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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, July 2016
Scheduling medicines and poisons
3.7 Amyl & hexyl cinnamaldehyde
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- Green italicised text indicates text that has been added.
Referred scheduling proposal
An application was submitted to create new Schedule 6 entries for amyl cinnamal (amyl cinnamaldehyde) and hexyl cinnamal (hexyl cinnamaldehyde) with an appropriate cut-off to exempt from scheduling for preparations with low concentrations.
Current scheduling status and relevant scheduling history
Amyl and hexyl cinnamaldehyde are not specifically scheduled.
Amyl and hexyl cinnamaldehyde have not been previously considered for scheduling; therefore, scheduling history is not available.
Other relevant regulations
Although the uses of amyl and hexyl cinnamaldehyde in cosmetic and domestic products in Australia are not known, the chemicals are reported to have widespread use in cosmetic and domestic products overseas, which introduce the potential availability of these chemicals for use in Australia (US HHPD and CIUCUS). While the European Union (EU) and New Zealand (NZ) have outlined restrictions on the use of amyl and hexyl cinnamaldehyde in cosmetics (see International Restrictions below) there are no restrictions currently in Australia regarding the use of these chemicals in cosmetic products. In the absence of any regulatory controls, the characterised critical local health effects have the potential to pose an unreasonable risk under the identified uses. It is suggested that the risk could be mitigated by implementing concentration limits and restricting uses to limit dermal exposure.
Amyl and hexyl cinnamaldehyde are restricted for cosmetic use in the EU. They are listed on the EU Cosmetics Regulation 1223/2009 Annex III - the presence of the chemical must be indicated in the list of ingredients when its concentration exceeds 0.001 % in leave-on products and 0.01 % in rinse-off products.
Amyl and hexyl cinnamaldehyde are listed on the following:
- The New Zealand Cosmetic Products Group Standard - Schedule 5, with the same use restrictions as described above for the EU; and
- The International Fragrance Association (IFRA) Standards - Restricted.
The application's proposed amendments to the SUSMP are as follows:
Schedule 6 - New Entries
The applicant's reasons for the request are:
- Amyl and hexyl cinnamaldehyde have reported uses in a range of cosmetic and domestic products;
- Amyl and hexyl cinnamaldehyde are potential sensitisers with an LLNA derived EC3 of 6.6 -11.5%; and
- There are overseas restrictions for the use of amyl and hexyl cinnamaldehyde in cosmetic products, where the presence of the chemical must be indicated in the list of ingredients when its concentration exceeds 0.001% in leave-on products and 0.01% in rinse-off products.
Alpha-amyl cinnamaldehyde (CAS No. 122-40-7) and alpha-hexyl cinnamaldehyde (CAS No. 101-86-0) (Figure 3.7A and 3.7B) are alkyl-substituted cinnamaldehydes, grouped together because of their close structural relationship and the resulting physico-chemical and toxicological properties. Amyl and hexyl cinnamaldehyde are identified as GRAS ('generally regarded as safe') for use as flavouring substances by the United States Food and Drug Administration (US FDA) and World Health Organisation (WHO).
Figure 3.7: Amyl cinnamaldehyde (A) and hexyl cinnamaldehyde (B)
The acute toxicity profile for amyl and hexyl cinnamaldeyde is outlined in Table 3.7. Briefly, amyl and hexyl cinnamaldehyde display low oral toxicity based on animal test results following oral exposure with the lethal dose (LD50) in rats reported to be >2000 mg/kg bw. Amyl and hexyl cinnamaldehyde display low acute dermal toxicity based on results from animal tests in rabbits following dermal exposure (LD50 >2000 mg/kg bw). The concentrations used in the animal studies for skin sensitisation are above the reported concentrations of up to 0.1%, used in cosmetic and domestic products available on the domestic market. Based on the limited available data, these chemicals are expected to have low acute inhalation toxicity based on results from animal tests following inhalation exposure. Based on the available data from animal studies in rabbits the chemicals in this group are irritating to the skin and cause slight eye irritation. Amyl and hexyl cinnamaldehyde are considered to be weak to moderate skin sensitisers (Mice LLN assay EC = 6.6-11.5%) according to the SPF classification with hexyl cinnamaldehyde being commonly used as a positive control in skin sensitisation studies. Human data for hexyl cinnamaldehyde using the Human Repeat Insult Patch Test (HRIPT) do not indicate sensitisation. Amyl and hexyl cinnamaldehyde are not considered to be genotoxic and are not expected to cause reproductive or developmental toxicity. No information is available regarding the carcinogenicity of these chemicals. (See the NICNAS IMAP Human Health Tier II group assessment report for amyl & hexyl cinnamaldehyde for more information.)
