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

Scheduling medicines and poisons

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2 February 2017

1.5 HC Red 13 (2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol and its monohydrochloride)

Part A - Interim decisions on matters referred to an expert advisory committee (November 2016)

Advisory Committee on Chemicals Scheduling (ACCS #18)

1.5 HC Red 13, (2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol and its monohydrochloride)

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 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol and its monohydrochloride in hair dyes and eyebrow/eyelash colouring products and to determine whether an appropriate exemption cut-off is required.

Scheduling application

General application.

The applicant's proposed amendments to the Poisons Standard are as follows:

Schedule 6 - New Entry

2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL except when used in hair dye preparations containing 1.25 per cent or less of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol or its monohydrate under oxidative conditions (after mixing with hydrogen peroxide), or 2.5 per cent of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol or its monohydrate under non-oxidative conditions, and 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 1.5mm in height.

Appendix E, Part 2 - New Entry

2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL AND ITS MONOHYDROCHLORIDE

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

Appendix F, Part 3 - New Entry

2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL AND ITS MONOHYDROCHLORIDE

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

The applicant's reasons for the request are:

  • The 2,2'-((4-amino-3-nitrophenyl)imino)bisethanol hydrochloride salt is reported to be used in semi-permanent hair dye preparations in Australia.
  • Both the free based and the salt have reported cosmetic uses overseas, as hair dye substances in oxidative (permanent) and non-oxidative (semi-permanent) hair dye products, that are potentially available for use in Australia.
  • The chemicals are moderate skin sensitisers.
  • Existing overseas restrictions for use of the chemicals in hair dyes where the maximum concentration allowed in the finished cosmetic product as a hair dye substance in non-oxidative hair dye products is 2.5% and the maximum use concentration upon application is 1.25% (after mixing under oxidative conditions), with labelling requirements at lower concentrations.
  • The risk could be controlled by including warning statements on labels for hair dye formulations containing the chemicals at any concentration.
  • When 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol and its monohydrochloride are used as hair dyes, 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.
Current scheduling status

2,2'-[(4-Amino-3-nitrophenyl)imino]bisethanol (HC Red 13) and its monohydrochloride are not currently scheduled and have not been previously considered for scheduling; therefore, scheduling history is not available.

Australian regulatory history

The salt of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol is reported to be used in semi-permanent hair dye preparations in Australia. Currently, there are no restrictions in Australia for using these chemicals in cosmetic products.

International regulations

The use of the chemicals in this group as cosmetics in the European Union (EU) is subject to the restrictions described in the EU Cosmetics Regulation 344/2013 (as an amendment to the listing under Annex III of Regulation 1223/2009). These chemicals may be used as a hair dye substance in ready-for-use preparations of non-oxidising hair dye products at a maximum concentration of 2.5 % (as hydrochloride salt). Additionally, after mixing under oxidative conditions (i.e. with hydrogen peroxide), the maximum concentration applied to hair must not exceed 1.25 % (as hydrochloride salt). The Cosmetics Regulation also mandates label warning statements relating to the sensitisation potential of the chemical.

The chemicals in this group are also listed, with the same use restrictions as described above for the EU, as follows:

  • The Association of Southeast Asian Nations (ASEAN) Cosmetic Directive Annex III-Part 1.
  • The New Zealand Cosmetic Products Group Standard-Schedule 5.
Substance summary

Structures of HC Red 13 (A) and its monohydrochloride (B)

Figure 1.5: Structures of HC Red 13 (A) and its monohydrochloride (B)

Table 1.5A: Chemical information
Property 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol monohydrochloride
CAS names Ethanol, 2,2'-[(4-amino-3-nitrophenyl)imino]bis- Ethanol, 2,2'-[(4-amino-3-nitrophenyl)imino]bis-, monohydrochloride
CAS numbers 29705-39-3 94158-13-1
IUPAC and/or common and/or other names HC Red 13 (INCI) 2,2'-((4-amino-3-nitrophenyl)imino)bisethanol hydrochloride

The following information was extracted from the NICNAS IMAP Human Health Tier II group assessment report for Ethanol, 2,2'-[(4-amino-3-nitrophenyl)imino]bis- and its monohydrochloride.

The hazards of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol and its monohydrochloride were assessed together using the toxicological data available. Where data was unavailable for the parent base, the data available for the salt is considered relevant for the hazard assessment due to the structural similarity of the two chemicals. However, the monohydrochloride salt could have different properties from the parent base with respect to local effects.

