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Scheduling delegate's final decisions, June 2016

Scheduling of medicines and poisons

23 June 2016

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1.5 2-Methylresorcinol

Part A - Final decisions on matters referred to an expert advisory committee

1. Scheduling proposals referred to the March 2016 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#16)

1.5 2-Methylresorcinol

Referred Delegate's scheduling proposal
  • In response to issues raised in a NICNAS IMAP Human Health Tier 2 assessment report on 2-methylresorcinol, the scheduling proposal is to create a new Schedule 6 entry for 2-methylresorcinol, with appropriate exemption and cut-off to regulate its use in hair dye and eyelash colouring products.
Applicant's application and scheduling proposal

In December 2015, the NICNAS, under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) programme, referred the following proposal to be considered by the delegate:

  • To create a new entry for 1,3-benzenediol, 2-methyl- in Schedule 6 of the SUSMP with an appropriate cut-off to use in hair dyes.

The reasons for the request are:

  • the chemical is a severe eye irritant and weak skin sensitiser;
  • the chemical has moderate acute oral toxicity; and
  • International restrictions for use of this chemical in hair dyes (the maximum concentration allowed on hair is 1.8 %) (SCCS, 2008).
Substance summary

Please refer to the NICNAS IMAP assessment report for 1,3-benzenediol, 2-methyl-. This report is publicly available on the NICNAS website.

Figure 5. Structure of 1,3-benzenediol, 2-methyl- (2-methylresorcinol)
Figure 5. Structure of 1,3-benzenediol, 2-methyl- (2-methylresorcinol)

Acute toxicity

The acute toxicity end-points for 2-methylresorcinol are listed in the table below.

Toxicity Species Results SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Mice 390 Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) N/A No data -
Acute inhalational toxicity LC50 (mg/m3/4h) N/A No data -
Skin irritation Rabbit Mild irritant Schedule 5
Eye irritation Rabbit Severe irritant Schedule 6
Skin sensitisation (local lymph node assay (LLNA)) Mice Weak sensitiser (EC3 = 50 %) Schedule 5/6

*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)

Skin irritation

2-Methylresorcinol is considered to be slightly irritating to skin. In an OECD Guideline 404 compliant study, 0.5 g of the test material was moistened and applied to the intact, shaved back skin of rabbits (three males/group) for four hours under semi-occlusive patches. Very slight erythema developed in one animal after one hour.

Eye irritation

2-Methylresorcinol is a severe eye irritant. In a OECD guideline 405 study, 0.1 mL of undiluted test chemical (equivalent to 50.6 mg) was instilled into one eye of one rabbit and left for 24 hours. The test chemical caused corneal opacity (maximum grade 3) and epithelial damage (maximum 100 % of the corneal surface). These effects were not fully reversible within the observation period. Iridial irritation (grade 1) was observed for the first seven days of observation. Conjunctival irritation (consisting of erythema and chemosis) was observed. The nictitating membrane and eyelids exhibited white discolouration, consistent with necrosis.

Sensitisation

2-Methylresorcinol is a weak skin sensitiser, according to a LLNA assay conducted CBA mice (5/group) had 25 μL of the test material (at 1, 10, 25 or 50 %) applied to the dorsal surface of each ear, once daily for three consecutive days. Five days after the first topical application, all mice were administered radiolabelled thymidine (3HTdR), draining lymph nodes were excised and thymidine incorporation into the lymph node cells was assessed. Stimulation Indices (SI) of 0.7, 0.6, 1.1 and 3 were calculated for the 1, 10, 25 and 50 % groups, respectively. An EC 3 of 50 % was determined accordingly.

Repeat-dose toxicity

Based on the data available, 2-methylresorcinol is not expected to cause serious damage to health from repeated oral exposure. No information was available for repeated dose toxicity by dermal and inhalation routes.

Genotoxicity

Based on the weight of evidence from the available well-conducted in vitro and in vivo genotoxicity studies, 2-methylresorcinol is not considered to be genotoxic.

