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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March and July 2017

Scheduling medicines and poisons

15 September 2017

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2.10 Cinnamaldehyde

Referred scheduling proposal

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.

Scheduling application

This was a general application. The applicant's proposed amendments to the Poisons Standard are:

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

CINNAMALDEHYDE

Standard Statement: E1 (If in eyes wash out immediately with water).

Appendix F – New Entry

CINNAMALDEHYDE

Warning Statements: 28 ((Over) (Repeated) exposure may cause sensitisation), 79 (Will irritate eyes).

Safety Direction: 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.

Current scheduling status and relevant scheduling history

Cinnamaldehyde is not currently scheduled and has not previously been considered for scheduling. Therefore, a scheduling history is not available.

In July 2016, the ACCS recommended 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.

Australian regulatory information

Cinnamaldehyde, as well as alpha-methyl cinnamaldehyde, alpha-hexylcinnamaldehyde and alpha-amyl cinnamaldehyde are listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 3 of 2017 as follows:

Table 2.10.1: Permissible ingredients and requirements applying to cinnamaldehyde, alpha-methyl cinnamaldehyde, alpha-hexylcinnamaldehyde and alpha-amyl cinnamaldehyde when contained in a medicine
Column 1 Column 2
Ingredient Name
Column 3
Purpose of the ingredient in the medicine
Column 4
Specific requirements(s) applying to the ingredient in Column 2
453 ALPHA-AMYL CINNAMALDEHYDE E

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%.

459 ALPHA-HEXYLCINNAMALDEHYDE E

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%.

468 ALPHA-METHYL CINNAMALDEHYDE E

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%.

1340 CINNAMALDEHYDE E

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.

International regulations

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.

Substance summary

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.[26]

Table 2.10.2: Chemical information for cinnamaldehyde
Property Cinnamaldehyde
Chemical structure chemical structure of cinnamaldehyde
Molecular formula C9H8O
Molecular weight 132.2 g/mol
CAS name 2-Propenal, 3-phenyl-
CAS number 104-55-2
IUPAC and/or common and/or other names (2E)-3-phenylprop-2-enal (IUPAC);
Cinnamal; cinnamic aldehyde.

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The following information was extracted from the NICNAS New Chemical assessment report for cinnamaldehyde, publicly available on the NICNAS website. Further information can also be found in the publicly available SCCS (2012) Opinion on fragrance allergens in cosmetic products (pdf,4.15Mb*.

Table 2.10.3: Acute toxicity end-points for cinnamaldehyde
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 -
Skin irritation Rabbit Severe skin irritation (undiluted) Schedule 6
Rabbit Mild skin irritation (3-5% solution)
Rabbit No irritation (1% solution)
Eye irritation Rabbit Mild to severe eye irritation (0.125-1%) Schedule 6
Rabbit Severe chemosis and discharge at 1.25%
Skin sensitisation LLNA Mouse Moderate to strong skin sensitiser (EC3 0.2-3.1%) Schedule 6
GPMT Guinea pig Positive reactions in 90-100% of animals tested at 0.75%. Sensitisation effects seen as low as 0.1%.

Acute toxicity

Cinnamaldehyde has low acute oral toxicity, but moderate acute dermal toxicity based on results from animal tests (Table 2.10.3).

Irritation

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.

Sensitisation

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.

Repeat-dose toxicity

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.

Genotoxicity

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.

Carcinogenicity

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

Irritation

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.

Sensitisation

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.

Public exposure

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 and all three opposed the proposal.

Main points opposed:

  • 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 recommended that a new Schedule 6 entry be created for cinnamaldehyde as follows:

Schedule 6 – New Entry

CINNAMALDEHYDE except:

  1. in preparations intended for therapeutic use; or
  2. 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
  3. in leave-on cosmetic and personal care preparations containing 0.001 per cent or less of cinnamaldehyde; or
  4. 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 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 were:

  • 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.

Delegate's considerations

The delegate considered the following regarding 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's interim decision is to create a new Schedule 6 entry for cinnamaldehyde. The proposed Schedule entry is as follows:

Schedule 6 - New Entry

CINNAMALDEHYDE except:

  1. in preparations intended for therapeutic use; or
  2. in domestic preparations not intended for direct skin contact containing 0.4 per cent or less of cinnamaldehyde when declared on the label; or
  3. in leave-on cosmetic and personal care preparations containing 0.001 per cent or less of cinnamaldehyde; or
  4. in rinse-off cosmetic and personal care preparations containing 0.01 per cent or less of cinnamaldehyde.

The proposed implementation date is 1 June 2018. While it is noted that the earliest implementation date for decisions is 1 February 2018, the delegate considers that a 1 June 2018 implementation date is more appropriate as cinnamaldehyde is already in the marketplace and allows sufficient time for industry to make necessary adjustments. The proposed scheduling amendment is not expected to have a significant enough impact to warrant a longer implementation following the final decision.

The matters under subsection 52E(1) of the Therapeutic Goods Act 1989 considered relevant by the delegate 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 (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the interim decision are:

  • The delegate acknowledges the committee's advice.
  • 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.

Footnotes

  1. Singh, G., et al., (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

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