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Publication of interim decisions proposing to amend, or not amend, the current Poisons Standard, September 2018

Scheduling medicines and poisons

10 September 2018

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2.3 Aliphatic allyl esters

2. Joint Advisory Committee on Medicines and Chemicals Scheduling (Joint ACMS-ACCS #19)

Delegate's interim decision

The delegate's interim decision under regulation 42ZCZN of the Therapeutic Goods Regulations 1990 (the Regulations) is to amend the current Poisons Standard in relation to aliphatic allyl esters as follows:

Note

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Schedule 7 - Amend Entry

ALLYL ALCOHOL except

  1. in preparations containing 5 per cent or less of allyl esters with 0.1 per cent or less of free allyl alcohol by weight of allyl ester; or
  2. when separately specified in these Schedules.

Schedule 6 - New Entry

ALLYL ESTERS in preparations containing 0.1 per cent or less of free allyl alcohol by weight of allyl ester except in preparations containing 5 per cent or less of allyl esters with 0.1 per cent or less of free allyl alcohol by weight of allyl esters.

Proposed implementation date: 1 February 2019

Reasons

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

  1. the risks and benefits of the use of a substance:
    • Allyl esters are widely used without significant adverse events.
    • Benefits: Allyl esters are used as an excipient in biologicals, and medicines.
    • Risks: Potential for the toxic metabolites (allyl alcohol and acrolein) to be formed following oral exposure to allyl esters.
  2. the purposes for which a substance is to be used and the extent of use of a substance:
    • Allyl esters are generally used as flavours or fragrances in cosmetics, therapeutic goods, household products and commercial products.
    • Aliphatic allyl esters are used in therapeutic products, including listed medicines at concentrations at or below 5%.
    • 5% cut-off consistent with the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018 listing of these substances.
  3. the toxicity of a substance:
    • Based on the toxicological data (specifically acute oral and dermal toxicity), allyl esters have a lower acute toxicity profile than allyl alcohols.
    • Allyl esters have an acute oral and dermal toxicity profile consistent with Schedule 6 Scheduling Policy Framework (SPF) criteria:
      • Moderate to high oral and dermal toxicity.
      • Low to moderate acute toxicity via inhalational exposure.
      • Allyl acetate is corrosive.
      • Allyl cyclohexanepropionate is a moderate skin sensitiser in guinea pigs.
      • Potential for the toxic metabolites (allyl alcohol and acrolein) to be formed following oral exposure to allyl esters;
    • Allyl alcohol is reported to have very high acute oral, dermal and inhalation toxicity.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Align with international regulations for cosmetic products where aliphatic allyl esters are used in fragrance ingredients, provided that the free allyl alcohol is less than 0.1% in the ester

Delegate's considerations

The delegate considered the following in regards to this interim decision:

  • The application to amend the current Poisons Standard with respect to aliphatic allyl esters;
  • The advice received from the Joint Advisory Committees on Medicines and Chemicals Scheduling (Joint ACMS-ACCS #19);
  • the public submission received before the first closing date;
  • The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
  • Section 52E of the Therapeutic Goods Act 1989, in particular (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.

Scheduling proposal

The pre-meeting scheduling proposal was published on the TGA website on 12 April 2018 at Consultation: Proposed amendments to the Poisons Standard being referred to the June 2018 meetings of the ACCS, ACMS and Joint ACCS/ACMS.

Background information for aliphatic allyl esters

Delegate's referral to ACCS/ACMS

An application was submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS), under its Inventory Multi-tiered Assessment and Prioritisation (IMAP) program to amend the Poisons Standard with respect to aliphatic allyl esters. The application proposed to amend the Schedule 7 entry for allyl alcohol and create a new Schedule 6 entry for allyl esters.

