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

Scheduling medicines and poisons

12 May 2016

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1.4 p-Aminophenol

Part A - Interim decisions on scheduling proposals referred to an advisory committee (March 2016)

1. Advisory Committee on Chemicals Scheduling (ACCS#16)

1.4 p-Aminophenol

Referred scheduling proposal
  • In response to issues raised in a NICNAS IMAP Human Health Tier 2 assessment report, the scheduling proposal is to create a new Schedule 6 entry for p-aminophenol with appropriate exemption and cut-off to regulate its use in hair dyes and eyelash colouring products.
Scheduling application

The reasons for the request are:

  • p-aminophenol has reported cosmetic use in permanent hair dye preparations in Australia;
  • p-aminophenol is a skin sensitiser and is mutagenic;
  • overseas information indicates that the chemical is to be used in oxidative hair dye formulations and in the bottle on the market at a maximum concentration of 1.8% and be typically mixed in a 1:1 ratio with an oxidative agent thereby reaching a concentration of 0.9% for in use application (SCCP, 2005);
  • the overseas restrictions for use of this chemical in hair dyes (EU Cosmetic Regulation Annex III) indicate that the maximum concentration applied to hair must not exceed 0.9 % (after mixing under oxidative conditions).

The critical health effects for risk characterisation are mutagenicity and skin sensitisation. Given the potential for mutagenicity and skin sensitisation, the risk would be better controlled by inclusion of warning statements on the label for preparations containing the chemical at any concentration. This chemical has similar use and hazard profile 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's reasons for referring this to the Committee include the following: p-aminophenol is one of several oxidative hair dye ingredients that have been referred for scheduling in the past three years. Generally, these have been listed in either schedules 5 or 6, with cut-offs to exempt at a relevant concentration that minimises the risks of skin sensitisation and/or irritancy. In some cases, scheduling exemptions have been allowed via ‘reverse labelling’, where products labelled with specified warning statements may be exempted from the generic scheduling controls of Schedule 5 or 6. Further restrictions may have been applied where products are used in eyebrow/eyelash tinters as well as in hair dyes. Additional restrictions (Schedule 10 listing) have been placed where there is a significant risk of genotoxicity and/or carcinogenicity, or where precluded use in products for skin colouration (tattooing) have been required. In some cases where there was no evidence of significant use in Australia, the delegate’s decision was not to schedule the substance (e.g. o-aminophenol from the July 2014 meeting).

The delegate sought advice from the Committee on the following questions:

  • Does the ACCS agree that the toxicological profile of p-aminophenol (acute toxicity, putatively positive mutagenicity, skin-eye irritancy and sensitisation potential) 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 p-aminophenol 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 0.9% after mixing, 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?
  • The NICNAS report suggests that there may be uses other than in hair dyes. Should a Schedule 6 listing be specific for use in hair dyes or cosmetic products (as for some other hair dye ingredients)?
  • Does the mixed evidence of mutagenicity in a range of in vivo tests (and a lack of data in in vitro mutagenicity tests) suggest a more restrictive scheduling (Schedule 7 or 10) be applied, rather than listing in Schedule 6?
  • What name should be used for any schedule entry – p-aminophenol or 4-hydroxyaniline?
  • Is there a need for specific entries in Appendices E and F to manage labelling of scheduled products?
Substance summary

Please refer to the NICNAS IMAP Tier II report for p-aminophenol that is publicly available on the NICNAS website.

Figure 4. Structure of p-aminophenol

Figure 4. Structure of p-aminophenol

Acute toxicity

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

Toxicity Species Result SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 671 (SD rats) Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) Rat >5000 N/A
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >3.42 mg/L N/A
Skin irritation Rabbit Slight irritant Schedule 5
Eye irritation Rabbit Slight irritant Schedule 5
Skin sensitisation (maximisation test and Buehler test) Guinea pig Skin sensitiser Schedule 6
Skin sensitisation (human data) Human

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

The chemical has moderate acute oral toxicity and low acute dermal toxicity. The available data for inhalation were inconclusive.

Irritation

Based on the available information, p-aminophenol is a slight skin and eye irritant.

Sensitisation

Based on the available animal and human data, p-aminophenol is a skin sensitiser.

In a study similar to the Buehler test, Pirbright Dunkin Hartley guinea pigs were treated with 0.1, 0.5, 1 or 2 % preparations of p-aminophenol. Dose-dependent, positive skin responses were observed in 3/10, 5/10, 6/10 and 9/10 animals, respectively.

Freund's complete adjuvant tests were conducted in guinea pigs using two methods of induction. In the first method, Freund's adjuvant was injected alone before 0.18 mmol/L of p-aminophenol was topically administered twice (over two days); p-aminophenol did not induce any skin sensitisation reactions. In the second method, Freund's adjuvant was injected with 0.18 mmol/L of p-aminophenol (ratio 1:1) (induction), followed by a 0.09 mmol/L of p-aminophenol 16 days later (challenge). The treatment induced positive reactions in 40 % of the animals.

P-aminophenol gave positive skin reactions in patch tests in 25 % (1/4) and 17 % (2/12) of patients with dermatitis (among 13 beauticians and 33 hairdressers respectively, tested for occupational dermatitis).

