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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March 2017

Scheduling medicines and poisons

17 May 2017

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3.4 2-Chloro-6-(ethylamino)-4-nitrophenol

3. Advisory Committee on Chemicals Scheduling (ACCS #19)

3.4 2-Chloro-6-(ethylamino)-4-nitrophenol

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 2-chloro-6-(ethylamino)-4-nitrophenol to restrict its use in hair dyes and to determine an appropriate exemption concentration cut-off.

Current scheduling status and relevant scheduling history

2-Chloro-6-(ethylamino)-4-nitrophenol is not currently scheduled.

On 16 January 2017, the delegate made a delegate-only final decision to enter 2-chloro-6-(ethylamino)-4-nitrophenol in Schedule 6 and Appendices E and F of the Poisons Standard as follows:

Schedule 6

2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL except when in hair dye preparations containing 1.5 per cent or less of 2-chloro-6-(ethylamino)-4-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. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye, and

written in letters not less than 1.5 mm in height.

Appendix E, Part 2 − 2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL

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 − 2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL

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, industry feedback indicated that the wording of the Schedule 6 entry may require further amendment. On 31 January 2017, the Schedule 6 entry for 2-chloro-6-(ethylamino)-4-nitrophenol was removed (by amendment) from the 1 February 2017 Poisons Standard. This final decision was implemented as Amendment No. 1 of SUSMP 16. 2-Chloro-6-(ethylamino)-4-nitrophenol was subsequently referred to the March 2017 ACCS meeting to enable a consultation process on the proposed scheduling.

Scheduling application

This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:

Schedule 6 - New Entry

2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 3 per cent for ready-for-use preparations and 1.5 % 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 - New Entry

2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL

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

Appendix F - New Entry

2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL

Warning statement: Repeated exposure may cause sensitisation (28)

The applicant's reasons for the request are:

  • Reported use of 2-chloro-6-(ethylamino)-4-nitrophenol as an ingredient in both permanent and semi-permanent hair dyes in Australia;
  • 2-Chloro-6-(ethylamino)-4-nitrophenol is a skin sensitiser;
  • 2-Chloro-6-(ethylamino)-4-nitrophenol is acutely toxic following oral exposure;
  • Overseas restrictions for use of 2-chloro-6-(ethylamino)-4-nitrophenol in hair dyes; and
  • When 2-chloro-6-(ethylamino)-4-nitrophenol 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

2-Chloro-6-(ethylamino)-4-nitrophenol is present on the 'List of chemicals used as dyes in permanent and semi-permanent hair dyes in Australia' (NICNAS, 2007).

2-Chloro-6-(ethylamino)-4-nitrophenol is not listed on the Therapeutic Goods (Permissible Ingredients, 26BB) Determination No. 1 of 2017 and a search of the Australian Register of Therapeutic Goods (ARTG) found it not listed in any products.

International regulations

Use of 2-chloro-6-(ethylamino)-4-nitrophenol in cosmetics in the European Union (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). 2-Chloro-6-(ethylamino)-4-nitrophenol may be used at maximum concentrations of 3.0% in ready-for-use preparations of oxidising (permanent) and non-oxidising (semi-permanent) colouring agents for hair dyeing. Additionally, after mixing under oxidative conditions (i.e. with hydrogen peroxide) the maximum concentration applied to hair must not exceed 1.5% for both permanent and semi-permanent application types. The Cosmetics Regulation also mandates label warning statements relating to the sensitisation potential of 2-chloro-6-(ethylamino)-4-nitrophenol.

Use of 2-chloro-6-(ethylamino)-4-nitrophenol in hair dyes is also restricted in several other countries as according to inclusion in the following listings:

  • the Association of Southeast Asian Nations (ASEAN) Cosmetic Directive Annex III-Part 1, with the same use restrictions as described above for the EU; and
  • the New Zealand Cosmetic Products Group Standard-Schedule 5-Table 1: Components cosmetic products must not contain except subject to restrictions and conditions laid down. While a maximum concentration (of 3.0%) only appears to apply to ready for use preparations of non-oxidising (semi-permanent) colouring agents for hair dyeing, the maximum concentration applied to hair must not exceed 1.5% for both permanent and semi-permanent application types.
Substance summary

2-Chloro-6-(ethylamino)-4-nitrophenol has reported cosmetic use as an ingredient in both permanent and semi-permanent hair dyes in Australia and internationally.

Figure 3.4: Chemical structure of 2-Chloro-6-(ethylamino)-4-nitrophenol

Figure 3.4: Chemical structure of 2-Chloro-6-(ethylamino)-4-nitrophenol

Table 3.4A: Chemical information
Property 2-chloro-6-(ethylamino)-4-nitrophenol
CAS names Phenol, 2-chloro-6-(ethylamino)-4-nitro-
CAS numbers 131657-78-8
IUPAC and/or common and/or other names 2-Chloro-6-(ethylamino)-4-nitrophenol (INCI and IUPAC)
Molecular formula C8H9ClN2O3
Molecular weight 216.62 g/mol

The following toxicology information was extracted from the NICNAS IMAP Human Health Tier II assessment report for 2-chloro-6-(ethylamino)-4-nitro-phenol.[83]

Table 3.4B: Acute toxicity end-points for 2-chloro-6-(ethylamino)-4-nitrophenol
Toxicity Species Result SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 1728 Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) Rat >2000 Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) - No data N/A
Skin irritation Rabbit Not irritating to the skin N/A
Eye irritation Rabbit Insufficient data N/A
Skin sensitisation (Local lymph node assay, LLNA) Mouse Skin sensitiser Schedule 6
Acute toxicity

2-Chloro-6-(ethylamino)-4-nitrophenol has moderate acute oral toxicity, but low acute dermal toxicity based on results from animal tests. Additionally, 2-chloro-6-(ethylamino)-4-nitrophenol is classified as hazardous with the risk phrase ‘Harmful if swallowed' (Xn; R22) in the HSIS. The available data support this classification.

