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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March 2017
Scheduling medicines and poisons
2. Joint meeting of the Advisory Committee on Chemicals and Medicines Scheduling (ACCS/ACMS #15)
Referred scheduling proposal
The scheduling delegate is seeking advice from the Joint Advisory Committees on Chemicals and Medicines Scheduling (ACCS-ACMS) on an application submitted by the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) under their IMAP program to create a new Schedule 6 entry for cinnamaldehyde for use in cosmetics and domestic preparations with appropriate warning labels and exemption cut-off concentrations in line with international standards.
Current scheduling status and relevant scheduling history
Cinnamaldehyde is not currently scheduled and has not previously been considered for scheduling.
In July 2016, the ACCS advised that structurally similar substances, hexyl and amyl cinnamaldehyde, be listed in Appendix B, PART 3 - 'Substances considered not to require control by scheduling', due to their low toxicity. The implementation date is 1 February 2017. Please see Final Decision.
This was a general application. The applicant's proposed amendments to the SUSMP are as follows:
Schedule 6 - New Entry
CINNAMALDEHYDE except in preparations for dermal use containing 0.01/0.05 per cent or less of cinnamaldehyde.
Appendix E - New Entry
Standard statements: E1 (If in eyes wash out immediately with water).
Appendix F - New Entry
Warning statements: 28 [(Over) (Repeated) exposure may cause sensitisation], 79 (Will irritate eyes).
Safety directions: 4 (Avoid contact with skin).
The applicant's reasons for the request are:
- Cinnamaldehyde is an established contact allergen in humans;
- Cinnamaldehyde is a potential strong skin sensitiser, based on a local lymph node assay (LLNA)-derived EC3 (estimated concentration to produce a three-fold increase in lymphocyte proliferation) value of 0.2%;
- The existing overseas restrictions (New Zealand, EU) on the use of cinnamaldehyde in cosmetic products, where the presence of cinnamaldehyde 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;
- The most recent SCCS opinion on cinnamaldehyde recommends a concentration limit of 0.01% for safe use of cinnamaldehyde as a fragrance in cosmetic products; and
- The current IFRA guidelines restrict use of cinnamaldehyde to concentrations of 0.02% in lip care and deodorant/anti-perspirant products, 0.04% in intimate wipes, 0.4% in mouthwashes and 0.05% in all other personal care products including fragrances.
Australian regulatory information
Cinnamaldehyde, as well as alpha-methyl cinnamaldehyde, alpha-hexylcinnamaldehyde and alpha-amyl cinnamaldehyde, are listed as excipients in the Therapeutic Goods (Permissible Ingredients) Determination No. 1 of 2017. The specific requirements applying to all these substances are:
- Permitted for use only in combination with other permitted ingredients as a flavour or a fragrance.
- If used in a flavour the total flavour concentration in a medicine must be no more than 5%.
- If used in a fragrance the total fragrance concentration in a medicine must be no more 1%.
Cinnamaldehyde is included as an excipient in 215 formulations at present on the ARTG, including listed and registered medicines, both OTC and prescription-only. These products range from disinfectants, hand hygiene formulations, sunscreens, nicotine gum, children's pain relief and cold preparations, toothpaste, vitamins and mineral supplements and probiotics.
Use of cinnamaldehyde in cosmetics in the European Union (EU) is subject to the restrictions described in EU Cosmetics Regulation 344/2013 (as an amendment to the listing under Annex III of Regulation 1223/2009). The presence of the substance 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.
Use of cinnamaldehyde in cosmetics and domestic articles in several other countries is also restricted in accordance with the following listings:
- European Commission (EC) Toy Safety Directive 2009/48/EC: Allergenic fragrances toys shall not contain; and
- the New Zealand Cosmetic Products Group Standard: Schedule 5 - Components cosmetic products must not contain except subject to the restrictions and conditions laid down. The presence of the substance 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.
