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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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2.9 Benzyl salicylate

Referred scheduling proposal

An application was submitted by the National Industrial Chemicals

Notification and Assessment Scheme (NICNAS) under their IMAP program to create a new Schedule 6 entry for benzyl salicylate.

Scheduling application

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

Schedule 6 – New Entry

BENZYL SALICYLATE in cosmetic and domestic products except:

  1. in leave-on preparations containing 0.001 per cent or less of benzyl salicylate when labelled with the following statement:

    WARNING – This product contains ingredients which may cause skin sensitisation to certain individuals; or

  2. in rinse-off products containing 0.01 per cent or less of benzyl salicylate when labelled with the following statement:

    WARNING – This product contains ingredients which may cause skin sensitisation to certain individuals.

Appendix E, Part 2 – New Entry

BENZYL SALICYLATE

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

Appendix F, Part 3 – New Entry

BENZYL SALICYLATE

Warning Statement: 28 ((Over) (Repeated) exposure may cause sensitisation).

The applicant's reasons for the request are:

  • Benzyl salicylate is a skin sensitiser;
  • Benzyl salicylate is an eye irritant;
  • Benzyl salicylate is reported to be used in cosmetic and domestic products overseas, in particular, as a fragrance, solvent and UV light absorber at concentrations up to 7%. In the absence of specific Australian information, this is taken as being representative of its use in Australia;
  • There are overseas restrictions for the use of benzyl salicylate in cosmetics; and
  • Skin sensitisation from use of benzyl salicylate in cosmetic products can only be mitigated by implementation of concentration limits.

Current scheduling status and relevant scheduling history

Benzyl salicylate is not currently scheduled. Therefore, a scheduling history is not available.

A derivative of benzyl salicylate, salicylic acid, is in Schedule 3 of the Poisons Standard as follows:

Schedule 3

SALICYCLIC ACID in preparations for dermal use except in preparations containing 40 per cent or less of salicylic acid.

Australian regulatory information

Benzyl salicylate is the AAN (reference Merck Index).

Benzyl salicylate is listed in the Therapeutic Goods (Permissible Ingredients) Determination No. 3 of 2017 as follows:

Table 2.9.1: Permissible ingredients and requirements applying to benzyl salicylate 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
791 BENZYL SALICYLATE 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%.

Benzyl salicylate is an excipient in 331 listed and registered products (both oral and topical) on the ARTG.

According to the TGA Ingredient Database, benzyl salicylate is available for use as an:

  • Active Ingredient in: Biologicals, Prescription Medicines; and
  • Excipient Ingredient in: Biologicals, Devices, Listed Medicines, Prescription Medicines.

International regulations

Benzyl salicylate is in the EU Cosmetic Regulation EC No. 1223/2009, Annex III—List of substances which cosmetic products must not contain except subject to the restrictions laid down. It states that:

'This chemical may be used in cosmetics and personal care products, but the presence of the substance must be indicated in the list of ingredients referred to in Article 19(1)g when its concentration exceeds 0.001% in leave-on products and 0.01% in rinse-off products.'

Substance summary

Benzyl salicylate is a salicylic acid benzyl ester occurring naturally in a variety of plant extracts. It is a clear, colourless to pale yellow oil with a balsamic clean herbal oily sweet scent. Benzyl salicylate is commonly used as a flavour and fragrance agent and as a UV absorber.[21]

Table 2.9.2: Chemical information for benzyl salicylate
Property Benzyl salicylate
Chemical structure chemical structure of benzyl salicylate
Molecular formula C14H12O3
Molecular weight 228.2 g/mol
CAS name Benzoic acid, 2-hydroxy-, phenylmethyl ester
CAS Number 118-58-1
IUPAC and/or common and/or other names Benzyl salicylate (INCI and AAN);
Salicylic acid, benzyl ester; benzyl 2-hydroxybenzoate (IUPAC);
Phenylmethyl 2-hydroxybenzoate.
Table 2.9.3: Acute toxicity end-points for benzyl salicylate
Toxicity Species Benzyl salicylate SPF (2015) Classification
Acute oral toxicity LD50 (mg/kg bw) Rats[22] 2227 Schedule 5
Acute dermal toxicity LD50 (mg/kg bw) Rabbits[23] 14150 N/A
Acute inhalational toxicity LC50 (mg/m3/4h) N/A No data N/A
Skin irritation New Zealand White Rabbits
Dunkin Hartley Guinea pigs
Slightly irritating
Slight erythema
Schedule 5
Eye irritation Rabbit[24] Irritating Schedule 6
Skin sensitisation Local lymph node assay, LLNA Mice[25] Sensitising (EC3 1.5-2.9%) Schedule 6
Guinea pig maximisation test, GPMT Dunkin Hartley Guinea pig Sensitising

Acute toxicity

Based on the available data, benzyl salicylate has low acute oral and dermal toxicity. No data are available for acute inhalation toxicity.