Applicant's scheduling proposal and reasons

The application proposed the following amendments to the Poisons Standard:

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  1. Amend the current Schedule 7 entry for allyl alcohol to exclude allyl esters as its derivatives, and to allow low levels of allyl alcohol as an impurity in preparations containing allyl esters at 5 per cent or less as follows:

    Schedule 7 - Amend Entry

    ALLYL ALCOHOL (including its derivatives) except

    1. when included in Schedule 6; and
    2. in preparations containing 5 per cent or less of allyl esters and containing less than 0.1 per cent allyl alcohol by weight of allyl esters.
  2. Create a new Schedule 6 entry for allyl esters for use in consumer products, with a purity criterion and a concentration cut-off at 5 per cent, below which the requirements of the standard do not apply as follows:

    Schedule 6 - New Entry

    ALLYL ESTERS containing less than 0.1 per cent allyl alcohol by weight of allyl ester except in preparations containing 5 per cent or less of allyl esters and containing less than 0.1 per cent allyl alcohol by weight of allyl esters.

The applicant's reasons for the proposal were:

  • Aliphatic allyl esters have international restrictions on their use in cosmetic products - the level of free allyl alcohol in preparations is restricted to be less than 0.1 %, based on the delayed irritant potential of allyl alcohol;
  • As derivatives, allyl esters fall within the scope of the Schedule 7 entry for allyl alcohol;
  • Aliphatic allyl esters are reported to be used as fragrance ingredients in cosmetic and domestic products overseas at concentrations ≤5 %, and are therefore likely to be used in similar products in Australia at ≤5 %; and
  • Acute toxicity values for aliphatic allyl esters are consistent with inclusion in Schedule 6.

Current scheduling status

Aliphatic allyl esters are not specifically scheduled in the Poisons Standard but are captured by the Schedule 7 and Appendix J entries for allyl alcohol as derivatives, as follows:

Schedule 7

ALLYL ALCOHOL.

Appendix J, Part 2

ALLYL ALCOHOL
Conditions for availability and use: 1 (Not to be available except to authorised or licensed persons).

Scheduling history

Aliphatic allyl esters are not currently specifically scheduled and have not been previously considered for scheduling. Therefore a scheduling history is not available.

Scheduling of allyl alcohol

Allyl alcohol was placed in Schedule 7 between 1972 and 1980. In February 1989, the Drugs and Poisons Schedule Committee (DPSC) considered the toxicology of allyl alcohol as part of the review of Schedule 7 substances. The committee noted the toxicological profile of allyl alcohol as a severely toxic substance with an LD50 (oral, rat) of 64 mg/kg, LD50 (oral mice) 85 mg/kg, and LC50 (inhalation rat) of 391 mg/m3. Allyl alcohol was assessed as a severe dermal irritant in rabbits as well as a severe eye irritant sometimes leading to opacity. In sub-chronic studies in rats, rabbits, guinea pigs and dogs the liver and kidneys were seen as the target organs, but the effects seen were considered mild and reversible. Furthermore, allyl alcohol was considered to be mutagenic. In view of the severe acute toxic potential in humans, the good penetration by all routes of exposure and the lack of animal data, the committee recommended that allyl alcohol should remain in Schedule 7. Appendix J would be reviewed (no agricultural uses permitted) following information from industry if allyl alcohol has an industrial use.

In November 1989, the DPSC noted that no reply had been received from industry regarding industrial uses of allyl alcohol. Nevertheless, the committee decided that the Appendix J entry for allyl alcohol should be amended to include restrictions 3 (Should be available to authorised or licensed persons), 5 (Should be available for approved research purposes) and 7(Should be available for industrial and manufacturing purposes).

Australian regulations

Aliphatic allyl esters CAS 1797-74-6, 2835-39-4, 4728-82-9, 68132-80-9 and 7493-72-3 are not included in the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018 and do not appear to be included in any products on the Australian Register of Therapeutic Goods (ARTG).

Aliphatic allyl ester CAS 2705-87-5 (under the name 'ALLYL CYCLOHEXANEPROPIONATE') is included in the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018 as follows:

Column 1

Column 2

Ingredient Name

Column 3

Purpose of the ingredient in the medicine

Column 4

Specific requirements(s) applying to the ingredient in Column 2

441 ALLYL CYCLOHEXANEPROPIONATE E

Permitted for use only in combination with other permitted ingredients as a flavour or a fragrance.

If used in a flavour the total flavour concentration in a medicine must be no more than 5%.