Cinnamaldehyde is an organic compound which occurs naturally as predominately the trans (E) isomer, it gives cinnamon its flavour and odour. This pale yellow, viscous liquid occurs in the bark of cinnamon trees and other species of the genus Cinnamomum. The essential oil of cinnamon bark is approximately 50% cinnamaldehyde.
|Molecular weight||132.16 g/mol|
|Alternative names||(2E)-3-phenylprop-2-enal (IUPAC); cinnamal; cinnamic aldehyde; 2-Propenal, 3-phenyl- (CAS)|
The following information was extracted from the NICNAS New Chemical assessment report for cinnamaldehyde. Further information can also be found in the SCCS (2012) opinion on fragrance allergens in cosmetic products.
|Toxicity||Species||Cinnamaldehyde||SPF (2015) Classification|
|Acute oral toxicity LD50 (mg/kg bw)||Rat||>2000||Schedule 5|
|Acute dermal toxicity LD50 (mg/kg bw)||Rat||620-1260||Schedule 6|
|Acute inhalational toxicity LC50 (mg/m3/4h)||N/A||No data||-|
Severe skin irritation (undiluted)
Mild skin irritation (3-5% solution)
No irritation (1% solution)
Mild to severe eye irritation (0.125-1%)
Severe chemosis and discharge at 1.25%
|Skin sensitisation||Mouse (LLNA)||Moderate to strong skin sensitiser (EC3 0.2-3.1%)||Schedule 6|
|Guinea pig (GPMT)||Positive reactions in 90-100% of animals tested at 0.75%. Sensitisation effects seen as low as 0.1%.|
Cinnamaldehyde has low acute oral toxicity, but moderate acute dermal toxicity based on results from animal tests.
The available data from animal and human studies indicate that cinnamaldehyde is irritating to the skin, eyes and respiratory system, warranting hazard classification:
- Cinnamaldehyde produced severe irritation in rabbits when applied undiluted, mild irritation in mice and guinea pigs at concentrations of 3-5%, and it was non-irritating to rabbits at 1%. The US EPA considers cinnamaldehyde a strong skin irritant in guinea pigs (no study details provided).
- In New Zealand White rabbits, cinnamaldehyde produced eye irritation when applied undiluted, and effects were not completely reversed after 7 days. In three separate experiments, concentrations of 0.125%, 1% and 1.25% cinnamaldehyde were instilled in rabbit eyes. Intense to mild conjunctival irritation was observed and, at the highest concentration (1.25%), severe chemosis and considerable discharge were observed. The effects were reversible after a week at all concentrations except the highest.
- Respiratory irritation was assessed in CF-1 female mice by recording their respiratory rate following exposure to nebulised cinnamaldehyde for 1 minute, either through nose-only exposure or via a tracheal cannula. Marked respiratory depression with nose-only exposure was observed. The ED25 (dose providing a 25% reduction in respiratory rate) was calculated to be 241 µg/L. No significant effects were observed when inhalation was via the tracheal cannula.
Based on the available animal and human data, cinnamaldehyde is considered to be a moderate to strong contact skin sensitiser:
- In a study equivalent to OECD Test Guideline (TG) 429, cinnamaldehyde was reported to be positive for skin sensitisation in an in vivo mouse LLNA. The mice were administered 0, 0.1, 0.3, 1.0, 3.0 or 10.0% (w/v) of cinnamaldehyde in ethanol/diethyl phthalate (ratio of 3:1). Stimulation indices (SI) were not reported; however, the EC3 was determined to be 0.2%. A similar study with cinnamaldehyde, at doses of 0, 0.5, 1.0, 2.5, 5 and 10% in acetone/olive oil (ratio of 4:1), reported positive results for skin sensitisation with SI of 1, 1.4, 0.9, 1.9, 7.1 and 15.8 respectively. An EC3 of 3.1% was calculated.
- Cinnamaldehyde has also been reported as sensitising at almost all concentrations (0.1-20%) studied in various guinea pig sensitisation tests. A recent review of cinnamaldehyde by the Danish EPA reported skin sensitisation effects in 90-100% of animals tested at a concentration of 0.75% in three separate guinea pig maximisation tests (GPMTs). Strong sensitisation effects were also reported with 3% cinnamaldehyde, although further study details were not provided. In a modified Draize test, an injection challenge concentration of 0.25% cinnamaldehyde with a 20% topical application challenge dose resulted in sensitisation effects after the challenge was repeated a week later. In addition, concentrations of 0.1-1.0% cinnamaldehyde in acetone have resulted in skin sensitisation effects at all doses in a Buehler delayed hypersensitivity test.