Skin Irritation

Based on the available data in animals and humans (see Observation in humans section), benzyl salicylate is slightly irritating to skin:

  • In two studies in female New Zealand White rabbits, slight erythema and slight oedema was reported in one study, and well defined erythema and very slight to slight oedema was reported in another study when benzyl salicylate was semi-occlusively applied to the shaved flanks.

Slight irritation was observed in Dunkin Hartley guinea pigs after benzyl salicylate was dermally administered (non-occlusively) for 24 or 48 h at 10% (1/5 animals) and 30% (5/5 animals).

Eye irritation

Based on the available data in animals, benzyl salicylate is considered to be an eye irritant:

  • In an in vivo study (Draize method) conducted in albino rabbits (n = 3), 0.1 mL of benzyl salicylate at a 10% concentration in alcohol was instilled into the right eye and animals were observed for 10 days. Mild conjunctival irritation was observed in all rabbits and corneal opacity in one rabbit. All effects were reversed within 7 days. The mean scores reported for iritis (0/4), conjunctival redness (1.89/4), chemosis (1.22/4) and corneal opacity (0.33/4) were below the cut-off for classification. However, individual average (24, 48 and 72 h) scores for 2 rabbits for conjunctival redness were 2/4, which is sufficient for classification by GHS criteria (but not by Approved Criteria). Considering the effects observed at this concentration, benzyl salicylate is expected to be irritating to the eyes if exposed at higher or neat concentrations.

Sensitisation

Based on the available data in mice, benzyl salicylate is considered to be a skin sensitiser.

LLNA

  • Mice were topically administered 25 µL of benzyl salicylate at 10% in 4:1 acetone/olive oil to the ear lobe for three days. The estimated concentration required to produce a three-fold increase in lymphocyte proliferation (EC3) was reported to be 1.5%.
  • The EC3 value was determined to be 2.9% in mice after treatment with benzyl salicylate at 2.5, 5, 10, 25 or 50% in 1:3 ethanol:diethyl phthalate.

GPMT

  • Hartley guinea pigs were intra-dermally and topically induced with benzyl salicylate at 10% and 50%, respectively and challenged at 5, 10 or 20%. Positive reactions were observed at the 20% challenge (2/20) and there were some 'questionable' reactions at other concentrations (3/20 at 5%, 5/20 at 10% and 4/20 at 20%).
  • Hartley albino guinea pigs were intra-dermally and topically induced at 10 and 30%, respectively. After three weeks, the animals were challenged twice at 0.003, 0.01 or 0.03%. No reactions were observed after the first challenge. After the second challenge, positive reactions were reported at 0.03% after 24 h, and at all concentrations after 48 h and 72 h.
  • Female albino Dunkin Hartley guinea pigs were intra-dermally induced with benzyl salicylate at 10%. Following a seven day rest period, benzyl salicylate at 10% in acetone was topically applied to the shoulder region for 48 h. Two weeks later, challenge doses of benzyl salicylate at 5, 10 or 20% in acetone were applied to the shaved flanks of each animal and observations made at 24, 48 and 72 h. Positive reactions were observed at all challenge concentrations.
  • Sensitisation was not reported in outbred Himalayan white-spotted guinea pigs when benzyl salicylate was used at 5% for intradermal induction, 25% in petrolatum for topical induction and <0.1% in petrolatum for the topical challenge.
  • Similarly, no positive reactions were reported in a Magnusson–Kligman GPMT after benzyl salicylate was intra-dermally applied at 1% in ethanol and dermally at 100%; no further study details are available.

Repeat-dose toxicity

No data are available for benzyl salicylate. However, based on data for the metabolites benzyl alcohol (CAS No. 100-51-6) and salicylic acid (CAS No. 69-72-7), benzyl salicylate is not expected to cause serious health effects from repeated oral or inhalation exposure.

Genotoxicity

Limited data are available for benzyl salicylate. However, based on data for the metabolite benzyl alcohol (CAS No. 100-51-6), benzyl salicylate is not considered to be genotoxic.

Carcinogenicity

No data are available for benzyl salicylate. However, based on the data for the metabolites benzyl alcohol (CAS No. 100-51-6) and salicylic acid (CAS No. 69-72-7), benzyl salicylate is not considered to be carcinogenic.