|Toxicity endpoint||Species||Results||SPF (2015) Classification|
|Acute oral toxicity LD50 (mg/kg bw)||Rat||>2000||-|
|Acute dermal toxicity LD50 (mg/kg bw)||Rabbit||>2000||-|
|Acute inhalational toxicity LC50 (mg/m3/4h)||Rat||Low**||-|
|Skin irritation||Rabbits||Irritant (amyl cinnamaldehyde) (Classified as irritant)||-|
|Eye irritation||Rabbits||Slight irritant||Schedule 5|
|Skin sensitisation (LLNA)||Mice, Guinea pigs||Weak to moderate skin sensitisers (EC = 6.6-11.5%)||Schedule 6|
|Skin sensitisation (HRIPT)||Human||
Mild erythema with moderate oedema was seen in 1 volunteer out of 138, which subsided after 96 hrs.
|Genotoxicity||Salmonella typhimurium, Mice||Not genotoxic*||N/A|
|Reproduction and developmental toxicity||Rats||Not expected*||N/A|
* See the NICNAS IMAP Human Health Tier II group assessment report for amyl & hexyl cinnamaldehyde for more information
Repeated dose toxicity
While no data is available regarding repeat exposure through inhalation, based on the available data, repeated oral exposures to the amyl and hexyl cinnamaldehyde are not considered to cause serious damage to health (see the NICNAS IMAP Human Health Tier II group assessment report for amyl & hexyl cinnamaldehyde for more information). In contrast, repeated dermal exposure to the chemicals in this group at high doses can cause systemic and local effects according to animal studies in male rats. The lowest LOAEL was reported to be 125 mg/kg bw/day based on changes in the liver and local effects on the skin.
Pre-meeting public submissions
One (1) public submission was received which proposed that scheduling is not required due to international regulation through IFRA. The submission also proposed that, if scheduling is determined necessary then, a Schedule 6 entry with different cut-offs for leave-in and rinse off products should be used, specifically 0.001% in leave-on cosmetics and > 0.01% in rinse-off cosmetics. The submission also requested a prolonged implementation date.
The public submission is available on the TGA website.
Summary of ACCS advice to the delegate
The committee advised that amyl and hexyl cinnamaldehyde do not require scheduling in the SUSMP. The committee advised that the Delegate list amyl and hexyl cinnamaldehyde in Appendix B. Members agreed that the relevant matters under Section 52E (1) of the Therapeutic Goods Act 1989 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; and (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the advice included:
- Public exposure is only likely to occur through the use of these substances as fragrances in cosmetic and household cleaning products containing up to 0.1%;
- Low acute toxicity; and
- Slight/mild skin sensitization data observed in animal studies and absence of skin sensitisation observed in human studies.
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 that amyl and hexyl cinnamaldehyde do not require scheduling in the SUSMP, but that an Appendix B listing for amyl and hexyl cinnamaldehyde is more appropriate. The delegate notes that amyl and hexyl cinnamaldehyde have low acute toxicity; and although slight/mild skin sensitization data is observed in animal studies, there was an absence of skin sensitisation observed in humans. Furthermore, public exposure to amyl and hexyl cinnamaldehyde is only likely to occur through their use as fragrances in cosmetic and household cleaning products containing up to 0.1%.
The proposed implementation date is 1 February 2017. Since listing in Appendix B is not equivalent to a decision to list a substance in a schedule, an implementation date is not strictly relevant. However, amendment of Appendix B at the earliest revision of the SUSMP is recommended.
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; and (f) any other matters that the Secretary considers necessary to protect public health.
Appendix B - New Entries