If used in a fragrance the total fragrance concentration in a medicine must be no more 1%.

Allyl cyclohexanepropionate is permitted for use as an excipient in biologicals, listed medicine and prescription medicines; and as an active ingredient in biologicals and prescription medicines.

Allyl cyclohexanepropionate is in 158 products (Medicine and Other Therapeutic Good) on the ARTG.

Allyl cyclohexanepropionate is used in 10 proprietary ingredient (PI) formulations.

Aliphatic allyl ester CAS 123-68-2 (under the name 'ALLYL HEXANOATE') is included in the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018 as follows:

Column 1

Column 2

Ingredient Name

Column 3

Purpose of the ingredient in the medicine

Column 4

Specific requirements(s) applying to the ingredient in Column 2

445 ALLYL HEXANOATE E

Permitted for use only in combination with other permitted ingredients as a flavour or a fragrance.

If used in a flavour the total flavour concentration in a medicine must be no more than 5%.

If used in a fragrance the total fragrance concentration in a medicine must be no more 1%.

Allyl hexanoate is permitted for use as an excipient in biologicals, devices, listed medicine and prescription medicines; and as an active ingredient in biologicals and prescription medicines.

Allyl hexanoate is in 420 products (Medicine and Other Therapeutic Good) on the ARTG.

Allyl hexanoate is used in 10 PI formulations.

Aliphatic allyl ester CAS 142-19-8 (under the names 'ALLYL HEPTANOATE' and 'ALLYL HEPTYLATE') is included in the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018 as follows:

Column 1

Column 2

Ingredient Name

Column 3

Purpose of the ingredient in the medicine

Column 4

Specific requirements(s) applying to the ingredient in Column 2

443 ALLYL HEPTANOATE E

Permitted for use only in combination with other permitted ingredients as a flavour or a fragrance.

If used in a flavour the total flavour concentration in a medicine must be no more than 5%.

If used in a fragrance the total fragrance concentration in a medicine must be no more 1%.

444 ALLYL HEPTYLATE E

Permitted for use only in combination with other permitted ingredients as a flavour.

If used in a flavour the total flavour concentration in a medicine must be no more than 5%.

Allyl heptanoate is permitted for use as an excipient in biologicals, devices, listed and prescription medicines, and as an active ingredient in biologicals and prescription medicines. Allyl heptylate is permitted for use as an excipient in listed medicines.

Allyl heptanoate is in 100 products (Medicine and Other Therapeutic Good) on the ARTG; and allyl heptylate is not in any products on the ARTG.

Allyl heptanoate is used in 10 PI formulations; and allyl heptylate is used in 2 PI formulations.

Aliphatic allyl ester CAS 4230-97-1 (under the name 'ALLYL CAPRYLATE') is included in the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2018 as follows:

Column 1

Column 2

Ingredient Name

Column 3

Purpose of the ingredient in the medicine

Column 4

Specific requirements(s) applying to the ingredient in Column 2

440 ALLYL CAPRYLATE E

Permitted for use only in combination with other permitted ingredients as a flavour.

If used in a flavour the total flavour concentration in a medicine must be no more than 5%.

Allyl caprylate is permitted for use as an excipient in biologicals, devices, listed medicine and prescription medicines; and as an active ingredient in biologicals and prescription medicines.

Allyl caprylate is not in any products on the Australian Register of Therapeutic Goods (ARTG).

Allyl caprylate is used in 2 PI formulations.

International regulations

Aliphatic allyl esters are listed on the following:

  • European Union Cosmetics Regulation 1223/2009 Annex III - List of substances which cosmetic products must not contain except subject to the restrictions and conditions laid down (the level of free allyl alcohol in the ester shall be less than 0.1 %); and
  • New Zealand Cosmetic Products Group Standard - Schedule 5: Components cosmetic products must not contain except subject to the restrictions and conditions laid down.
  • Allyl esters are specified as 'should only be used when the level of free allyl alcohol in the ester is less than 0.1 %. This recommendation is based on the delayed irritant potential of allyl alcohol' (IFRA, 2017).

