You are here

Scheduling delegates' interim decisions and invitation for further comment: ACCS/ACMS, November 2017

Scheduling medicines and poisons

5 February 2018

Book pagination

3.6. Phenyl methyl pyrazolone

Referred scheduling proposal

An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) to create a new entry for phenyl methyl pyrazolone in Schedule 6 or 5 with an exemption cut-off of 0.25% in the Standard for the Uniform Scheduling of Medicines and Poisons (SUSMP) – the Poisons Standard.

Scheduling application

This was a general application. The applicant’s proposed amendments to the Poisons Standard are:

  • Schedule 5 OR 6 – New Entry
  • PHENYL METHYL PYRAZOLONE except when used in hair dye and eyebrow/eyelash preparations at a concentration of 0.25 per cent or less after mixing for use 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 – New Entry
  • PHENYL METHYL PYRAZOLONE
  • 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)), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).
  • Appendix F, Part 3 – New Entry
  • PHENYL METHYL PYRAZOLONE
  • Warning Statement: 28 ((over) (repeated) exposure may cause sensitisation).
  • Safety Directions: 4 (Avoid contact with skin), 8 (Avoid breathing dust (or) vapour (or) spray mist).

The applicant's reasons for the request are:

  • Phenyl methyl pyrazolone is used in cosmetic products in Australia (in permanent and semi-permanent hair dyes).
  • Phenyl methyl pyrazolone is used in cosmetic products overseas at concentrations up to 0.25%.
  • Phenyl methyl pyrazolone is a skin sensitiser in animal studies. There is no epidemiological data showing cases of sensitisation in humans.
  • Restrictions on the cosmetic use of phenyl methyl pyrazolone overseas (EU, NZ and ASEAN) are considered appropriate to mitigate the risk.
Current scheduling status

Phenyl methyl pyrazolone is not currently scheduled in the current Poisons Standard. Phenyl methyl pyrazolone has not been previous considered for scheduling. Therefore, a scheduling history is not available for phenyl methyl pyrazolone.

Phenyl methyl pyrazolone shares some structural similarity with aminophenazone (amidopyrine), which is in Schedule 10 for human therapeutic use and Schedule 4 for the treatment of animals as follows:

Schedule 10

AMINOPHENAZONE (amidopyrine) and its derivatives for human therapeutic use.

Schedule 4

AMINOPHENAZONE (amidopyrine) and derivatives for the treatment of animals.

Australian regulatory information

Phenyl methyl pyrazolone does not appear to be in any products listed on the ARTG.

Phenyl methyl pyrazolone is not listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 4 of 2017.

International regulations

In New Zealand and the Association of Southeast Asian Nations, phenyl methyl pyrazolone may be used in oxidative hair dyes at a maximum concentration applied to hair of 0.25%, after mixing under oxidative conditions.

In the European Union (EU) (Annex III / Cosmetics Regulation (EC) No. 1223/2009 no. 228), the current restriction for phenyl methyl pyrazolone is as follows:

  • Product type, body parts: 'Oxidising colouring agents for hair dyeing'
  • Maximum concentration in ready for use preparations: '0.5%'
  • Other: 'In combination with hydrogen peroxide the maximum use concentration upon application is 0.25% Not to be used after 31.12.2009'
Substance summary
Table 3.6.1: Chemical information for phenyl methyl pyrazolone
Property Alpha-cypermethrin
CAS number 89-25-8
Chemical structure chemical structure of
Molecular formula C10H10N2O
Molecular weight 174.2 g/mol
IUPAC and/or common and/or other names Phenyl methyl pyrazolone (INCI);3H-pyrazol-3-one, 2,4-dihydro-5-methyl-2-phenyl- (CAS); 5-methyl-2-phenyl-4H-pyrazol-3-one (IUPAC); 3H-pyrazol-3-one, 2,4-dihydro-5-methyl-2-phenyl- (AICS); 3-methyl-1-phenyl-5-pyrazolone (EINECS); Evaravone; Radicut; norphenazone; norantipyrine; MCI 186

The following information was extracted from the NICNAS IMAP Human Health Tier II assessment report for 3H-Pyrazol-3-one, 2,4-dihydro-5-methyl-2-phenyl-.

