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

1.3 Hydroxyethyl-3,4-methylenedioxyaniline

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

Advisory Committee on Chemicals Scheduling (ACCS #18)

1.3 Hydroxyethyl-3,4-methylenedioxyaniline

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 hydroxyethyl-3,4-methylenedioxyaniline and its hydrochloride salt in hair dyes and eyebrow/eyelash colouring products and to determine whether appropriate exemption cut-off and labelling is required.

Scheduling application

General application.

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

Schedule 6 - New Entry

HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE AND ITS HYDROCHLORIDE except in hair dye preparations containing 1.5 per cent or less of hydroxyethyl-3,4-methylenedioxyaniline or its hydrochloride under oxidising conditions (after mixing with hydrogen peroxide), and when the immediate container and primary pack are labelled with the following statement:

KEEP OUT OF REACH OF CHILDREN; and

WARNING - This product contains ingredients which may cause skin sensitisation to certain individuals, and when used for eyelash or eyebrow tinting may cause injury to the eye. 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

HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE AND ITS 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 3 - New Entry

HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE AND ITS HYDROCHLORIDE

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

The applicant's reasons for the request are:

  • The hydrochloride salt of hydroxyethyl-3,4-methylenedioxyaniline has reported cosmetic use in permanent and semi-permanent hair dye preparations in Australia. Overseas, the hydrochloride salt is used in oxidative hair dye products, that are potentially available for use in Australia.
  • Existing overseas restrictions for use of the hydrochloride salt of hydroxyethyl-3,4-methylenedioxyaniline in hair dyes where the maximum concentration allowed in the finished cosmetic product as a hair dye substance in oxidative hair dye products is 1.5%.
  • The chemicals are secondary amines and thus prone to nitrosation, and should not be used in combination with nitrosating substances; the maximum nitrosamine content should be less than 50 ppb and should be kept in nitrite-free containers for the hydrochloride salt.
  • The hydrochloride salt of hydroxyethyl-3,4-methylenedioxyaniline is a strong skin sensitiser and has moderate systemic acute oral toxicity.
  • The risk could be controlled by including warning statements and first aid instructions on labels for hair dye formulations containing the chemicals.
  • Many countries, including those in the European Union (EU), have restricted the use of the hydrochloride salt in cosmetics (refer to International Regulations).
  • When hydroxyethyl-3,4-methylenedioxyaniline and its hydrochloride 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

Hydroxyethyl-3,4-methylenedioxyaniline and its hydrochloride salt are not currently scheduled and have not been previously considered for scheduling; therefore, scheduling history is not available.

International regulations

The following restrictions are reported for the chemical. Similar restrictions to those in the European Union (EU) Cosmetics Directive apply to all jurisdictions:

  • The EU Cosmetics Regulation No 1223/2009 Annex III-List of substances provisionally allowed in cosmetic products with restriction stated as 'after mixing under oxidative conditions the maximum concentration applied to hair must not exceed 1.5%: do not use with nitrosating agents, maximum nitrosamine content 50 microgram/kg, and keep in nitrite-free containers'. There is a requirement to label products containing these chemicals at lower concentrations as potentially sensitising.
  • The Association of South East Asian Nations (ASEAN) Cosmetic Directive Annex III—Part 1 List of substances which cosmetic products must not contain except subject to restrictions and conditions laid down. The restriction is stated as 'after mixing under oxidative conditions the maximum concentration applied to hair must not exceed 1.5%; Do not use with nitrosating systems; Maximum nitrosamine content: 50 µg/kg; Keep in nitrite-free containers'.
  • The New Zealand (NZ) Cosmetic Products Group Standard—Schedule 5, Table 1 Components cosmetic products must not contain except subject to restrictions and conditions laid down. The restriction is stated as 'in combination with hydrogen peroxide the maximum use concentration upon application is; 1.5%; Do not use with nitrosating systems; Maximum nitrosamine content: 50 μg/kg; Keep in nitrite-free containers'.
Substance summary

Structure of hydroxyethyl-3,4-methylenedioxyaniline (A) and its hydrochloride (B)

Figure 1.3: Structure of hydroxyethyl-3,4-methylenedioxyaniline (A) and its hydrochloride (B)

Table 1.3A: Chemical information
Property Hydroxyethyl-3,4-methylenedioxyaniline Hydroxyethyl-3,4-methylenedioxyaniline hydrochloride
CAS names Ethanol, 2-(1,3-benzodioxol-5-ylamino)- Ethanol, 2-(1,3-benzodioxol-5-ylamino)-, hydrochloride
CAS numbers 81329-90-0 94158-14-2
IUPAC and/or common and/or other names Hydroxyethyl-3,4-methylenedioxyaniline Hydroxyethyl-3,4-methylenedioxyaniline HCl (INCI)

The following toxicology information was extracted from the NICNAS IMAP Human Health Tier II assessment for Ethanol, 2-(1,3-benzodioxol-5-ylamino)-, hydrochloride. Further information can also be found in the European Commission Scientific Committee on Consumer Safety (SCCS) report for hydroxyethyl-3,4-methylenedioxyaniline hydrochloride (pdf,260kb).

