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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March 2016
Scheduling medicines and poisons
Part A - Interim decisions on scheduling proposals referred to an advisory committee (March 2016)
1. Advisory Committee on Chemicals Scheduling (ACCS#16)
Referred scheduling proposal
- In response to issues raised in a NICNAS IMAP Human Health Tier 2 assessment report on 2,4-diamino-5-methylphenetole, the scheduling proposal is to create a new Schedule 6 entry for 2,4-diamino-5-methylphenetole with an appropriate exemption and cut off to regulate its use in hair dyes and eyelash colouring products.
The reasons for the request are:
- 2,4-diamino-5-methylphenetole has reported cosmetic use overseas in permanent hair dye preparations;
- 2,4-diamino-5-methylphenetole could have moderate skin sensitisation potential;
- lack of data on reproductive and developmental toxicity, and acute or repeated dose dermal and inhalation toxicity; and
- the use of 2,4-diamino-5-methylphenetole in cosmetics is prohibited overseas. 2,4-diamino-5-methylphenetole is prohibited by the Commission Directive 2006/65/EC as 'permanent hair dye substances for which no explicit interest was expressed during the public consultation in defence of their use in hair dyes' (EC, 2006).
The critical health effect for risk characterisation is skin sensitisation. Given the potential for skin sensitisation, the risk would be better controlled by inclusion of warning statements on the label of preparations containing the chemical at any concentration. Similar chemicals have been listed in Schedule 6 of the SUSMP with reverse scheduling requirements.
Specific issues/questions raised by the delegate
The Delegate's reasons for referring this to the Committee were as follows: 2,4-diamino-5-methylphenetole is one of several oxidative hair dye ingredients that have been referred for scheduling in the past three years. Generally, these have been listed in either schedules 5 or 6, with cut-offs to exempt at a relevant concentration that minimises the risks of skin sensitisation and/or irritancy. In some cases, scheduling exemptions have been allowed via 'reverse labelling', where products labelled with specified warning statements may be exempted from the generic scheduling controls of Schedule 5 or 6. Further restrictions may have been applied where products are used in eyebrow/eyelash tinters as well as in hair dyes.
Additional restrictions (Schedule 10 listing) have been placed where there is a significant risk of genotoxicity and/or carcinogenicity, or where precluded use in products for skin colouration (tattooing) have been required. In some cases where there was no evidence of significant use in Australia, the delegate’s decision was not to schedule the substance (e.g. o-aminophenol from the July 2014 meeting).
The delegate has sought advice from the Committee on the following questions:
- Does the ACCS agree that the toxicological profile of 2,4-diamino-5-methylphenetole (acute toxicity, lack of skin-eye irritancy (at 3% concentration) and moderate-strong sensitisation potential) warrants controls over use in cosmetics and consumer products?
- What weight should be given to the evidence of moderate-strong skin sensitisation potential? Does the data suggest a suitable cut off for the sensitisation potential?
- Does the ACCS consider that including 2,4-diamino-5-methylphenetole in Schedule 6 is the best option for controlling its use in consumer products and cosmetics, including hair dyes and eyebrow/eyelash products? Should there be a cut off to exempt at 1.8% in on-hair formulations, as suggested in the NICNAS report?
- If the ACCS recommends listing in Schedule 6, should exemptions apply when the product is labelled with appropriate warning statements, consistent with other oxidative hair dye ingredients with similar toxicological profiles?
- Although there are no notified commercial uses other than in cosmetics, should a Schedule 6 listing be specific for use in hair dyes or cosmetic products (as for some other hair dye ingredients)?
- What name should be used for any schedule entry – 2,4-diamino-5-methylphenetole; 4-ethoxy-6-methyl-m-phenylenediamine, or 2,4-diamino-5-ethoxytoluene?
- Would this substance be considered to be a phenylenediamine derivative, and therefore captured by the existing Schedule 6 entry?
- Is there a need for specific entries in Appendices E and F to manage labelling of scheduled products?
Please refer to the publicly available report on the NICNAS website.
Figure 6. Structure of 2,4-diamino-5-methylphenetole.
The acute toxicity end-points for 2,4-diamino-5-methylphenetole are listed in the table below.
|Acute oral toxicity LD50 (mg/kg bw)||Rat and mouse||Approximately 200-2000||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 an irritant at 3 % concentration||N/A|
|Eye irritation||Guinea pig||Not an irritant at 3 % concentration||N/A|
|Skin sensitisation: QSAR - LLNA||N/A||Skin sensitiser (predicted EC3 = 5.1)||Schedule 6|
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
Based on the available data, 2,4-diamino-5-methylphenetole has been reported to have moderate acute oral toxicity, although the data are not sufficient to validate this conclusion. No information was available for acute toxicity by dermal and inhalation routes.
Based on the available data, 2,4-diamino-5-methylphenetole is not irritating to the skin and eyes at a 3 % concentration.
Based on the available data, 2,4-diamino-5-methylphenetole is expected to be a skin sensitiser.
Ten female guinea pigs were induced with a 0.1 % solution of 2,4-diamino-5-methylphenetole in Ringer's solution via intradermal injection to the clipped shoulder region, followed by a topical application of a 40 % solution of 2,4-diamino-5-methylphenetole. After two weeks, the animals were challenged with a 30 % solution of the chemical. Two of 10 test animals showed slight to moderate erythema (EC SCC, 2000). The SCCNFP (1999) reported that this study used an intradermal induction concentration that was too low. The cosmetic product containing the chemical was reported to have a label warning for risk of sensitisation (SCCNFP, 1999).
