3.1. Interim decision in relation to arbutin

Interim decision on proposed amendment referred to the Advisory Committee on Medicines and Chemicals Scheduling in joint session (Joint ACCS/ACMS #22 June 2019)

Interim decision in relation to arbutin

Interim decision

Pursuant to regulation 42ZCZN of the Regulations, a Delegate of the Secretary has, in relation to the proposed amendment, made an interim decision to amend the current Poisons Standard in relation to arbutin as follows:

Proposed date of effect of the proposed amendment

1 June 2020

Reasons for the interim decision (including findings on material questions of fact)

In this section: Applicant's scheduling proposal and reasons for the proposal | Current scheduling status | Scheduling history | Australian regulations | International regulations | Substance summary | Summary of pre-meeting public submissions | Summary of Joint ACCS-ACMS advice/recommendations to the Delegate | Delegate's considerations | Reasons for the interim decision

Applicant's scheduling proposal and reasons for the proposal

An application to amend the Poisons Standard with respect to arbutin was considered.

The Applicant's proposed amendments to the Poisons Standard were:

Additional proposed amendment to the hydroquinone index entry as follows:

The Applicant's main points provided in support of the proposed amendments were as follows:

• Commonplace and frequent population exposure to arbutin and hydroquinone via common dietary components at levels equal to likely levels arising from herbal exposure, combined with a lack of reports of adverse or toxic effects linked to naturally occurring arbutin, provides an established history of safety;
• Available evidence shows that almost all hydroquinone released upon ingestion of arbutin is rapidly conjugated and eliminated with the urine;
• Available evidence shows that the quantity of free, unconjugated hydroquinone released from arbutin in vivo is two orders of magnitude lower than the European Medicines Agency's (EMA) permitted daily exposure (PDE) level for hydroquinone; and
• Naturally occurring arbutin in herbal medicines therefore does not present an unacceptable risk to human health.

Current scheduling status

Arbutin is not specifically scheduled in the Poisons Standard but has a cross reference to hydroquinone in the index of the Poisons Standard as follows:

Hydroquinone is listed in the Poisons Standard as follows:

Hydroquinone is also included in Appendix E and F as follows:

Scheduling history

Hydroquinone

In 1969, hydroquinone was first included in Schedule 4 by the Poisons Schedule Sub-Committee (PSSC). This listing was due to concerns raised about the promotion and free availability of skin lightening creams which were being targeted to the PNG and Indigenous Australian populations.

In February 1971, the PSSC agreed to amend the Schedule 4 entry for hydroquinone to allow an exemption from scheduling for preparations of hydroquinone containing ≤2 per cent.

In May 1986, the Drugs and Poisons Schedule Committee (DPSC) considered deleting the ≤2 per cent exemption i.e. all human use hydroquinone and monobenzone becoming Schedule 4. The DPSC considered the overall Adverse Drug Reactions Advisory Committee (ADRAC) profile for hydroquinone and monobenzone and recommended that these substances warranted a Schedule 4 listing. However, this recommendation was not implemented.

In May 1987, the DPSC agreed to foreshadow creation of a new Schedule 2 entry for hydroquinone for human therapeutic or cosmetic use at ≤2 per cent (with an Appendix F Warning Statement). This was confirmed at the July 1987 Meeting.

In June 2008, the National Drugs and Poison Schedule Committee (NDPSC), following a request from the Over the Counter (OTC) Medicines Section of the TGA, gave consideration as to whether hydroquinone was appropriately scheduled. The NDPSC noted concerns about possible carcinogenicity of hydroquinone with prolonged usage.

In October 2008, the NDPSC foreshadowed consideration of the rescheduling of hydroquinone and possible up-scheduling hydroquinone in preparations for human external use (excluding hair dyes) to Schedule 3.