Table 3.6.2: Acute toxicity end-points for phenyl methyl pyrazolonecaption
Toxicity Species Phenyl methyl pyrazolone SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat (Sprague Dawley) >2000 mg/kg bw Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) No data available N/A N/A
Acute inhalational toxicity LC50 (mg/m3/4h) No data available N/A N/A
Skin irritation Rabbit (New Zealand White) Slight irritating Schedule 5
Eye irritation Rabbit (New Zealand White) Not irritating N/A
Skin sensitisation (Buehler)

Mouse (CBA)

Mouse (CBA)

Strong (EC3=1%)

Moderate (EC3 >2.5%)
Schedule 6
Acute toxicity

Phenyl methyl pyrazolone has low acute oral toxicity:

  • Phenyl methyl pyrazolone is not acutely toxic. The median lethal dose (LD50) was consistently above 2000 mg/kg. 4 different vehicles were used. The repeated daily oral administration of Phenyl methyl pyrazolone to rats for 13 weeks at 20, 100, and 500 mg/kg/day was mainly associated with changes indicative of regenerative haemolytic anaemia at 500 mg/kg/day. Clinical signs attributed to Phenyl methyl pyrazolone but related to the mode of administration were observed at 100 mg/kg/day and higher. In males, the exposure of 100 mg/kg/day resulted in lower blood levels of glucose. The NOAEL was determined to be 100 mg/kg/day. The NOEL was set at 20 mg/kg bw. Phenyl methyl pyrazolone had no teratogenic potential. Maternal toxicity was seen at 1000 mg/kg/day. The NOAEL of maternal and developmental toxicity was 200 mg/kg/day (SCCS 2006).

No data are available for other routes of exposure.

Skin irritation

Phenyl methyl pyrazolone has been reported to slightly irritate the skin but to have no effect on the eyes. The limited data available are insufficient to warrant hazard classification for skin or eye irritation.

Norantipyrine (Phenyl methyl pyrazolone), at a concentration of 1 %, showed no signs of irritation (SCCS 2006).

Sensitisation

Phenyl methyl pyrazolone is a moderate to strong skin sensitiser based on the results of two local lymph node assays (LLNA) on CBA mice, indicating an estimated concentration required to produce a three-fold increase in lymphocyte proliferation (EC3) of 1% in one test and >2.5% in the other test.

  • 'The sensitisation test was carried out inadequately. In the 28-day study with rats, effects were still found in the 1000 mg/kg bw group. The dose level without effect is 200 mg/kg bw' (SCCS 2006).
Repeat-dose toxicity

Phenyl methyl pyrazolone is not expected to be harmful to health following repeated oral exposure. A no observed adverse effect level (NOAEL) of 100 mg/kg bw/day for Sprague-Dawley rats was determined in a guideline subchronic toxicity study. No data are available for other routes of exposure.

Genotoxicity

Based on the weight of evidence from the available in vitro and in vivo studies conducted in accordance with OECD test guidelines, phenyl methyl pyrazolone is not considered to be genotoxic. Two in vitro genotoxicity tests showed positive results, but all in vivo tests were negative.

Mutagenicity

Phenyl methyl pyrazolone did not induce gene mutations in bacteria. It was also not mutagenic in an in vitro gene mutation test with mammalian cells (hprt locus). A mutagenic response was observed in the Mouse Lymphoma assay (tk locus) but only in the presence of S9. In an in vitro micronucleus assay no genotoxic effect (structural and/or numerical chromosomal aberrations) was observed. An in vivo bone marrow micronucleus assay in mice and an in vivo UDS assay in rats were negative. The results of the tests performed indicate that phenyl methyl pyrazolone itself is not mutagenic in vivo. To reach a definitive conclusion, the SCCS requested appropriate tests with m-aminophenol in combination with hydrogen peroxide have to be provided (SCCS 2006).

Carcinogenicity

Based on the available data, phenyl methyl pyrazolone is not expected to be carcinogenic.

  • In a carcinogenicity study in rats, groups of Fischer 344 (F344) rats (n = 50/sex/dose) were administered phenyl methyl pyrazolone at 0, 2500 or 5000 ppm in the diet for 102 weeks, equivalent to 0, 125 and 250 mg/kg bw/day respectively. There was no dose-relationship or statistical significance in the occurrences of individual tumours between treated and control rats of both sexes.
  • In a carcinogenicity study in mice, groups of B6C3F1 mice (n = 50/sex/dose) were administered phenyl methyl pyrazolone at 0, 7500 or 15000 ppm in the diet for 102 weeks. There was no significant association between dosage and mortality, with an 80% or more survival rate in all groups. A number of neoplastic and non-neoplastic lesions were observed in all treated groups, but there was no association or statistical significance between dosage and tumour incidence.
Reproduction and developmental toxicity

Based on the limited information available, phenyl methyl pyrazolone does not show specific reproductive or developmental toxicity. Developmental effects were only observed secondary to maternal toxicity. A NOAEL of 200 mg/kg bw/day was determined for both maternal and developmental toxicity incidence.

Public exposure

The critical health effect for risk characterisation is skin sensitisation. Phenyl methyl pyrazolone is a slight skin irritant at a concentration of 1%.

Phenyl methyl pyrazolone has cosmetic use identified in Australia in hair dye products. No use concentrations of phenyl methyl pyrazolone in these products are available, although it is known to be used overseas at a maximum concentration of 0.25% on the hair. Based on this use, the general public may be exposed to phenyl methyl pyrazolone via dermal contact.

