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

Scheduling medicines and poisons

17 May 2017

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3.6 Isoeugenol

3. Advisory Committee on Chemicals Scheduling (ACCS #19)

3.6 Isoeugenol

Referred scheduling proposal

An application was initiated by the chemicals scheduling delegate to amend the Schedule 5 and Schedule 6 entries for isoeugenol to specify concentration cut-offs in products both intended and not intended for skin contact.

Current scheduling status

Isoeugenol is currently in Schedules 5 and 6 of the Poisons Standard (February 2017) as follows:

Schedule 6

ISOEUGENOL except:

  1. when included in Schedule 5; or
  2. in preparations containing 10 per cent or less of isoeugenol.

Schedule 5

ISOEUGENOL in preparations containing 25 per cent or less of isoeugenol except in preparations containing 10 per cent or less of isoeugenol.

On 1 June 2017 (decision from the July 2016 ACCS meeting), the Schedule 5 and 6 entries for isoeugenol were to be amended in the Poisons Standard; however, this decision has been deferred to accommodate this recent proposal to amend the scheduling entry.

July 2016 ACCS scheduling decision:

Schedule 6

ISOEUGENOL except:

  1. when included in Schedule 5; or
  2. in preparations intended for contact with skin containing 0.5 per cent or less of isoeugenol.

Schedule 5

ISOEUGENOL in preparations not intended for skin contact containing 25 per cent or less of isoeugenol except in preparations intended for contact with skin containing 0.5 per cent or less of isoeugenol.

Scheduling history

Isoeugenol was first considered for scheduling in November 1996 by the NDPSC and at that time, the acute toxicity profile of isoeugenol warranted inclusion in Schedules 5 and 6 because of skin and eye irritancy, skin sensitisation potential and the oral LD50.

Isoeugenol was considered for scheduling again in July 2016 at the Advisory Committee on Chemicals Scheduling (ACCS). The committee advised that the Schedule 5 and Schedule 6 cut-off should be amended from 10% to 0.5% in preparations intended for contact with the skin due to the use pattern and skin sensitisation potential of isoeugenol. The implementation date for this decision was to be 1 June 2017.

After publication of the July 2016 ACCS final decision industry indicated that, while the exemption cut-off of 0.5% of isoeugenol in products intended for skin contact was appropriate, there should be a separate concentration cut-off for products not intended for skin contact (and that 10% was appropriate).

Scheduling application

The delegate-initiated scheduling proposal is to amend the Schedule 5 and Schedule 6 entries for isoeugenol to specify concentration cut-offs in products both intended and not intended for skin contact. Consideration has been given to the current Schedule 5 and Schedule 6 entries with a specified 10 per cent cut-off, and the previous application to amend the Schedule 5 and Schedule 6 entries for isoeugenol, with a specified 1 per cent cut-off.

The proposed changes to the Poisons Standard are:

Schedule 6 - Amend Entry

ISOEUGENOL except:

  1. when included in Schedule 5; or
  2. in preparations not intended for skin contact containing 10/1 per cent or less of isoeugenol; or
  3. in preparations intended for skin contact containing 0.5 per cent or less of isoeugenol.

Schedule 5 - Amend Entry

ISOEUGENOL in preparations not intended for skin contact containing 25 per cent or less of isoeugenol except:

  1. in preparations not intended for skin contact containing 10/1 per cent or less of isoeugenol; or
  2. in preparations intended for skin contact containing 0.5 per cent or less of isoeugenol
Australian regulatory information

Isoeugenol is listed on the Australian Inventory of Chemical Substances (AICS) (NICNAS, 2007). No specific Australian industrial use, import, or manufacturing information has been identified.

Isoeugenol is available for use as an Active Ingredient in: Biologicals, Prescription Medicines and is available for use as an Excipient Ingredient in: Biologicals, Devices, Listed Medicines, Prescription Medicines. Isoeugenol is permitted for use in a medicine as a flavour, at no more than 5 per cent, or a fragrance at no more 1 per cent.

