1.3. 2-Chloro-6-(ethylamino)-4-nitrophenol
Final decisions on matters not referred to an expert advisory committee
1. Chemicals not referred to the November 2016 ACCS
1.3. 2-Chloro-6-(ethylamino)-4-nitrophenol
Referred scheduling proposal
An application was submitted to create a new entry for 2-chloro-6-(ethylamino)-4-nitrophenol in Schedule 6 to restrict its use in hair dyes and to determine whether an appropriate exemption concentration cut-off is required.
Current scheduling status and relevant scheduling history
2-Chloro-6-(ethylamino)-4-nitrophenol is not currently scheduled and has not been previously considered for scheduling; therefore, scheduling history is not available.
However, a homologue of 2-chloro-6-(ethylamino)-4-nitrophenol, 2-amino-6-chloro-4-nitrophenol is currently listed in Schedule 6 for use in hair dye and eyebrow/eyelash colouring preparations as follows:
Schedule 6
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.
b) 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.
Appendix E, Part 2 - 2-AMINO-6-CHLORO-4-NITROPHENOL
Standard statements: A, E1.
Appendix F, Part 3 - 2-AMINO-6-CHLORO-4-NITROPHENOL
Warning statement: 28.
International regulations
Use of the chemical in cosmetics in the European Union (EU) is subject to the restrictions described in EU Cosmetics Regulation 344/2013 (as an amendment to the listing under Annex III of Regulation 1223/2009). This chemical may be used at maximum concentrations of 3.0% in ready-for-use preparations of oxidising (permanent) and non-oxidising (semi-permanent) colouring agents for hair dyeing. Additionally, after mixing under oxidative conditions (i.e. with hydrogen peroxide) the maximum concentration applied to hair must not exceed 1.5% for both permanent and semi-permanent application types. The Cosmetics Regulation also mandates label warning statements relating to the sensitisation potential of the chemical.
Use of the chemical in hair dyes is also restricted in several other countries as according to inclusion in the following listings:
- the Association of Southeast Asian Nations (ASEAN) Cosmetic Directive Annex III-Part 1, with the same use restrictions as described above for the EU; and
- the New Zealand Cosmetic Products Group Standard-Schedule 5-Table 1: Components cosmetic products must not contain except subject to restrictions and conditions laid down. While a maximum concentration (of 3.0%) only appears to apply to ready for use preparations of non-oxidising (semi-permanent) colouring agents for hair dyeing, the maximum concentration applied to hair must not exceed 1.5% for both permanent and semi-permanent application types.
Scheduling application
General application.
The applicant's proposed amendments to the SUSMP are as follows:
Schedule 6 - New Entry
2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 1.5 per cent or less of 2-chloro-6-(ethylamino)-4-nitrophenol after mixing for use 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.
Written in letters not less than 1.5 mm in height.
Appendix E, Part 2 - 2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL
Standard statements: E1 (if in eyes wash out immediately with water).
Appendix F, Part 3 - 2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
The applicant's reasons for the request are:
- Reported use of 2-chloro-6-(ethylamino)-4-nitrophenol as an ingredient in both permanent and semi-permanent hair dyes in Australia;
- 2-Chloro-6-(ethylamino)-4-nitrophenol is a skin sensitiser;
- 2-Chloro-6-(ethylamino)-4-nitrophenol is acutely toxic following oral exposure;
- Overseas restrictions for use of 2-chloro-6-(ethylamino)-4-nitrophenol in hair dyes; and
- When 2-chloro-6-(ethylamino)-4-nitrophenol is used as a hair dye, 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.
Substance summary
The following toxicology information was extracted from the NICNAS IMAP Human Health Tier II assessment report for phenol, 2-chloro-6-(ethylamino)-4-nitro-.
