You are here

Scheduling delegate's final decisions, March 2017

Scheduling medicines and poisons

23 March 2017

Book pagination

1.5 2,2'-[(4-Amino-3-nitrophenyl)imino]bisethanol and its monohydrochloride

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

Advisory Committee on Chemicals Scheduling (ACCS#18)

1.5 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

This was a 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 and relevant scheduling history

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

2,2'-[(4-Amino-3-nitrophenyl)imino]bisethanol and its salt 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
Table 1.5A: Chemical information
Property 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol monohydrochloride
CAS No. 29705-39-3 94158-13-1
Alternative names Ethanol, 2,2'-[(4-amino-3-nitrophenyl)imino]bis- (CAS) 2,2'-((4-amino-3-nitrophenyl)imino)bisethanol hydrochloride; Ethanol, 2,2'-[(4-amino-3-nitrophenyl)imino]bis-, monohydrochloride (CAS); HC Red 13 (INCI)
Chemical structure Chemical structure of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol Chemical structure of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol monohydrochloride
Molecular formula C10H15N3O4 C10H16ClN3O4
Molecular weight 241.2 g/mol 277.7 g/mol

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 monohydrochloride8.

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 139 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 follow:

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)
  • Other relevant information.
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 1310 with exemption cut-off concentrations for oxidative and non-oxidative hair dye preparations.

The proposed wording for the schedule, appendix and index entries are 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 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.
  • 2,2'-[(4-Amino-3-nitrophenyl)imino]bisethanol and its monohydrochloride (HC Red 13) are used cosmetically in hair dyes.
  • 2,2'-[(4-Amino-3-nitrophenyl)imino]bisethanol and its monohydrochloride (HC Red 13) are moderate skin sensitisers consistent with Schedule 6 factors.
Public submissions on the interim decision

One (1) submission was received which supported the delegate's interim decision with amendments. The main point in support was that the proposed schedule entry concentration cut-offs would be in alignment with international regulations in the EU. The main points were:

  • Incorrect use of synonyms. HC Red 13 is the INCI name for the hydrochloride salt of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol. The phrase 'including its salts' in the schedule entry is therefore redundant.
  • No Appendix E Standard Statements are proposed. The submission suggests that Standard Statements should be applied in a way that is consistent with other existing entries for scheduled hair dye substances.
  • The submission questions the use of the warning statement, 'This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye' and whether the reason for its inclusion is eye irritancy or sensitisation.
  • The appropriateness of the proposed 'earliest possible implementation date' of 1 June 2017. The submission stresses that an adequate transition period of at least 12 months must be allowed for any labelling changes and/or reformulation that may be required where no immediate risk has been identified; and that there is no evidence to suggest immediate action is required for the risk management of this substance.
Delegate's final decision

The delegate's final decision is to create a new Schedule 6 entry for 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol with exemption cut-off concentrations for oxidative and non-oxidative hair dye preparations and new Appendices E & F and Index entries as follows:

Schedule 6 - New Entry

2,2'-[(4-AMINO-3-NITROPHENYL)IMINO]BISETHANOL (including its salts) except:

  1. in non-oxidative hair dye preparations containing 2.5 per cent or less of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol after mixing 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 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol 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

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

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

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

Index - New Entry

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

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

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

The implementation date has been extended to 1 February 2018.

The delegate confirms that the reasons for the final decision are the same as those provided from the interim decision. Additional reasons for the final decision include:

  • The delegate notes that HC Red 13 specifically refers to the hydrochloride salt of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol and has amended the wording of the schedule entry to capture all salts of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol.
  • The words 'after mixing' have been added to the schedule entry for clarity
  • The delegate notes that a longer implementation time is required to allow for labelling changes and/or reformulation.

8 Publicly available from the NICNAS website at: https://www.nicnas.gov.au/chemical-information/imap-assessments/imap-group-assessment-report?assessment_id=1796

9 A public submission received in response to the interim decision indicated that HC Red 13 is the INCI name for the hydrochloride salt of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol specifically. The phrase 'including its salts' in the schedule entry is therefore redundant.

10 A public submission received in response to the interim decision indicated that HC Red 13 is the INCI name for the hydrochloride salt of 2,2'-[(4-amino-3-nitrophenyl)imino]bisethanol specifically. The phrase 'including its salts' in the schedule entry is therefore redundant.

Book pagination