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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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1.11 1-(1,1-Dimethylethyl)-2-methoxy-4-methyl-3,5-dinitrobenzene (musk ambrette)

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)

1.11 1-(1,1-Dimethylethyl)-2-methoxy-4-methyl-3,5-dinitrobenzene (musk ambrette)

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 1-(1,1-dimethylethyl)-2-methoxy-4-methyl-3,5-dinitrobenzene- (musk ambrette) in Schedule 10 to prohibit the use in cosmetic and domestic products.
Scheduling application

In August 2015, the National Industrial Chemicals Notification and Assessment Scheme (NICNAS), under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) programme, referred the proposal to be considered by the delegate. The reasons for the request are:

  • the chemical has reported cosmetic and domestic uses internationally. Use in Australia is unknown;
  • the chemical is neurotoxic and a reproductive toxicant at low doses;
  • the chemical is prohibited in cosmetics overseas; and
  • the chemical is prohibited under the international fragrance association (IFRA) Standard.

Musk ambrette is a strong neurological and testicular toxicant at low exposures and also has a potential for photosensitisation. The chemical is toxic via dermal contact and hence, there is a concern for the use in cosmetic and domestic products. The environmental assessment also concluded that the chemical is expected to be persistent in the environment.

The European (EU) and Association of Southeast Asian Nations (ASEAN) countries as well as New Zealand have prohibited the use of musk ambrette in cosmetic products. While musk ambrette is generally considered to be phased out the chemical was reported to be used in Denmark in 2012.

Based on the scheduling factors the appropriate parent Schedule is 7 or 10. However, considering that the use of the chemical as a fragrance is prohibited overseas, and other uses are not likely to occur in Australia, Schedule 10 is probably appropriate in this case.

Specific issues/questions raised by the delegate

The delegate asked the committee the following questions:

  • The ACCS has previously considered a number of fragrance chemicals for scheduling, where sensitisation potential has often been the adverse health effect on which scheduling has been recommended. The ACCS has generally recommended that scheduling is not an appropriate process to regulate those chemicals likely to be present at such low concentrations that there should be no public health hazard.
  • The NICNAS IMAP notes the photosensitisation potential for musk ambrette (not direct skin sensitisation), but it also draws attention to the potential for neurotoxicity and reproductive toxicity. Neurotoxicity was dose-related from 40-240 mg/kg/d in a dermal rat study. The reproductive toxicity (testicular atrophy) was demonstrated in studies in rats at low oral doses (2.5 mg/kg/d) but only at somewhat higher dermal doses (240 mg/kg/d). Is the evidence for potential photoallergenicity, neurotoxicity and reproductive toxicity sufficient to warrant a new entry for musk ambrette in Schedule 10?
  • Should such a Schedule 10 entry be specific to prevent use in cosmetics only, or should this restrictive schedule relate to its use as a fragrance ingredient in domestic cleaning products?
Substance summary

Please refer to the NICNAS IMAP Human Health Tier II assessment report for benzene, 1-(1,1-dimethylethyl)-2-methoxy-4-methyl-3,5-dinitro-. This report is publicly available on the NICNAS website.

Chemical structure of musk ambrette

Figure 8. Chemical structure of musk ambrette

Acute toxicity

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

Toxicity Species Musk ambrette SPF* Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 339 Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) Rabbit >2000 N/A
Acute inhalational toxicity LC50 (mg/m3/4h) N/A No data N/A
Skin irritation Rabbit Not expected to be an irritant N/A
Eye irritation Rabbit Not expected to be an irritant N/A
Skin sensitisation N/A No data N/A

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

Photoallergy studies

In a photosensitivity study in guinea pigs with limited data, musk ambrette was positive for photosensitivity after application to abraded skin, or under occlusive conditions.

In a local lymph node assay, musk ambrette did not induce a positive photo-allergic response. No further details were provided.

Human data also indicate photosensitisation potential of musk ambrette.

Repeat-dose toxicity

Based on the data available from the NICNAS IMAP report, the chemical is neurotoxic via oral and dermal exposure.

Oral

In a repeated dose oral toxicity study in rats (strain not provided), 0.5-4 mg/kg bw/day of musk ambrette was fed to rats in the diet. Treatment-related clinical signs included growth retardation and progressive paralysis of hind limbs at 1.5 mg/kg bw/day. Observations at 16-40 weeks showed complete hind limb paralysis in the animals at the high dose. Depressed erythrocyte counts and haemoglobin values in female rats were observed at doses of ≥1.5 mg/kg bw/day of the chemical. Jaundice at all dose levels was observed. Neuropathological changes reported were primary demyelination and distal axonal degeneration.

In a 12-week repeated dose oral toxicity study, young Sprague Dawley (SD) male and female rats were orally administered musk ambrette at 1500 ppm (approximately 75 mg/kg bw/day) of the chemical. Clinical and haematological examinations were conducted after six and 12 weeks. Hind limb weakness was observed in 20/40 treated animals.