Figure 1.3: Chemical structure of 2-chloro-6-(ethylamino)-4-nitrophenol
| Property/identifier | 2-Chloro-6-(ethylamino)-4-nitrophenol |
|---|---|
| Molecular formula | C8H9ClN2O3 |
| Molecular weight | 216.62 g/mol |
| CAS name | Phenol, 2-chloro-6-(ethylamino)-4-nitro- |
| CAS number | 131657-78-8 |
| IUPAC and/or common and/or other names | 2-Chloro-6-(ethylamino)-4-nitrophenol (INCI name) |
| Toxicity | Species | 2-Chloro-6-(ethylamino)-4-nitrophenol | SPF (2015) Classification |
|---|---|---|---|
| Acute oral toxicity LD50 (mg/kg bodyweight (bw)) | Rat | 1728 | Schedule 6 |
| Acute dermal toxicity LD50 (mg/kg bw) | Rat | >2000 | Schedule 5 |
| Acute inhalational toxicity LC50 (mg/m3/4h) | - | No data | N/A |
| Skin irritation | Rabbit | Not irritating to the skin | N/A |
| Eye irritation | Rabbit | Insufficient data. | N/A |
| Skin sensitisation (LLNA) | Mouse | Skin sensitiser | Schedule 6 |
Acute Toxicity
2-Chloro-6-(ethylamino)-4-nitrophenol has moderate acute oral toxicity, but low acute dermal toxicity based on results from animal tests. Additionally, the chemical is classified as hazardous with the risk phrase 'Harmful if swallowed' (Xn; R22) in the HSIS. The available data support this classification.
Irritation
The available data from animal studies indicate that 2-chloro-6-(ethylamino)-4-nitrophenol is not irritating to the skin, but is a potential eye irritant. However, insufficient details on the eye irritation study are available, which do not allow for hazard classification.
Sensitisation
2-Chloro-6-(ethylamino)-4-nitrophenol is classified as hazardous with the risk phrase 'May cause sensitisation by skin contact' (R43) in the HSIS. The positive results, reported in a local lymph node assay (LLNA), support this classification.
In an LLNA conducted according to OECD TG 429, the skin sensitising potential of 2 chloro 6 (ethylamino)-4-nitrophenol was tested in mice (5 animals/dose group) at concentrations ranging from 0.5–10% using a DMSO vehicle, and at 0.5–2.5% using an acetone/water/olive oil vehicle (mix ratio of 2:2:1). The estimated concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3) value of 2.79% was determined based on the concentrations used with the DMSO vehicle; a stimulation index greater than three was not observed at the lower concentrations used with the acetone/water/olive oil vehicle (up to 2.5%).
Repeat-dose toxicity
Based on the available information, 2-chloro-6-(ethylamino)-4-nitrophenol is not considered to cause serious damage to health through repeated oral exposure.
Mutagenicity/Genotoxicity
Based on the weight of evidence from the available, well-conducted, in vitro and in vivo genotoxicity studies, the chemical is not considered to be genotoxic.
Carcinogenicity
No animal toxicity data are available on the carcinogenicity of the chemical. Based on the available genotoxicity data and mechanistic information, the chemical is not considered to be carcinogenic.
Reproduction and developmental toxicity
Based on the available information, the chemical is not expected to be a developmental toxin. No reliable data examining the effect of the chemical on fertility are available.
Observation in humans
No information was available.
Public exposure
Considering that the chemical is reported to be used in hair dye products in Australia, the main route of public exposure is expected to be dermal.
Delegate's considerations
The delegate considered the following in regards to this proposal:
- Scheduling proposal
- NICNAS IMAP Tier II Report
- Section 52E of the Therapeutic Goods Act 1989;
- Scheduling Policy Framework (SPF 2015) criteria
- Other relevant information.
Delegate's final decision
The delegate's final decision is to create a new Schedule 6 entry for 2 chloro 6 (ethylamino) 4 nitrophenol with a 1.5 per cent cut-off of 2 chloro 6 (ethylamino) 4 nitrophenol after mixing for use in hair dye preparations as follows:
Schedule 6 - New Entry
2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL except when in hair dye preparations containing 1.5 per cent or less of 2-chloro-6-(ethylamino)-4-nitrophenol 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 - 2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL
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 - 2-CHLORO-6-(ETHYLAMINO)-4-NITROPHENOL
Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).
The delegate notes that the main route of exposure to 2-chloro-6-(ethylamino)-4-nitrophenol is through the skin. The acute oral toxicity and skin sensitisation are consistent with Schedule 6 criteria. Recent decisions for previously considered similar sensitising hair dyes have allowed for some products to be exempted where there are label statements warning of the potential for skin sensitisation, and recommending testing for individual susceptibility before use. This scheduling decision is in alignment with international regulations for 2-chloro-6-(ethylamino)-4-nitrophenol and is consistent with recent decisions agreed on previously considered similar sensitising hair dyes.
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 the substance; (b) the purposes for which the substance is to be used and (c) the toxicity of the substance.
The implementation date is 1 February 2017.