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Scheduling delegate's final decisions: ACCS, November 2015
Scheduling medicines and poisons
2.10 4-amino-2-hydroxytoluene (Phenol, 5-amino-2-methyl)
Part A - Final decisions on matters referred to an expert advisory committee
2. Scheduling proposals referred to the August 2015 ACCS meeting
2.10 4-amino-2-hydroxytoluene (Phenol, 5-amino-2-methyl)
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
- In February 2015 the delegate received a request to consider creating a new entry for 4-amino-2-hydroxytoluene in Schedule 6 to include use in hair dyes and eyelash colouring products.
In February 2015, the National Industrial Chemicals Notification and Assessment Scheme (NICNAS), under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) programme, referred the following proposal to be considered by the delegate for inclusion in the Poisons Standard:
- A proposal to create a new entry for 4-amino-2-hydroxytoluene in Schedule 6 to include use in hair dyes and eyelash colouring products.
The reasons for the request were:
- the chemical has reported cosmetic use in permanent hair dye preparations in Australia;
- the chemical is a strong to moderate skin sensitiser;
- only limited data are available on eye and skin irritation;
- there is a lack of data on acute or repeated dose inhalation toxicity and repeated dose dermal toxicity;
- the overseas restrictions for use of this chemical in hair dyes state that the maximum concentration allowed in an oxidative hair dye substance is 1.5 % (after mixing with hydrogen peroxide); and
- that as many hair dye formulations come under Schedule 6 due to p-phenylenediamine content, inclusion in Schedule 6 with a cut-off is not likely to give an effective upper concentration limit for the chemical.
As a strong sensitiser, 4-amino-2-hydroxytoluene could be hazardous even below the maximum concentration of 1.5 % permitted under the EU Cosmetic Regulation. The appropriate parent Schedule is 5 or 6. Given the potential for induction and elicitation of sensitisation below the cut-off, the risk would be better controlled by inclusion of warning statements on the label of preparations containing the chemical below the cut-off. This is consistent with Schedule 6 entries for some other hair dye ingredients.
Delegate's reasons for referring this to the committee
The toxicological issues in this scheduling proposal are similar to those considered by the ACCS in November 2013 for 2-amino-5-ethyl-phenol and in July 2014 for o-aminophenol. The delegate's reasons for referring the current proposal for 4-amino-2-hydroxytoluene are similar, in that it is an ingredient in hair dyes and cosmetic products for dyeing eyebrows and eyelashes and it has the following toxicological issues: acute toxicity, mutagenicity and sensitisation potential. The NICNAS recommendation was for scheduling controls to restrict use in hair dye and other cosmetic preparations. Its use in cosmetics is restricted in various overseas regulations. ACCS advice is needed to determine the optimal scheduling actions to achieve the requested controls.
The delegate asked the committee the following questions:
- Does the ACCS agree that the toxicological profile of 4-amino-2-hydroxytoluene (acute toxicity, mutagenicity and sensitisation potential) warrants stringent controls over use in cosmetics and consumer products?
- What weight should be given to the evidence of moderate to severe skin sensitisation potential? Does the data suggest a suitable cut-off for the sensitisation potential?
- In the light of insufficient information on carcinogenicity, what weight should be given to the range of positive (in vitro) and negative (in vivo) studies on genotoxicity?
- Does the ACCS consider that including 4-amino-2-hydroxytoluene in Schedules 6 ,7 or 10 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 1.5%, 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?
- What name should be used for any schedule entry - 5-amino-2-methyl-phenol, 5-amino-o-cresol or 2-hydroxy-p-toluidine?
- Is there a need for specific entries in Appendices E & F to manage labelling of scheduled products?
Refer to the NICNAS IMAP report which is publicly available on the NICNAS website: NICNAS IMAP assessment ID 928.
The acute toxicity end-points for this chemical are listed in the table below.
|Acute oral toxicity LD50 (mg/kg bw)||Rat||3600||Schedule 5|
|Acute dermal toxicity LD50 (mg/kg bw)||Rabbit||>5000||N/A|
|Acute inhalational toxicity LC50 (mg/m3/4h)||N/A||No data||N/A|
|Skin irritation||Rabbit||Not irritant at concentrations up to 10 % (limited data)||N/A|
|Eye irritation||Rabbit||Not irritant at concentrations up to 2.5 %||N/A|
The chemical is considered to be a strong to moderate skin sensitiser, based on the following results from the NICNAS IMAP report.
Two LLNAs were conducted (OECD TG 429) in female CBA mice (n = five/concentration), using two different vehicles (first assay with water/acetone 1:1 mixed with olive oil at 4:1 and the second assay with dimethyl sulfoxide (DMSO)). All test concentrations of 0.5, 1.5, 3 and 5 % produced a stimulation index (SI) over three (3.2, 5.9, 5.3 and 9.4, respectively) in the first assay; only the 5 % concentration produced a SI over three (SI = 3.9) in the second assay. The positive control, para-phenylenediamine at a 1 % concentration, exhibited an SI of 31.2 in the first assay and 12.7 in the second. The effective concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3), which was calculated to be 0.44 % in the first assay and 3.4 % in the second, indicated a strong and moderate sensitising potential, respectively.
In another LLNA study (not validated by the NTP), BALB/c mice exposed to the chemical at concentrations of 0.625, 1.25, 2.5, 5 and 10 % (in acetone and olive oil) exhibited a significant increase of lymphocyte proliferation at 5 % and 10 % concentrations, but only the highest dose induced a three-fold increase. The chemical was reported to be weakly sensitising.