Pre-meeting public submissions

Two (2) pre-meeting submission were received, neither of which objected to the proposed scheduling for phenyl methyl pyrazolone.

The main points were:
  • Alignment with the following EU regulations is supported:
    • Phenyl methyl pyrazolone is included in Annex III of the EU Cosmetics Regulation, allowing its use as a hair dye substance in oxidative hair dye products with an in-use concentration (after mixing under oxidative conditions) not exceeding 0.25%.
    • Any warning statements and safety directions should be consistent with those for other scheduled hair dye substances with similar risk profiles, and as much as possible with those required in the EU to allow for harmonisation.
  • The implementation date should be 12-24 months to allow for any labelling changes that may be required. These changes could affect products currently in the Australian market with an established history of safe use. There is no evidence that would suggest immediate action is required for the risk management of this substance.
  • Phenyl methyl pyrazolone is not entered in the TGA eBS ingredients list, nor is it entered in the TGA Permitted Ingredients List. It is therefore assumed that the scheduling proposal will not impact therapeutic goods. Should any inadvertent impact be revealed, comment will be provided during the public consultation phase of the interim decision.

The public submissions will be made available on the TGA website.

Summary of ACCS advice to the delegate

The committee recommended that a new Schedule 6 and Appendix E and F entries for phenyl methyl pyrazolone be created as follows:

Schedule 6 – New Entry

PHENYL METHYL PYRAZOLONE except when used in hair dye and eyebrow/eyelash preparations at a concentration of 0.25 per cent or less after mixing for use 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 – New Entry

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)), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F, Part 3 – New Entry

Warning Statement: 28 ((Over) (repeated) exposure may cause sensitisation).

Safety Direction: 4 (Avoid contact with skin).

The committee also recommended an implementation date of 1 June 2018 as this is the earliest practicable implementation date.

Members agreed that the relevant matters under Section 52E(1) of the Therapeutic Goods Act 1989 included: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the recommendation comprised the following:

  1. the risks and benefits of the use of a substance:
  • Risk: potential skin sensitiser.
  • Benefit: use in hair dyes.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • Phenyl methyl pyrazolone is used as a hair dye in oxidising hair dyes and possibly other cosmetics.
  • the toxicity of a substance:
    • Phenyl methyl pyrazolone is a moderate sensitiser.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • The known use of phenyl methyl pyrazolone is as a hair dye, in oxidising hair dyes, with in-use concentration of 0.25% or less. The product is provided in small packages and is intended to be mixed with hydrogen peroxide in 1:1 ratio before use.
    • A warning statement on the packaging for potential sensitisation is warranted.
  • the potential for abuse of a substance:
    • Nil
  • any other matters that the Secretary considers necessary to protect public health
    • Consumers have extensive experience with the use of hair dye products.
    • Harmonises with international regulations.
    Delegate's considerations

    The delegate considered the following regarding this proposal:

    • Scheduling proposal
    • ACCS advice
    • Public submissions received
    • Section 52E of the Therapeutic Goods Act 1989
    • Scheduling Policy Framework (SPF 2015)
    Delegate's interim decision

    The delegate’s interim decision is to create a new Schedule 6 and Appendix E and F entries for phenyl methyl pryazolone. The proposed Schedule entry is:

    Schedule 6 – New Entry

    PHENYL METHYL PYRAZOLONE except when used in hair dye and eyebrow/eyelash preparations at a concentration of 0.25 per cent or less after mixing for use 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 – New Entry

    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)), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

    Appendix F, Part 3 – New Entry

    Warning Statement: 28 ((Over) (repeated) exposure may cause sensitisation).

    Safety Direction: 4 (Avoid contact with skin).

    The proposed implementation date is 1 June 2019 to allow for any labelling changes that may be required.

    The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included:(a) the risks and benefits of the use of the substance; (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; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

    The reasons for the interim decision are the following:

    1. the risks and benefits of the use of a substance:
    • Risk: potential skin sensitiser.
    • Benefit: use in hair dyes.
  • the purposes for which a substance is to be used and the extent of use of a substance:
    • Phenyl methyl pyrazolone is used as a hair dye in oxidising hair dyes and possibly other cosmetics.
  • the toxicity of a substance:
    • Phenyl methyl pyrazolone is a moderate sensitiser.
  • the dosage, formulation, labelling, packaging and presentation of a substance:
    • The known use of phenyl methyl pyrazolone is as a hair dye, in oxidising hair dyes, with in-use concentration of 0.25% or less. The product is provided in small packages and is intended to be mixed with hydrogen peroxide in 1:1 ratio before use.
    • A warning statement on the packaging for potential sensitisation is warranted.
  • the potential for abuse of a substance:
    • Nil
  • any other matters that the Secretary considers necessary to protect public health
    • Consumers have extensive experience with the use of hair dye products.
    • Harmonises with international regulations.

    Book pagination