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Scheduling delegate's final decisions, January 2017

Scheduling medicines and poisons

16 January 2017

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1.4. 2,4-Diaminophenoxyethanol hydrochloride

Final decisions on matters not referred to an expert advisory committee

1. Chemicals not referred to the November 2016 ACCS

1.4. 2,4-Diaminophenoxyethanol hydrochloride

Referred scheduling proposal

An application was submitted to create a new entry for 2,4-diaminophenoxyethanol hydrochloride in Schedule 6 with appropriate concentration cut-off for use in hair dyes.

Current scheduling status and relevant scheduling history

2,4-Diaminophenoxyethanol is already in Schedule 6 of the Poisons Standard as follows:

Schedule 6

2,4-DIAMINO-PHENOXYETHANOL in hair dye preparations except in preparations containing 4 per cent or less of 2,4-diaminophenoxyethanol when the immediate container and primary pack are labelled with the following:

KEEP OUT OF REACH OF CHILDREN

WARNING – this product contains ingredients which may cause skin irritation to certain individuals. A preliminary test according to the accompanying directions should be made before use. This product must not be used for dying eyelashes and eyebrow; to do so may be injurious to the eye.

Written in letters not less than 1.5 mm in height.

Appendix E, Part 2 – 2,4-DIAMINO-PHENOXYETHANOL

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 - 2,4-DIAMINO-PHENOXYETHANOL

Warning statement: 21 (WARNING – This product contains ingredients which may cause skin irritation to certain individuals. A preliminary test according to 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.).

Relevant scheduling history

In March 2014, the Advisory Committee on Chemicals Scheduling (ACCS) included 2,4 diaminophenoxyethanol in Schedule 6 and Appendices E and F of the Poisons Standard. Although the applicant's scheduling proposal specifically referenced the sulfate salt, it was noted at the meeting that the hydrochloride salt (2,4-diaminophenoxyethanol dihydrochloride) was used in the toxicity assessment and that the sulfate salt and free alcohol will likely have comparable physical/chemical and toxicological properties. The implementation date was 1 October 2014.

Australian regulatory information

2,4-Diaminophenoxyethanol hydrochloride is listed on the Australian Inventory of Chemical Substances (AICS) and is reported to be used in permanent hair dye preparations in Australia (NICNAS, 2007).

International regulations

The Association of South East Asian Nations (ASEAN), Canada, New Zealand and the European Union (EU) have restricted the use of this chemical in cosmetics. Following a safety evaluation, the Scientific Committee on Consumer Products (SCCP) concluded that the use of the chemical 'as an oxidative hair dye at a maximum concentration of 2.0% in the finished cosmetic product (after mixing with hydrogen peroxide) does not pose a risk to the health of the consumer, apart from its sensitising potential' (SCCP, 2006).

The chemical is listed on the following:

  • The ASEAN Cosmetic Directive Annex III-Part 1: List of substances which cosmetic products must not contain except subject to restrictions and conditions laid down: 'After mixing under oxidative conditions the maximum concentration applied to hair must not exceed 2.0% (as hydrochloride)';
  • The EU Regulation (EC) No 1197/2013 of the European Parliament and of the Council of 1 July 2014 on cosmetic products Annex III-List of substances which cosmetic products must not contain except subject to the restrictions laid down: 'After mixing under oxidative conditions the maximum concentration applied to hair or eyelashes must not exceed 2.0% (as hydrochloride) and for professional use only'. The Cosmetic Regulation also mandates label warning statements relating to the sensitisation potential of the chemical;
  • New Zealand Cosmetic Products Group Standard-Schedule 5: Components cosmetic products must not contain except subject to the restrictions and conditions laid down: 'In combination with hydrogen peroxide the maximum use concentration upon application is 2.0% as hydrochloride'; and
  • Health Canada List of prohibited and restricted cosmetic ingredients (The Cosmetic Ingredient 'Hotlist').
Scheduling application

General application.

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

Schedule 6 – New Entry

2,4-DIAMINOPHENOXYETHANOL HYDROCHLORIDE except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 2 per cent or less of 2 (2,4 diaminophenoxy)ethanol hydrochloride 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 22,4-DIAMINOPHENOXYETHANOL HYDROCHLORIDE

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 32,4-DIAMINOPHENOXYETHANOL HYDROCHLORIDE

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

The applicant's reasons for the request are:

  • 2,4-Diaminophenoxy)ethanol hydrochloride has overseas restrictions, where the maximum concentration allowed in hair and eyelash products must not exceed 2.0% (as hydrochloride) and for professional use only;
  • 2,4-Diaminophenoxyethanol hydrochloride has reported cosmetic use in permanent hair dye preparations in Australia;
  • 2,4-diaminophenoxyethanol hydrochloride has moderate oral acute toxicity, is an eye irritant and a moderate skin sensitiser;
  • The risk could be controlled by including warning statements on the label of hair dye formulations containing 2,4-diaminophenoxyethanol hydrochloride at any concentration; and
  • When 2,4-diaminophenoxyethanol hydrochloride 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.
Substance summary

The following information was extracted from the NICNAS IMAP Human Health Tier II group assessment report for Ethanol, 2-(2,4-diaminophenoxy)-, hydrochloride.

