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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March 2017
Scheduling medicines and poisons
2. Joint meeting of the Advisory Committee on Chemicals and Medicines Scheduling (ACCS/ACMS #15)
Referred scheduling proposal
The scheduling delegate is seeking advice from the Joint Advisory Committees on Chemicals and Medicines Scheduling (ACCS-ACMS) on an application submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) under their IMAP program to create a new entry for trans-anethole in Schedule 6 to include use in cosmetic and domestic products with an exemption concentration cut-off.
Current scheduling status and relevant scheduling history
Trans-anethole is not specifically scheduled and has not been previously considered for scheduling.
This was a general application. The applicant's proposed amendments to the Poisons Standard are as follows:
Schedule 6 - New Entry
TRANS-ANETHOLE in cosmetic and domestic products except in preparations containing 10 per cent or less of trans-anethole.
Appendix E, Part 2 - New Entry
Standard statements: E1 (If in eyes wash out immediately with water).
Appendix F, Part 3 - New Entry
Warning statements: 28 [(Over) (Repeated) exposure may cause sensitisation].
The applicant's reasons for the request are:
- Trans-anethole is a skin sensitiser;
- Trans-anethole is reported to be used in cosmetic and domestic products overseas, particularly as a fragrance ingredient at concentrations up to 10%. In the absence of specific Australian information, this is taken as being representative of its use in Australia; and
- Internationally, there is a recommendation for use of trans-anethole at concentrations up to 10%; however, the available data does not preclude skin sensitisation occurring following exposure to concentrations below 10% (Scientific Committee on Consumer Safety (SCCS), 2012.
Australian regulatory information
Trans-anethole is included in the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2017 for use as an excipient.
Trans-anethole is as an ingredient in 249 products on the ARTG, including disinfectants, sunscreens, dental hygiene preparations, cold and cough relief products, anti-depressants, nicotine chewing gum products and gastric reflux relief preparations.
Anethole is unclassified in New Zealand.
A number of over the counter (OTC) products containing anethole have been cancelled post market in Canada. There are no approved products containing anethole currently available in Canada.
Anethole has a "Generally Recognised as Safe" status in the USA.
Anethole is in the European Chemicals Agency (ECHA) Annex III inventory requiring REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) Registration.
Trans-anethole is a component of a number of essential oils, such as anise, fennel, anise myrtle, guarana, camphor and star anise. Trans-anethole is also present in absinthe, magnolia blossoms and liquorice and is closely related to estragole, present in tarragon and basil.
Trans-anethole is a precursor for paramethoxyamphetamine (PMA).
Anethole is used broadly in multiple sectors due to its presence in essential oils, some of which have already been scheduled. It contributes a large component of the odour and flavour of the substances listed in the table below.
|Anethole-containing substance||Plant genus/family||Schedule||% of Anethole|
|Anise (seed) oil||Pimpinella anisum / Apiaceae||
Part 2, Section Two Containers
Name of the Poison: Anise oil when included in Schedule 5.
Nominal capacity: 200 millilitres or less
ANISE OIL except:
Appendix E, Part 2 - ANISE OIL
Standard Statement: A, G3.
|Fennel oil||Foeniculum vulgare / Apiaceae||
Not currently scheduled.
Considered for scheduling at November 2016 meeting of the Joint Advisory Committee on Chemicals and Medicines Scheduling.
|Star anise||Illicium verum / Illiciaceae||
STAR ANISE OIL except:
|Anise myrtle oil||Syzygium anisatum / Myrtaceae||Not scheduled.||90%,|
|Liquorice||Glycyrrhiza glabra / Fabaceae||
Appendix B, Part 3
Date of entry: May 2009
|Dill||Anethum graveolens / Apiaceae||Not scheduled.||11%|
|Magnolia blossoms||Magnolia salicifolia / Magnoliaceae||Not scheduled.||6.0%|
|Coriander||Coriandrum sativum / Apiaceae||Not scheduled.||Trace|
|Cicely||Myrrhis odorata / Apiaceae||Not scheduled.||85%|
|Sweet cicely||Osmorhiza longistylis / Apiaceae||Not scheduled.||95%15|
|Marigold pepper||Piper marginatum / Piperaceae||Not scheduled.||80%15|
|Molecule weight||148.21 g/mol|
|Alternative names||trans-anethole (INCI); anisole; anise camphor; p-propenyl-, (E )-; (E)-1-p-methoxyphenylpropene; anethole (AAN); benzene, 1-methoxy-4-(1-propenyl)-, (E)- (CAS); 1-Methoxy-4-[(1E)-prop-1-en-1-yl]benzene (IUPAC); p-Propenylanisole; Isoestragole|
The following information was extracted from the NICNAS IMAP Human Health Tier II assessment report for trans-anethole.
|Toxicity||Species||Trans-anethole||SPF (2015) Classification|
|Acute oral toxicity LD50 (mg/kg bw)||Osborne-Mendel Rats||2090-3200||Schedule 5|
|Acute dermal toxicity LD50 (mg/kg bw)||Rabbits (strain not specified)||>4900||Schedule 5|
|Acute inhalational toxicity LC50 (mg/m3/4h)||Rats (strain not specified)||>5100||N/A|
|Skin irritation||New Zealand White Rabbits||Not irritating (slight erythema)||N/A|
|Eye irritation||New Zealand White Rabbits||Not irritating||N/A|
|Skin sensitisation||CBA Mice (LLNA)||Sensitising (EC3 <25%)||Schedule 6|
|Guinea pig (strain not specified) (GPMT)||Sensitising|
Trans-anethole has low acute toxicity based on results from animal tests following oral, dermal and inhalation exposure.
