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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, February 2016

Scheduling medicines and poisons

3 February 2016

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1.4 2,6-Dimethoxy-3, 5-pyridinediamine

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

1. Scheduling proposals referred to the November 2015 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#15)

1.4 2,6-Dimethoxy-3,5-pyridinediamine

Scheduling proposal

The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):

  • To create a new entry for 2,6-dimethoxy-3,5-pyridinediamine in Schedule 6 to include use in hair dyes with an appropriate cut-off.
Scheduling application

In August 2015, the National Industrial Chemicals Notification and Assessment Scheme (NICNAS), under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) assessment programme, referred the proposal to be considered by the delegate for inclusion in the Poisons Standard.

The reasons for the request were:

  • The chemical has reported cosmetic use in permanent hair dye preparations in Australia;
  • The chemical has high acute oral toxicity;
  • The chemical is a moderate to severe skin sensitiser;
  • Severe health effects observed in rats during repeated oral exposure; and
  • The overseas restrictions for use of this chemical in hair dyes (the maximum concentration allowed in a hair dye substance is 0.25 % after mixing with hydrogen peroxide.
  • The critical health effect for risk characterisation is skin sensitisation. Given the potential for induction and elicitation of sensitisation below the overseas concentration cut-off, the risk would be better controlled by inclusion of warning statements on the label of hair dye formulations containing the chemicals below the cut-off concentration. The chemical has similar use and hazard profile to a number of chemicals which have been listed in Schedule 6 with reverse scheduling requirements.
Specific issues/questions raised by the delegate

The delegate asked the committee the following questions:

  • Does the ACCS agree that the toxicological profile of 2,6-dimethoxy-3,5-pyridinediamine (acute toxicity, negative mutagenicity, skin-eye irritancy and moderate-severe sensitisation potential) warrants controls over use in cosmetics and consumer products?
  • What weight should be given to the evidence of moderate-severe skin sensitisation potential? Does the data suggest a suitable cut-off for the sensitisation potential?
  • Does the ACCS consider that including 2,6-dimethoxy-3,5-pyridinediamine in Schedules 6 is the best option for controlling its use in consumer products and cosmetics, including hair dyes and eyebrow/eyelash products? Should there be a cut-off to exempt at 0.5% (EU regulation) or 0.25% when in combination with hydrogen peroxide? Should there be no cut-off, based on the sensitisation potential?
  • If the ACCS recommends listing in Schedule 6, should exemptions apply when the product is labelled with appropriate warning statements, consistent with other oxidative hair dye ingredients with similar toxicological profiles?
  • Although there are no notified commercial uses other than in cosmetics, should a Schedule 6 listing be specific for use in hair dyes or cosmetic products (as for some other hair dye ingredients)?
  • What name should be used for any schedule entry - 2,6-dimethoxy-3,5-pyridinediamine or 3,5-diamino-2,6-dimethoxypyridine?
  • Is there a need for specific entries in Appendices E & F to manage labelling of scheduled products?
Substance summary

This report, containing more detailed information about the substance, is publicly available on the NICNAS website.

Chemical structure of 2,6-dimethoxy-3,5-pyridinediamine

Figure 3. Chemical structure of 2,6-dimethoxy-3,5-pyridinediamine

Acute toxicity

The acute toxicity end-points for this chemical are listed in the below table.

Toxicity Species 2,6-dimethoxy-3,5-pyridinediamine SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 187.5 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 Not irritating N/A
Eye irritation Guinea pig Not irritating at 3 % concentration (limited data) N/A
Skin sensitisation (LLNA) Mouse Skin sensitiser Schedule 6

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

Skin sensitisation

The chemical is a moderate to severe skin sensitiser.

In the local lymph node assay (LLNA), female CBA/J mice (n = 5/group) were topically treated with 0.25 µL of the chemical at 0, 0.5, 1.5, 5.0 and 10.0 % concentrations (w/v) in dimethyl sulfoxide (DMSO) or in water/acetone (1:1) mixed with olive oil (4:1), once a day for three days (Organisation for Economic Co-operation and Development test guideline. The lymphoproliferation response, determined by the incorporation of (3H)-methyl thymidine was greater than the stimulation index (SI) threshold of three for concentrations ³1.5 % in DMSO (SI = 3.6, 4.5 and 4.2 for 1.5, 5 and 10 % concentrations, respectively). The effective concentration needed to produce a three-fold increase in lymphocyte proliferation (EC3) was calculated as 1.25 % in DMSO. The SI was greater than three only at the 10 % concentration in a mixture of water/acetone (1:1) mixed with olive oil (4:1), with a calculated EC3 of 6.88 %. Both treatments indicated the chemical was a skin sensitiser.

