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Scheduling delegate's final decisions, January 2017

Scheduling medicines and poisons

31 January 2017

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1. m-Aminophenol

Amendment to delegate-only final decisions not referred to an expert advisory committee

m-Aminophenol

Scheduling proposal

The chemicals scheduling delegate initiated a scheduling proposal to delete the Schedule 6 entry for m-aminophenol.

Current scheduling status and relevant scheduling history

m-Aminophenol is currently in Schedule 6 of the Poisons Standard.

In August 2016, the chemicals scheduling delegate received an application to create a new Schedule 6 entry for m-aminophenol. The delegate made a delegate-only decision in January 2017 with a 1 February 2017 implementation date. Prior to this date, m-aminophenol was unscheduled and had not previously been considered for scheduling.

Australian regulatory information

New Zealand, ASEAN countries and the EU have restricted the use of m-aminophenol in cosmetics (see International regulations below); however, there are currently no restrictions in Australia on the use of the chemical in cosmetics or domestic products.

Considering the use of this chemical in permanent hair dyes in Australia and other potential domestic uses (based on overseas information), the main routes of public exposure are expected to be through the skin and inhalation from products applied as aerosols.

In the absence of regulatory controls, the characterised critical health effects (acute toxicity and skin sensitisation) have the potential to pose an unreasonable risk under the identified uses. The risk could be mitigated by implementing restrictions for the use of the chemical in hair dyes and other cosmetic products.

International regulations

Use of the chemical 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 the chemical 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 the chemical is present at lower concentrations, sensitisation labelling is required.

Use of the chemical 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 the chemical in hair dyes is restricted to a maximum concentration of 1.2% applied to hair after mixing under oxidative conditions.

Scheduling application

Delegate-initiated application.

The delegate's proposed amendments to the Poisons Standard are as follows:

Schedule 6 – Delete Entry

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:

KEEP OUT OF REACH OF CHILDREN, and

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 1.5 mm in height.

Appendix E, Part 2 – Delete Entry

m-AMINOPHENOL

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 – Delete Entry

m-AMINOPHENOL

Warning statements: 28 ((over) (repeated) exposure may cause sensitisation).

Index – Delete Entry

m-AMINOPHENOL

Schedule 6
Appendix E, Part 2
Appendix F, Part 3

The delegate's reasons for the proposal include:

  • Information has been received from industry to indicate that the wording of the Schedule 6 entry may require further amendment to account for the use of m-aminophenol in other industry sectors.
  • The delegate will review the previous January 2017 decision and seek advice from the scheduling committees (ACCS and ACMS).

Substance summary

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.

Figure 1: Chemical structure of m-aminophenol
Figure 1: Chemical structure of m-aminophenol

Table 1A: Chemical properties and identifiers of m-aminophenol
Property/identifier m-Aminophenol
Molecular formula C6H4
Molecular weight 109.13 g/mol
CAS name Phenol, 3-amino-
CAS number 591-27-5
IUPAC and/or common and/or other names 3-hydroxyaniline (IUPAC); m-aminophenol (INCI)
SUSMP name Not listed in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP). Based on previously considered isomers, p-aminophenol (March 2016 ACCS meeting cycle) and o-aminophenol (July 2014 ACCS meeting cycle), the recommended SUSMP name is m-aminophenol.
Table 1B: Acute toxicity end-points for m-aminophenol
Toxicity Species m-Aminophenol SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bodyweight (bw)) Rat 812-1000 Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) N/A No data N/A
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 (LLNA) Mouse Moderate to strong skin sensitiser (EC3 0.24-3.2%) Schedule 6
Skin sensitisation (Guinea pig maximisation test (GPMT)) Guinea pig Sensitiser. Positive reactions in 100% of animals tested at 5%, following 1% intradermal induction and 1% topical induction.
Acute toxicity

m-Aminophenol has moderate acute oral and inhalation toxicity, warranting hazard classification. No data were available for acute dermal toxicity.

Irritation

The available data from animal and human studies indicate that the chemical is not irritating to the skin or eyes.

Sensitisation

Based on the available animal and human data, the chemical 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 the chemical 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 the chemical 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 the chemical.
  • In another mouse LLNA study, CBA/Ca mice were administered the chemical 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 the chemical 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 the chemical one week later. After two weeks, a topical challenge dose of 5% resulted in positive reactions observed in all animals tested.
Repeat-dose toxicity

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.

Genotoxicity

Based on the weight of evidence from the available in vitro and in vivo genotoxicity studies, m-aminophenol is not considered to be genotoxic.

Carcinogenicity

Based on the available data and the lack of genotoxicity, m-aminophenol is not expected to be carcinogenic.

Reproduction and developmental toxicity

Based on the available information, m-aminophenol is not expected to be a reproductive or developmental toxin.

Observation in humans
Sensitisation:

Sensitisation in humans exposed to the chemical 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 the chemical

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; and
  • Other relevant information

Delegate's final decision

The delegate's final decision is to delete the Schedule 6 entry for m-aminophenol.

The implementation date is 1 February 2017.

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 reasons for the decision comprise the following:

  • Information has been received from industry to indicate that the wording of the previous Schedule 6 entry may require further amendment to account for the use of m-aminophenol in other industry sectors.
  • The delegate will review the previous January 2017 decision and seek advice from the scheduling committees (ACCS and ACMS).

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