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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March and July 2017

Scheduling medicines and poisons

15 September 2017

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2.11 Anise alcohol

Referred scheduling proposal

An application submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) under their IMAP program to create a new Schedule 6 entry for anise alcohol for use in cosmetic and domestic products with appropriate concentration exemption cut-offs in alignment with international regulations.

Scheduling application

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

Schedule 6 – New Entry

ANISE ALCOHOL in cosmetic and domestic products except:

  1. in leave-on preparations containing 0.001 per cent or less of anise alcohol when labelled with the following statement:

    WARNING – This product contains ingredients which may cause skin sensitisation to certain individuals; or

  2. in wash-off preparations containing 0.01 per cent or less of anise alcohol when labelled with the following statement:

    WARNING – This product contains ingredients which may cause skin sensitisation to certain individuals.

Appendix E – New Entry

ANISE ALCOHOL

Standard Statement: E1 (If in eyes wash out immediately with water).

Appendix F – New Entry

ANISE ALCOHOL

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

The applicant's reasons for the request are:

  • Anise alcohol is a skin sensitiser;
  • Anise alcohol has moderate acute oral toxicity;
  • Anise alcohol is expected to be an eye irritant;
  • There is reported to be widespread use of anise alcohol in cosmetic and domestic products overseas at concentrations up to 2.5%; this is assumed to be representative of its use in Australia;
  • There are overseas restrictions for use of anise alcohol (the International Fragrance Association (IFRA) standard, 2015; and
  • As a sensitiser, when applied directly to skin in cosmetic and domestic products, the risk can only be mitigated by concentration limits and warning statements.

Current scheduling status and relevant scheduling history

Anise alcohol is not currently listed in the Poisons Standard and has not been previously considered for scheduling. Therefore, a scheduling history is not available.

Benzyl alcohol (read across in eye irritation study) is not currently scheduled. However, similar substances, anise oil and star anise oil, are currently scheduled.

Australian regulatory information

Anise alcohol is listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 3 of 2017 as follows:

Table 2.11.1: Permissible ingredients and requirements applying anise alcohol when contained in a medicine
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
593 ANISE ALCOHOL 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%.

Anise alcohol is included as an excipient in 98 formulations on the ARTG, including listed and registered medicines. These products include topical and oral preparations such as sunscreen, children preparations for cold and pain relief, anti-nausea preparations, anti-depressants and oral probiotics. The listed products are therapeutic goods that are not evaluated prior to being released for sale.

International regulations

EU

Anise alcohol is listed in the EU Cosmetic Regulation EC No. 1223/2009, Annex III: List of substances which cosmetic products must not contain except subject to the restrictions laid down. Anise alcohol may be used in cosmetics and personal care products, but must be specified in the list of ingredients referred to in article 19(1)g in 0.001% leave-on and 0.01% in rinse-off products.

Additionally, IFRA has restricted the use of Anise alcohol in finished products at concentrations of 0.04–2.5% depending on the product category.

USA

Anise alcohol (listed as anisyl alcohol) is a food additive in the USA.

Canada

Anise alcohol is a flavour enhancer and fragrance ingredient in Canada.

New Zealand

Anise alcohol is not regulated in New Zealand.

Substance summary

Anise alcohol is a colourless to slightly yellow liquid having a pleasant floral odour.

Table 2.11.2: Chemical information for anise alcohol
Property Anise alcohol
Chemical structure chemical structure of anise alcohol
Molecular formula C8H10O2
Molecular weight 138.7 g/mol
CAS name Benzenemethanol, 4-methoxy- (CAS)
CAS number 105-13-5
IUPAC and/or common and/or other names

Anise alcohol (INCI and AAN);

Anisyl alcohol; 4-methoxybenzyl alcohol; anisic alcohol;

p-methoxybenzyl alcohol.

The following information has been extracted from the NICNAS IMAP Human Health Tier II assessment report for anise alcohol, publicly available on the NICNAS website.