- A 3-day application of 10% cinnamaldehyde on the ear dorsum in mice resulted in a high differentiation index (DI) of 8.7, according to OECD standards. The DI is defined as a ratio of maximum response percentages in lymph node activation and skin inflammation, where a DI >1 indicates an allergic reaction pattern.
Based on the available information, cinnamaldehyde is not considered to cause serious damage to health through repeated oral exposure. Systemic toxicity has not been demonstrated via the dermal route. No information was available for repeated dose toxicity by inhalation route.
Based on the weight of evidence from the available, well-conducted, in vitro and in vivo genotoxicity studies, cinnamaldehyde is not considered to be genotoxic.
No animal toxicity data are available on the carcinogenicity of cinnamaldehyde. Based on the available genotoxicity data, mechanistic information and history of human oral exposure, cinnamaldehyde is not considered to be carcinogenic.
Reproduction and developmental toxicity
Based on the available information, cinnamaldehyde is not expected to be a reproductive or developmental toxin.
Observation in humans
Cinnamaldehyde has been shown to cause skin irritation in humans in a number of reports. Cinnamaldehyde produced irritation in 10/63 volunteers at 3% in diethyl phthalate/ethanol (ratio of 3:1). Severe skin irritation was observed in 5/5 volunteers treated with 8% cinnamaldehyde in petrolatum. In another study, doses of 40 and 48 mg of cinnamaldehyde in petrolatum (concentrations not reported) were applied under occlusive conditions to human skin for 48 hours. Cinnamaldehyde was concluded to be severely irritating to human skin. A review carried out by the Research Institute for Fragrance Materials (RIFM) Expert Panel reported that cinnamaldehyde produced no skin irritation effects in 171 volunteers at concentrations of 0.125-1.25% in a variety of vehicles.
In a limited data eye irritation study, a solution of 8% cinnamaldehyde was instilled in human eyes. Cinnamaldehyde produced slight irritant effects. It was noted that the cornea was not affected; however, no further details were described.
Cinnamaldehyde induced coughing in all ten human subjects following inhalation of nebulised chemical (dose levels from 125-800 mM), with a distinct dose-response relationship observed - the response being the number of coughs recorded after exposure to cinnamaldehyde. Cinnamaldehyde was found to be a specific agonist of the TRPA-1 receptor, and induced cough due to chemaesthesis of the airways.
Cinnamaldehyde is a well-recognised and frequently reported consumer contact allergen. It is one of eight components of the diagnostic test, the fragrance mix, used by dermatologists to determine if a patient has allergies to common chemicals used in fragrances. It is an established contact allergen in humans according to the Scientific Committee on Consumer Safety (2012), and accounts for 5-36% of the reactions to the fragrance mix.
A number of human repeat insult patch tests (HRIPTs) have been undertaken to determine the skin sensitisation potential of cinnamaldehyde in healthy volunteers, as well as groups of subjects suspected of skin allergies to fragrances. Although fewer cases of sensitisation were found when the concentration of cinnamaldehyde was less than 1%, positive allergic responses have been reported in cases where the administered concentration of cinnamaldehyde was as low as 0.2%. Skin irritation effects were generally predominant at concentrations above 3% cinnamaldehyde, and often impeded the interpretation of results from the patch testing.
Many cases of skin sensitisation have occurred following occupational and consumer exposure to cinnamaldehyde. Workers in spice manufacturing plants, hairdressing salons and bakeries have reported cases of contact dermatitis that were traced back to cinnamaldehyde. In addition, exposure of consumers to toothpaste, cosmetics and perfumes containing cinnamaldehyde as a fragrance ingredient have resulted in a number of case studies identifying cinnamaldehyde as an agent responsible for the allergic reactions.