Trans-anethole is not considered to be a skin or eye irritant:
- slight erythema (fully resolved after 8 h) was observed after trans-anethole was semi-occlusively applied to clipped, intact dorsal skin of New Zealand White rabbits for 4 h; and
- no signs of pain or irritation were observed after neat trans-anethole was instilled into the eyes of New Zealand White rabbits.
Trans-anethole is considered to be a skin sensitiser based on the positive results seen in a mouse LLNA and GPMT:
- In a mouse LLNA conducted according to OECD TG 442B, female CBA mice (n = 4 animals/dose) were exposed to trans-anethole at 25, 50, or 100% in acetone/olive oil (4:1 v/v). The stimulation indices (SI) calculated were 3.49, 3.53 and 3.85 for the low, mid and high doses, respectively, indicating that trans-anethole was positive for skin sensitisation.
- In a GPMT conducted according to the OECD TG 406, 10 guinea pigs were induced with trans-anethole at 2% (intradermal) and 50% (topical). Trans-anethole at 10% was administered as a challenge dose and 10/10 animals tested positive for skin sensitisation. Each guinea pig was then challenged weekly, at a non-irritating concentration and 10/10 guinea pigs tested positive for skin sensitisation.
Based on the available data, repeated oral exposure to trans-anethole is not considered to cause serious damage to health. No data are available for repeated dermal and inhalation toxicity.
Based on the negative results from several in vitro and in vivo studies, trans-anethole is not considered to be genotoxic.
Based on the data available, trans-anethole is not considered to be carcinogenic.
Reproduction and developmental toxicity
Trans-anethole does not show any signs of reproductive or developmental toxicity. Any developmental effects seen were secondary to maternal toxicity.
Trans-anethole has been identified to be used in cosmetic (perfumes and fragrances) and domestic products (polishes and waxes; softeners; soaps and cleaning products; and air care products) overseas at concentrations up to 10%. This use pattern is taken to be representative of its use in Australia [see Australian regulatory information].
Due to the use patterns of trans-anethole, direct dermal exposure is expected.
Pre-meeting public submissions
Two (2) public submissions were received. Both submissions opposed the scheduling proposal. The main points were:
- An Appendix B entry has been previously considered for other flavour/fragrance ingredients used in cosmetic and household hygiene products with low acute toxicity and low public exposure.
- Due to the similarity of this substance with other scheduled items, regulatory control must be consistent with other related existing schedule entries and across all current uses of the substance (both therapeutic and cosmetic/domestic).
The public submissions will be made available on the TGA website.
Summary of ACCS-ACMS advice to the delegate
The committee advised that further consideration of exemption cut-offs applied to associated essential oils, such as star anise, anise oil and fennel oil, for the purposes of scheduling consistency before any advice can be provided on this application.
The committee advised that no scheduling is required at this stage, pending further advice to ensure consistency in any scheduling decision.
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; (d) the dosage, formulation, labelling, packaging and presentation of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the advice comprised the following:
- Anethole is a large and natural component of essential oils, used as a fragrance and flavour ingredient. It is found in 249 products on ARTG and these products have a wide range of uses. Anethole is also used in an unknown amount of cosmetic and household hygiene/domestic products, such as perfumes, fragrances, polishes, waxes, soaps, cleaning products, air care products and food flavourings. These products are used orally, topically and domestically with greatly varied packaging/labelling.
- The benefits of anethole were not presented for both medicinal and domestic use, however its presence in a number of essential oils and wide range of products means the substance should continue to be available and accessible. Anethole is typically found in products that are designed to be applied topically and consumed up to 10%.
- The potential for misuse or abuse is low. However, there is a risk that anethole can be synthesised to create a recreational drug, paramethoxyamphetamine (PMA), that has been known to cause death in users.
- Anethole has skin sensitising potential (EC3 50 >~2g/kg). The severity of skin sensitisation does not appear to be well established. There is no evidence of human poisoning presented.
- A new Schedule 6 entry for anethole will require a review of all scheduled essential oils of which trans-anethole is a major component of as they are currently either Schedule 5 or unscheduled (fennel oil).
The delegate considered the following in regards to 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 has decided to defer the interim decision for trans-anethole to allow for further consideration of its use in therapeutic goods and the potential to elicit skin sensitisation reactions at very low concentrations. The advice of the scheduling committee was to create a new Schedule 6 entry with very low exemption cut-off concentrations for domestic or personal products that would result in skin contact during use due to potent skin sensitisation. Similar restrictions are likely to apply to listed therapeutic products when applied topically.
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