Table 2.11.3: Acute toxicity end-points for anise alcohol
Toxicity Species Anise alcohol SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat (strain/species not specified) 1200–1340 Schedule 6
Mice (strain/species not specified) 1600–1784
Acute dermal toxicity LD50 (mg/kg bw) Rabbits (strain/species not specified) >2500 <5000 Schedule 5
Mice (strain/species not specified) >10 000
Acute inhalational toxicity LC50 (mg/m3/4h) (Predicted, QSAR studies) Rat (strain/species not specified) 1019 Schedule 6
Mice (strain/species not specified) 1070
Skin irritation Rat (strain/species not specified),
Mice and Rabbits
Moderate irritation (erythema and oedema) Schedule 5
Eye irritation (Read across, benzyl alcohol) New Zealand White rabbit Expected to be irritating Schedule 5
Skin sensitisation CBA/Ca mice [LLNA] Sensitising (EC3 5.9%) Schedule 6
Guinea pig (strain/species not specified), Hartley; Epicutaneous test, Draize method Not sensitising N/A

Acute toxicity

Anise alcohol has moderate acute oral toxicity based on results from animal tests. Anise alcohol has low acute dermal toxicity in rabbits and mice. Acute inhalation toxicity is predicted to be moderate.

Irritation

Based on animal studies, anise alcohol is reported to moderately irritate the skin.

  • Anise alcohol (0.5 mL) was applied to albino rats (n=12, 6 with normal and 6 with abraded skin) under occlusive conditions for 24 h. Rats were monitored for 72 h. Moderate irritation including erythema and slight oedema were observed.
  • In two studies conducted in mice (n=10) and rabbits (n=4), anise alcohol was administered at doses of 1250, 2500 or 5000 mg/kg bw. Moderate irritation (primary irritation score=4) was observed including moderate erythema and oedema.
  • No data are available for anise alcohol for eye irritation. Based on the available data for an analogue chemical (benzyl alcohol, CAS No. 100-51-6) with similar physicochemical properties, anise alcohol is expected to be an eye irritant.
  • Irritation was reported after application of the analogue chemical, benzyl alcohol, to the eyes of New Zealand White rabbits. The irritation scores were 1–2 for corneal opacity, 0.3–1 for iritis, 2–2.7 for conjunctivitis and 0.7–2.2 for chemosis.

Sensitisation

Based on the weight of evidence from the available animal and human (see Observation in humans below) studies, anise alcohol is considered to be a skin sensitiser.

  • In a murine LLNA compliant with the principles of good laboratory practice (GLP), anise alcohol was diluted using 1:3 ethanol:diethyl phthalate and 25 µL was applied to the dorsal surface of each ear of CBA/Ca mice (n = 4 females/dose) at doses of 2.5, 5, 10, 25 and 50% w/v for three consecutive days. The EC3 (estimated concentration that elicits a three-fold increase in lymphocyte proliferation) value was found to be 5.9%, confirming anise alcohol as a skin sensitiser.

However, positive skin reactions were not reported in several studies conducted in guinea pigs, where:

  • animals were subjected to anise alcohol at 1, 3, 10, 30 or 100% in water, acetone or petrolatum for induction and challenged with anise alcohol at 5% in the same vehicle;
  • animals were subjected to a modified Draize test, using anise alcohol in petrolatum at 0.625% for induction and 10% for challenge; and
  • neat anise alcohol was intra-dermally injected into the animals for the induction phase, and following a two week rest period, the animals were subjected to a modified Draize test, involving an injection of 0.25% and topical exposure of 10% to anise alcohol.

Repeat-dose toxicity

No data are available for repeated oral and inhalation exposure.

Based on the limited information available, anise alcohol is not considered to cause serious damage to health from repeated dermal exposure.

Genotoxicity

Based on the limited data available, anise alcohol is not considered to be genotoxic.

Carcinogenicity

Based on the available data in mice, anise alcohol is not expected to be carcinogenic.

Reproduction and developmental toxicity

No data are available.

Observation in humans

Irritation

Irritation was observed in a closed patch study in 11/465 (2.3%) of human subjects after application of anise alcohol (under occlusion to the forearm) at 0.05–5% in a cream base solution.

In an irritation screening study, anise alcohol did not produce skin reactions at 5% in petrolatum when applied under occlusion to the skin of human subjects (n = 7) for 48 h.

Skin sensitisation

The IFRA reported a No Expected Sensitisation Induction Level (NESIL) of 1500 µg/cm2 based on a human maximisation test and, therefore, classified anise alcohol as a weak sensitiser.

Reports from the Scientific Committee on Consumer Safety (SCCS), 2012, list anise alcohol as an allergen.