Isoeugenol is not listed on the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2017.

Isoeugenol is included in 171 listed products on the ARTG. The types of product vary, ranging from sunscreens and skin lotions, complementary medicines and dietary supplements, cough preparations, epilepsy drugs, anti-fungal ointments and hospital-grade disinfectants.

International regulations

Isoeugenol is listed on the following:

  • European Union (EU) Cosmetics Regulation 76/768/EEC Annex III Part 1-List of substances which cosmetic products must not contain except subject to the restrictions and conditions laid down-maximum authorised concentration in the finished cosmetic product: 0.02%; and
  • New Zealand Cosmetic Products Group Standard-Schedule 5-Table 1: Components cosmetic products must not contain except subject to the restrictions and conditions laid down.
  • Based on qualitative risk assessment, the International Fragrance Association (IFRA) has indicated an acceptable concentration for isoeugenol in skin contact products should be 0.02%.
Substance summary

Isoeugenol is one of several structurally similar phenylpropenoid compounds produced by plants. It has been extracted from calamus, savoury, basil, ylang-ylang, clove, tuberose, jonquil, nutmeg, tobacco, sandalwood, dill seed, mace, gardenia, petunia, and other flowers. Isoeugenol can also be produced by isomerization of eugenol, which occurs naturally in clove, pimento, bay leaf, and cinnamon.

As a fragrance with a spicy, carnation-like odour, isoeugenol is incorporated into numerous household and personal hygiene products, including perfumes, cream lotions, soaps, and detergents. As a flavouring agent, isoeugenol is added to non-alcoholic drinks, baked foods, and chewing gums.[87]

Figure 3.6: Chemical structure of Isoeugenol

Figure 3.6: Chemical structure of Isoeugenol

Table 3.6A: Chemical information
Property Isoeugenol
CAS name phenol, 2-methoxy-4-(1-propenyl)
CAS number 97-54-1
Alternative names 2-methoxy-4-(prop-1-en-1-yl)phenol; phenol, 2-methoxy-4-(1-propenyl)
Molecular formula C10H12O2
Molecular weight 164.2 g/mol

The following has been extracted from the NICNAS IMAP Human Health Tier II assessment report for phenol, 2-methoxy-4-(1-propenyl)-.[88]

Table 3.6B: Acute toxicity endpoints for isoeugenol
Toxicity Species Result SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 1290-1880 Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) Rabbit 1910 Schedule 6
Acute inhalational toxicity LC50 (mg/m3/4h) N/A N/A N/A
Skin irritation Rabbit Evidence of severe irritation (non-guideline study) Schedule 6
Eye irritation Rabbit Evidence of irritation Schedule 5
Skin sensitisation (LLNA) Various 2% (weighted mean from over 40 tests) Schedule 6
Acute toxicity

Isoeugenol is classified as hazardous with the risk phrase 'Harmful if swallowed' (Xn; R22) in the HSIS (Safe Work Australia). The available data support the existing classification for isoeugenol as 'harmful if swallowed: (Xn; R22)'.

A review of the literature by the US National Toxicology Program (2010) found that oral LD50 values for isoeugenol ranged from 1290 to 1880 mg/kg bw for rats and 1130 to 1780 mg/kg bw for guinea pigs.

Irritation

The potential for isoeugenol to irritate the skin has been assessed in a number of animal studies. In a non-guideline study, undiluted isoeugenol was applied to the dorsal skin of albino Angora rabbits and guinea pigs under occlusion for 24 hours. Patches were removed and a second application was made 30 minutes later. Macro and microscopic examination of excised skin revealed evidence of severe irritation.

Sensitisation

Isoeugenol is considered to be a skin sensitiser based on human data, positive results seen in guinea pig maximisation tests (GPMT) and LLNAs.

The estimated concentration to produce a three-fold increase in lymphocyte proliferation (EC3) was determined from over 40 separate LLNA tests conducted using isoeugenol. The weighted mean EC3 value of 2% was reported from the combined data. Lower EC3 values have been reported elsewhere in the literature, including as low as 0.54%.

