Source: https://www.tga.gov.au/book-page/33-m-aminophenol
Timestamp: 2020-07-05 20:31:17
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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March 2017: 3.3 m-Aminophenol | Therapeutic Goods Administration (TGA)
3.3. m-Aminophenol
An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new Schedule 6 entry for m-aminophenol with an appropriate exemption cut-off for hair dye use.
m-Aminophenol is not currently scheduled.
In August 2016, NICNAS, under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) Scheme submitted a proposal to create a new entry for m-aminophenol in Schedule 6 for restriction in cosmetic and domestic products. Prior to this date, m-aminophenol was unscheduled and had not previously been considered for scheduling.
In January 2017, the delegate made a delegate-only final decision to enter m-aminophenol in Schedule 6 and Appendices E and F of the Poisons Standard as follows:
m-AMINOPHENOL except when in hair dye preparations containing 1.2 per cent or less of m-aminophenol when the immediate container and primary pack are labelled with the following statements:
Appendix E, Part 2 - m-AMINOPHENOL
Appendix F, Part 3 - m-AMINOPHENOL
Following the release of the final decision on 16 January 2017, feedback from industry indicated that the wording of the Schedule 6 entry may require further amendment.
On 31 January 2017, the Schedule 6 entry for m-aminophenol was removed by amendment from the 1 February 2017 Poisons Standard. This final decision was implemented as Amendment No. 1 of SUSMP 16. m-Aminophenol was subsequently referred to the March 2017 ACCS meeting to enable a consultation process on the proposed scheduling.
An isomer of m-aminophenol, p-aminophenol is in Schedule 6 and Appendices E and F of the Poisons Standard as follows:
p-AMINOPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 1 per cent or less of p-aminophenol after mixing for use when the immediate container and primary pack are labelled with the following statements:
Appendix E, Part 2 - p-AMINOPHENOL
Appendix F, Part 3 - p-AMINOPHENOL
Homologues of m-aminophenol, 4-amino-m-cresol and 4-amino-2-hydroxytoluene, are listed with reference to use in hair dyes with 1.5 per cent or less cut-offs in the SUSMP as follows:
Current schedule of related substance 4-amino-m-cresol
4-AMINO-m-CRESOL in hair dyes and eyebrow/eyelash colouring preparations except:
in hair dye preparations containing 1.5 per cent or less of 4-amino-m-cresol after mixing for use when the immediate container and primary pack are labelled with the following statements:
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-m-cresol after mixing for use when the immediate container and primary pack are labelled with the following statement:
Appendix E, Part 2 - 4-AMINO-m-CRESOL
Appendix F, Part 3 - 4-AMINO-m-CRESOL
Current schedule of related substance 4-amino-2-hydroxytoluene
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:
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:
Appendix E, Part 2 - 4-AMINO-2-HYDROXYTOLUENE
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 - 4-AMINO-2-HYDROXYTOLUENE
cross reference: 4-AMINO-2-HYDROXYTOLUENE
m-AMINOPHENOL except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 1.2 per cent or less after mixing for use when the immediate container and primary pack are labelled with the following statements:
Standard statements: E1 - If in eyes wash out immediately with water.
Appendix F, Part 3- New Entry
Warning statement: Repeated exposure may cause sensitisation (28)
Currently, there are no restrictions on introducing or using m-aminophenol in Australia. In the absence of any regulatory controls, the characterised critical health effects (particularly skin sensitisation) have the potential to pose an unreasonable risk if m-aminophenol is used in cosmetic products without an appropriate concentration cut-off (exemption) for hair dye use. Whilst domestic use of m-aminophenol will result in lower levels of exposure, there is sufficient uncertainty regarding the safety of such products to warrant some restriction;
m-Aminophenol was reported to be used in permanent hair dye preparations in Australia, and overseas hair products and other personal care products;
m-Aminophenol is a contact allergen in humans;
m-Aminophenol is a strong skin sensitiser in animals, based on a local lymph node assay (LLNA)-derived EC3 (estimated concentration to produce a three-fold increase in lymphocyte proliferation) value of 0.24-3.2%;
The existing overseas restrictions (Association of Southeast Asian Nations (ASEAN), New Zealand, European Union (EU)) on the use of m-aminophenol in cosmetic products, where the use of m-aminophenol in hair dyes is restricted to a maximum concentration of 1.2% applied to hair after mixing under oxidative conditions (a 1:1 mixture of 2.4% 3-aminophenol with hydrogen peroxide); and
When m-aminophenol 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.
