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Scheduling delegate's final decisions, July 2016

Scheduling medicines and poisons

27 October 2016

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2.5 Phenoxymethyl oxirane

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)

2.5 Phenoxymethyl oxirane

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 create a new Schedule 6 entry for phenoxymethyl oxirane.

Scheduling history

Phenoxymethyl oxirane is not specifically scheduled and has not been previously considered for scheduling; therefore, scheduling history is not available.

Other relevant regulations
Public exposure

No specific Australian use, import or manufacture information have been identified. Phenoxymethyl oxirane is however, known to be used in domestic and commercial products overseas.

International regulations

Phenoxymethyl oxirane is listed in:

  • EU regulation (EC) No 1223/2009 Annex II: List of substances which must not form part of the composition of cosmetic products; and
  • New Zealand Cosmetic Products Group Standard - Schedule 4: Components cosmetic products must not contain.
Scheduling application

General application.

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

Schedule 6 - New Entry

PHENOXYMETHYL OXIRANE for domestic use.

The applicant's reasons for the request are:

  • Although there is no information to confirm that phenoxymethyl oxirane is currently used in domestic products in Australia, use in domestic products such as paints and varnishes has been identified overseas;
  • The main critical effects to human health are carcinogenicity following long-term occupational exposure, potential for mutagenicity and sensitisation from dermal contact. Phenoxymethyl oxirane also possesses other hazardous properties such as skin, eye and respiratory tract irritation; and
  • Adverse skin effects including sensitisation have been reported in humans from long-term exposure to phenoxymethyl oxirane; and the European Union and New Zealand have banned the use of this chemical in cosmetics. There are no restrictions in Australia to prevent this chemical being used in cosmetics or domestic products. However, no cosmetic use for this chemical has been identified in Australia.
Substance summary
Figure 2.5: Structure of phenoxymethyl oxirane

Figure 2.5: Structure of phenoxymethyl oxirane

The following is extracted from the NICNAS IMAP Human Health Tier II assessment report for phenoxymethyl oxirane.

Acute toxicity

The acute toxicity end-points for phenoxymethyl oxirane (Figure 2.5) are listed in Table 2.5. Briefly, phenoxymethyl oxirane has low acute toxicity via oral and dermal route of exposure and is currently classified with the risk phrase 'Harmful by inhalation' (R20) (Safe Work Australia). Although the data available do not warrant a hazard classification, in the absence of more reliable data and considering the local effects seen in the repeat dose inhalation toxicity study (See below), the existing hazard classification was not amended. Phenoxymethyl oxirane is an eye irritant and respiratory irritant upon single or repeated inhalation exposure and is classified as hazardous with the risk phrase 'Irritating to skin' (R38) (Safe Work Australia). Phenoxymethyl oxirane has skin sensitising effects in guinea pigs (Buehler Patch test) and is classified as hazardous with the risk phrase 'May cause sensitisation by skin contact' (R43) (Safe Work Australia). Based on the available data, phenoxymethyl oxirane is not considered to have reproductive or developmental toxicity.

Toxicity Species Results SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rats 3850 mg/kg bw Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) Rats 3850 mg/kg bw Schedule 5
Acute inhalational toxicity LC50 (mg/m3/4h) Rats, Mice >100 ppm/4 hour Schedule 5
Skin irritation Rabbit, Human Irritating Schedule 5
Eye irritation (Standard Draize test) Rabbit, Human Mild to severe irritation Schedule 5/6
Skin sensitisation (Buehler) Guinea pig Sensitising Schedule 6
Skin sensitisation (HRIPT) Humans Sensitising, allergic dermatitis reaction -
Genotoxicity In vivo (bacterial and mammalian cells) Genotoxic -
Carcinogenicity Rats Carcinogenic -
Reproduction and developmental toxicity Rats Negative* -

* See the NICNAS IMAP Human Health Tier II assessment report for phenoxymethyl oxirane for more information.

Genotoxicity

Phenoxymethyl oxirane is classified as hazardous in the HSIS with the risk phrase 'Possible risk of irreversible effects' (R68) (Safe Work Australia). The available in vitro genotoxicity data support this classification.

In vitro genotoxicity assays with phenoxymethyl oxirane were conducted using bacterial and mammalian cells. Positive results were observed in bacterial assays and some assays with mammalian cells. There are no in vitro studies conducted in germ cells showing positive results.

Phenoxymethyl oxirane has been reported to alkylate nucleic acid bases in vitro; however, it did not bind to DNA in Escherichia coli with or without metabolic activation (HSDB). All epoxide-containing compounds including glycidyl ethers elicited alkylation activity and mutagenic potency. There was no correlation between rate of alkylation and mutagenic potency. Most in vivo genotoxicity assays with phenoxymethyl oxirane showed negative results, except for one host-mediated assay.

