You are here

Scheduling delegate's final decisions, July 2016

Scheduling medicines and poisons

27 October 2016

Book pagination

2.8 Isoeugenol

Part A - Final decisions on matters referred to an expert advisory committee

2. Scheduling proposals referred to the July 2016 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#17)

2.8 Isoeugenol

Note

  • Red strikethrough text indicates text that has been deleted.
  • Green italicised text indicates text that has been added.
Referred scheduling proposal

An application was submitted to amend the existing Schedule 6 entry for isoeugenol to lower the concentration cut-off from 10 to 1 per cent.

Current scheduling status and relevant scheduling history

Isoeugenol was considered for scheduling by the National Drugs and Poisons Schedule Committee (NDPSC) in November 1996 and at that time, the acute toxicity profile of isoeugenol warranted inclusion in Schedules 5 and 6 due to skin and eye irritancy, the potential for skin sensitisation and the level of oral toxicity.

Schedule 5

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

Schedule 6

ISOEUGENOL except:

  1. when included in Schedule 5; or
  2. in preparations containing 10 per cent or less of isoeugenol.
Other relevant regulations
Public exposure

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

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%;
  • 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; and
  • 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%.
Scheduling application

General application.

The application's proposed amendments to the SUSMP are as follows:

Schedule 6 - Amend Entry

ISOEUGENOL except:

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

The applicant's reasons for the request are:

  • Isoeugenol is classified as a carcinogen;
  • It is a strong skin sensitiser with Local Lymph Node Assay estimated concentration to produce a three-fold increase in lymphocyte proliferation (EC3) values as low as 0.54 %;
  • It has induced sensitisation in Human Repeat Insult Patch Tests at 1 %;
  • It may be widely present due to it being a constituent of a range of essential oils; and
  • Isoeugenol is restricted to 0.02 % in cosmetics in the European Union.
Substance summary

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

Figure 2.8: Structure of isoeugenol (2-methoxy-4-(1-propenyl)phenol)

Figure 2.8: Structure of isoeugenol (2-methoxy-4-(1-propenyl)phenol)

Acute toxicity

The acute toxicity end-points for isoeugenol (Figure 2.8) are listed in Table 2.8. Briefly, 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. Isoeugenol has been identified as a severe skin irritant in a number of animal studies. Isoeugenol is also considered to be a skin sensitiser based on human data (HRIPT), positive results seen in guinea pig maximisation tests (GPMT) and LLNAs. Isoeugenol is not considered to be genotoxic and does not show specific reproductive or developmental toxicity.

Toxicity Species Results 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 inhalation 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
Genotoxicity Various Not genotoxic*
Carcinogenicity Rats, Mice Carcinogenic
Reproduction and developmental toxicity Rats Negative*

* See the NICNAS IMAP Human Health Tier II assessment report for phenol, 2-methoxy-4-(1-propenyl)- for more information.

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).

Repeat-dose toxicity

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

Pre-meeting public submissions

One (1) public submission was received what supported lowering the cut-off concentration to 1% or less for cosmetic use only. For other products with no intended skin contact, the lowering of the exemption concentration cut-off was not supported.

The public submission is available on the TGA website.

Summary of ACCS advice to the delegate

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

Schedule 6 - Amend Entry

ISOEUGENOL except:

  1. when included in Schedule 5; or
  2. in preparations intended for contact with skin containing 10 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 in preparations intended for contact with skin containing 10 0.5 per cent or less of isoeugenol.

Members agreed that the relevant matters under Section 52E (1) of the Therapeutic Goods Act 1989 included: (b) the purpose for which a substance is to be used and the extent of use; and (c) the toxicity of a substance.

The ACCS advised an implementation date of 1 June 2017.

The reasons for the advice included:

  • Isoeugenol is a chemical fragrance with widespread use in cosmetic and household products;
  • Acute oral and dermal toxicity and irritancy classifies isoeugenol as a Schedule 6 substance;
  • Skin sensitisation recorded at 1% v/v isoeugenol; and
  • Isoeugenol is identified as carcinogenic although the evidence is limited.
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); and
  • Other relevant information.
Delegate's interim decision

The delegate notes and accepts the advice of the ACCS to amend the Schedule 5 and Schedule 6 entries for isoeugenol. The delegate notes that this advice is based primarily on the acute oral and dermal toxicity and irritancy for isoeugenol, including the skin sensitisation data recorded at 1 per cent. Evidence is limited regarding the classification of isoeugenol as a carcinogen. The use profile of isoeugenol as a chemical fragrance is widespread in cosmetic and household products.

A late implementation date of 1 June 2017 is proposed to allow for the re-labelling of isoeugenol-containing products already on the market.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (b) the purpose for which a substance is to be used and the extent of use; and (c) the toxicity of a substance.

Schedule 6 - Amend Entry

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 - Amend Entry

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.

Public submissions on the interim decision

Two (2) submissions were received. One (1) opposed the 0.5 per cent cut-off and one (1) supported the interim decision to lower the cut-off for isoeugenol to 0.5 per cent but suggested minor rewording of the proposed schedule entry.

Delegate's final decision

The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the final decision and reasons are in keeping with those for the interim decision.

The implementation date is 1 June 2017.

Book pagination