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Scheduling delegate's final decisions, March 2016

Scheduling medicines and poisons

17 March 2016

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1.6 4-Amino-3-nitrophenol

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)

1.6 4-Amino-3-nitrophenol

Scheduling proposal

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

  • To create a new entry for 4-amino-3-nitrophenol 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 following proposal to be considered by the delegate:

The reasons for the request were:

  • the chemical is used in permanent hair dye preparations in Australia;
  • the chemical is a severe skin sensitiser; and
  • the overseas restrictions for use of this chemical in cosmetics.
  • The critical health effect for risk characterisation is skin sensitisation. Given the potential for induction and elicitation of sensitisation below the concentration 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. This chemical has a 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 asked the committee the following questions:

  • Does the ACCS agree that the toxicological profile of 4-amino-3-nitrophenol (acute toxicity, equivocal mutagenicity, skin-eye irritancy and strong sensitisation potential) warrants controls over use in cosmetics and consumer products?
  • What weight should be given to the evidence of strong skin sensitisation potential? Does the data suggest a suitable cut-off for the sensitisation potential?
  • Does the ACCS consider that including 4-amino-3-nitrophenol 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 1%, as suggested in the NICNAS report, or 3% as recommended in the SCCP report? Should there be no cut-off on the basis of the strong 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 - 4-amino-3-nitrophenol; 3-nitro-4-aminophenol; 1-hydroxy-3-nitro-4-aminobenzene or 2-nitro-4-hydroxyaniline?
  • Would this substance be covered (as a derivative) by the current generic Schedule 6 entry for - NITROPHENOLS, ortho, meta and para except when separately specified in these schedules?
  • Is there a need for specific entries in Appendices E & F to manage labelling of scheduled products? Note that there is a current Appendix F requirement for statements 1,4, and 8 for nitrophenols covered by the generic S6 entry?
Substance summary

Please refer to the NICNAS Inventory Multi-tiered Assessment Prioritisation (IMAP) Human Health Tier II Assessment Report for 4-amino-3-nitrophenol and its related compounds. This report is publically available on the NICNAS website.

Chemical structure of 4-amino-3-nitrophenol

Figure 5. Chemical structure of 4-amino-3-nitrophenol

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

Toxicity Species 4-amino-3-nitrophenol SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 500 - 1000 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 Not irritating at 6 % concentration (limited data) -
Eye irritation Rabbit Irritating Schedule 5
Skin sensitisation (LLNA) Mouse Severe skin sensitiser (EC3 = 0.2 %) Schedule 6

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

Sensitisation

Based on the data available, the chemical is considered to be a severe skin sensitiser.

In a local lymph node assay (LLNA) test, groups of female CBA/J mice were topically treated with 25 µL of the chemical (in an acetone/olive oil mixture) at 0.05, 0.1, 0.5, 1 or 2.5 % concentrations, once daily for three days. The lympho-proliferation response, determined by the incorporation of (3H)-methyl thymidine exceeded the threshold of three (stimulation index (SI) >3) at concentrations >0.5 %. The estimated concentration needed to produce three-fold increase in lymphocyte proliferation (EC3) was calculated to be 0.2 %, indicating the chemical to be a severe skin sensitiser.

Repeat-dose toxicity

Based on the data available, the chemical is not considered 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 in vivo genotoxicity data, the chemical is not considered to be genotoxic. However, it was reported that the data available are insufficient to exclude potential gene mutation.

Carcinogenicity

Based on the available genotoxicity data, mechanistic considerations and mitigating factors of the chemical structure, the chemical is not considered to be carcinogenic.

Reproduction and developmental toxicity

Based on the data available, the chemical is not considered to have reproductive or developmental toxicity.

Public exposure

The chemical is reported to be used in permanent hair dye preparations in Australia. Internationally, the chemical is used in oxidative and non-oxidative hair dyes.

Currently, there are no restrictions in Australia on using this chemical in cosmetics or hair dye products. 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

Many countries, including New Zealand and the EU, have restricted the use of this chemical in cosmetics.

