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Scheduling delegate's final decisions: ACCS, November 2015

Scheduling medicines and poisons

19 November 2015

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2.1 Cyclopropylmethyl, 3-hexenoate

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

2. Scheduling proposals referred to the August 2015 ACCS meeting

2.1 Cyclopropylmethyl, 3-hexenoate

Scheduling proposal

The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):

  • In April 2015, the delegate received a request to consider creating a new entry for cyclopropylmethyl, 3-hexenoate in Schedule 6 when used in cosmetic and household products, except when used at appropriately low usage concentrations.
Scheduling application

The reasons for the request were:

  • The chemical has moderate to high acute oral toxicity, consistent with the Schedule 6 factors
  • The chemical presents a moderate-high hazard from repeated use.
Delegates reasons for referring this to the committee

The previous ACCS has considered a number of fragrance chemicals referred from NICNAS. For chemicals with a low toxicity profile and likely to be present at quite low concentrations in products in the retail market, the ACCS has advised that there is insufficient public health risk to warrant inclusion in a schedule of the SUSMP. At the November 2014 ACCS, there were five fragrance chemicals that generated such advice. At the November 2013 and July 2014 ACCS meetings, similar advice was offered in relation to two other fragrance ingredients. However, at the July 2014 meeting, ACCS advice in relation and one other fragrance chemical (4,4-dimethyl-1-cyclohexene-1 propanal) was to list it is Schedule 6, with exempt cut-offs at 0.1% to 1% for various cosmetic and other product types. The different ACCS advice appears to be related to the severity of the toxicity potential of the pure compound, with 4,4-dimethyl-1-cyclohexene-1 propanal recommended a Schedule 6 listing because of the severity of the skin/eye irritancy potential and sensitization potential.

The delegate asked the committee the following questions:

  • Does the ACCS consider that the toxicological profile of cyclopropylmethyl, 3-hexenoate  is sufficiently similar to the seven fragrance chemicals where no scheduling action was recommended, or is it more like 4,4-dimethyl-1-cyclohexene-1 propanal, where listing in Schedule 6 was recommended, along with different product-related exemption cut-offs?
  • If scheduling is recommended, is the chemical name cyclopropylmethyl, 3-hexenoate the preferred name for listing (or some other name)?
  • Does the ACCS support different exempt cut-offs for a Schedule 6 entry for different product types, as proposed in the NICNAS report?
Substance summary
Figure 1. Structure of Cyclopropylmethyl, 3-hexenoate

Figure 1. Structure of Cyclopropylmethyl, 3-hexenoate

Acute toxicity
The acute toxicity end-points for this chemical are listed in the below table.
Toxicity Species Cyclopropylmethyl, 3-Hexenoate SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 300-2000 Consistent with Schedule 6
Acute dermal toxicity LD50 (mg/kg bw) Rat > 2000 None
Acute inhalation toxicity LC50 (mg/L/4h) Rat > 5.18 None
Skin irritation Rabbit Slightly irritating None
Eye irritation Rabbit Slightly irritating None
Skin sensitisation (Local lymph node assay) Mouse No evidence of sensitisation None
Repeat dose toxicity

An NOAEL of 30 mg/kg bw/day was established in a 28 day repeat dose oral toxicity study in rats. The study was conducted at dose levels of 30, 100 and 300 mg/kg bw/day, with adverse effects in the heart and liver noted in animals treated at ≥ 100 mg/kg bw/day. Additional effects in the stomach, testes, epididymis, female reproductive organs and eyes were observed in animals treated at 300 mg/kg bw/day.

Mutagenicity

The chemical was not mutagenic in a bacterial reverse mutation assay.

Genotoxicity

The chemical was not clastogenic in an in vitro mammalian chromosome aberration test.

Carcinogenicity

No information was provided.

Reproduction and developmental toxicity

No information was provided.

Observation in humans

No information was provided.

Public exposure

There will be widespread and repeated exposure of the public to the notified chemical (at ≤ 0.05% concentration) through the use of a wide range of cosmetic and household products. The principal route of exposure will be dermal, while ocular and inhalation exposures (e.g. through the use of spray products) are also possible.

International regulations

No information was provided.

Scheduling status

Cyclopropylmethyl, 3-hexenoate is not specifically scheduled.

Scheduling history

Cyclopropylmethyl, 3-hexenoatehas not been previously considered for scheduling; therefore, scheduling history is not available. However, for the one fragrance ingredient where the ACCS did recommend scheduling (see notes below), the wording used in the listing was:

Schedule 6 - New Entry

Cyclopropylmethyl, 3-hexenoate except:

  1. when used in fine fragrances at a concentration of 0.05 per cent or less;
  2. when used in other cosmetic products at a concentration of 0.03 per cent or less;
  3. when used in household products at a concentration of 0.05 per cent or less.
Reasons for the suggested cut-offs

As stated above, the NICNAS recommended usage concentrations of 0.05 per cent in fine fragrances, 0.03 per cent in other cosmetic products and 0.05 per cent in household products correspond to the maximum proposed usage concentrations by the notifier. The NICNAS assessment determined that there was no unreasonable risk to the public when used at these concentrations.

Pre-meeting public submissions

One public submission was received. The submission proposed that it is unnecessary to schedule Cyclopropylmethyl, 3-hexenoate. The reason given was that there is in place an international standard of scheduling fragrances, imposed by the International Fragrance Association (IFRA), and companies internationally already comply with this standard. The public submissions are available at Public submissions on scheduling matters.

Summary of ACCS advice to the delegate

The Committee recommended a new Schedule 6 entry be created for cyclopropylmethyl, 3-hexenoate with except in preparations containing 0.05 per cent or less.

The committee recommended an implementation date of 1 February 2016.

The committee also recommended changing the name from its original reference of 3-hexanoic acid, cyclopropylmethyl ester to CYCLOPROPYLMETHYL, 3-HEXENOATE.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (c) the toxicity of a substance; and (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the recommendations comprised the following:

  • Meets the criteria for schedule 6
  • Restricting to a cut-off of 0.05 per cent. The risk to public health at very low concentrations is minimal
Delegate's interim decision

Not to schedule this substance.

The reasons for the interim decision comprised the following:

The delegate notes that the ACCS advice to include this fragrance ingredient in Schedule 6 is based primarily on the fact that its acute toxicity, but not skin/eye irritancy or sensitisation potential is consistent with SPF criteria for listing in Schedule 6, and that a 0.05% exemption cut-off has been proposed. The delegate also notes that this advice is inconsistent with advice previously given by the ACCS in relation to scheduling fragrance ingredients where there are no strong signals of toxicity at expected use concentrations. The delegate has therefore decided to maintain consistency with previous decisions on fragrance ingredients and to not schedule this substance.

Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors3;
  • Other relevant information.
Public submissions on the interim decision

One submission was received. The submission supported the delegate's interim decision.

Edited versions of these submissions are available at Public submissions on scheduling matters.

Delegate's final decision

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


Footnotes

  1. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)

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