Substance summary

Table 2.3A: Chemical information of aliphatic allyl esters
Table 2.3B: Acute toxicity end-points for allyl esters
Toxicity Species Allyl Esters SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg) Rat 218-1400 mg/kg (for suitable analogues) Schedule 6
Mouse ≥500 mg/kg (for suitable analogues)
Guinea pig 280-444 mg/kg (for suitable analogues)
Acute dermal toxicity LD50 (mg/kg) Rabbit 300-1600 mg/kg (for suitable analogues) Schedule 6
Acute inhalational toxicity LC50 (mg/m3/4h) N/A No data available. N/A
Skin irritation Rabbit Suitable analogue chemicals slightly to moderately irritating to the skin when applied undiluted. Schedule 5
Human Skin irritation in humans assessed by patch testing.
Eye irritation Rabbit Slightly irritating (allyl hexanoate and allyl cyclohexanepropionate). Schedule 5

Skin sensitisation

(Guinea pig maximisation test and human case reports)

Guinea pig Not sensitising (allyl heptanoate) and moderately sensitising (allyl cyclohexanepropionate). Schedule 5
Human Suitable analogue chemicals were not skin sensitisers.
Table 2.3C: Acute toxicity end-points for allyl alcohol
Toxicity Species Allyl Esters SPF (2018) Classification
Acute oral toxicity LD50 (mg/kg) Rat 64-105 mg/kg Schedule 6
Mouse 85-96 mg/kg
Rabbit 52-72 mg/kg
Acute dermal toxicity LD50 (mg/kg) Rabbit 45 and 89 mg/kg Schedule 7
Acute inhalational toxicity LC50 (mg/m3/4h) Rat >240 mg/m3 and >530 mg/m3 Schedule 7
Skin irritation Rabbit Slightly irritating to the skin when applied undiluted. Schedule 7 (human)
Human Intensely irritating to the skin.
Eye irritation Rabbit Irritating undiluted. Schedule 7
Human Irritating at 5 ppm (11.9 mg/m3) as vapour and corneal necrosis and temporary blindness at 25 ppm (59.4 mg/m3).

Skin sensitisation

(Guinea pig maximisation test and human case reports)

Guinea pig Not sensitising. N/A
Human
Acute toxicity
Allyl esters

Allyl esters are considered to have moderate to high acute oral and dermal toxicity in animals. No data are available for acute inhalation toxicity.

  • Oral - The reported oral median lethal dose (LD50) values were:
    • allyl hexanoate, 218-393 mg/kg in rats and 280 mg/kg in guinea pigs;
    • allyl heptanoate, 500 mg/kg in rats, 630 mg/kg in mice, and 444 mg/kg in guinea pigs
    • allyl isovalerate, 230 mg/kg in rats and ≥500 mg/kg in mice;
    • allyl phenylacetate, 650 mg/kg in rats;
    • allyl cyclohexanepropionate, 585 mg/kg in rats and 380 mg/kg in guinea pigs;
    • allyl cyclohexaneacetate, 900 mg/kg in rats; and
    • allyl trimethylhexanoate, 1400 mg/kg in rats.
  • Dermal - The reported dermal LD50 values in rabbits are:
    • allyl hexanoate, 300 mg/kg;
    • allyl heptanoate, 810 mg/kg;
    • allyl isovalerate, 560 mg/kg;
    • allyl cyclohexanepropionate, 1600 mg/kg; and
    • allyl cyclohexaneacetate, 1250 mg/kg.
Allyl alcohol

Allyl alcohol is reported to have very high acute oral, dermal and inhalation toxicity in animals. The chemical is extremely toxic to humans.

