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Scheduling delegate's final decisions: ACCS, November 2015
Scheduling medicines and poisons
2.11 2-amino-6-chloro-4-nitrophenol (Phenol, 2-amino-6-chloro-4-nitro)
Part A - Final decisions on matters referred to an expert advisory committee
2. Scheduling proposals referred to the August 2015 ACCS meeting
2.11 2-amino-6-chloro-4-nitrophenol (Phenol, 2-amino-6-chloro-4-nitro)
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
- In April 2015 the delegate received a request to consider creating a new entry for 2-amino-6-chloro-4-nitrophenol and its hydrochloride in Schedule 6 to include use in hair dyes with an appropriate cut-off.
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 on the Poisons Standard:
- A proposal to create a new entry for 2-amino-6-chloro-4-nitrophenol and its hydrochloride in Schedule 6 to include use in hair dyes with an appropriate cut-off.
The reasons for the request were:
- the chemicals have reported cosmetic use in permanent hair dye preparations in Australia
- the chemicals are strong to moderate skin sensitisers;
- only limited data are available on eye and skin irritation;
- there is a lack of data on acute or repeated dose inhalation toxicity; and
- the overseas restrictions for use of these chemicals in hair dyes state that the maximum concentration allowed in an oxidative hair dye substance is 2 % (after mixing with hydrogen peroxide) (SCCP, 2006). This concentration may be based on the lowest EC3 value calculated (0.68 %) for skin sensitisation of the parent base.
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 hair dye formulations containing the chemicals 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 2-amino-6-chloro-4 nitro-phenol 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 2-amino-5-chloro-4-nitro-phenol (primarily sensitisation potential) warrants appropriate controls over use in cosmetics and consumer products? Does the data suggest that 2% is a suitable cut-off for the sensitisation potential?
- Does the ACCS have concerns about the limited information available about mutagenic and/or carcinogenic potential? More stringent scheduling controls imposed on other aminophenolic oxidative dyes have generally been based on stronger evidence of mutagenicity. The NICNAS IMAP report points out that electron-withdrawing groups (Cl and nitro) on aminophenols tends to weaken their genotoxic potential.
- If the ACCS recommends listing in Schedule 6, should exemptions only apply when the product is labelled with appropriate warning statements, consistent with other oxidative hair dye ingredients with similar toxicological profiles?
- Which of the names in the NICNAS IMAP report should be used for any schedule entry? Would this substance be covered (as a derivative) by the current generic Schedule 6 entry for - NITROPHENOLS, ortho, meta and para except when separately specified in these schedules?
- Is there a need for specific entries in Appendices E & F to manage labelling of scheduled products? Note that there is a current Appendix F requirement for statements 1,4, and 8 for nitrophenols covered by the generic S6 entry.
Please refer to the NICNAS IMAP report available on the NICNAS website: NICNAS IMAP assessment ID 1078.
The acute toxicity end-points for the chemicals are listed in the table below.
|Toxicity||Species||2-amino-6-chloro-4-nitrophenol and/or its hydrochloride||SPF Classification|
|Acute oral toxicity LD50 (mg/kg bw)||Rat||>2000||N/A|
|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||Not irritant at concentrations up to 0.5 % (limited data)||N/A|
|Eye irritation||Rabbit||Not irritant at concentrations up to 2 %||N/A|
Based on the data available for the parent base from the NICNAS IMAP report, both chemicals are considered to be skin sensitisers.
Data are available for the parent base. In a local lymph node assay (LLNA) (OECD TG 429), groups of female CBA mice were topically treated with 25 μL of the chemical at 0, 0.5, 5 and 10 % concentrations (using two vehicles: DMSO and acetone/water/olive oil), once a day for three consecutive days. The effective concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3) was calculated as 6.85 % with dimethyl sulfoxide (DMSO) and 0.68 % with acetone/water/olive oil. The EC3 of 0.68 % may be an overestimate as there was no clear dose response below the 10 % concentration. The chemical is considered to be a skin sensitiser.