In an open epicutaneous test with albino guinea pigs, the chemical at a 3 % concentration (in a vehicle containing 2 % Natrosol 250HR, 2 % Tween 80, 0.05 % sodium sulfite, 82.95 % deionised water and 10 % isopropanol) induced positive reactions in 4/19 animals.
In a Magnusson Kligman study in female Hartley guinea pigs, the chemical was used at 1 % and 25 % in propylene glycol for intradermal and epidermal induction applications, respectively. Challenge with epidermal application of the chemical at a 25 % concentration produced a positive reaction in 4/10 guinea pigs.
Repeat dose toxicity
Based on the data available from the NICNAS IMAP report, the chemical 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 negative results observed in several in vivo genotoxicity studies, the chemical is not expected to be genotoxic.
Based on the available genotoxicity data for the chemical and its N-acetylated metabolites, and information available from Quantitative Structure Activity Relationship (QSAR) modelling, 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. However, some reproductive and developmental effects were reported at very high doses in rats (at 1000 mg/kg bw/d), probably due to severe maternal toxicity effects.
The chemical is reported to be used in permanent hair dye preparations in Australia. The chemical may also be in products to colour eyelashes.
Many countries, including New Zealand and the European Union, have restricted the use of this chemical in cosmetics. Following a safety evaluation, the SCCP (2006) concluded that the use of the chemical 'as an oxidative hair dye substance at a maximum concentration of 1.5 % 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'.
If the chemical is included in cosmetic products containing N-nitrosating agents, carcinogenic N-nitrosamine compounds could be formed (SCCS, 2012b).
Currently, there are no restrictions in Australia on using this chemical in cosmetics/hair dyes or eyelash colouring products. In the absence of any regulatory controls, the characterised critical health effects (skin sensitisation) have the potential to pose an unreasonable risk to public under the uses identified.
The chemical is listed on the following registers:
- Association of South East Asian Nations (ASEAN) Cosmetic Directive Annex III Part 2—List of substances provisionally allowed;
- EU Cosmetics Regulation 1223/2009 Annex III - List of substances which cosmetic products must not contain except subject to the restrictions laid down: '(a) Hair dye substance in oxidative hair dye products; (b) Products intended for colouring eyelashes; For (a) and (b): After mixing under oxidative conditions the maximum concentration applied to hair or eyelashes must not exceed 1.5%; (b) For professional use only; and
- New Zealand Cosmetic Products Group Standard - Schedule 5: Components cosmetic products must not contain except subject to the restrictions and conditions laid down.
4-amino-2-hydroxytoluene is not specifically scheduled.
4-amino-2-hydroxytoluene has not been previously considered for scheduling; therefore, scheduling history is not available.
Pre-meeting public submissions
One public submission was received. The submission states that there are no objections to aligning the Australian scheduling with those in the EU. It also suggested 4-amino-2-hydroxytoluene should be cross-referenced to 5-amino-o-cresol and 4-amino-2-hydroxytoluene.
The public submissions are available at Public submissions on scheduling matters.
Summary of ACCS advice to the delegate
The committee recommended a new Schedule 6 entry be created for 4-amino-2-hydroxytoluene with cut-offs for hair dye preparations containing 1.5% or less of the substance after mixing for use when the containers are labelled with the appropriate warning labels.
The committee also recommended Appendix E and F entries be created as follows:
Appendix E: Statements A and E1; and
Appendix F: Statement 28, part 1
The committee also recommended changing the name from its original reference of Phenol, 5-amino-2-methyl is 4-AMINO-2-HYDROXYTOLUENE.
The committee recommended an implementation date of 1 February 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (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 recommendations comprised the following:
- Hair dye, eyelash and eyebrow tinting products.
- Fits the criteria in Schedule 6: skin sensitiser.
Delegate's interim decision
The Committee recommended a new Schedule 6 entry be created for 4-amino-m-cresol with appropriate exempt cut-offs as follows:
Schedule 6 - New Entry
4-AMINO-2-HYDROXYTOLUENE in hair dyes and eyebrow/eyelash colouring products except:
- in hair dye preparations containing 1.5 per cent or less of 4-amino-2-hydroxytoluene 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. This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye.
Written in letters not less than 1.5mm in height; or
- in eyelash and eyebrow tinting products containing 1.5 per cent or less of 4-amino-2-hydroxytoluene after mixing for use when the immediate container and primary pack are labelled with the following statement:
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.
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
|4-AMINO-2-HYDROXYTOLUENE||28 - (Over) (Repeated) exposure may cause sensitisation|
Index - New Entry
5-AMINO-O-CRESOL see 4-AMINO-2-HYDROXYTOLUENE
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; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance.
The proposed implementation date is 1 June 2016.
A later implementation date is proposed to allow for an orderly process of re-labelling of products already on the market.
The reasons for the interim decision comprised the following:
4-amino-2-hydroxytoluene is an ingredient of oxidative hair dyes. In common with other amine hair dye ingredients, there is a risk of skin/eye irritation and skin sensitisation. This risk has been managed for other oxidative hair dye ingredients by listing in Schedule 6, with 'reverse scheduling' provisions that exempt some preparations when labelled with appropriate warning statements. The delegate accepts ACCS advice that 4-amino-2-hydroxytoluene scheduling should be managed in the same way as previously scheduled hair dye ingredients.
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 factors12;
- Other relevant information.
Public submissions on the interim decision
One submission was received. The submission supported the delegate's interim decision.
Edited versions of these submissions are available at Public submissions on scheduling matters.
Delegate's final decision
The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.