m-Aminophenol is listed on the Australian Inventory of Chemical Substances (AICS).[79] Currently there are no restrictions on the use of m-aminophenol in cosmetics or domestic products in Australia. m-Aminophenol is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2017 and a search of the Australian Register of Therapeutic Goods (ARTG) found it is not an ingredient in any listed products.
Use of m-aminophenol in cosmetics in the 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). The use of m-aminophenol in hair dyes is restricted to a maximum concentration of 1.2% applied to hair after mixing under oxidative conditions (1:1 ratio with hydrogen peroxide). If m-aminophenol is present at lower concentrations, sensitisation labelling is required.
Use of m-aminophenol in cosmetics and domestic products is also restricted in several other countries as follows:
ASEAN Cosmetic Directive Annex III Part 1: List of substances which cosmetic products must not contain except subject to restrictions and conditions; and
New Zealand Cosmetic Products Group Standard - Schedule 5, Table 1: Components cosmetic products must not contain except subject to restrictions and conditions.
Under the above regulations, the use of m-aminophenol in hair dyes is restricted to a maximum concentration of 1.2% applied to hair after mixing under oxidative conditions.
m-Aminophenol is used in hair colourants and is an important starting material for dyes, including a variety of latent dyes used in imaging technology, optical bleaches and fluorescent agents, drugs, agricultural chemicals and high performance polymers.[80]
Figure 3.3: Chemical structure of m-aminophenol
Table 3.3A: Chemical information
CAS names Phenol, 3-amino
CAS numbers 591-27-5
m-aminophenol (INCI)
The following toxicology information was extracted from the NICNAS IMAP Human Health Tier II assessment report for 3-aminophenol. Further information can also be found in the SCCP report for m-aminophenol.[82]
Table 3.3B: Acute toxicity end-points for m-aminophenol
Acute oral toxicity LD50 (mg/kg bw) Rat 812-1000 Schedule 6
Acute inhalational toxicity LC50 (mg/m3/4h) Rat 1162 Schedule 6
Skin irritation Rabbit No irritation (2% m-aminophenol in a suspension of 0.5% methylcellulose in purified water) N/A
Eye irritation Rabbit Mild irritation (2% m-aminophenol in a suspension of 0.5% methylcellulose in purified water) N/A
Skin sensitisation Mouse (LLNA) Moderate to strong skin sensitiser (EC3 0.24-3.2%) Schedule 6
Guinea pig (GPMT) Sensitiser. Positive reactions in 100% of animals tested at 5%, following 1% intradermal induction and 10% topical induction.
m-Aminophenol has moderate acute oral and inhalation toxicity, warranting hazard classification. No data were available for acute dermal toxicity.
The available data from animal and human studies indicate that m-aminophenol is not irritating to the skin or eyes.
Based on the available animal and human data, m-aminophenol is considered to be a moderate to strong skin sensitiser and is recommended for classification.
In an in vivo mouse LLNA conducted in accordance with OECD Test Guideline (TG) 429, 28 female CBA/J mice (four animals/group) were administered m-aminophenol at concentrations of 0, 1, 2.5, 5, 10 or 25% (w/v) in dimethylformamide. Stimulation indices (SI) of 0, 7.6, 12.6, 10.4, 7.2 and 6.0 were reported, respectively. In a second experiment, concentrations of 0, 0.05, 0.1, 0.5, 1.0 and 2.5% of m-aminophenol in the same vehicle were administered to the animals. SIs of 1.0, 1.4, 5.9, 9.0 and 11.0 were reported, respectively. The calculated EC3 value (0.24%) indicated strong sensitisation potential for m-aminophenol.