In August 2018, the TGA outlined changes that would be made to the Therapeutic Goods (Permissible Ingredients) Determination in June 2018. This included clarification of the Poisons Standard requirements for arbutin. As of 1 July 2018 ingredients known to contain arbutin will have arbutin listed as a mandatory component with associated specific requirements in line with the Poisons Standard. The affected ingredients include Achillea millefolium, Arctostaphylos uva-ursi (leaf), Chimaphila umbellate, Kalmia latifolia, Ledum palustre, Origanum majorana, Pyrus communis, Pyrus pyrifolia, Rhododendron ferrugineum, Turnera diffusa, Vaccinium vitis-idaea (leaf). The concentration of arbutin in the medicine must be no more than 25 mg/kg or 25mg /L or 0.0025 per cent unless used on the hair. This cut-off is based on the exemption in Part 1, Interpretation of the Poisons Standard, which states a scheduled substance (in Schedules 1 to 6 only) can be present at a concentration below 10 mg per litre or 10 mg per kg. The 25 mg/kg or 25mg /L or 0.0025 per cent cut-off for arbutin has been calculated based on the amount of hydroquinone converted into arbutin.

Hair preparations

In July 1987, the DPSC agreed to a general exemption from scheduling for ≤1 per cent hydroquinone in hair preparations.

In October 2008, the NDPSC noted that the European Union (EU) cut-offs for hydroquinone as an unapproved cosmetic ingredient (≤0.3 per cent in hair dyes) were more restrictive than the Poisons Standard controls (allowing ≤1 per cent).

In February 2009, the NDPSC considered a proposal to amend the exemption for use in hair dyes from 1 per cent to 0.3 per cent, in line with the European Union (EU) cut-offs. The NDPSC decided to amend the exemption for hair preparations containing hydroquinone from 1 per cent to 0.3 per cent or less.

Salts and derivatives

In May 1987, the DPSC noted that monobenzone was actually more potent than hydroquinone and agreed to foreshadow that it should be in Schedule 4, together with other derivatives of hydroquinone for human therapeutic or cosmetic use, with no exceptions (whereas hydroquinone had a Schedule 2 entry). The NDPSC also noted that the other ether derivatives of hydroquinone were more potent than hydroquinone and had a similar side effect level to monobenzone.

In July 1987, the DPSC amended the foreshadowed monobenzone entry by specifying capture of 'other alkyl ethers of hydroquinone for human therapeutic use or cosmetic use' rather than all derivatives. [No reason was recorded]. This remains the wording in the current monobenzone entry.

In February and June 2009, the NDPSC considered the scheduling of hydroquinone for therapeutic and cosmetic use. Both meetings supported deferring a decision on the scheduling of hydroquinone in skin bleaching products (for external therapeutic use) until the USFDA report was available. The Committee agreed that arbutin for cosmetic use should continue to be scheduled as a derivative of hydroquinone and that a cross reference with glycosylated hydroquinone in the Poisons Standard index be created.

Australian regulations

• According to the TGA Ingredient Database:
  • Arbutin is not available for use as an active ingredient or excipient in any application. However, arbutin is available for use as an equivalent ingredient in export only and listed medicines.
  • Hydroquinone derivatives calculated as anhydrous arbutin are not available for use as an active ingredient or excipient in any application. However, it is available for use as equivalent ingredients in export only and over the counter medicines.
  • The following plant extracts are sources of arbutin and are available for use as follows:
    • Achillea millefolium: available for use as an active ingredient in export only, listed medicines, over the counter, and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in export only, listed medicines, over the counter, and prescription medicines. Not available as an equivalent ingredient in any application.
    • Arctostaphylos uva-ursi: available for use as an active ingredient in export only, listed medicines, over the counter and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in export only, listed medicines, over the counter and prescription medicines. Not available as an equivalent ingredient in any application.
    • Kalmia latifolia: available for use as an active ingredient in export only, listed medicines, over the counter and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in prescription medicines. Not available as an equivalent ingredient in any application.
    • Ledum palustre: available for use as an active ingredient in export only, listed medicines, over the counter and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in prescription medicines. Not available as an equivalent ingredient in any application.
    • Origanum majorana: available for use as an active ingredient in export only, listed medicines, over the counter, and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in prescription medicines. Not available as an equivalent ingredient in any application.
    • Pyrus communis: available for use as an active ingredient in export only, listed medicines, over the counter and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in devices, export only, listed medicines, over the counter and prescription medicines. Not available as an equivalent ingredient in any application.
    • Pyrus pyrifolia: available for use as an active ingredient in listed medicines and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in prescription medicines. Not available as an equivalent ingredient in any application.
    • Rhododendron ferrugineum: available for use as an active ingredient in export only, listed medicines, over the counter and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in prescription medicines. Not available as an equivalent ingredient in any application.
    • Turnera diffusa: available for use as an active ingredient in export only, listed medicines, over the counter and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in export only, listed medicines, over the counter and prescription medicines. Not available as an equivalent ingredient in any application.
    • Vaccinium vitis-idaea: available for use as an active ingredient in listed medicines and prescription medicines. Available for use as a homoeopathic ingredient in listed medicines. Available for use as an excipient ingredient in prescription medicines. Not available as an equivalent ingredient in any application.
• As of 8 May 2019, there are no medicines currently active on the Australian Register of Therapeutic Goods (ARTG)^[43] that contain arbutin as an active ingredient. However, the following plants, which are known sources or arbutin, are found on the ARTG as follows:
  • Achillea millefolium: 17 products;
  • Arctostaphylos uva-ursi: 21 products;
  • Kalmia latifolia: 2 products;
  • Ledum palustre: 3 products;
  • Origanum majorana: 12 products;
  • Pyrus communis: 4 products;
  • Turnera diffusa: 51 products; and
  • Vaccinium vitis-idaea: 1 product.
• The following plant extracts which are sources of arbutin are permitted to be included in listed medicines according to the Therapeutic Goods (Permissible Ingredients) Determination No.2 of 2019^[44] as follows:

Item	Ingredient name	Purpose	Specific requirements
333	Achillea millefolium	A, E, H	Arbutin is a mandatory component of Achillea millefolium. The concentration of arbutin in the medicine must be no more than 25 mg/kg or 25mg/L or 0.0025% unless used on the hair. When for use on hair, the concentration of arbutin in the medicine must be no more than 0.74%.
646	Arctostaphylos uva-ursi	A, E, H	Arbutin is a mandatory component of Arctostaphylos uva-ursi. The concentration of arbutin in the medicine must be no more than 25 mg/kg or 25mg/L or 0.0025% unless used on the hair. When for use on hair, the concentration of arbutin in the medicine must be no more than 0.74%.
1314	Chimaphila umbellata	A, H	Arbutin is a mandatory component of Chimaphila umbellata. The concentration of arbutin in the medicine must be no more than 25 mg/kg or 25mg/L or 0.0025% unless used on the hair. When for use on hair, the concentration of arbutin in the medicine must be no more than 0.74%.
2826	Kalmia latifolia	A, H	Arbutin is a mandatory component of Kalmia latifolia. The concentration of arbutin in the medicine must be no more than 25 mg/kg or 25mg /L or 0.0025% unless used on the hair. When for use on hair, the concentration of arbutin in the medicine must be no more than 0.74%.
2946	Ledum palustre	A, H	Arbutin is a mandatory component of Ledum palustre. The concentration of arbutin in the medicine must be no more than 25 mg/kg or 25mg/L or 0.0025% unless used on the hair. When for use on hair, the concentration of arbutin in the medicine must be no more than 0.74%. When the route of administration is other than topical, the maximum recommended daily dose must not contain more than 0.001 mg of the equivalent dry herbal material of Ledum palustre.
3575	Origanum majorana	A, H	Arbutin is a mandatory component of Origanum majorana. The concentration of arbutin in the medicine must be no more than 25 mg/kg or 25mg/L or 0.0025% unless used on the hair. When for use on hair, the concentration of arbutin in the medicine must be no more than 0.74%. When the plant preparation is oil or distillate, the nominal capacity of the container must be no more than 50 millilitres. When the concentration of Origanum majorana oil or distillate in the preparation is greater than 50%, a restricted flow insert must be fitted on the container and following warning statement is required on the medicine label: (CHILD) 'Keep out of reach of children' (or words to that effect).
4204	Pyrus communis	A, E, H	Arbutin is a mandatory component of Pyrus communis. The concentration of arbutin in the medicine must be no more than 25 mg/kg or 25mg/L or 0.0025% unless used on the hair. When for use on hair, the concentration of arbutin in the medicine must be no more than 0.74%.
4205	Pyrus pyrifolia	A, H	Arbutin is a mandatory component of Pyrus pyrifolia. The concentration of arbutin in the medicine must be no more than 25 mg/kg or 25mg/L or 0.0025% unless used on the hair. When for use on hair, the concentration of arbutin in the medicine must be no more than 0.74%.
4284	Rhododendron ferrugineum	A, H	Arbutin is a mandatory component of Rhododendron ferrugineum. The concentration of arbutin in the medicine must be no more than 25 mg/kg or 25mg/L or 0.0025% unless used on the hair. When for use on hair, the concentration of arbutin in the medicine must be no more than 0.74%.
5022	Turnera diffusa	A, E, H	Arbutin is a mandatory component of Turnera diffusa. The concentration of arbutin in the medicine must be no more than 25 mg/kg or 25mg/L or 0.0025% unless used on the hair. When for use on hair, the concentration of arbutin in the medicine must be no more than 0.74%.
5070	Vaccinium vitis-idaea	A, H	Arbutin is a mandatory component of Vaccinium vitis-idaea. The concentration of arbutin in the medicine must be no more than 25 mg/kg or 25mg/L or 0.0025% unless used on the hair. When for use on hair, the concentration of arbutin in the medicine must be no more than 0.74%.
A = active ingredient, E = excipient, H = homoeopathic preparation ingredient