Table 1.5B: Acute toxicity end-points for 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol hydrochloride
Toxicity Species 2,2'-((4-amino-3-nitrophenyl)imino)bisethanol hydrochloride SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 2120 Schedule 5
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 Limited reliability. Not irritating at low concentrations -
Eye irritation Rabbit Limited reliability. Not irritating at low concentrations -
Skin sensitisation (Local lymph node assay, LLNA) Mice Moderate sensitiser Schedule 6
Acute toxicity

2,2'-((4-Amino-3-nitrophenyl)imino)bisethanol hydrochloride is expected to have low acute toxicity based on results from animal tests following oral exposure. No acute dermal or inhalation toxicity data are available.

Irritation

The limited available data from experimental animal studies, suggest that 2,2'-((4-amino-3-nitrophenyl)imino)bisethanol hydrochloride, at 2.5%, is not irritating to the skin or eyes. However, it is noted that a concentration of 2.5% is too low for hazard evaluation.

Sensitisation

Based on the available data, the chemicals are considered to be moderate skin sensitisers.

  • In a LLNA, the monohydrochloride salt, in a mixture of water/acetone (1:1) with olive oil (3:1) or in dimethyl sulfoxide (DMSO), was applied to the surface of the ear of female CBA/J mice (n=5/group) once daily for three consecutive days. The salt at test concentrations of 0.5, 1.5, 5 or 10% in water/acetone/olive oil produced stimulation indices (SIs) of 1.3, 2.2, 1.2 or 1.4, respectively. The estimated concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3) could not be calculated as all values were below three. The salt, at test concentrations of 0.5, 1.5, 5 or 10% in DMSO, produced SIs of 1.5, 1.8, 2.1 or 3.5, respectively. The EC3 was 8.2%, indicating a moderate skin sensitisation potential.
  • No dermal allergic reaction was reported in a guinea pig maximisation test (GPMT) and a Landsteiner-Draize guinea pig sensitisation test in female Pirbright guinea pigs. However, due to the low test concentrations (1-3%) used in these studies, they were considered inadequate for hazard evaluation.
Repeat-dose toxicity

The available data suggest that the chemicals have low to moderate repeated dose toxicity based on results from animal tests following repeated oral exposure. Based on the limited data available from animal studies, the chemicals are not expected to have systemic toxicity following repeated dermal exposure. No repeated inhalation toxicity data are available.

Genotoxicity

Based on the weight of evidence from the available in vitro and in vivo genotoxicity studies, the chemicals are not considered to be genotoxic. Positive results were seen in some in vitro genotoxicity tests, but all in vivo tests were negative.

Carcinogenicity

No carcinogenicity studies are available for the chemicals, except for a dermal study conducted using the salt at low concentrations. The data available do not provide sufficient information to make a conclusion on the carcinogenicity of the chemicals. Based on the available genotoxicity data, the chemicals are not considered to be genotoxic carcinogenic.

Reproduction and developmental toxicity

Based on the available data, the chemicals are not expected to have reproductive or developmental toxicity.

Pre-meeting public submissions

One (1) pre-meeting submission was received in support. The main points were that the new schedule entry would be in alignment with international regulators in the EU, ASEAN and NZ.

Summary of ACCS advice to the delegate

The committee advised that 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol be entered in Schedule 6 under the INCI name, HC Red 13 with exemption cut-off concentrations as follows:

Schedule 6 - New Entry

HC RED 13 (including its salts) except:

  1. in non-oxidative hair dye preparations containing 2.5 per cent or less of HC Red 13 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 1.25 per cent or less of HC Red 13 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. 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.

The committee also that advised that appendix and index entries are created as follows:

Appendix E, Part 2 - New Entry

HC RED 13

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

Appendix F, Part 3 - New Entry

HC RED 13

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

Index - New Entry

HC RED 13
cross reference: 2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL

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

The committee recommended an implementation date of 1 June 2017.

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:

  • HC Red 13 is used cosmetically as a hair dye.
  • HC Red 13 is a moderate skin sensitiser consistent with Schedule 6 factors.
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)
Delegate's interim decision

The delegate's interim decision is to create a new Schedule 6 entry for 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol under the INCI name, HC Red 13 with exemption cut-off concentrations for oxidative and non-oxidative hair dye preparations.

The proposed Schedule entry is as follows:

Schedule 6 - New Entry

HC RED 13 (including its salts) except:

  1. in non-oxidative hair dye preparations containing 2.5 per cent or less of HC Red 13 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 1.25 per cent or less of HC Red 13 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. 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 - New Entry

HC RED 13

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

Appendix F, Part 3 - New Entry

HC RED 13

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

Index - New Entry

HC RED 13
cross reference: 2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL

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

The proposed implementation date is 1 June 2017.

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; and c) the toxicity of the substance.

The reasons for the recommendation comprised the following:

  • The delegate acknowledges the committee's advice.
  • HC Red 13 is used cosmetically as a hair dye.
  • HC Red 13 is a moderate skin sensitiser consistent with Schedule 6 factors.
  • Earliest possible implementation date.

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