Cinnamaldehyde is a very widely used and easily available fragrance ingredient. Considering the range of domestic, cosmetic and personal care products that may contain cinnamaldehyde, the main route of public (non-food) exposure is expected to be dermal. There is also possible ocular and inhalation exposure from products applied as aerosols. At the applied concentrations, the irritant effects of cinnamaldehyde are unlikely to present a risk. However, there are recorded cases of human skin sensitisation attributed to fragrance use.
The risk of skin sensitisation could be mitigated by implementing concentration limits and restricting uses to limit dermal exposure. The restrictions on the use of cinnamaldehyde in cosmetic products in New Zealand and the European Union are considered appropriate to mitigate the risk.
Pre-meeting public submissions
Three (3) public submissions were received. All three opposed the scheduling proposal. The main points were:
- An Appendix B entry as has been previously considered for other flavour/fragrance ingredients used in cosmetic and household hygiene products with low acute toxicity and low public exposure.
- The EU only requires the inclusion of cinnamaldehyde in the ingredients list, on the label of products, if the concentration in the finished product is ≥0.001% in leave-on products, and ≥0.01% in rinse-off products.
- IFRA standards already exist for cinnamaldehyde and therefore scheduling is not required. cinnamaldehyde should be considered to be included in Appendix B.
- Cinnamaldehyde does not require scheduling due to the derivatives amyl and hexyl cinnamaldehyde being included in Appendix B in September 2016.
- If there are any decisions to schedule cinnamaldehyde, then these should align with IFRA standards.
The public submissions will be made available on the TGA website.
Summary of ACCS-ACMS advice to the delegate
The committee advised that a new Schedule 6 entry be created for cinnamaldehyde:
Schedule 6 - New Entry
- in preparations intended for therapeutic use; or
- in domestic preparations not intended for direct skin contact containing 0.4 per cent or less of cinnamaldehyde when included in the list of ingredients; or
- in leave-on cosmetic and personal care preparations containing 0.001 per cent or less of cinnamaldehyde; or
- in rinse-off cosmetic and personal care preparations containing 0.01 per cent or less of cinnamaldehyde.
The committee also recommended an implementation date of 1 June 2018.
The committee also recommended other actions by the delegate as follows:
- The derivatives definition to be reviewed to provide greater transparency for industry as part of the SPF review.
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 extent of use; (c) the toxicity of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.
The reasons for the advice comprised the following:
- Cinnamaldehyde is a known human allergen and there is evidence of potentially strong sensitisation potential.
- Cinnamaldehyde is a naturally occurring fragrance and flavour substance used internationally in a wide range of products including in food, therapeutic goods, cosmetics and consumer products. There is therefore a potential for significant impact from any scheduling decision.
- Cinnamaldehyde is listed in the US FDA GRAS list.
- Risk and benefit profile of cinnamaldehyde is very similar to another scheduled substance, citral.
- The toxicity profile of cinnamaldehyde show that it is a skin and eye irritant, has acute dermal toxicity, is a strong skin sensitiser and is a respiratory irritant at high concentrations.
- There is a potential for significant impact from any scheduling decision due to the wide range of uses and potentially large numbers of products affected.
The delegate considered the following in regards to this proposal:
- Scheduling proposal
- ACCS-ACMS 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 has decided to defer the interim decision for cinnemaldehyde to allow for further consideration of its use in therapeutic goods and the potential to elicit skin sensitisation reactions at very low concentrations. The advice of the scheduling committee was to create a new Schedule 6 entry with very low exemption cut-off concentrations for domestic or personal products that would result in skin contact during use due to potent skin sensitisation. Similar restrictions are likely to apply to listed therapeutic products when applied topically.
- Singh, Gurdip; Maurya, Sumitra; deLampasona, M.P.; Catalan, Cesar A.N. (2007). "A comparison of chemical, antioxidant and antimicrobial studies of cinnamon leaf and bark volatile oils, oleoresins and their constituents". Food and Chemical Toxicology. 45 (9): 1650-1661
- This report is publicly available on the NICNAS website: Human Health Tier II Assessment for 2-Propenal, 3-phenyl-.
- This report is publicly available at Scientific Committee on Consumer Safety: Opinion on Fragrance allergens in cosmetic products