International regulations

• The European Chemicals Agency (ECHA) hazard classification for arbutin is, 'Warning! According to the classification provided by companies to ECHA in CLP notifications this substance causes serious eye irritation, causes skin irritation and may cause respiratory irritation'.
• In 2018, the European Medicines Agency (EMA) Herbal Medicinal Products Committee (HMPC) concluded that on the basis of its long-standing use, bearberry leaf preparations (Arctostaphylos uva-ursi) can be used for treating symptoms of mild, recurrent infections in the lower urinary tract, such as a burning sensation when passing urine and/or frequently passing urine. The HMPC conclusions on the use of these bearberry leaf medicines for lower urinary tract infections are based on their 'traditional use'. This means that, although there is insufficient evidence from clinical trials, the effectiveness of these herbal medicines is plausible and there is evidence that they have been used safely in this way for at least 30 years (including at least 15 years within the EU). Moreover, the intended use does not require medical supervision. In its assessment, the HMPC considered laboratory studies which showed bearberry leaf preparations to have antibacterial action. No clinical studies are available with preparations containing only bearberry leaf.
• European Scientific Cooperative on Phytotherapy (ESCOP) supports the use of Arctostaphylos uva-ursi for uncomplicated infections of the lower urinary tract, such as cystitis. The ESCOP monograph states that Arctostaphylos uva-ursi should contain a minimum of 7.0% anhydrous arbutin.
• In the United States (US), the use of bearberry (extract of uva ursi) and bearberry fluidextract (extract of bearberry) as a 'menstrual/diuretic' is regulated under 21 CFR 310.545(a)(24); marketing of products for these uses requires an approved new drug application.

Substance summary

Table 1: Chemical information for arbutin

Property	Arbutin
Chemical structure
Molecular formula	C12H16O7
Molecular weight	272.25 g/mol
CAS name	β-D-Glucopyranoside, 4-hydroxyphenyl
CAS number	497-76-7
IUPAC and/or common and/or other names	Arbutin, arbutoside, (2R,3S,4S,5R,6S)-2-Hydroxymethyl-6- (4-hydroxyphenoxy)oxane-3,4,5-triol (IUPAC), Hydroquinone 1-O-beta-D-glucopyranoside, Hydroquinone β-D-glucopyranoside, 4-hydroxyphenyl-beta-D-glucopyranoside

Hydroquinone 1-O-beta-D-glucopyranoside is the chemical identity of arbutin (Quintus 2005). The molecular weight is 272.25 g/mol (de Arriba 2013).

The three major metabolites of arbutin in vivo in order of decreasing concentration are hydroquinone glucuronide > hydroquinone sulfate > free hydroquinone (Schindler 2002).

Arbutin is a naturally occurring phenolic glycoside in many widely consumed food plants, including blueberry, cranberry (and other Vaccinium species), pear, bean, wheat, coffee, wine and broccoli (Deisinger 1996, Blaut 2006, Booth 2012). The amount of arbutin in a pear (12.7 mg) would be metabolised to hydroquinone in 1-4 hrs (Blaut 2006). A typical dietary consumption of arbutin rich foods of 2-3 cups of tea/coffee, plus 1 glass of red wine in a person of 60 kg would result in exposure of free hydroquinone from 0.66-4.5 mcg/kg bw/d to 9.3 mcg/kg bw/d (de Arriba 2013).