Dermal

In a 12-week repeated dose dermal toxicity study, young SD rats of both sexes were treated by dermal application of a patch with musk ambrette solution in phenyl ethyl alcohol (PEA) at concentrations of 10, 40, 80, or 240 mg/kg bw/day. Clinical and haematological examinations were conducted after six and 12 weeks. No adverse skin reactions to the patch were seen in any of the treatment groups. Hind limb weakness was observed in 1/30 animals treated at 40 mg/kg bw/day, 15/30 animals treated at 80 mg/kg bw/day and all animals treated at 240 mg/kg bw/day. All animals treated with 240 mg/kg bw/day showed severe neuropathological changes in the central and peripheral nervous system. The severity of the changes was dose-related.

Genotoxicity

The limited data available from several equivocal genotoxicity studies are insufficient for the chemical to be considered genotoxic.

Carcinogenicity

No data are available on the chemical. The data for the structurally related chemical, musk xylene suggest that the mode of action for induction of liver tumours in mice is similar to that for phenobarbital. The relevance of this mode of action to humans has been questioned.

Reproduction and developmental toxicity

The chemical is considered to be a severe reproductive toxicant at low doses.

In a repeated dose oral toxicity study in rats (strain not provided), 0.5-4 mg/kg bw/day of musk ambrette was fed to rats in the diet. Histopathological investigation showed treatment-related testicular atrophy at 2.5 mg/kg bw/day.

In a 12-week repeated dose dermal toxicity study, young SD rats of both sexes were treated by dermal application of a patch with musk ambrette solution in phenyl ethyl alcohol (PEA) at concentrations of 10, 40, 80, or 240 mg/kg bw/day. Clinical and haematological examinations were conducted after six and 12 weeks. Necropsy revealed depressed testicular weight and testicular tubular degeneration in animals receiving 240 mg/kg bw/day.

Public exposure

While no Australian use information is available, the chemical is reported to be used as a fragrance ingredient in cosmetic and domestic products at up to 2 % concentration in consumer end products.

Many countries, including the European Union, New Zealand and Canada, have prohibited the use of this chemical in cosmetic products.

Currently, there are no restrictions in Australia on using this chemical in cosmetic and or domestic products. In the absence of any regulatory controls, the characterised critical health effects (neurotoxicity and reproductive toxicity) have the potential to pose an unreasonable risk to the public in relation to the uses identified.

International regulations

The chemical is listed on the following:

  • EU Cosmetics Regulation 1223/2009 Annex II - List of substances prohibited in cosmetic products;
  • Association of Southeast Asian Nations (ASEAN): Cosmetic Directive Annex III, part 1: List of substances which must not form part of the composition of cosmetic products;
  • New Zealand Cosmetic Products Group Standard - Schedule 4: Components cosmetic products must not contain; and
  • Health Canada List of prohibited and restricted cosmetic ingredients (The Cosmetic Ingredient 'Hotlist').

This chemical is prohibited under the IFRA Standard (47th Amendment).

Scheduling status

Musk ambrette is not specifically scheduled.

Scheduling history

Musk ambrette has not been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

One public submission was received. The submission raised no objections to the proposal to include the substance in Schedule 10.

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

ACCS advice to the delegate

The committee recommended that a new Schedule 10/Appendix C entry be created for benzene, 1-(1,1-dimethylethyl)-2-methoxy-4-methyl-3,5-dinitro- (musk ambrette) as follows:

Schedule 10 - New Entry

BENZENE, 1-(1,1-DIMETHYLETHYL)-2-METHOXY-4-METHYL-3,5-DINITRO-

Cross reference entry: Amber Musk, Musk Ambrette

The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included c) the toxicity of the substance; and f) any other matters that the Secretary considers necessary to protect public health.

The committee recommended an implementation date of 1 June 2016.

The reasons for the recommendations comprised the following:

  • The substance is neurotoxic and a reproductive toxicant at low doses; and
  • there is potential for public exposure to the substance due to its accumulation in the environment.
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 factors11;
  • Other relevant information.
Delegate's interim decision

The delegate notes, and accepts, ACCS advice that musk ambrette be listed in Schedule 10, to control its use as a fragrance ingredient in cosmetics and other products. Fragrance ingredients previously considered by the delegate and the ACCS may have either been listed in Schedules 5 or 6 because of their skin sensitising potential. In some cases, scheduling was not considered to be necessary based on the very low concentrations expected to be used in products. Musk ambrette warrants the more stringent controls available via listing in Schedule 10 because of demonstrated neurotoxicity and testicular toxicity in rat studies at relatively low doses applied dermally. The delegate agrees that the Schedule 10 listing be made under the chemical name 1-(1,1-dimethylethyl)-2-methoxy-4-methyl-3,5-dinitrobenzene, with the common name musk ambrette included in parenthesis and a cross reference to amber musk added to the index of the Poisons Standard.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989 to be (c) the toxicity of a substance.

The proposed implementation date is 1 June 2016.

Because of the potential health risks associated with any continued use of this fragrance ingredient in products in Australia, and the fact that its use is prohibited in some overseas jurisdictions, the earliest possible implementation date is warranted.

Schedule entry
Schedule 10 - New Entry

1-(1,1-DIMETHYLETHYL)-2-METHOXY-4-METHYL-3,5-DINITROBENZENE- (musk ambrette)

Cross reference entry in Index: Amber Musk


Footnotes

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

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