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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-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine, the scheduling proposal is to create a new Schedule 6 entry for 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine with an appropriate exemption and cut-off to regulate its use in hair dye and eyelash colouring products.
The reasons for the request are:
- the chemical has reported cosmetic use in permanent and semi-permanent hair dye preparations in Australia;
- overseas use indicate that 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine a maximum concentration of 2 % is to be included in hair dyes and 1 % concentration in hair tinting and colour setting lotions (EC SCC, 2000);
- the chemical is potentially a moderate to strong skin sensitiser;
- only limited data are available for eye and skin irritation, indicating low concentrations of the chemical could be slightly irritating to the eyes and non-irritating to the skin;
- there is a lack of data on acute dermal and inhalation toxicity, repeated dose inhalation toxicity, and reproductive and developmental toxicity;
- many countries, including those in the European Union, have banned the use of 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine in cosmetics. The chemical is regulated by the EU Commission Directive 2007/54/EC for 'Substances for which no updated safety files are submitted allowing an adequate risk assessment should be included in Annex II' (EC, 2007).
The critical health effect is the potential for skin sensitisation, and this risk would be better controlled by inclusion of warning statements on the label of preparations containing 2 chloro 5 nitro N hydroxyethyl p-phenylenediamine 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 the application to the Committee were: 2-chloro-5-nitro-N-hydroxyethy p-phenylenediamine 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 sought advice from the Committee on the following questions:
- Does the ACCS agree that the toxicological profile of 2-chloro-5-nitro-N-hydroxyethy p-phenylenediamine (acute toxicity, lack of skin-eye irritancy (at 3% concentration) and predicted sensitisation potential) warrants controls over use in cosmetics and consumer products?
- What weight should be given to the evidence of essentially negative skin sensitisation potential in in vivo tests, but prediction of strong sensitisation potential from structure-activity alerts? Does the data suggest a suitable cut-off for the sensitisation potential?
- Does the ACCS consider that including 2-chloro-5-nitro-N-hydroxyethy p-phenylenediamine in Schedules 6 or in Schedule 5 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% after mixing, as suggested in the NICNAS report?
- If the ACCS recommends listing in Schedules 5 or 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 5 or 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-chloro-5-nitro-N-hydroxyethy p-phenylenediamine; or ethanol, 2-0(4-amino-2-chloro-5nitropheny)amino?
- Would this substance be considered to be a phenylenediamine derivative or a nitrophenol, and therefore captured by the existing Schedule 6 entries?
- Is there a need for specific entries in Appendices E and F to manage labelling of scheduled products?
The report, containing more detailed information about the substance, is publicly available on the NICNAS website.
Figure 7. Structure of 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine
The acute toxicity end-points for 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine are listed in the table below.
|Acute oral toxicity LD50 (mg/kg bw)||Mice||2850||Schedule 5|
|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 0.25 % concentration||N/A|
|Eye irritation||Guinea pig||Slightly irritating at 0.25 % concentration||Schedule 5|
|Skin sensitisation: QSAR prediction based on LLNA||N/A||Skin sensitiser (predicted EC3= 2.7)||Schedule 6|
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine has low acute oral toxicity in female CF1 mice. There are no data on acute dermal and inhalation toxicity.
Only limited data are available in guinea pigs. 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine at a 0.25 % concentration is not irritating to the skin. The chemical at a 0.25 % concentration is slightly irritating to the eyes.
Although the animal data (two limited quality non-guideline studies) indicate that the chemical is not a skin sensitiser, predictions from QSAR modelling indicated that the chemical was a moderate to strong skin sensitiser.
A 0.5 % solution of 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine (in 50 % ethanol) was administered as intracutaneous injections (0.1 mL) to the shaved skin of 15 female guinea pigs, twice/day, 6 days/week for three weeks. A control group of five female guinea pigs was used. After four weeks, the animals were challenged with an intracutaneous injection (0.1 mL) containing a 0.5 % solution of the chemical (in 50 % ethanol) at dilutions of 1:10, 1:100, 1:500 and 1:1000 in Ringer's solution. Severe erythema was observed 24 hours after challenge in both treated and control animals, which reduced to slight-well-defined erythema after 48 hours. 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine was reported to have 'shined through the skin' during the challenge phase, making it difficult to evaluate. However, this effect was not mentioned during the induction phase. The chemical was reported as non-sensitising (EC SCC, 2000).
