied (25 µL) to the dorsal surface of both ears of CBA/J mice, once daily for three days. The treated animals were monitored daily for mortality and clinical signs. The study reported a dose-related increase in the stimulation index (SI), with 2.5 % and 5 % concentrations, exceeding the value of three. The effective concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3) was calculated to be 2.2 %, indicating the chemical as a moderate to severe skin sensitiser.

In a skin sensitisation test, albino Hartley guinea pigs (n = 10/sex) were treated topically (occlusive, behind the right shoulder blade) with 0.5 g of p-methylaminophenol, three times per week for three weeks and once on week four. The animals also received two intradermal injections of Freund's complete adjuvant on days one and 10. Twelve days after induction, the untreated left flank was challenged with 0.5 g of the chemical for 48 hours under occlusion. No skin reactions were observed.

Although a guinea pig skin sensitisation study with p-methylaminophenol gave negative results, based on the positive results observed for p-methylaminophenol sulfate in a more reliable assay, both chemicals are expected to be skin sensitisers.

Repeat-dose toxicity

Based on the data available for p-methylaminophenol sulfate, the chemicals are expected to cause serious damage to health from repeated oral exposure. In a 13-week oral gavage study, SD rats were dosed with p-methylaminophenol sulfate (suspended in 0.5 % carboxymethylcellulose) at 0, 3, 10, or 30 mg/kg bw/day. A no observed adverse effect level (NOAEL) of 10 mg/kg bw/day was reported based on tubular epithelial degeneration/single cell necrosis in the kidneys of most males and in half of the female rats at 30 mg/kg bw/day. In addition, some males of this group had higher urinary volumes with lower specific gravity. However, these changes were reported as completely reversible within the four-week recovery period.

No information was available for repeated dose toxicity by inhalation route and dermal routes.

Genotoxicity

The available data are not sufficient to derive a conclusion on the genotoxicity of the chemicals.

Carcinogenicity

Only limited data are available. The chemicals are not expected to be carcinogenic via dermal exposure at 1 % concentration.

Reproductive and developmental toxicity

Based on the limited data available, the chemicals are not known to cause reproductive or developmental toxicity.

Public exposure

Considering the use of these chemicals in permanent hair dyes in Australia, the main route of public exposure is expected to be through the skin.

The Association of Southeast Asian Nations (ASEAN), European Union (EU) and New Zealand have restricted the use of these chemicals in cosmetics. Following a safety evaluation, the SCCP (2006) concluded that the 'use of p-methylaminophenol sulphate itself as an oxidative hair dye at a maximum concentration of 0.68% in the finished cosmetic product (after mixing with hydrogen peroxide) does not pose a risk to the health of the consumer, apart from its sensitising potential.'

Currently, there are no restrictions in Australia on using these chemicals in cosmetics or hair dyes. In the absence of any regulatory controls, the characterised critical health effects (skin sensitisation) have the potential to pose an unreasonable risk for the uses identified.

International regulations

The chemicals are listed on the following:

  • ASEAN Cosmetic Directive Annex III - List of substances which cosmetic products must not contain except subject to the restrictions laid down;
  • EU Cosmetics Regulation 1223/2009 Annex III - List of substances which cosmetic products must not contain except subject to the restrictions laid down - 'after mixing under oxidative conditions, the maximum applied to hair must not exceed 0.68 % (as sulphate)'; Under 'wording and conditions of use and warnings' indicated to include 'Hair colourants can cause severe allergic reactions'; and
  • New Zealand Cosmetic Products Group Standard - Schedule 5 - Table 1: Components cosmetic products must not contain except subject to the restrictions and conditions laid down.
Scheduling status

p-Methylaminophenol and its sulfate are not specifically scheduled.

Scheduling history

p-Methylaminophenol and its sulfate have not been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

One public submission was received.

No objections to aligning with EU were raised. It was noted in the submission that it is important to maintain "in-use" concentrations for hair dye preparations, due to the mode of use being mixing with an oxidising substance prior to use.

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

ACCS advice to the delegates

The Committee recommended that new Schedule 6 and Appendix F entries for p-methylaminophenol be created with exceptions or cut-offs as follows:

Schedule 6 - New Entry

p-METHYLAMINOPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 1 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 F - New Entry

p-METHYLAMINOPHENOL

Part 1, Warning Statement: 28

The ACCS recommended an implementation date of 1 June 2016.

The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included (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.

The reasons for the recommendations comprised the following:

  • The substance is used in hair dye products
  • The substance has potential for skin sensitisation and acute oral toxicity and therefore fits the criteria for inclusion in Schedule 6
  • Its use at low concentrations can be managed by reverse scheduling labelling requirements in hair dye products
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 factors13;
  • Other relevant information.
Delegate's interim decision

Oxidative hair dyes of the aromatic diamine and aminophenolic classes have some common toxicological properties that warrant controls over scheduling. These features are primarily skin-eye irritancy and sensitization potential. These toxicological properties generally align with SPF criteria for listing in Schedule 6. Several of these dyes (e.g. phenylenediamines, toluenediamines; aminophenols) have already been listed in Schedule 6, but previous scheduling policies have allowed for some products to be exempted where there are label statements warning of the potential for skin irritancy and sensitization, and recommending testing for individual susceptibility before use. This approach is commonly called ‘reverse scheduling’. Where there is potential mutagenicity, or the need to prevent uses for skin colouration (tattooing) or use to dye eyebrows or eyelashes, some of these substances have been listed in Schedule 10 to prevent such uses.

This is one of six oxidant hair dyes that were referred to the November 2015 meeting of the ACCS for advice to the delegate on scheduling. The key issues were whether their toxicological profiles sufficiently match the SPF criteria for inclusion in Schedule 6 and whether product exemptions based on 'reverse scheduling' could be applied, consistent with labelling provisions applied to other oxidative hair dyes. Given that some products containing oxidative hair dyes require mixing with an oxidant, such as hydrogen peroxide, before application to the hair, consideration was given to appropriate exemption cut-off concentrations that take account of the final concentration applied to the hair.

The delegate notes, and accepts, ACCS advice that p-methylaminophenol should be listed in Schedule 6, with an exemption cut-off at 1%, provided products are labelled with the warning statements about potential skin sensitisation that have been required for similar oxidative hair dyes. The delegate also notes ACCS advice that warning statements relating to use for dyeing eyebrows and eyelashes are not needed, because the substance is not a strong irritant. The delegate also notes ACCS advice that p-methylaminophenol is the INCI name and is the preferred name for listing in Schedule 6.

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

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; c) the toxicity of the substance; d) the dosage, formulation, labelling, packaging and presentation of a substance.

Schedule entry
Schedule 6 - New Entry

p-METHYLAMINOPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 1 per cent or less of p-methylaminophenol 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 F - New Entry

p-METHYLAMINOPHENOL

Part 1, Warning Statement: 28

Public submissions on the interim decision

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

Edited versions of public 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.

Schedule entry
Schedule 6 - New Entry

p-METHYLAMINOPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 1 per cent or less of p-methylaminophenol 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 F - New Entry (Part 3)

p-METHYLAMINOPHENOL

Warning Statement: 28

The proposed implementation date is 1 October 2016.


Footnotes

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

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