Another LLNA study (OECD TG 429) calculated the EC3 as 2.2 %.
Repeat dose toxicity
Based on the data available for the parent base, both chemicals are not considered 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, the chemicals are not considered to be genotoxic.
No animal toxicity data are available on the carcinogenicity of the parent base and the salt. Based on the available genotoxicity data and information available from Quantitative Structure Activity Relationship (QSAR) modelling, the chemicals are not considered to be carcinogenic.
Reproduction and developmental toxicity
No reproductive toxicity data are available. Based on the data available for the parent base, both chemicals are not considered to have developmental toxicity.
2-amino-6-chloro-4-nitrophenol and its hydrochloride are reported to be used in semi-permanent hair dye preparations and the parent base is also reported to be used in permanent hair dye preparations in Australia.
New Zealand and the European Union have restricted the use of these chemicals in hair dye preparations to a maximum of 2 % concentration when applied directly to the hair.
If these chemicals are included in cosmetic products containing N-nitrosating agents, carcinogenic N-nitrosamine compounds could be formed.
Currently, there are no restrictions in Australia on using these chemicals in hair dyes. The skin sensitisation risk could be mitigated by implementing concentration limits for use in hair dyes.
2-amino-6-chloro-4-nitrophenol and its hydrochloride are both listed on the following:
- EU Cosmetics Regulation 1223/2009 Annex III, part 1 - List of substances which cosmetic products must not contain except subject to the restrictions and conditions laid down. The restrictions include the following: for use as a hair dye substance in either oxidative or non-oxidative hair dye products; a maximum concentration of 2 % in ready-for-use preparations; and after mixing under oxidative conditions, the maximum concentration applied to hair must not exceed 2 %.
The parent base is listed on the following (Galleria Chemica):
- New Zealand Cosmetic Products Group Standard (2006) - Schedule 5: Components cosmetic products must not contain except subject to the restrictions and conditions laid down. These restrictions and conditions are similar to the ones indicated above.
2-amino-6-chloro-4-nitrophenol and its hydrochloride are not specifically scheduled.
2-amino-6-chloro-4-nitrophenol or its hydrochloride have not been previously considered for scheduling; therefore, scheduling history is not available.
Pre-meeting public submissions
One public submission was received. The submission stated that for nitrophenols there is currently a S6 entry with no exemptions for preparations containing small quantities of the substances. The submission also stated that there were no objections to aligning Australian scheduling with those of the EU where there are exemptions for use in hair dyes in small quantities.
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 2-amino-6-chloro-4-nitrophenol with cut-offs for hair dye preparations applied directly contains 2% or less of the substance and when the immediate container is labelled with the appropriate warning labels.
The committee also recommended Appendix E/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, 2-amino-6-chloro-4-nitro is 2-AMINO-6-CHLORO-4-NITROPHENOL.
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 as a skin sensitiser.
Delegate's interim decision
Schedule 6 - New Entry
2-AMINO-6-CHLORO-4-NITROPHENOL in hair dye and eyebrow/eyelash colouring preparations, except:
- in preparations containing 2 per cent or less of 2-amino-6-chloro-4-nitrophenol when applied directly to the hair, or containing 2 per cent or less of 2-amino-6-chloro-4-nitrophenol after mixing and 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.
- in eyelash and eyebrow tinting products containing 1.5 per cent or less of 2-amino-6-chloro-4-nitrophenol 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
|2-AMINO-6-CHLORO-4-NITROPHENOL||28 - (Over) (Repeated) exposure may cause sensitisation.|
The delegate considered the relevant matters under subsection 52E (1) of the Therapeutic Goods Act 1989: b) the purposes for which a substance is to be used and the extent of use of a substance; c) the toxicity of the 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:
2-amino-6-chloro-4-nitrophenol 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 2-amino-6-chloro-4-nitrophenol 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 factors13;
- 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.