In another study, guinea pigs (10/sex/dose) were induced with two intradermal injections (0.05 mL each); one containing Freund's complete adjuvant (FCA) (1:1 with distilled water) and the other containing a 3 % solution of 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine in water. The animals were then treated with a dermal application of 10 % sodium lauryl sulfate in white vaseline (unoccluded) on the following day. This was followed by (6-8 hours later) an occluded application (0.5 mL) of the chemical at 3 % in white vaseline. Forty-eight hours after the first induction, two intradermal injections (0.05 mL each) were given with 3 % of the chemical in FCA (diluted with 1:1 arachis oil). The animals were challenged 14 days later using a patch test (occluded for 24 hours) using 0.5 mL of 1, 2 or 3 % of the chemical in FCA (1:1 in arachis oil). No primary irritation or sensitisation was observed in the animals, either immediately after the challenge or 24 hours later, when compared with the control group (EC SCC, 2000). However, the EC SCC (2000) reported that the test protocol deviated from the OECD Test Guidelines for the Magnusson-Kligman test.
The sensitisation potency of 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine was predicted in a study on 229 hair dye substances using a QSAR model based on the local lymph node assay (LLNA). The study predicted the chemical to be a moderate to strong skin sensitiser, with an estimated concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3) value of 2.7 (Sosted, 2004).
Skin sensitisation prediction using the OECD QSAR Toolbox v3.2 model was negative for the parent chemical—there were no protein binding alerts. However, of the nine possible chemical metabolites, three were predicted to be skin sensitisers. Potential protein binding reactions of the metabolites were Michael additions or Schiff Base formation.
Skin sensitisation prediction using OASIS-TIMES v2.27.14 (Optimized Approach based on Structural Indices Set-Tissue Metabolism Simulator) modelling was also negative for the parent chemical, although the model prediction was out of applicability domain, which indicates greater uncertainty about its reliability. The possible metabolites of the chemical, based on the metabolism simulators of OASIS-TIMES, were predicted to be strong skin sensitisers.
Based on a 90-day study in rats, 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine is not expected to cause serious damage to health from repeated oral exposure. Only limited data were available on repeated dose dermal toxicity and no data were available on repeated dose inhalation toxicity.
Based on the available data from in vitro and in vivo genotoxicity studies, the chemical is not expected to be genotoxic.
Only limited animal data were available. Based on the available genotoxicity data, mitigating factors relating to the mechanisms of aromatic amine carcinogenicity and due to its chemical structure, this chemical is not considered to be carcinogenic.
Reproduction and developmental toxicity
Only limited data were available and are not sufficient to derive a conclusion on reproductive or developmental toxicity of the chemical.
The chemical is reported to be used in permanent and semi-permanent hair dye preparations in Australia (NICNAS, 2007). Many countries, including those in the European Union, have banned the use of this chemical in cosmetics.
Currently, there are no restrictions in Australia on using this chemical in cosmetics. 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 under the identified uses.
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;
- New Zealand Cosmetic Products Group Standard - Schedule 4: Components cosmetic products must not contain;
- The Association of Southeast Asian Nations (ASEAN) Cosmetic Directive Annex II Part 1: List of substances which must not form part of the composition of cosmetic products.
- EU Commission Directive 2007/54/EC: Amending Council Directive 76/768/EEC, concerning cosmetic products, for the purpose of adapting Annexes II and III thereto to technical progress.
Current scheduling status
2-Chloro-5-nitro-N-hydroxyethyl p-phenylenediamine is not specifically scheduled.
Relevant scheduling history
2-Chloro-5-nitro-N-hydroxyethyl p-phenylenediamine has not been previously considered for scheduling; therefore, scheduling history is not available.
Pre-meeting public submissions
One public submission was received. The submission had no objections to aligning the scheduling controls for this substance with the EU. It noted that 2-chloro-5-nitro-N-hydroxyethyl-p-*phenylenediamine 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 that the substance warrants control over use in cosmetics and hair dye products consistent with other similar hair dyes (specifically phenylenediamine entry in Schedule 6) on the basis of potential for skin sensitisation.
The committee advised that 2-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine does not require a separate schedule entry, as the substance was considered to be captured by the existing general entry for phenylenediamines in Schedule 6. However, the committee recommended inclusion of the substance in the index with cross reference to the general entry. This editorial change to the index will be made during the next update of the SUSMP.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: a) risk of skin sensitisation resulting from use as hair colourant; b) used in permanent and semi-permanent hair dyes in Australia and in concentrations of up to 2% and 1% overseas for oxidative and semi-permanent hair dyes, respectively. Many countries including EU have banned use in cosmetics; c) toxicity of the substance including predicted moderate to strong skin sensitisation potential from QSAR modelling; d) Labelling as per similar Schedule 6 chemicals used in oxidative hair colourant process; f) The committee noted the data was not sufficient to warrant consideration in a lower schedule.
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 factors7;
- Other relevant information.
Delegate's interim decision
2-Chloro-5-nitro-N-hydroxyethyl p-phenylenediamine 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 chloro 5 nitro N hydroxyethyl p-phenylenediamine 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-chloro-5-nitro-N-hydroxyethyl p-phenylenediamine 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