The sensitisation potency of 2,4-diamino-5-methylphenetole was predicted in a study on 229 hair dye substances using a QSAR model based on the LLNA. The study predicted the chemical to be a moderate to strong sensitiser, with an estimated concentration needed to produce a 3-fold increase in lymphocyte proliferation (EC3) value of 5.1 (Sosted et al., 2004).
Based on the available data, 2,4-diamino-5-methylphenetole 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.
Based on the available data from in vitro and in vivo genotoxicity studies, 2,4-diamino-5-methylphenetole is not considered to be genotoxic.
No animal toxicity data are available on the carcinogenicity of 2,4-diamino-5-methylphenetole. Based on the available genotoxic data and information available from QSAR modelling, the chemical is not considered to be carcinogenic.
Reproduction and developmental toxicity
Limited data are available and are not sufficient to derive a conclusion on the reproductive and developmental toxicity of 2,4-diamino-5-methylphenetole.
Observation in humans
No information was available.
2,4-diamino-5-methylphenetole was not reported to be used in hair dye preparations in Australia in 2007. It has overseas use in hair dye preparations at a maximum concentration of 2 % (maximum concentration of 1 % when mixed with hydrogen peroxide) (SCCNFP, 1999).
The Association of South East Asian Nations (ASEAN), European Union (EU) and New Zealand Cosmetic Products Group Standard have prohibited the use of this chemical in cosmetics. Currently, there are no restrictions in Australia for using this chemical in cosmetic products. In the absence of any regulatory controls, the characterised critical health effects, particularly skin sensitisation, have the potential to pose an unreasonable risk to the public if used in cosmetics.
The chemical is listed on the following:
- EU Cosmetic Directive 76/768/EEC Annex II - List of Substances which must not form part of the composition of cosmetic products;
- EU Commission Directive 2006/65/EC of 19 July 2006 amending Council Directive 76/768/EEC;
- New Zealand Cosmetic Products Group Standard - Schedule 4: Components cosmetic products must not contain; and
- ASEAN Cosmetic Directive Annex II - Part 1: List of substances which must not form part of the composition of cosmetic products.
Current scheduling status
2,4-diamino-5-methylphenetole is not specifically scheduled.
Relevant scheduling history
2,4-diamino-5-methylphenetole has not been previously considered for scheduling; therefore, scheduling history is not available.
Pre-meeting public submissions
One public submission was received. In that submission no objections to aligning the scheduling controls for this substance with the EU were raised. The submission notes that 2,4-diamino-5-methylphenetole is listed in Annex II of the EU Cosmetics Regulations and cannot be used in cosmetics in the EU.
The public submission is available at: Public submissions on scheduling matters.
ACCS advice to the delegate
In response to the Delegate's questions, the Committee advised the toxicity profile of the substance warrants control over use in cosmetics and consumer products. The committee agreed a Schedule 6 entry for phenylenediamines was appropriate and with no exemption cut off concentration specified. The committee advised that inclusion in Schedule 6 effectively prohibits use of 2,4 diamino 5 methylphenetole in cosmetics.
The committee advised that 2,4-diamino-5-methylphenetole does not require separate scheduling, as the substance is considered to already be captured by the existing entries for phenylenediamines. However the Committee advised that the substance should be included in the index with cross reference to the general entry to provide clarity for industry on its scheduling. This editorial change will be included in the next update of the SUSMP.
The Committee recommended an early implementation date for the index amendment.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: a) low risk with oral toxicity as it is for topical use; b) Chemical has reported use overseas in cosmetic preparations. No reports of use in Australia; c) substance demonstrates skin sensitisation and acute oral toxicity consistent with Schedule 6 criteria; d) appropriate to use labelling similar to that used by other Schedule 6 oxidative hair colourant chemicals; f) the committee considered the substance was already captured by the existing entry for phenylenediamine and does not warrant separate scheduling.
The delegate considered the following in regards to this proposal:
- Scheduling proposal;
- Public submissions received;
- ACCS advice;
- Section 52E of the Therapeutic Goods Act 1989;
- Scheduling factors6;
- Other relevant information.
Delegate's interim decision
2,4-Diamino-5-methylphenetole is one of four oxidant hair dyes that were referred to the March 2016 meeting of the ACCS for advice to the delegate on scheduling. The key issues were whether their toxicological profiles sufficiently match the SPF criteria for inclusion in Schedule 6 and whether product exemptions based on 'reverse scheduling' could be applied, consistent with labelling provisions applied to other oxidative hair dyes. Given that some products containing oxidative hair dyes require mixing with an oxidant, such as hydrogen peroxide, before application to the hair, consideration was given to appropriate exemption cut-off concentrations that take account of the final concentration applied to the hair.
The delegate notes, and accepts, ACCS advice that the toxicity profile of 2,4-diamino-5-methylphenetole is consistent with other phenylenediamine-based hair dye ingredients and that it could be considered to be covered by the generic Schedule 6 listing for PHENYLENEDIAMINES. Accordingly, the only scheduling action proposed is to cross-reference 2,4-diamino-5-methylphenetole in the index with the generic entry.
An implementation date is not relevant, since the substance is already covered by the generic PHENYLENEDIAMINES entry. The addition of the index cross-reference should be done at the earliest possible time.
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 a substance; (b) the purposes for which a substance is to be used and the extent of use of a substance; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.
Index – new entry
cross reference: PHENYLENEDIAMINES