  • Oral - The chemical has very high acute toxicity in rats, mice and in rabbits. Additionally, the chemical is classified as hazardous with hazard category 'Acute Toxicity Category 3' and hazard statement 'Toxic if swallowed' (H301) in the Hazardous Chemicals Information System (HCIS) (Safe Work Australia) aligned with the Globally Harmonised System of Classification and Labelling of Chemicals (GHS). The available data support this classification.
  • Dermal - The chemical has very high acute toxicity in rabbits with reported dermal LD50 values at 45 and 89 mg/kg. The chemical is classified as hazardous with the hazard category 'Acute Toxicity Category 3' and hazard statement 'Toxic in contact with skin' (H311) in the HCIS (Safe Work Australia). The available data support an amendment to this classification to 'Acute Toxicity Category 2' and hazard statement 'Fatal in contact with skin' (H310) which was recommended in the NICNAS IMAP report.
  • Inhalation - The reported median lethal concentration (LC50) values in rats for 4-hour exposures to the mist or vapour of the chemical are >240 mg/m3 and >530 mg/m3. The chemical is classified as hazardous with the hazard category 'Acute Toxicity Category 3' and hazard statement 'Toxic if inhaled' (H331) in the HCIS (Safe Work Australia). The available data support an amendment to this classification to 'Acute Toxicity Category 2' and hazard statement 'Fatal if inhaled' (H330).
  • Observation in Humans - In a case report, a 55-year old man who ingested the chemical (estimated maximum dose of 212 g) died within 100 minutes.
Irritation
Allyl esters
  • Skin - Allyl isovalerate, allyl hexanoate, allyl heptanoate, allyl phenylacetate and allyl cyclohexaneacetate have been reported as slightly to moderately irritating to rabbit skin. However, data available are not sufficient for hazard classification. The skin irritation potential of allyl cyclohexanepropionate was assessed using the Human Skin Model Test (OECD TG 439) and was not considered to be a potential skin irritant.
  • Eye - Allyl hexanoate and allyl cyclohexanepropionate are slight eye irritants. However, the incidence and severity of these effects are not sufficient to warrant hazard classification.
  • Observation in Humans - In a 48-hour patch test, allyl hexanoate was applied on the forearms of human volunteers (n = 5). Four subjects displayed grade 1 irritation. However in a subsequent study by the same author using both allyl hexanoate and heptanoate, no signs of irritation were observed in 5 volunteers. Allyl isovalerate was not irritating when applied to the backs of 28 subjects in a closed patch test. Allyl cyclohexaneacetate produced slight irritation at a concentration of 4 % in petrolatum in a 48-hour closed-patch test on human subjects.

    Allyl cyclohexanepropionate was not an irritant in a patch test on 129 human volunteers at concentrations up to 2 %. The chemical (0.3 mL) was applied (occlusively) to the back of the volunteers for 24 hours and responses were assessed up to 5 days following exposure. The chemical caused less irritation compared with the other allyl esters tested (allyl hexanoate, allyl cyclohexyloxyacetate, allyl phenoxyacetate). In another 24-hour patch test, allyl cyclohexanepropionate (20 µg) was positive in 8 out of 10 volunteers, and allyl heptanoate was positive in 9 out of 10 volunteers. The concentrations were not reported. Although these chemicals were reported to be acute irritants, the data were not considered to be relevant for classification.

    Allyl phenylacetate showed mixed results in two 48-hour closed patch tests on human subjects, when tested up to 12 % in petrolatum. No irritation reactions were reported initially, but were observed when retested. When tested at 6 %, it was a significant irritant in a majority of human subjects.

Allyl alcohol
  • Skin - Allyl alcohol is slightly irritating to the skin of rabbits when applied undiluted. The chemical is classified as hazardous with hazard category 'Skin irritation - category 2' and hazard statement 'Causes skin irritation' (H315) in the Safe Work Australia. The available data in humans (see Observation in Humans) support this classification.
  • Eye - Allyl alcohol was irritating to the eyes of male rabbits when applied undiluted for 4 hours. The mean scores at 24, 48 and 72 hours for erythema, chemosis, and corneal opacity were 2.89, 1.23 and 2.09, respectively. Additionally, the chemical is classified as hazardous with hazard category 'Eye irritation - Category 2' and hazard statement 'Causes serious eye irritation' (H319) in the HCIS (Safe Work Australia). The available data in animals (conjunctival and corneal damage) and in humans (see Observation in Humans) support this classification.
  • Observation in humans - Reported toxicity effects for allyl alcohol vapour include eye discomfort at 5 ppm, and corneal necrosis and temporary blindness at 25 ppm. Exposure to air that is moderately contaminated with the chemical (concentration not stated) causes excessive secretion of tears, pain behind the eyes, sensitivity to light and blurring of vision. Despite effects persisting for several hours, neither increased sensitivity nor tolerance developed for the above effects. The vapour and liquid of the chemical is reported to be intensely irritating to the skin and mucous membranes.