Carcinogenicity

No data were available.

Reproduction and developmental toxicity

Based on the available data, 2-methylresorcinol is not expected to have reproductive or developmental toxicity.

Public exposure

2-Methylresorcinol is reported to be used in permanent hair dye preparations in Australia.

Currently, there are no restrictions in Australia on using this chemical in cosmetics/hair dyes or eyelash colouring products. In the absence of any regulatory controls, the characterised critical health effects (skin sensitisation) have the potential to pose an unreasonable risk to public under the uses identified.

International regulations

The following international regulations apply:

  • EU Cosmetic Directive 76/768/EEC Annex III Part 1: List of substances which cosmetic products must not contain except subject to the restrictions and conditions laid down-maximum concentration in ready to use formulation; 1.8 %;
  • ASEAN Cosmetic Directive Annex III-Part 1 List of substances which cosmetic products must not contain except subject to restrictions and conditions laid down;

New Zealand Cosmetic Products Group Standard-Schedule 5-Table 1: Components cosmetic products must not contain except subject to the restrictions and conditions laid down.

Current scheduling status

2-Methylresorcinol is not specifically scheduled.

Scheduling history

2-Methylresorcinol 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. The submission noted that 2-methylresorcinol is included in Annex III of the EU Cosmetics Regulations, restricting its use to hair dyes with in-use concentration not exceeding 1.8%. They proposed a specific Schedule entry in line with recent decisions on hair dye products. They also sought a later implementation date to allow relabelling of existing products.

The public submission is available at Public submissions on scheduling matters.

Summary of ACCS advice to the delegate

In response to the Delegate's questions, the Committee advised that the toxicological profile of the substance warrants controls over use in hair dye products, including warning statements indicating products should not be used for dying eyebrows/eye lashes. The committee advised the toxicity profile of the substance was consistent with inclusion in Schedule 6.

In regards to the sensitization potential of the substance, the committee advised that, with a suitable cut off concentration consistent with that in the EU, the risk of sensitization from use of the hair dye products was low. As such, the Committee recommended a cut off concentration of 1.8%.

Members agreed 2-methylresorcinol was an appropriate name and consistent with the INCI name.

The committee recommended that a new Schedule 6 entry be created for 2-methylresorcinol with appropriate exemptions and cut off as follows:

Schedule 6 - New Entry

2-METHYLRESORCINOL except:

  1. in non-oxidative hair dye preparations containing 1.8 per cent or less of 2 methylresorcinol when the immediate container and primary pack are labelled with the following statements:
    • KEEP OUT OF REACH OF CHILDREN, and
    • WARNING - This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye.
    • Written in letters not less than 1.5 mm in height; or
  2. in oxidative hair dye preparations containing 1.8 per cent or less of 2-methylresorcinol after mixing under oxidative conditions when the immediate container and primary pack are labelled with the following statements:
    • KEEP OUT OF REACH OF CHILDREN, and
    • WARNING - This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye.
    • Written in letters not less than 1.5 mm in height.

Appendix E, Part 2 - New Entry

2-METHYLRESORCINOL

Standard statements: A, E1

Appendix F, Part 3 - New Entry

2-METHYLRESORCINOL

Safety direction: 1

The committee recommended a late implementation date (1 February 2017) to allow relabelling of existing products on the market.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: a) Potential for severe eye damage when used as a hair dye, particularly eyebrow and eyelash tinting products; c) It is a severe eye irritant and has an acute LD50 of 390mg/kg bw which warrants a Schedule 6 entry. Exposure would occur to the public and professional users of hair colourants; d) Restricted to 1.8% for hair dye only.

