You are here

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

Scheduling medicines and poisons

17 May 2017

Book pagination

3.5 2,4-Diaminophenoxyethanol

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

3.5 2,4-Diaminophenoxyethanol

Referred scheduling proposal

An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a Schedule 6 entry for 2,4-diaminophenoxyethanol with appropriate concentration cut-off for use in hair dyes.

Current scheduling status

2,4-Diaminophenoxyethanol is currently in Schedule 6 and Appendices E and F 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).

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.

In August 2016, NICNAS, under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) Scheme submitted a proposal to create a new Schedule 6 entry [Secretariat note: an entry already exists] for 2,4-diaminophenoxyethanol except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 2 per cent or less after mixing for use when the immediate container and primary pack are labelled appropriately.

On 16 January 2017, the delegate made a delegate-only final decision to amend the Schedule 6 entry for 2,4-diaminophenoxyethanol as follows:

Schedule 6

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.

The delegate also amended the Appendix F, Part 3 warning statement from 21[84] to 28.[85]

Scheduling application

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

Schedule 6

ETHANOL, 2-(2,4-DIAMINOPHENOXY)-, DIHYDROCHLORIDE except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 2 per cent or less of Ethanol, 2-(2,4-diaminophenoxy)-, dihydrochloride 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.

Appendix E, Part 2

ETHANOL, 2-(2,4-DIAMINOPHENOXY)-, DIHYDROCHLORIDE

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

ETHANOL, 2-(2,4-DIAMINOPHENOXY)-, DIHYDROCHLORIDE

Warning statement: Repeated exposure may cause sensitisation (28)

The applicant's reasons for the request are:

  • 2,4-Diaminophenoxy)ethanol dihydrochloride 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 dihydrochloride has reported cosmetic use in permanent hair dye preparations in Australia;
  • 2,4-diaminophenoxyethanol dihydrochloride 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 dihydrochloride at any concentration; and
  • When 2,4-diaminophenoxyethanol dihydrochloride 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

2,4-Diaminophenoxyethanol dihydrochloride 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).

2,4-Diaminophenoxyethanol dihydrochloride is not listed on the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2017.

A search of the Australian Register of Therapeutic Goods (ARTG) found 2,4-diaminophenoxyethanol dihydrochloride not in any listed products.

International regulations

The Association of South East Asian Nations (ASEAN), Canada, New Zealand and the European Union (EU) have restricted the use of 2,4-diaminophenoxyethanol in cosmetics. Following a safety evaluation, the Scientific Committee on Consumer Products (SCCP) concluded that the use of 2,4-diaminophenoxyethanol '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).

2,4-Diaminophenoxyethanol 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 2,4-diaminophenoxyethanol;
  • 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').
Substance summary

2,4-Diaminophenoxyethanol is a light grey to light pink (dihydrochloride) or white powder (sulfate) used primarily in hair dye formulations.

Figure 3.5: Chemical structure of 2,4-Diaminophenoxyethanol

Figure 3.5: Chemical structure of 2,4-Diaminophenoxyethanol

Table 3.5A: Chemical information
Property 2,4-diaminophenoxyethanol dihydrochloride
CAS names ethanol, 2-(2,4-diaminophenoxy)-, dihydrochloride
CAS numbers 66422-95-5
IUPAC and/or common and/or other names 2,4-diaminophenoxyethanol HCL (INCI); 2-(2,4-diaminophenoxy)ethanol dihydrochloride (IUPAC).
Molecular formula C8H14Cl2N2O2
Molecular weight 241.1 g/mol

The following information was extracted from the NICNAS IMAP Human Health Tier II group assessment report for Ethanol, 2-(2,4-diaminophenoxy)-, dihydrochloride.[86]

Table
Toxicity Species Result SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw)

Rat

Mouse

1000

1160

Schedule 6
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

Mouse

Moderate sensitiser Schedule 6
Acute toxicity

2,4-Diaminophenoxyethanol 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, 2,4-diaminophenoxyethanol is not considered to be a skin irritant.