    Contact with the liquid causes delayed-onset skin irritation and burns. Additionally, skin absorption leads to deep pain which may be due to muscle spasm.

Sensitisation
Allyl esters

The chemicals overall are not expected to have skin sensitisation potential. However, allyl cyclohexanepropionate was reported as a moderate skin sensitiser in guinea pigs.

Limited human data have shown that the chemicals are not skin sensitisers in human volunteers.

Allyl alcohol

Allyl alcohol is not expected to have skin sensitisation potential based on data in a guinea pig maximisation study. No allergic responses were reported in humans.

Repeat-dose toxicity
Allyl esters

The effects observed in the repeated dose studies suggest that the liver, stomach and hematopoietic system in rats and mice are the primary sites affected following treatment with allyl esters. The mechanism of hepatotoxicity of allyl esters is linked to its rapid hydrolysis in the liver to the metabolites allyl alcohol and acrolein. Many studies on allyl alcohol and acrolein have showed liver damage, often localised to the periportal region. Short chain allyl esters which are not fragrance ingredients (e.g. allyl acetate) have reported effects at doses above 12 mg/kg/day in rats. Other longer chain allyl esters in the group have effect levels above 84 mg/kg/day. No data are available for repeated dermal and repeated inhalation exposure.

Allyl alcohol

Allyl alcohol is considered to cause serious damage to health from repeated oral exposure. The effects observed in the repeat dose oral studies indicate that the liver and forestomach in rats and mice are the primary target sites, with mice being less sensitive to toxicity than rats. Forestomach effects may be due to primary irritation. Hepatotoxicity was evident at ≥25 mg/kg/day in rats and is stated to be due to biotransformation to acrolein. A sex difference in hepatotoxicity in rats was reported to be correlated with the greater alcohol dehydrogenase activity in female rats than in male rats. In a sub-chronic toxicity study, the no observed adverse effect level (NOAEL) in rats was 3 mg/kg based on histopathological effects seen at 6 mg/kg/day. The NOAEL in mice was 6 mg/kg/day based on forestomach squamous epithelial hyperplasia seen at 12 mg/kg/day.

Genotoxicity

Allyl esters and allyl alcohol are not considered to be genotoxic.

Carcinogenicity
Allyl esters

Results from a two-year carcinogenicity study suggested that allyl isovalerate caused increased incidence of haematopoietic system neoplasms (mononuclear cell leukaemia in male rats and malignant lymphomas in female mice). However, in the absence of more comprehensive information and based on the results for allyl alcohol, allyl esters cannot be considered possible human carcinogens.

Allyl alcohol

Based on the available data for the chemical and its metabolite acrolein, the chemical does not have carcinogenic potential.

Reproduction and developmental toxicity

Based on the data available, allyl esters and allyl alcohol are not likely to be reproductive or developmental toxicants.

Public exposure

Two of these chemicals (CAS Nos. 123-68-2 and 2705-87-5) have reported domestic uses in Australia. The chemicals in this group are also reported to be used in cosmetics and domestic products, particularly perfumery, overseas. The general public could be exposed through the skin when using cosmetic and domestic products containing the chemicals.

At present, as derivatives, the chemicals fall within the scope of the listing of 'ALLYL ALCOHOL' in Schedule 7 of the SUSMP, and it is probable that perfumery imported from the EU or elsewhere is not compliant with this scheduling entry. Therefore, it is recommended that allyl esters are exempted from the Schedule 7 entry, considering the acute toxicity values are consistent with inclusion in Schedule 6. A concentration cut-off (5 %) for allyl esters is recommended. At this concentration, the product LD50 based on allyl ester content would be close to or greater than 5000 mg/kg. This proposed cut-off is also consistent with the maximum concentration reported in fragrance products (not intended for direct human contact, such as air fresheners) as stated in the NICNAS IMAP report. In addition, to maintain alignment with EU restrictions, it is also recommended that a concentration cut-off for allyl alcohol in allyl esters be included.