In a GPMT with isoeugenol, animals were intra-dermally induced at 0.15% followed by topical induction at 25%. A challenge phase was conducted seven days later with topical application of a 5% solution. Responses were seen in 100% of animals.

Similar effects were observed when isoeugenol was tested in Freund's complete adjuvant tests. In one test, guinea pigs (10/group) were intra-dermally induced at 1, 3 or 10% followed by a challenge using a topical application of isoeugenol at the same respective concentrations. Responses were seen in 5/10, 9/10 and 10/10 animals in the 1, 3 and 10% induction and challenge groups, respectively. In another FCA test, eight guinea pigs were intra-dermally induced at 5%, followed by a challenge by topical application at the same concentration. Responses were seen in all eight animals.

HRIPTs have also indicated that isoeugenol is a skin sensitiser in humans.

Repeat-dose toxicity

The available data suggest that isoeugenol has low repeated dose toxicity, based on results from animal tests following oral exposure.

Genotoxicity

Based on the weight of evidence from the available in vitro and in vivo genotoxicity studies, isoeugenol is not considered to be genotoxic. Some in vitro genotoxicity tests indicated weakly positive results, but all in vivo tests were negative.

Carcinogenicity

Isoeugenol is classified as hazardous-Category 3 carcinogenic substance-with the risk phrase 'Limited evidence of carcinogenic effect' (Xn; R40) in the HSIS (Safe Work Australia). The available data support this classification.

In a two-year carcinogenicity study, Fischer 344 (F344) rats (50/sex/group) were dosed with isoeugenol by oral gavage at 0, 75, 150, or 300 mg/kg bw, five days per week for 105 weeks. Survival rates of the exposed animals were comparable to controls. Mean body weights of males in the high dose group were increased compared with controls. Two males in the high dose group developed thymomas, while two other males in this group developed mammary gland carcinomas. Some animals in the mid and high dose groups showed olfactory epithelial metaplasia and mild atrophy of the olfactory nerves.

A similar experiment was conducted in B6C3F1 mice (50/sex/group) where animals were dosed with isoeugenol by oral gavage at 0, 75, 150 or 300 mg/kg bw, 5 days/week for 104 weeks (females) and 105 weeks (males). Survival was decreased in males in the high dose group and body weights were reduced in both males and females in this group. In all groups, males exhibited increased incidences of hepatocellular adenoma, hepatocellular carcinoma and hepatocellular carcinoma and adenoma (combined). Incidences of hepatic clear cell foci were also increased in the male mice that received 75 or 150 mg/kg bw/day. There was also a significant increase in the incidence of histiocytic sarcomas (at multiple tissue sites) in females across all groups. Olfactory epithelial metaplasia was observed in all exposed groups. Bowman's gland hyperplasia was also significantly increased in all exposed groups. Mild renal papillary necrosis and renal tubule necrosis were also significantly increased in the high dose group females. There were dose-dependent increases in the incidences of forestomach squamous hyperplasia, inflammation (statistically significant in high dose males and females) and ulceration (for high dose males only).

Reproduction and developmental toxicity

Isoeugenol does not show specific reproductive or developmental toxicity. The reproductive and developmental effects seen in studies were secondary to maternal toxicity.

Public exposure

Although the use of isoeugenol in cosmetic/domestic products in Australia is not known, it is reported to be used overseas in cosmetic products (as a perfuming agent) and domestic products (including cleaning and surface treatment products).

Pre-meeting public submissions

One (1) pre-meeting public submission was received with no objections to the proposed scheduling for isoeugenol. The main points of the submission were:

  • Scheduling of isoeugenol should align with regulations in other international jurisdictions, such as the EU, as well as IFRA standards.
  • Isoeugenol scheduling has been ambiguous and it is appreciated by industry that the wording of the Schedule 5 entry is being revisited.
  • An adequate transition period of at least 12 months is requested to allow for any labelling changes and/or reformulation that may be required where no immediate risk has been identified. There is no evidence to suggest immediate action is required for the risk management of this substance.