Eye irritation

Based on the available data, 2,4-diaminophenoxyethanol 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 dihydrochloride was instilled into the conjunctival sac of the left eye of each animal. The eyes were not rinsed following instillation of 2,4-diaminophenoxyethanol. 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 2,4-diaminophenoxyethanol did not produce any irritation.
Sensitisation

Based on the available data, 2,4-diaminophenoxyethanol 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). 2,4-Diaminophenoxyethanol 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 dihydrochloride 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, 2,4-diaminophenoxyethanol are not expected to be genotoxic.

Carcinogenicity

Based on the available data, 2,4-diaminophenoxyethanol is not considered to be carcinogenic.

Reproduction and developmental toxicity

Based on the available data, 2,4-diaminophenoxyethanol is not expected to have reproductive and developmental toxicity.

Pre-meeting public submissions

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

  • Scheduling of 2,4-diaminophenoxy-ethanol should align with regulations in other international jurisdictions, such as the EU.
  • 2,4-Diaminophenoxy-ethanol is used in approximately 70-95% of hair dye products in Australia.
  • An adequate transition period of at least 12 months in 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 the Schedule 6 and Appendix E/F entries for 2,4-diaminophenoxyethanol be amended as follows:

Schedule 6 - Amend Entry

2,4-DIAMINOPHENOXYETHANOL in hair dye preparations except in preparations containing 4 except when used in hair dye and eyebrow/eyelash preparations at a concentration of 2 per cent or less of 2,4-diaminophenoxyethanol 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 2 - Amend Entry

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.), E2 (If in eyes, hold eyelids apart and flush the eye continuously with running water. Continue flushing until advised to stop by a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor, or for at least 15 minutes.), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F, Part 3 - Amend Entry

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), 28 ((over) (repeated) exposure may cause sensitisation), 79 (Will irritate eyes).

Safety directions: 1 (Avoid contact with eyes), 4 (Avoid contact with skin).

The committee also advised an implementation date of 1 June 2018 to allow industry to make the necessary changes to labelling.

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:

  • 2,4-Diaminophenoxyethanol is a strong to moderate skin sensitiser.
  • Primary consumer use of 2,4-diaminophenoxyethanol is in hair dye and eyelash dye products. Although dermal contact of 2,4-diaminophenoxyethanol is unavoidable when used in hair dye preparations, risk can be appropriately managed by limiting concentration and applying warning statements.
  • The acute oral toxicity and skin sensitisation of 2,4-diaminophenoxyethanol is consistent with the factors for Schedule 6.
  • 2,4-Diaminophenoxyethanol is an irreversible eye irritant at high concentrations.
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 amend the Schedule 6 and Appendix E/F entries for 2,4-diaminophenoxyethanol. The proposed Schedule entry is as follows:

Schedule 6 - Amend Entry

2,4-DIAMINOPHENOXYETHANOL except when used in hair dye and eyebrow/eyelash preparations at a concentration of 2 per cent or less of 2,4-diaminophenoxyethanol 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 2 - Amend Entry

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)], E2 (If in eyes, hold eyelids apart and flush the eye continuously with running water. Continue flushing until advised to stop by a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor, or for at least 15 minutes.), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F, Part 3 - Amend Entry

2,4-DIAMINO-PHENOXYETHANOL

Warning statement: 28 ((over) (repeated) exposure may cause sensitisation), 79 (Will irritate eyes).

Safety directions: 1 (Avoid contact with eyes), 4 (Avoid contact with skin).

The proposed implementation date is 1 June 2018.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989or 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.
  • 2,4-Diaminophenoxyethanol is a strong to moderate skin sensitiser.
  • Primary consumer use of 2,4-diaminophenoxyethanol is in hair dye and eyelash dye products. Although dermal contact of 2,4-diaminophenoxyethanol is unavoidable when used in hair dye preparations, risk can be appropriately managed by limiting concentration and applying warning statements.
  • The acute oral toxicity and skin sensitisation of 2,4-diaminophenoxyethanol is consistent with the factors for Schedule 6.
  • 2,4-Diaminophenoxyethanol is an irreversible eye irritant at high concentrations.
  • A long implementation date is proposed in order to allow industry to make the necessary changes to labelling.

Footnotes

  1. (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).
  2. ((Over) (repeated) exposure may cause sensitisation).
  3. Publicly available at Human Health Tier II Assessment for Ethanol, 2-(2,4-diaminophenoxy)-, dihydrochloride

Book pagination