Figure 1.4: Structure of 2-(2,4-diaminophenoxy)ethanol hydrochloride
Figure 1.4: Structure of 2-(2,4-diaminophenoxy)ethanol hydrochloride

Table 1.4A: Chemical properties and identifiers of 2,4-diaminophenoxyethanol hydrochloride
Property/identifier 2,4-Diaminophenoxyethanol hydrochloride
Molecular formula C8H12N2O22HCl
Molecular weight 241.119 g/mol
CAS name ethanol, 2-(2,4-diaminophenoxy)-, hydrochloride (1:2)
CAS number 66422-95-5
IUPAC and/or common and/or other names 2,4-diaminophenoxyethanol HCL (INCI); 2,4-diaminophenoxyethanol hydrochloride.
Table 1.4B: Acute toxicity end-points for 2-(2,4-diaminophenoxy)ethanol hydrochloride
Toxicity Species 2,4-diaminophenoxyethanol hydrochloride SPF (2015) Classification/th>
Acute oral toxicity LD50 (mg/kg bw) Rat 1000 Schedule 6
Mouse 1160
Acute dermal toxicity LD50 (mg/kg bw) N/A No data N/A
Acute inhalational toxicity LC50 (mg/m3/4h) N/A No data N/A
Skin irritation Rabbit Non-irritant N/A
Eye irritation Rabbit Irritant Schedule 5/6
Skin sensitisation (local lymph node assay, LLNA) Guinea pig Moderate sensitiser Schedule 6
Mouse
Acute toxicity

The chemical is considered to have moderate acute toxicity based on results from animal tests following oral exposure. The median lethal dose (LD50) was approximately 1000 mg/kg bw in Sprague Dawley (SD) rats and 1160 mg/kg bw in Swiss albino mice. No data were available for acute dermal and inhalation toxicity.

Skin Irritation

Based on the limited available data, the chemical is not considered to be a skin irritant.

Eye Irritation

Based on the available data, the chemical is considered to be an eye irritant:

  • In an eye irritation study conducted according to OECD TG 405 with three female New Zealand White rabbits, the undiluted 2,4-diaminophenoxyethanol hydrochloride was instilled into the conjunctival sac of the left eye of each animal. The eyes were not rinsed following instillation of the chemical. Moderate to marked chemosis, slight to moderate conjunctival redness, slight to moderate corneal opacification and slight iridial lesions were observed in the animals. These effects were not fully reversed at the end of the study (day 15). It was concluded that the undiluted chemical was irritating to rabbit eyes.
  • In two other eye irritation studies carried out in three female New Zealand White rabbits and three albino Bouscat rabbits, a 4% solution of the chemical did not produce any irritation.
Sensitisation

Based on the available data, the chemical is considered to be a moderate skin sensitiser:

  • One LLNA was conducted according to OECD TG 429 in female CBA/J mice (n=4/group). The chemical at 0.5, 1.0, 2.5, 5.0 or 10% dilutions produced a stimulation index (SI) of 0.92, 1.56, 1.17, 4.21 and 7.42, respectively. The estimated concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3) was calculated to be 3.2%, indicating a moderate sensitising potential.
  • In a Buehler test (OECD TG 406) conducted using ten Dunkin Hartley guinea pigs per sex, no sensitisation reaction was observed with topical induction and challenge applications of the undiluted chemical after 48 hours.
Repeat-dose toxicity

Based on the available data, 2,4-diaminophenoxyethanol hydrochloride is not expected 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 results observed in several in vitro and in vivo genotoxicity studies, the chemicals are not expected to be genotoxic.

Carcinogenicity

Based on the available data, the chemical is not considered to be carcinogenic.

Reproduction and developmental toxicity

Based on the available data, the chemical is not expected to have reproductive and developmental toxicity.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal
  • NICNAS IMAP Tier II Report
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling Policy Framework (SPF 2015) criteria
Delegate's final decision

The delegate's final decision is to amend the Schedule 6 entry for 2,4-diaminophenoxyethanol to include a 2 per cent exemption cut-off in oxidative hair dye preparations as follows:

Schedule 6 − Amend Entry

2,4-DIAMINOPHENOXYETHANOL (including its salts) except:

  1. in non-oxidative hair dye preparations containing 4 per cent or less of 2,4 diaminophenoxyethanol 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 2 per cent or less of 2,4 diaminophenoxyethanol 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 – Current Entry

2,4-DIAMINOPHENOXYETHANOL

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 – Amend Entry

2,4-DIAMINOPHENOXYETHANOL

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

The delegate notes that the main route of exposure to 2,4-diaminophenoxyethanol is through the skin, with acute oral toxicity, eye irritancy and skin sensitisation consistent with Schedule 6 SPF criteria. The amendment to include a concentration cut-off for use in oxidative hair dye preparations is consistent with international regulations (EU Regulation (EC) No 1197/2013 of 1 July 2014) and with recent newly scheduled and similarly sensitising hair dyes.

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 the substance; (b) the purposes for which the substance is to be used and (c) the toxicity of the substance.

The implementation date is 1 February 2017.

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