The public submission is available on the TGA website.

Summary of ACCS advice to the delegate

The committee advised that the Schedule 6 and Schedule 5 entries for isoeugenol be amended as follows:

Schedule 6 - Amend Entry

ISOEUGENOL except:

  1. when included in Schedule 5; or
  2. in preparations not intended for skin contact containing 10 per cent or less of isoeugenol; or
  3. in preparations intended for skin contact containing 0.02 per cent or less of isoeugenol.

Schedule 5 - Amend Entry

ISOEUGENOL in preparations not intended for skin contact containing 25 per cent or less of isoeugenol except in preparations containing 10 per cent or less of isoeugenol.

Appendix E, Part 2 - New Entry

ISOEUGENOL

Standard statements: 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)], E1 (if in eyes wash out immediately with water), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F, Part 3 - New Entry

ISOEUGENOL

Warning statements: 19 (WARNING - Skin contact may be dangerous. Take every precaution to avoid contact - wash off after spillage and after use), 28 ((Over) (Repeated) exposure may cause sensitisation), 79 (Will irritate eyes).

Safety directions: 1 (Avoid contact with eyes), 4 (Avoid contact with skin).

The committee also advised an implementation date of 1 October 2017 to allow industry to make the necessary changes to product labelling.

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 and 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 comprised the following:

  • Isoeugenol has moderate acute toxicity consistent with Schedule 6 criteria. Isoeugenol is a skin and eye irritant at 1% and a strong sensitiser at low concentrations (EC3 0.54%). There is evidence of carcinogenicity in male mice and possible carcinogen in female mice and male rats.
  • Isoeugenol is used widely internationally in a large range of products including foods, therapeutic, household and cosmetic products.
  • Risk can be mitigated with appropriate warning and first aid statements.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal
  • ACCS 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 amend Schedule 6 and Schedule 5 for isoeugenol and to create new entries for isoeugenol in Appendix E/F. The proposed Schedule entry is as follows:

Schedule 6 - Amend Entry

ISOEUGENOL except:

  1. when included in Schedule 5; or
  2. in preparations not intended for skin contact containing 10 per cent or less of isoeugenol; or
  3. in preparations intended for skin contact containing 0.02 per cent or less of isoeugenol.

Schedule 5 - Amend Entry

ISOEUGENOL in preparations not intended for skin contact containing 25 per cent or less of isoeugenol except in preparations containing 10 per cent or less of isoeugenol.

Appendix E, Part 2 - New Entry

ISOEUGENOL

Standard statements: 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)], E1 (if in eyes wash out immediately with water), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F, Part 3 - New Entry

ISOEUGENOL

Warning statements: 19 (WARNING - Skin contact may be dangerous. Take every precaution to avoid contact - wash off after spillage and after use), 28 ((Over) (Repeated) exposure may cause sensitisation), 79 (Will irritate eyes).

Safety directions: 1 (Avoid contact with eyes), 4 (Avoid contact with skin).

The proposed implementation date is 1 October 2018.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (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 following:

  • The delegate acknowledges the committee's advice.
  • Isoeugenol has moderate acute toxicity consistent with Schedule 6 criteria. Isoeugenol is a skin and eye irritant at 1% and a strong sensitiser at low concentrations (EC3 0.54%). There is evidence of carcinogenicity in male mice and possible carcinogen in female mice and male rats.
  • Isoeugenol is used widely internationally in a large range of products including foods, therapeutic, household and cosmetic products.
  • Risk can be mitigated with appropriate warning and first aid statements.
  • The long implementation date is proposed in order to allow industry to make the necessary changes to product labelling.

Footnotes

  1. Natl Toxicol Program Tech Rep Ser. 2010 Sep;(551):1-178
  2. Publicly available on the NICNAS website: Human Health Tier II Assessment for Phenol, 2-methoxy-4-(1-propenyl)-

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