In another mouse LLNA study, CBA/Ca mice were administered m-aminophenol at concentrations of 0, 2.5, 5 or 10% (w/v) in acetone/olive oil (ratio of 4:1). SIs of 0, 2.8, 3.5 and 5.7 were reported, respectively. The EC3 value was reported to be 3.2%.
In a non-guideline GPMT, guinea pigs were administered m-aminophenol at a concentration of 1.0% (v/v) in acetone/olive oil (ratio of 4:1) by intradermal injection, followed by topical induction with a 10% solution of m-aminophenol one week later. After two weeks, a topical challenge dose of 5% resulted in positive reactions observed in all animals tested.
Based on the available information, m-aminophenol is not considered to cause serious damage to health through repeated oral exposure at low doses. Systemic toxicity has not been demonstrated via the dermal route. No information was available for repeated dose toxicity by inhalation.
Based on the weight of evidence from the available in vitro and in vivo genotoxicity studies, m-aminophenol is not considered to be genotoxic.
Based on the available data and the lack of genotoxicity, m-aminophenol is not expected to be carcinogenic.
Based on the available information, m-aminophenol is not expected to be a reproductive or developmental toxin.
Sensitisation in humans exposed to m-aminophenol has been observed both in repeat insult patch tests and during diagnostic patch testing.
In two semi-occlusive repeat insult patch tests, 0.1 mL doses of m-aminophenol (3% solution in Schultz vehicle II or similar) were applied to the backs of 98 and 99 test subjects over a six week period. There were 10 consecutive induction patch applications at 48-72 hours, followed by one day of no application. Challenge patch applications on previously unexposed skin on backs of humans were conducted 48 hours following the rest period. In both studies, irritant effects (erythema) were observed in several subjects during the induction phase. In the first study (98 subjects), no reactions to the challenge patches were observed. In the second study (99 subjects), two subjects showed reactions following application of the challenge patches, as well as following application of additional rechallenge patches on different parts of the body.
In an Australian case study, 164 hairdressers and hairdressing apprentices who presented with allergic contact dermatitis at a dermatology clinic were patch-tested against 36 chemicals used in hair salons. Four subjects, previously exposed to m-aminophenol in the workplace, had positive reactions when patch tested with m-aminophenol.
One (1) pre-meeting public submission was received with no objections to the proposed scheduling for m-aminophenol. The main points of the submission were:
The scheduling of m-Aminophenol should align with regulations in other international jurisdictions, such as the EU.
m-Aminophenol is used in approximately 85-95% of hair dye products in Australia.
An adequate transition period of at least 12 months is requested to allow for any labelling changes and/or reformulation that may be required where no immediate risk has been identified; and that there is no evidence to suggest immediate action is required for the risk management of this substance.
The committee advised that a new Schedule 6 entry for m-aminophenol be created as follows:
The committee recommends Appendix E/F entries be created as follows:
The committee also recommended an implementation date of 1 June 2018 to allow for the necessary labelling changes to be implemented by industry.
m-Aminophenol is a strong to moderate skin sensitiser.
The primary consumer use of m-aminophenol is in hair dye and eyelash dye products, and therefore dermal contact is unavoidable. However, risk can be managed by limiting concentration and applying warning statements.
The acute oral toxicity and skin sensitisation of m-aminophenol are consistent with the factors for Schedule 6.
The delegate's interim decision is to create a new Schedule 6 entry for m-aminophenol. The proposed Schedule entry is as follows:
A long implementation date is proposed in order to allow for the necessary labelling changes to be implemented by industry.
Chemical: Phenol, 3-amino-
Dressler, H. (1994) ‘m-Aminophenol', Resorcinol: Its Uses and Derivatives, Springer US, p 125-134.
Publicly available on the NICNAS website at: Human Health Tier II Assessment for Phenol,3-amino-
Publicly available at Opinion on M-aminophenol (pdf,222kb)
URL:https://www.tga.gov.au/node/755901