Irritation

The available data from animal studies indicate that 2-chloro-6-(ethylamino)-4-nitrophenol is not irritating to the skin, but is a potential eye irritant. However, insufficient details on the eye irritation study are available, which do not allow for hazard classification.

Sensitisation

2-Chloro-6-(ethylamino)-4-nitrophenol is classified as hazardous with the risk phrase ‘May cause sensitisation by skin contact' (R43) in the HSIS. The positive results, reported in a local lymph node assay (LLNA), support this classification.

In an LLNA conducted according to OECD TG 429, the skin sensitising potential of 2-chloro-6-(ethylamino)-4-nitrophenol was tested in mice (5 animals/dose group) at concentrations ranging from 0.5-10% using a DMSO vehicle, and at 0.5-2.5% using an acetone/water/olive oil vehicle (mix ratio of 2:2:1). The estimated concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3) value of 2.79% was determined based on the concentrations used with the DMSO vehicle; a stimulation index greater than three was not observed at the lower concentrations used with the acetone/water/olive oil vehicle (up to 2.5%).

Repeat-dose toxicity

Based on the available information, 2-chloro-6-(ethylamino)-4-nitrophenol is not considered to cause serious damage to health through repeated oral exposure.

Mutagenicity/Genotoxicity

Based on the weight of evidence from the available, well-conducted, in vitro" and in vivo genotoxicity studies, 2-chloro-6-(ethylamino)-4-nitrophenol is not considered to be genotoxic.

Carcinogenicity

No animal toxicity data are available on the carcinogenicity of 2-chloro-6-(ethylamino)-4-nitrophenol. Based on the available genotoxicity data and mechanistic information, 2-chloro-6-(ethylamino)-4-nitrophenol is not considered to be carcinogenic.

Reproduction and developmental toxicity

Based on the available information, 2-chloro-6-(ethylamino)-4-nitrophenol is not expected to be a developmental toxin. No reliable data examining the effect of 2-chloro-6-(ethylamino)-4-nitrophenol on fertility are available.

Observation in humans

No information was available.

Public exposure

Considering that 2-chloro-6-(ethylamino)-4-nitrophenol is reported to be used in hair dye products in Australia, the main route of public exposure is expected to be dermal.

Pre-meeting public submissions

One (1) pre-meeting public submission was received with no objections to the proposed scheduling for 2-chloro-6-(ethylamino)-4-nitrophenol. The main points of the submission were:

  • Scheduling of 2-chloro-6-(ethylamino)-4-nitrophenol should align with regulations in other international jurisdictions, such as the EU.
  • 2-chloro-6-(ethylamino)-4-nitrophenol substance is used in the approximately 24% 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. There is no evidence to suggest immediate action is required for the risk management of this substance.

The public submission is available on the TGA website.

Summary of ACCS advice to the delegate

The committee advised that a new Schedule 6 entry for 2-chloro-6-(ethylamino)-4-nitrophenol be created as follows:

Schedule 6 - New Entry

2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL except:

  1. in non-oxidative hair dye preparations containing 3 per cent or less of 2-chloro-6-(ethylamino)-4-nitrophenol 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, and

    written in letters not less than 1.5 mm in height; or

  2. in oxidative hair dye preparations containing 1.5 per cent or less of 2-chloro-6-(ethylamino)-4-nitrophenol 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, and

    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

2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL

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

2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL

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

Safety directions: 4 (Avoid contact with skin).

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:

  • 2-Chloro-6-(ethylamino)-4-nitrophenol is a strong to moderate skin sensitiser.
  • Primary consumer use of 2-chloro-6-(ethylamino)-4-nitrophenol 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 2-chloro-6-(ethylamino)-4-nitrophenol 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 new Schedule 6 and Appendix E/F entries for 2-chloro-6-(ethylamino)-4-nitrophenol. The proposed Schedule entry is as follows:

Schedule 6 - New Entry

2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL except:

  1. in non-oxidative hair dye preparations containing 3 per cent or less of 2-chloro-6-(ethylamino)-4-nitrophenol 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, and

    written in letters not less than 1.5 mm in height; or

  2. in oxidative hair dye preparations containing 1.5 per cent or less of 2-chloro-6-(ethylamino)-4-nitrophenol 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, and

    written in letters not less than 1.5 mm in height.

Appendix E, Part 2 - New Entry

2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL

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

2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL

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

Safety directions: 4 (Avoid contact with skin).

The proposed implementation date is 1 June 2018. This implementation date is proposed in order to allow for the necessary labelling changes to be implemented by industry.

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.
  • 2-Chloro-6-(ethylamino)-4-nitrophenol is a strong to moderate skin sensitiser.
  • Primary consumer use of 2-chloro-6-(ethylamino)-4-nitrophenol 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 2-chloro-6-(ethylamino)-4-nitrophenol are consistent with the factors for Schedule 6.

Footnotes

  1. Publicly available on the NICNAS website at: Human Health Tier II Assessment for Phenol,2-chloro-6-(ethylamino)-4-nitro.

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