Reproduction and developmental toxicity

No data are available for benzyl salicylate. However, based on data for the metabolites benzyl alcohol (CAS No. 100-51-6) and salicylic acid (CAS 69-72-7), benzyl salicylate is not considered to cause developmental toxicity. Any developmental effects for the metabolites were only observed secondary to maternal toxicity.

Other effects

The oestrogenic activity of benzyl salicylate has been assessed in vitro, using MCF7 human breast cancer cells. Benzyl salicylate was used in a competitive binding assay to the cytosolic oestrogen receptor (ER) of MCF7 cells; a competitive binding assay to human recombinant ERα and ERβ; a gene expression assay using the stably transfected ERE-CAT reporter gene in MCF7 cells; and a cell proliferation assay. Benzyl salicylate mimicked oestrogenic responses in all assays. In the competitive binding assays, 3H-oestradiol was partially displaced by benzyl salicylate (when used at 3 x 106 molar excess) from cytosolic ER of MCF7 cells and from human recombinant ERα and ERβ. In the gene expression assay, benzyl salicylate increased the expression of the oestrogen-responsive reporter gene (ERE-CAT) and the endogenous oestrogen-responsive pS2 gene when cells were exposed at concentrations of 0.05–0.5 mM. In the cell proliferation assay, benzyl salicylate increased proliferation of oestrogen-dependent cells over a seven day period; proliferation was inhibited by an anti-oestrogen drug (fulvestrant). However, it was reported that benzyl salicylate was less potent (requiring 1 mM versus 0.1 µM) and took 2.5-fold longer duration (35 days versus 14 days) to achieve a similar magnitude of proliferation as endogenous 17β-oestradiol.

Further conclusions on the endocrine disruption potential of benzyl salicylate cannot be made. This is an area of concern given the lack of data available for reproductive and developmental toxicity, and due to structural similarity of benzyl salicylate to monobenzyl phthalate (CAS No. 2528-16-7) (unscheduled), which is known to have anti-androgenic activity and the potential to impair fertility and cause teratogenic effects.

Observation in humans

Irritation

In several skin irritation studies in humans, benzyl salicylate at 15–100% was applied to the skin via an occluded patch for 4–48 h. One study reported irritation in 2/22 subjects exposed to benzyl salicylate at 30%.

Skin sensitisation

The International Fragrance Association (IFRA) reported a No Expected Sensitisation Induction Level (NESIL) of 17 700 μg/cm2 based on a human maximisation test and therefore classified benzyl salicylate as a weak sensitiser.

Reports from the Scientific Committee on Cosmetic Products and Non-food Products (SCCNFP), 1999 and the Scientific Committee on Consumer Safety (SCCS), 2011 lists benzyl salicylate as an allergen.

In human patch test studies, results for sensitisation were varied:

  • In five maximisation tests using human volunteers (n = 22–25/study, males and females), benzyl salicylate was administered at 20–30% in petrolatum. Reactions were observed in two studies, affecting 2/25 and 1/25 subjects at 20%. No positive reactions were reported at 30%.
  • In a study that was conducted to determine the optimal patch testing concentration of benzyl salicylate, humans (n = 212) were dermally exposed to benzyl salicylate at 5% in petrolatum. Positive reactions were reported in 12/212 subjects.
  • In three human repeated insult patch tests (HRIPT) conducted on volunteers (n = 35, 52 or 101; males and females), benzyl salicylate was administered at 5–15% in various vehicles (diethyl phthalate:ethanol (3:1) or dimethyl phthalate or alcohol SD39) and observations were made up to 144 h after the final challenge exposure. Positive reactions were not observed in any study.
  • In a human patch test (HPT), 30 volunteers were dermally exposed to 0.2 mL of benzyl salicylate via application to the skin of the upper outer arm for 4 h and observed for 72 h. No reactions were reported.

Public exposure

Benzyl salicylate has been identified to be used in cosmetic (perfumes and fragrances; personal care products; and as an ultraviolet radiation absorber) and domestic products (polishes and waxes; softeners; surface treatments; air care products; and washing and cleaning products) overseas at concentrations up to 7%. This use pattern is taken to be representative of its use in Australia.

Due to the use patterns of benzyl salicylate, direct dermal exposure is expected.