Positive reactions were reported in the following human studies:

  • A study conducted on 20 perfume allergic patients: anise alcohol at 5% in petrolatum gave a positive reaction in 5/20 of the subjects;
  • Diagnostic patch studies on dermatological patients:
    • skin reactions in 4/20 patients who are sensitive to perfume treated with anise alcohol at 5% in petrolatum;
    • skin reactions in 1/2004 patients with dermatitis treated with anise alcohol at 1% in petrolatum; and
    • skin reactions in 3/167 patients sensitive to fragrance allergens and suspected of contact dermatitis treated with anise alcohol at 5% in petrolatum.

No skin reactions were reported in the following human studies:

  • A maximisation study: 25 subjects were pre-treated for 24 h with 5% aqueous sodium lauryl sulfate (SLS). Following a 10-14 day rest period, subjects were applied with anise alcohol (3450 µg/cm2, 5%) in petrolatum occlusively to the forearm/back region for five 48h periods and monitored for a further 48 h;
  • Diagnostic patch studies on dermatological patients:
    • 320 patients with eczema suspected of a contact allergy to fragrances or cosmetics were treated with anise alcohol at 5%; and
    • 115 patients with contact dermatitis were treated with anise alcohol at 5% in petrolatum.

Public exposure

Considering the range of domestic, cosmetic, therapeutic and personal care products that may contain anise alcohol, the main route of public exposure is expected to be through the skin, and inhalation from products applied as aerosols, and potential oral exposure from lip and oral hygiene products. Dermal application of products containing anise alcohol at high concentrations may give rise to allergic responses.

Pre-meeting public submissions

Three (3) public submissions were received and all three opposed the proposal.

Main points opposed:

  • An Appendix B entry should be considered as has been previously for other flavour/fragrance ingredients used in cosmetic and household hygiene products with low acute toxicity and low public exposure.
  • Based on IFRA standards, there are restrictions on concentration depending on use pattern of the product due to the concern that anise alcohol has skin sensitisation potential. Due to IFRA standards already existing for anise alcohol, scheduling is not required.
  • The EU only requires the inclusion of anise alcohol in the ingredients list if the concentration in the finished product is ≥0.001% in leave-on products, and ≥0.01% in rinse-off products.

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

Summary of ACCS-ACMS advice to the delegate

The committee recommended that a new Schedule 6 entry and Appendix E and F entries be created for anise alcohol as follows:

Schedule 6 – New Entry

ANISE ALCOHOL except:

  1. in preparations intended for therapeutic use; or
  2. in domestic preparations [not intended for direct skin contact] containing 5 per cent or less of anise alcohol when included in the list of ingredients; or
  3. in leave-on cosmetic and personal care preparations containing 2.5 per cent or less of anise alcohol when included in the list of ingredients and labelled with the following statement:

    WARNING – This product contains ingredients which may cause skin sensitisation to certain individuals.

    written in letters not less than 1.5 mm in height; or
  4. in rinse-off cosmetic and personal care preparations containing 5 per cent or less of anise alcohol when included in the list of ingredients and labelled with the following statement:

    WARNING – This product contains ingredients which may cause skin sensitisation to certain individuals.

    written in letters not less than 1.5 mm in height; or
  5. in leave-on cosmetic and personal care preparations containing 0.001 per cent or less of anise alcohol; or
  6. in rinse-off cosmetic and personal care preparations containing 0.01 per cent or less of anise alcohol.

Appendix E, Part 2 – New Entry

ANISE ALCOHOL

Standard Statement: 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)).

Appendix F, Part 3 – New Entry

ANISE ALCOHOL

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 February 2018 if no label change would be required by scheduling.

The committee also recommended an implementation date of 1 June 2018 to allow a 12 month phase in of the new label requirements.

