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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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2.13 Trans-anethole

Referred scheduling proposal

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.

Scheduling application

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

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

TRANS-ANETHOLE

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

Appendix F, Part 3 – New Entry

TRANS-ANETHOLE

Warning Statement: 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.

Current scheduling status and relevant scheduling history

Trans-anethole is not specifically scheduled and has not been previously considered for scheduling.

Australian regulatory information

Trans-anethole is listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 3 of 2017 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.

International regulations

New Zealand

Anethole is unclassified in New Zealand.

Canada

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.

USA

Anethole has a "Generally Recognised as Safe" status in the USA.[29]

EU

Anethole is in the European Chemicals Agency (ECHA) Annex III inventory requiring REACH (Registration, Evaluation, Authorisation and Restriction of Chemicals) Registration.

Substance summary

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 Table 2.13.1 below.

Table 2.13.1: Anethole-containing essential oils, herbs and plants
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

Schedule 5

ANISE OIL except:

  1. in medicines for human therapeutic use, when packed in containers having a nominal capacity of 50 mL or less fitted with a restricted flow insert and compliant with the requirements of the Required Advisory Statements for Medicine Labels;
  2. in preparations other than medicines for human therapeutic use, when packed in containers having a nominal capacity of 50 mL or less fitted with a restricted flow insert, and labelled with the warning:

    KEEP OUT OF REACH OF CHILDREN; or

  3. in preparations containing 50 per cent or less of anise oil.

Appendix E, Part 2 – ANISE OIL

Standard Statement: A, G3.
79-95%[30], [31]
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.
82-88%[32], [33], [34], [35]
Star anise Illicium verum/Illiciaceae

Schedule 5

STAR ANISE OIL except:

  1. in medicines for human therapeutic use, when packed in containers having a nominal capacity of 50 mL or less fitted with a restricted flow insert and compliant with the requirements of the Required Advisory Statements for Medicine Labels;
  2. in preparations other than medicines for human therapeutic use, when packed in containers having a nominal capacity of 50 mL or less fitted with a restricted flow insert, and labelled with the warning:

    KEEP OUT OF REACH OF CHILDREN; or

  3. in preparations containing 50 per cent or less of star anise oil.
77-92%[36], [37]
Anise myrtle oil Syzygium anisatum /Myrtaceae Not scheduled. 90%[38], [39]
Liquorice[40] Glycyrrhiza glabra/Fabaceae

Appendix B, Part 3

LIQUORICE, DEGLYCYRRHISINISED.

Date of entry: May 2009
Reason for Entry – a, low toxicity
Area of Use – 7.1, general, any use

Not found
Dill Anethum graveolens/Apiaceae Not scheduled. 11%[41]
Magnolia blossoms[42] Magnolia salicifolia/ Magnoliaceae Not scheduled. 6.0%[43]
Coriander Coriandrum sativum/ Apiaceae Not scheduled. Trace[44]
Cicely Myrrhis odorata/ Apiaceae Not scheduled. 85%[45]
Sweet cicely Osmorhiza longistylis/ Apiaceae Not scheduled 95%55
Marigold pepper Piper marginatum/ Piperaceae Not scheduled. 80%55
Table 2.13.2: Chemical information for trans-anethole
Property Trans-anethole
Chemical structure chemical structure of trans-anethole
Molecular formula C10H12O
Molecule weight 148.2 g/mol
CAS name Benzene, 1-methoxy-4-(1-propenyl)-, (E)-
CAS number 4180-23-8
IUPAC and/or common and/or other names

Trans-anethole (INCI);

1-Methoxy-4-[(1E)-prop-1-en-1-yl]benzene (IUPAC);

(E)-1-p-methoxyphenylpropene; anethole (AAN);

Anisole; anise camphor; p-propenyl-, (E)-; p-propenylanisole; isoestragole.

The following information was extracted from the NICNAS IMAP Human Health Tier II assessment report for trans-anethole, publicly available on the NICNAS website.

Table 2.13.3: Acute toxicity end-points for trans-anethole
Toxicity Species Trans-anethole SPF (2015) Classification
Acute oral toxicity
LD50 (mg/kg bw)
Osborne-Mendel Rats 2090–3200 Schedule 5
CD-1 Mice 1820–5000
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 Local lymph node assay, LLNA CBA Mice Sensitising (EC3 <25%) Schedule 6
Guinea pig maximisation test, GPMT Guinea pig (strain not specified) Sensitising

Acute toxicity

Trans-anethole has low acute toxicity based on results from animal tests following oral, dermal and inhalation exposure.

Irritation

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.

Sensitisation

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.

Repeat-dose toxicity

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.

Genotoxicity

Based on the negative results from several in vitro and in vivo studies, trans-anethole is not considered to be genotoxic.

Carcinogenicity

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.

Public exposure

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 and both opposed the proposal.

Main points opposed:

  • 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 recommended 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 recommended 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 were:

  • 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 <25%) and has low acute oral toxicity (LD50 >~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).

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 defer a decision on trans-anethole and refer the application back to the applicant for further consideration of an exemption cut-off to ensure consistency in any scheduling decision.

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; (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 interim decision are:

  • The delegate acknowledges the committee's advice.
  • 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 <25%) and has low acute oral toxicity (LD50 >~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 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.

Footnotes

  1. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=582.60
  2. Neşet Arslan, B et al., (2004) Turk. J. Agric. For., 28, 173-177.
  3. Zheljazkov, V.D.J et al., (2013) HORTSCIENCE, 48 (11), 1393-1396.
  4. Senatore, F et al., (2013) Fitoterapia, 90, 214-219.
  5. Dadaliogÿlu, I and Evrendilek G.A. (2004) J. Agric. Food Chem. 52, 8255-8260.
  6. Dio, W et al., (2014) Food Control, 35 (1), 109-116.
  7. Piccaglia, R and Marotti, M (1993) Flavour and Fragrance Journal, 8, 115-122.
  8. Gholivand, M. B., et al., (2009) Analytical Letters; 42 (10), 1382–1397.
  9. Wong, Y.C., et al., (2014) Oriental Journal of Chemistry, 30 (3), 1159-1171.
  10. Blewitt, M and Southwell, I.A. (2000) J. Ess. Oil Res., 12 (4), 445-454.
  11. Sultanbawa, Y (2016) ‘Chapter 23 Anise Myrtle (Syzygium anisatum) Oils' in Essential Oils in Food Preservation, Flavor and Safety, Elsevier Inc.
  12. Fenwick, GR (1990) Food Chemistry, 38, 119-143.
  13. Singh, G et al., (2005) J. Food Sci., 70(4).
  14. Kelm et al., (2008) International Journal of Pharmacognosy, 35(2), 84-90.
  15. Fujita, S-I and Fujita, Y (1975) Chem. Pharm. Bull., 23(10), 2443-2445.
  16. Baratta, MT et al., (2011) J. Ess. Oil Res., 10, 618-627. M208-M215.
  17. Surana, S.J. et al., (2006) Natural Product Radiance, 5(4), 270-278.

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