This requires consequential changes to scheduling of allyl alcohol to exclude the derivatives, allyl esters, meeting a purity criterion consistent with the EU.

While creation of a general exception for allyl esters could impact on the shorter chain allyl esters which have greater local effects, they do not have any reported cosmetic or domestic uses.

Pre-meeting public submissions

One (1) public submission was received before the first closing date in response to an invitation published on 12 April 2018 under regulation 42ZCZK of the Regulations. The submission supported the proposal with amendments.

The main points in provided in conditional support of the amendment were:

  • Support for the exclusion of the 9 aliphatic allyl esters listed from the Schedule 7 entry for allyl alcohol to allow the use of these globally available fragrance ingredients in domestic and consumer products in Australia. Support for aligning the regulatory treatment of these substances with that already in place in comparable overseas economies.
  • The 9 aliphatic allyl esters are currently listed in Annex III of the EU Cosmetics Regulation 'List of substances which cosmetic products must not contain except subject to the restrictions laid down' with a specific condition on the permissible level of free allyl alcohol: 'Level of free allyl alcohol in the ester should be less than 0.1%'. The proposed Poisons Standard schedule exemption for aliphatic allyl esters in the allyl alcohol entry should refer to the level of free allyl alcohol (the term 'free' is not currently included in the proposal as drafted).
  • There are no restrictions on the concentration of the esters (provided the level of free allyl alcohol is less than 0.1%) that may be used in cosmetic products marketed in the EU (and other countries which follow the EU Cosmetics Regulation such as the ASEAN countries and New Zealand which are geographically close trading partners). The proposed amendment as currently worded may result in the inadvertent regulation of substances other than those that have been listed above i.e. that have been identified to be of concern in the IMAP assessment. We would therefore urge consideration of an approach that scheduled only these 9 substances that have been identified as being of concern i.e. listing by CAS number.

The public submission will be made available on the TGA website at Public submissions on scheduling matters.

Joint ACMS-ACCS advice

The committee recommended that the current Schedule 7 entry for allyl alcohol be amended as follows:

Note

New text is shown as green, larger font, with a horizontal line above it.

Schedule 7 – Amend Entry

ALLYL ALCOHOL except

  1. in preparations containing 5 per cent or less of allyl esters with 0.1 per cent or less of free allyl alcohol by weight of allyl ester; or
  2. when separately specified in these Schedules.

The committee also recommended that a new Schedule 6 entry for allyl esters be created as follows:

Schedule 6 – New Entry

ALLYL ESTERS in preparations containing 0.1 per cent or less of free allyl alcohol by weight of allyl ester except in preparations containing 5 per cent or less of allyl esters with 0.1 per cent or less of free allyl alcohol by weight of allyl esters.

The committee also recommended an implementation date of 1 February 2019.

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 extent of use; (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the advice included

  1. risks and benefits of the use of a substance:
    • Allyl esters are widely used without significant adverse events.
    • Benefits: Allyl esters are used as an excipient in biologicals, and medicines.
    • Risks: Potential for toxic metabolites to be formed.
  2. the purpose for which a substance is to be used and the extent of use:
    • Allyl esters are generally used as flavours or fragrances in cosmetics, therapeutic goods, household products and commercial products.
  3. the toxicity of a substance:
    • Acute oral and dermal toxicity consistent with a schedule 6 listing.
      • 5% cut-off consistent with the Therapeutic Goods (Permissible Ingredients) Determination No. 2 of 2018 listings of these substances.
      • Moderate to high oral and dermal toxicity.
      • Low to moderate acute toxicity via inhalational exposure.
      • Allyl acetate is corrosive.
      • Allyl cyclohexanepropionate is a moderate skin sensitiser in guinea pigs.
      • Toxic metabolites formed: Allyl alcohol and acrolein.
  4. the dosage, formulation, labelling, packaging and presentation of a substance:
    • Align with international regulations where free allyl alcohol is less than 0.1% in the ester.

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