Table 1.3B: Acute toxicity end-points for hydroxyethyl-3,4-methylenedioxyaniline hydrochloride
Toxicity Species Hydroxyethyl-3,4-methylenedioxyaniline HCl SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw)

Rat

Mouse

1550 (male); 1650 (female)

850 (female)

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 Guinea pig Not irritating at 5% concentration N/A
Eye irritation Guinea pig Transiently irritating at 2% concentration N/A
Skin sensitisation (LLNA) Mouse Skin sensitiser (calculated EC3<0.5%) Schedule 6

A short summary of the toxicity, exposure, use, international risk management control of the substance are included below. For further information, please see assessment report.

Acute toxicity

The hydrochloride salt of hydroxyethyl-3,4-methylenedioxyaniline has moderate acute oral toxicity in male and female rats and in female mice. There are no data on acute dermal and inhalation toxicity.

Irritation

Limited data are available in guinea pigs. The chemical at a 5% concentration is not irritating to the skin. The chemical at a 2% concentration is transiently irritating to the eyes.

Sensitisation

In a local lymph node assay (LLNA) conducted according to the OECD TG 429 the hydrochloride salt of hydroxyethyl-3,4-methylenedioxyaniline, at dilutions of 0.5, 1.5, 5 or 10%, was applied to the ears of female CBA/J mice (5/group) for three consecutive days. Two separate vehicles were used, dimethyl sulfoxide (DMSO) or in a mixture (3:3:1) of water/acetone/olive oil (equal to the maximum solubility). For the DMSO vehicle, the mean stimulation indices (SIs) were dose-dependent at 6.4, 5.0, 8.0 and 12.4 for the 0.5, 1.5, 5 and 10% dilutions, respectively. For the other vehicle (water/acetone/olive oil), the SIs were 4.3, 3.6, 3.3 and 4.4 for the 0.5, 1.5, 5 and 10% dilutions, respectively. The estimated concentration (EC) needed to produce a three-fold increase in lymphocyte proliferation (EC3) was calculated to be <0.5%, indicating strong sensitising potential (SCCS, 2009).

Repeat-dose toxicity

Based on a 90-day study in rats, the chemical is not expected to cause serious damage to health from repeated oral exposure.

Mutagenicity and Genotoxicity

Based on the available data from in vitro and in vivo genotoxicity studies, the chemical is not considered to be genotoxic.

Carcinogenicity

No data were available for carcinogenicity.

Reproduction and developmental toxicity

Based on the available data, the chemical is not expected to have reproductive or developmental toxicity. Foetal effects observed in the animals at high doses are considered secondary to maternal 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 hydroxyethyl-3,4-methylenedioxyaniline be entered in Schedule in the Poisons Standard, with an exemption cut-off of 1.5% as follows:

Schedule 6 - New Entry

HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE (including its salts) except in oxidative hair dye preparations containing 1.5 per cent or less of hydroxyethyl-3,4-methylenedioxyaniline 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 advised that appendix entries be created as follows:

Appendix E, Part 2 - New Entry

HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE

Standard statements: E1 (if in eyes wash out immediately with water), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F, Part 3 - New Entry

HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE

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

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: (a) risks and benefits of the use of a substance (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:

  • Hydroxyethyl-3,4-methylenedioxyaniline is used in permanent hair dye preparations in Australia.
  • Hydroxyethyl-3,4-methylenedioxyaniline and its salt are strong skin sensitisers and have moderate systemic acute oral toxicity consistent with Schedule 6 factors.
  • Hydroxyethyl-3,4-methylenedioxyaniline and its salt are secondary amines and thus prone to nitrosation.
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 hydroxyethyl-3,4-methylenedioxyaniline, with an exemption cut-off of 1.5 per cent.

The proposed Schedule entry is as follows:

Schedule 6 - New Entry

HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE (including its salts) except in oxidative hair dye preparations containing 1.5 per cent or less of hydroxyethyl-3,4-methylenedioxyaniline 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

HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE

Standard statements: E1 (if in eyes wash out immediately with water), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F, Part 3 - New Entry

HYDROXYETHYL-3,4-METHYLENEDIOXYANILINE

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

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: a) the risks and benefits of the use of the substance; 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.
  • Hydroxyethyl-3,4-methylenedioxyaniline is used in permanent hair dye preparations in Australia.
  • Hydroxyethyl-3,4-methylenedioxyaniline and its salt are strong skin sensitisers and have moderate systemic acute oral toxicity consistent with Schedule 6 factors.
  • Hydroxyethyl-3,4-methylenedioxyaniline and its salt are secondary amines and thus prone to nitrosation.
  • Earliest possible implementation date.

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