In a Magnusson-Kligman maximisation study, female Dunkin Hartley guinea pigs (n = 20) were intradermally injected with the chemical (0.1 mL of a 1 % solution) in sterile water. Freund's complete adjuvant was also injected. On day seven after being injected, the animals were topically treated with 10 % sodium lauryl sulfate in petrolatum to induce slight inflammation and enhance potential absorption. On day eight, the animals were topically treated with the chemical (0.5 mL of a 75 % solution) under occlusive conditions for 24 hours. The animals were challenged on days 22 and 29 with 0.2 mL of a 75 % aqueous solution. A slight increase in skin fold thickness, compared with the vehicle control group, was observed during the challenge. Skin reactions were observed in 55 % and 45 % of the animals at 24 and 48 hours after challenge, respectively, indicating that the chemical is a skin sensitiser.

Repeat-dose toxicity

Based on the treatment-related effects reported in the 90-day study in rats, the chemical is considered to cause serious damage to health from repeated oral exposure. A no observed adverse effect level (NOAEL) of 5 mg/kg bw/day was established based on the effects observed at 15 mg/kg bw/day (significantly decreased blood glucose and creatine levels; significantly decreased absolute liver and kidney weights in females; enlarged cervical lymph nodes; and treatment related changes in the liver (necrosis, mononuclear cell foci), lungs (pneumonitis) and oesophagus (epithelial hyperplasia and hyperkeratosis).

Genotoxicity

Based on the negative results reported for all in vitro and in vivo genotoxicity studies, the chemical is not considered to be genotoxic.

Carcinogenicity

Based on the available genotoxicity data, mechanistic considerations and mitigating factors of the chemical structure, the chemical is not considered to be carcinogenic.

Reproduction and developmental toxicity

No reproductive toxicity data are available. The chemical is not expected to have developmental toxicity.

Public exposure

The chemical is reported to be used in permanent hair dye preparations in Australia. The chemical has reported international use in oxidative hair dye products.

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

International regulations

Many countries including Canada, New Zealand, and the European Union (EU) have restricted the use of this chemical in cosmetics.

The chemical is listed on the following:

  • Association of South East Asian Nations (ASEAN) Cosmetic Directive Annex III Part 2 - List of substances provisionally allowed;
  • European Union (EU) Cosmetics Regulation 344/2013 - Annex III - List of substances which cosmetic products must not contain except subject to the restrictions laid down (After mixing under oxidative conditions the maximum concentration applied to hair must not exceed 0,25 % (as hydrochloride));
  • 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 (no details available);
  • Health Canada List of prohibited and restricted cosmetic ingredients (The Cosmetic Ingredient "Hotlist"); and
  • In CosIng, under wording of conditions of use and warnings, the chemical is stated as 'Can cause allergic reaction'.
Scheduling status

2,6-dimethoxy-3,5-pyridinediamine is not specifically scheduled.

Scheduling history

2,6-dimethoxy-3,5-pyridinediamine has not been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

One public submission was received. No objections to aligning with the EU requirements were raised. It was noted however, that it is important to maintain "in-use" concentrations for hair dye preparations, due to the mode of use being mixing with an oxidising substance prior to use.

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

ACCS advice to the delegates

The committee recommended that a new Schedule 6 and Appendix F entries be created for 2,6-dimethoxy-3,5-pyridinediamine with appropriate exemptions or cut-offs as follows:

Schedule 6 - New Entry

2,6-DIMETHOXY-3,5-PYRIDINEDIAMINE except when used in hair dye and eyebrow/eyelash colouring products 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 F - New Entry

2,6-DIMETHOXY-3,5-PYRIDINEDIAMINE

Part 1, Warning Statement: 28

The committee recommended an implementation date of 1 June 2016.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (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.

The reasons for the recommendations comprised the following:

  • The substance is used in hair dye products
  • The substance has potential for strong sensitisation and acute toxicity and therefore meets the criteria for entry in Schedule 6
  • Use at low concentrations can be managed by reverse scheduling labelling requirements in hair dyes

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: 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.

Delegates' 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 factors4;
  • Other relevant information.
Delegates' interim decision

The delegate's interim decision is to create new Schedule 6, with appropriate exemption and cut-off, and Appendix F entries for 2,6-dimethoxy-3,5-pyridinediamine.

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.

This is one of six oxidant hair dyes that were referred to the November 2015 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 2,6-dimethoxy-3,5-pyridinediamine should be listed in Schedule 6, with an exemption cut-off at 0.25%, provided products are labelled with the warning statements about potential skin sensitisation that have been required for similar oxidative hair dyes. The delegate also notes ACCS advice that warning statements relating to use for dyeing eyebrows and eyelashes are not needed, because the substance is not a strong eye irritant.

The proposed implementation date is 1 October 2016.

A later implementation date is proposed to allow for an orderly process of re-labelling of products already on the market.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: 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.

Schedule entry
Schedule 6 - New Entry

2,6-DIMETHOXY-3,5-PYRIDINEDIAMINE except when used in hair dye and eyebrow/eyelash colouring products at a concentration of 0.25 per cent or less of 2,6-dimethoxy-3,5-pyridinediamine 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 F - New Entry

2,6-DIMETHOXY-3,5-PYRIDINEDIAMINE

Part 1, Warning Statement: 28


Footnotes

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

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