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 were:

  • Anise alcohol is a flavour and fragrance excipient used in many medicinal, cosmetic and personal care products: 98 products on ARTG include anise alcohol as an excipient. The risks of the substance at the currently used concentrations appear low.
  • It is listed as a Fragrance or Flavour Excipient (under Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2017).
  • The EU Cosmetic Regulation states 'This chemical may be used in cosmetics and personal care products, but the presence of the substance must be indicated in the list of ingredients referred to in Article 19(1)g when its concentration exceeds 0.001% in leave-on products and 0.01% in rinse-off products.'
  • The IRFA Standard restricts use to maximum of 2.5% depending on the product use (i.e. those with skin contact). Anise alcohol is currently specified within the Permissible Ingredients List and the requirements that apply to these ingredients when contained in a medicine are that the flavour is no more than 5% and the fragrance is no more than 1%.
  • In Australia, there are domestic products that contain up to 5% of anise alcohol available. Worldwide use is widespread in cosmetic and domestic products and is at concentrations of up to 2.5.
  • The risks of anise alcohol include systemic risks through oral exposure, local risks of eye irritation and skin sensitisation and inhalational risk (which is a predicted risk). It is also a known allergen listed on the List of Established Contact Allergens, (whilst low importance category however identified as a known fragrance allergen (SCCNFP 1999)).
  • The toxicity of anise alcohol includes a moderate acute oral toxicity (based on animal studies) and possible skin sensitisation (it is listed by SCCS).

Delegate's considerations

The delegate considered the following regarding this proposal:

  • Scheduling proposal
  • ACCS-ACMS advice
  • Public Submissions received
  • Section 52E of the Therapeutic Goods Act 1989
  • Scheduling Policy Framework (SPF 2015)
  • Other relevant information

Delegate's interim decision

The delegate's interim decision is to create new Schedule 6 and Appendix E/F entries for anise alcohol. The proposed Schedule entry is as follows:

Schedule 6 – New Entry

ANISE ALCOHOL except:

  1. in preparations intended for therapeutic use; or
  2. in domestic preparations not intended for direct skin contact containing 5 per cent or less of anise alcohol when declared on the label; or
  3. in leave-on cosmetic and personal care preparations containing more than 0.001 and up to 2.5 per cent of anise alcohol when declared on the label and labelled with the following statement:

    WARNING – This product contains ingredients which may cause skin sensitisation to certain individuals.

    written in letters not less than 1.5 mm in height; or
  4. in rinse-off cosmetic and personal care preparations containing more than 0.01 and up to 5 per cent or less of anise alcohol when declared on the label and labelled with the following statement:

    WARNING – This product contains ingredients which may cause skin sensitisation to certain individuals.

    written in letters not less than 1.5 mm in height; or
  5. in leave-on cosmetic and personal care preparations containing 0.001 per cent or less of anise alcohol; or
  6. in rinse-off cosmetic and personal care preparations containing 0.01 per cent or less of anise alcohol.

Appendix E, Part 2 – New Entry

ANISE ALCOHOL

Standard Statement: 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)).

Appendix F, Part 3 – New Entry

ANISE ALCOHOL

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

Safety Direction: 4 (Avoid contact with skin).

The proposed implementation date is 1 February 2019, to allow at least a 12 month phase for industry if label changes are 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 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.

The reasons for the interim decision are:

  • The delegate acknowledges the committee's advice.
  • Anise alcohol is a flavour and fragrance excipient used in many medicinal, cosmetic and personal care products: 98 products on ARTG include anise alcohol as an excipient. The risks of the substance at the currently used concentrations appear low.
  • It is listed as a Fragrance or Flavour Excipient (under Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2017).
  • The EU Cosmetic Regulation states:

'This chemical may be used in cosmetics and personal care products, but the presence of the substance must be indicated in the list of ingredients referred to in Article 19(1)g when its concentration exceeds 0.001% in leave-on products and 0.01% in rinse-off products.'

  • The IRFA Standard restricts use to maximum of 2.5% depending on the product use (i.e. those with skin contact). Anise alcohol is currently specified within the Permissible Ingredients List and the requirements that apply to these ingredients when contained in a medicine are that the flavour is no more than 5% and the fragrance is no more than 1%.
  • In Australia, there are domestic products that contain up to 5% of anise alcohol available. Worldwide use is widespread in cosmetic and domestic products and is at concentrations of up to 2.5.
  • The risks of anise alcohol include systemic risks through oral exposure, local risks of eye irritation and skin sensitisation and inhalational risk (which is a predicted risk). It is also a known allergen listed on the List of Established Contact Allergens, (whilst low importance category however identified as a known fragrance allergen (SCCNFP 1999)).
  • The toxicity of anise alcohol includes a moderate acute oral toxicity (based on animal studies) and possible skin sensitisation (it is listed by SCCS).

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