Among 24 hairdressers and eight barbers patch tested for occupational allergic contact dermatitis, p-aminophenol induced positive reactions in 25 % (2/8) of patients with dermatitis.

The application of p-aminophenol at 1 % gave positive results in 3 % (11/372) of patients patch tested with the chemical.

Repeat-dose toxicity

Based on the available data, p-aminophenol may cause severe effects from repeated oral exposure. The kidney is the target organ for repeated oral toxicity in rats, with nephrosis seen at doses of 30 mg/kg bw/day and above. However, there are uncertainties about the reversibility of kidney effects.

Genotoxicity

Based on the available in vitro and in vivo data, p-aminophenol may have mutagenic properties. Most of the in vivo tests conducted gave positive results for genotoxicity on somatic cells, including:

  • a significant increase in micronucleated polychromatic erythrocytes and inhibition of bone marrow cell proliferation in male CD1 mice orally administered the chemical at 125, 250 or 500 mg/kg bw in a micronucleus test (OECD TG 474);
  • positive results in four other micronucleus tests in mice receiving doses of the chemical up to 214.5 mg/kg bw (oral) or 872 mg/kg bw (intraperitoneal)
  • positive results for somatic mutations and recombinations (SMAR) in D. melanogaster fed with 20 mmol/L of p-aminophenol;
  • negative results in sex-linked recessive lethal (SLRL) test in D. melanogaster administered the chemical at doses up to 130 mmol/L (oral) or 30 mmol/L (injection); and
  • negative results in a dominant lethal test in male SD rats fed with p-aminophenol at doses up to 467 mg/kg bw/day for 20 weeks.
Carcinogenicity

Based on the limited information available, p-aminophenol is not expected to be carcinogenic.

Reproduction and developmental toxicity

Based on the available data, p-aminophenol is not expected to have reproductive or developmental toxicity. The foetal effects observed in rats at high doses (133 and 467 mg/kg bw/day) are considered secondary to maternal toxicity.

Public exposure

The chemical was reported to be used in permanent hair dyes in Australia in 2007.

Currently, there are no restrictions in Australia on using p-aminophenol in hair dyes. In the absence of any regulatory controls, the characterised critical health effects, particularly skin sensitisation and mutagenicity, have the potential to pose an unreasonable risk under the identified use. The risk could be mitigated by implementing restrictions for the use of the chemical in hair dyes.

International regulations

Using p-aminophenol in hair dyes in the EU is subject to the restrictions described in EU Regulation Annex III (amended by Regulation (EC) No 1197/2013): after mixing under oxidative conditions the maximum concentration applied to hair must not exceed 0.9 %.

Current scheduling status

p-Aminophenol is not specifically scheduled.

Relevant scheduling history

p-Aminophenol has not been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

One public submission was received. The submission raised no objections to aligning the scheduling controls with EU. They note substance is included in Annex III of the EU Cosmetics Regulations, restricting its use to oxidative hair dyes with in-use concentration not exceeding 0.9%. They propose schedule entry consistent with recent decisions on oxidative hair dye ingredients. They also request a later implementation date to allow time for relabelling of products already on the market.

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

ACCS advice to the delegate

The committee advised that the toxicological profile of p-aminophenol warrants controls over use in cosmetics and consumer products, as well as other products. Members agreed that a Schedule 6 entry is appropriate according to SPF criteria. On the evidence supporting a cut off concentration, the committee agreed there was sufficient data to recommend a 1% cut off concentration. The committee did not consider the evidence for mutagenicity was sufficient to recommend a higher schedule.

The committee advised that the appropriate name for use in the SUSMP was p-aminophenol and a new Schedule 6 entry be created for p-aminophenol with appropriate exemptions and cut off as follows:

Schedule 6 - New entry

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– New entry

p-AMINOPHENOL

Standard statements: A, S1

Appendix F, Part 3 – New entry

p-AMINOPHENOL

Warning Statement: 28

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: a) risk of skin sensitisation is reduced by limiting maximum concentration in bottle and after mixing. c) toxicity - the acute oral toxicity and skin sensitisation are consistent with Schedule 6 criteria. d) The positive skin sensitisation is dose-dependent and therefore Schedule 6 with appropriate RASML is appropriate.

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 factors4;
  • 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.

p-Aminophenol is one of four oxidant hair dyes that were referred to the March 2016 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-aminophenol should be listed in Schedule 6, with an exemption cut-off at 1%, provided products are labelled with the warning statements about skin sensitisation potential that have been required for similar oxidative hair dyes. The delegate also notes ACCS advice that the potential for eye irritation is not sufficient to require warning statements relating to use for dyeing eyebrows and eyelashes.

The proposed implementation date is 1 June 2017. A later implementation date is proposed to allow for an orderly process of re-labelling of products already on the market.

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 a substance; (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.

Schedule 6 - New entry

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– New entry

p-AMINOPHENOL

Standard statements: A, S1

Appendix F, Part 3 – New entry

p-AMINOPHENOL

Warning Statement: 28


Footnotes

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

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