The chemical is listed on the following:

  • EU Regulation (EC) No 344/2013 Annex III: List of Substances which cosmetic products must not contain except subject to the restrictions and conditions laid down
  • Product type: (a) Hair dye substance in oxidative hair dye products (b) Hair dye substance in non-oxidative hair dye products
  • Maximum concentration in ready for use preparation: (b) 1.0 %
  • Other: (a) After mixing under oxidative conditions the maximum concentration applied to hair must not exceed 1.5 %;
  • New Zealand Cosmetic Products Group Standard - Schedule 5 - Table 1: Components cosmetic products must not contain except subject to restrictions and conditions laid down; and
  • The Association of Southeast Asian Nations (ASEAN) Cosmetic Directive Annex III - Part 2 List of substances provisionally allowed.

In the EU, it is mandated that products containing the chemical at any concentration have warning labels indicating that the product can be allergenic.

Scheduling status

4-amino-3-nitrophenol is not specifically scheduled.

Scheduling history

4-amino-3-nitrophenol has not been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

One public submission was received. In that submission it was noted that for this substance the industry has been applying the NITROPHENOLS entry in Schedule 6, which does not allow for exemptions of small quantities of nitrophenols. In general, the submission indicated support in aligning with the EU with up to 1% in ready-to-use preps and 1.5% for preps intended to be diluted prior to application.

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

ACCS advice to the delegate

The Committee recommended that new Schedule 6, Appendix E and Appendix F entries be created for 4-amino-3-nitrophenol be created as follows:

Schedule 6 - New Entry

PHENOL, 4-AMINO-3-NITRO except:

  1. in non-oxidative hair dye preparations containing 1 per cent or less 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; or

  2. in oxidative hair dye preparations containing 1 per cent or less after mixing under oxidative conditions 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 - New Entry

PHENOL, 4-AMINO-3-NITRO

Part 1: Standard Statements: A

Appendix F - New Entry

PHENOL, 4-AMINO-3-NITRO

Part 1: Warning Statement: 28

The committee recommended an implementation date of 1 June 2016.

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.

The reasons for the recommendations comprised the following:

  • The substance is used in hair dye products
  • The substance is a strong skin sensitiser, has moderate to acute oral toxicity and therefore meets the criteria for inclusion in Schedule 6
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 factors6;
  • Other relevant information.
Delegate's interim decision

The delegate's interim decision is to accept the advice of the Committee and create a new Schedule 6, with appropriate exemption and cut-off, Appendix E and Appendix F entries.

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 4-amino-3-nitrophenol 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 4-amino-3-nitrophenol is the name used in EU cosmetics regulations, is the preferred name for listing in Schedule 6, and that the existing Schedule 6 entry for NITROPHENOLS would not capture this substance, since it would not be considered to be a 'derivative'.

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

4-AMINO-3-NITROPHENOL except:

  1. in non-oxidative hair dye preparations and eyebrow/eyelash colouring products containing 1 per cent or less of 4-amino-3-nitrophenol 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; or

  2. in oxidative hair dye preparations and eyebrow/eyelash colouring products containing 1 per cent or less of 4-amino-3-nitrophenol after mixing under oxidative conditions 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 - New Entry

4-AMINO-3-NITROPHENOL

Part 1: Standard Statements: A

Appendix F - New Entry

4-AMINO-3-NITROPHENOL

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

4-AMINO-3-NITROPHENOL except:

  1. in non-oxidative hair dye preparations and eyebrow/eyelash colouring products containing 1 per cent or less of 4-amino-3-nitrophenol 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; or

  2. in oxidative hair dye preparations and eyebrow/eyelash colouring products containing 1 per cent or less of 4-amino-3-nitrophenol after mixing under oxidative conditions 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

4-AMINO-3-NITROPHENOL

Standard Statements: A

Appendix F (Part 3) - New Entry

4-AMINO-3-NITROPHENOL

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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