Pre-meeting public submissions

Three (3) public submissions were received and all three opposed 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 benzyl salicylate in the ingredients list 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 benzyl salicylate and therefore scheduling is not required. An Appendix B listing should be considered for benzyl salicylate. If scheduling is to proceed, any scheduling decisions 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 and Appendix E and F entries be created for benzyl salicylate:

Schedule 6 – New Entry

BENZYL SALICYLATE except:

  1. in preparations intended for therapeutic use; or
  2. in domestic preparations:
    1. intended for skin contact containing 15 per cent or less of benzyl salicylate when included in the list of ingredients; or
    2. not intended for direct skin contact when included in the list of ingredients; or
  3. in leave-on cosmetic and personal care preparations:
    1. containing 0.001 per cent or less of benzyl salicylate; or
    2. when included in the list of ingredients; or
  4. in rinse-off cosmetic and personal care preparations:
    1. containing 0.01 per cent or less of benzyl salicylate; or
    2. when included in the list of ingredients.

Appendix E, Part 2 – New Entry

BENZYL SALICYLATE

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)), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F, Part 3 – New Entry

BENZYL SALICYLATE

Warning Statement: 28 ((Over) (Repeated) exposure may cause sensitisation).

Safety Direction: 4 (Avoid contact with skin).

The committee also recommended an implementation date of 1 June 2018.

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 (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the advice were:

  • Benzyl salicylate is a fragrance excipient used in many medicinal, cosmetic and personal care products. It is included as an excipient in 331 products listed on the ARTG. It is used in cosmetics and domestic products.
  • The EU Cosmetic Regulation states "This chemical may be used in cosmetics and personal care products, but the presence of the substance must be indicated in the list of ingredients referred to in Article 19(1)g when its concentration exceeds 0.001% in leave-on products and 0.01% in rinse-off products."
  • The IFRA Standard restricts use to maximum of 12.8% depending on the product use (i.e. those with skin contact). Worldwide use is widespread in cosmetic and domestic products up to 7% concentrations.
  • The risks at concentrations currently used appear low.
  • The toxicity profile for benzyl salicylate shows evidence of skin sensitisation in animals and humans, it is reported to slightly irritate the skin in animals but human studies show inconsistent reports and it is reported as an eye irritant at 10% concentrations in mice. It is a known contact allergen in humans. The toxicity profile meets the SPF requirements of a Schedule 6 item.

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 that new Schedule 6 and Appendix E/F entries be created for benzyl salicylate. The proposed Schedule entry is as follows:

Schedule 6 – New Entry

BENZYL SALICYLATE except:

  1. in preparations intended for therapeutic use; or
  2. in domestic preparations:
    1. intended for skin contact containing 15 per cent or less of benzyl salicylate when declared on the label; or
    2. not intended for direct skin contact when declared on the label; or
  3. in leave-on cosmetic and personal care preparations:
    1. containing 0.001 per cent or less of benzyl salicylate; or
    2. when declared on the label; or
  4. in rinse-off cosmetic and personal care preparations:
    1. containing 0.01 per cent or less of benzyl salicylate; or
    2. when declared on the label.

Appendix E, Part 2 – New Entry

BENZYL SALICYLATE

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)), S1 (If skin or hair contact occurs, remove contaminated clothing and flush skin and hair with running water).

Appendix F, Part 3 – New Entry

BENZYL SALICYLATE

Warning Statement: 28 ((Over) (Repeated) exposure may cause sensitisation).

Safety Direction: 4 (Avoid contact with skin).

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 benzyl salicylate 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 (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the interim decision are:

  • The delegate acknowledges the committee's advice.
  • Benzyl salicylate is a fragrance excipient used in many medicinal, cosmetic and personal care products. It is included as an excipient in 331 products listed on the ARTG. It is used in cosmetics and domestic products.
  • The EU Cosmetic Regulation states "This chemical may be used in cosmetics and personal care products, but the presence of the substance must be indicated in the list of ingredients referred to in Article 19(1)g when its concentration exceeds 0.001% in leave-on products and 0.01% in rinse-off products."
  • The IFRA Standard restricts use to maximum of 12.8% depending on the product use (i.e. those with skin contact). Worldwide use is widespread in cosmetic and domestic products up to 7% concentrations.
  • The risks at concentrations currently used appear low.
  • The toxicity profile for benzyl salicylate shows evidence of skin sensitisation in animals and humans, it is reported to slightly irritate the skin in animals but human studies show inconsistent reports and it is reported as an eye irritant at 10% concentrations in mice. It is a known contact allergen in humans. The toxicity profile meets the SPF requirements of a Schedule 6 item.

Footnotes

  1. http://www.thegoodscentscompany.com/data/rw1001791.html
  2. Strain not specified
  3. Strain not specified
  4. Strain not specified
  5. Strain not specified

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