Delegate's considerations

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 factors5;
  • Other relevant information.
Delegate's interim decision

Oxidative hair dyes of the aromatic diamine and aminophenolic classes have some common toxicological properties that warrant controls over scheduling. These features are primarily skin-eye irritancy and sensitization potential. These toxicological properties generally align with SPF criteria for listing in Schedule 6. Several of these dyes (e.g. phenylenediamines, toluenediamines; aminophenols) have already been listed in Schedule 6, but previous scheduling policies have allowed for some products to be exempted where there are label statements warning of the potential for skin irritancy and sensitization, and recommending testing for individual susceptibility before use. This approach is commonly called 'reverse scheduling'. Where there is potential mutagenicity, or the need to prevent uses for skin colouration (tattooing) or use to dye eyebrows or eyelashes, some of these substances have been listed in Schedule 10 to prevent such uses.

2-methylresorcinol 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 2-methylresorcinol should be listed in Schedule 6, with an exemption cut-off at 1.8% in products either without, or after, mixing with an oxidant , provided products are labelled with the warning statements about skin sensitisation potential that have been required for similar oxidative hair dyes. The delegate also notes ACCS advice that the potential for eye irritation is sufficient to require additional warning statements relating to use for dyeing eyebrows and eyelashes.

The delegate also notes ACCS advice that 2-methylresorcinol is the INCI name and is the preferred name for listing in Schedule 6.

The proposed implementation date is 1 June 2017 to allow for an orderly process of re-labelling of products already on the market.

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.

Schedule 6 - New Entry

2-METHYLRESORCINOL except:

  1. in non-oxidative hair dye preparations containing 1.8 per cent or less of 2 methylresorcinol when the immediate container and primary pack are labelled with the following statements:
    • KEEP OUT OF REACH OF CHILDREN, and
    • WARNING - This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye.
    • Written in letters not less than 1.5 mm in height; or
  2. in oxidative hair dye preparations containing 1.8 per cent or less of 2-methylresorcinol after mixing under oxidative conditions when the immediate container and primary pack are labelled with the following statements:
    • KEEP OUT OF REACH OF CHILDREN, and
    • WARNING - This product must not be used for dyeing eyelashes or eyebrows; to do so may be injurious to the eye.
    • Written in letters not less than 1.5 mm in height.

Appendix E, Part 2 - New Entry

2-METHYLRESORCINOL.

Standard statements: A, E1.

Appendix F, Part 3 - New Entry

2-METHYLRESORCINOL.

Safety direction: 1.

Public submissions on the interim decision

One submission was received. The submission supported the proposal but suggested adding the words "excluding salts and derivatives" to the proposed schedule entry to ensure no other substances are inadvertently captured. The submission further noted that some derivatives of resorcinol are restricted or banned in the EU for certain uses, but controls on each differ. Consequently, the submission recommended the proposed schedule entry be amended to exclude salts and derivatives, and other derivatives should be considered separately for scheduling to ensure appropriate scheduling controls are applied in each separate case.

Delegate's final decision

The delegate notes the submission that essentially supports the interim decision, although requesting the addition of words "excluding salts and derivatives" to the proposed entries. No evidence was presented to show that any salts or derivatives would be inadvertently captured by the proposed entries, or that the toxicological profiles of any such salts or derivatives would be sufficiently different from the listed chemical. The delegate notes that it has not been deemed necessary to add the words "excluding salts and derivatives" to other oxidative hair dye ingredient entries in Schedules 5 or 6.

The delegate further notes that some of the resorcinol 'derivatives' specified in the submission (e.g. 4-chlororesorcinol, 4-(phenylazo)resorcinol, hexylresorcinol, 4-isobutylresorcinol and phenylethyl resorcinol) would not be considered as 'derivatives' as defined in Part 1 of the Poisons Standard, but that consideration may need to be given to scheduling of these substances individually. Accordingly the delegate will draw the attention of NICNAS to the potential uses of these substances in Australian products.

The delegate has confirmed the interim decision relating to 2-methylresorcinol. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

The implementation date is 1 June 2017.


Footnote

  1. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)

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