Carcinogenicity

Phenoxymethyl oxirane is classified with the risk phrase 'May cause cancer' (R45 Category 2 carcinogen) in HSIS (Safe Work Australia).

Phenoxymethyl oxirane is classified by the International Agency for Research on Cancer (IARC) as Group 2B (possibly carcinogenic to humans) based on sufficient evidence of carcinogenicity in experimental animals (IARC 1989).

Phenoxymethyl oxirane is classified by American Conference of Governmental Industrial Hygienists (ACGIH) as A3 carcinogen (confirmed animal carcinogen with unknown relevance to humans).

In a chronic inhalation carcinogenicity bioassay, 100 rats were exposed to phenoxymethyl oxirane for 6 hours/day, 5 days/week for 24 months at 0, 1 or 12 ppm. After 621 exposure days, malignant nasal tumours were found in 9/85 (11 %) males and 4/89 (4.4 %) females exposed at 12 ppm (average latent period was 688 days). No nasal tumours were found in the rats exposed at 1 ppm (even up to 24 months). A nasal tumour was found in 1/89 male controls, while none were found in the female controls. Nasal tumours were primarily epidermoid carcinomas sharply limited to the anterior nasal cavity. Tumours were derived from respiratory epithelium and nasal glands (both of which revealed squamous metaplasia or dysplasia). Squamous metaplasia was seen in 72 % rats at 12 ppm, 4.7 % rats at 1 ppm, and 3.4 % in controls; rhinitis was observed in 78 % at 12 ppm, 22 % at 1 ppm, and 19 % in controls.

Repeat-dose toxicity

No data are available on its oral or dermal repeat-dose toxicity.

In a subchronic study, rats which inhaled aerosols of phenoxymethyl oxirane at a concentration of 29 ppm for 4h/day, 5 days/week for two weeks, showed weight loss, atrophic changes in the liver, kidneys, spleen, thymus, and testes, depletion of hepatic glycogen, and chronic catarrhal tracheitis (inflammation of mucous membrane lining the trachea). Local effects included respiratory irritation. The estimated NOAEC was 29 ppm in rats.

Pre-meeting public submissions

One (1) public submission was received which did not object to the scheduling proposal.

The public submission is available on the TGA website.

Summary of ACCS advice to the delegate

The committee advised that the proposal to create a Schedule 6 entry for phenoxymethyl oxirane was appropriate.

The ACCS advised an implementation date of 1 February 2017.

Members agreed that the relevant matters under Section 52E (1) of the Therapeutic Goods Act 1989 included: (c) the toxicity of a substance.

The reasons for the advice included:

  • Acute toxicity profile indicating low oral and dermal toxicity within the range of a Schedule 5 substance;
  • Skin and eye irritant;
  • Skin sensitiser; and
  • Genotoxic and potential carcinogen as indicated by respiratory tract tumours in rodent studies.
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 ACCS advice to create a new entry for phenoxymethyl oxirane in Schedule 6 with appropriate listings in Appendices E and F. While the acute toxicity profile of phenoxymethyl oxirane indicates low oral and dermal toxicity within the range of a Schedule 5 substance, the delegate agrees with the ACCS that on the basis of the skin sensitisation and eye irritation data, a Schedule 6 entry for phenoxymethyl oxirane is more appropriate. Furthermore, phenoxymethyl oxirane is a potential genotoxin and carcinogen as indicated by respiratory tract tumours in rodent studies.

An early implementation date of 1 February 2017 is proposed in order to bring the regulation of this ingredient in products sold in Australia into alignment with international regulations.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (c) the toxicity of a substance.

Schedule 6 – New Entry

PHENOXYMETHYL OXIRANE.

Appendix E - PHENOXYMETHYL OXIRANE

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).

Appendix F - PHENOXYMETHYL OXIRANE

Warning statements: 12 (vapour is harmful to health on prolonged exposure), 28 [(Over) (Repeated) exposure may cause sensitisation], 51 (irritant to skin, eyes, mucous membranes and upper respiratory tract).

Safety directions: 1 (avoid contact with eyes), 3 (wear eye protection when mixing or using), 4 (avoid contact with skin), 5 (wear protective gloves when mixing or using), 7 (wash hands thoroughly after use), 8 (avoid breathing vapour), 9 (use only when in well-ventilated areas).

Public submissions on the interim decision

No public submissions were received regarding the interim decision for phenoxymethyl oxirane.

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 February 2017.

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