Summary of pre-meeting public submissions

Nine (9) submissions were received in response to the notice published under regulation 42ZCZK advising of the proposed amendment. Seven (7) were in support and two (2) opposed the proposed amendments (one (1) of which suggested further amendments).

The main points in support of the proposed amendments:

• Arbutin is a constituent of a number of herbs, however the scheduling has particularly affected the supply of herbal preparations of bearberry (Arctostaphylus uva ursi) and Damiana (Turnera diffusa). These herbal preparations that contain arbutin have a long history of use by western herbal medicine practitioners in Australia without adverse effects. The un-scheduling of naturally occurring arbutin in herbal medicines does not present an unacceptable risk to human health.
• Naturally occurring arbutin in herbal preparations for internal human therapeutic use should not require restriction via scheduling as they have not been shown to present an unacceptable risk to public health. Arbutin itself is now approved for use in cosmetic products in the EU, with listed functions including antioxidant, skin conditioning and skin lightening.
• The NDPSC record of reason from 2009 stated '...that until more robust data was available regarding the actual risk of arbutin, then it remained appropriate to take a conservative approach and control arbutin under the current scheduling of hydroquinone as a derivative...'. Since the 2009 consideration, new data on the safety of arbutin when used in cosmetics has become available. The European Commission's Scientific Committee on Consumer Safety (SCCS) published two opinions relating to the substances α-arbutin and β-arbutin which came to the following conclusions:
  • The SCCS considers the use of α-arbutin safe for consumers in cosmetic products in a concentration up to 2% in face creams and up to 0.5 % in body lotions.
  • The SCCS considers the use of β-arbutin to be safe for consumers in cosmetic products in a concentration up to 7% in face creams provided that the contamination of hydroquinone in the cosmetic formulations remain below 1 ppm.^[45] Therefore, the cosmetic use of arbutin can now be reconsidered to allow its use in line with the findings of the SCCS opinions as detailed above.
• Pharmacists have noted that some arbutin-containing products carry claims that alpha-arbutin is 'much stronger in effect than arbutin or beta-arbutin'. As per the SCCS opinion on alpha and beta arbutin, the ACMS should consider whether different concentration limits need to be applied to the two arbutin derivatives if they are to be included in the Poisons Standard.
• The proposed limit for oral herbal preparations of 500 mg or less of arbutin per recommended daily dose appears to be within acceptable range. However, it is also reported that traditional use of arbutin can only be recommended for females. The use of arbutin by men is only recommended when advised by a medical practitioner due to the risk of more severe infections (and not on the basis of traditional use). There is also reference to the recommended time of use being limited to two weeks.
• Specific consideration is also warranted on whether different or additional controls should be applied for:
  • Different arbutin derivatives for external use;
  • The use of oral arbutin preparations for urinary tract infections in males; and
  • The recommended duration of use of oral arbutin preparations.
• The individual listing of arbutin rather than the current arrangement of being captured as a derivative of hydroquinone, with a cross-reference to arbutin in the index will ensure that the requirements for products containing arbutin are clear and more easily identified.
• The proposed upper limit of 500 mg of arbutin or less per daily recommended dosage is well within the EMA safe level of 840 mg per day as stated in their assessment report on Arctostaphylos uva-ursi.
• Whilst arbutin can be hydrolysed to hydroquinone, pharmacokinetic data indicate that it is stable in gastric acid and only deglycosylated once in the liver, whereby the liberated hydroquinone is immediately conjugated to hydroquinone glucuronide and hydroquinone sulfate. Subsequent hydrolysis to hydroquinone only occurs at the point of excretion in the urine, providing the known urinary antimicrobial effect of herbal medicines such as Arctostaphylos uva-ursi.
• The molar mass of arbutin is 272.243 g/mol compared to 110.112 g/mol for hydroquinone. Thus, from a toxicological perspective, arbutin and hydroquinone cannot be regarded as equivalent when consumed orally in the context of a herbal preparation

The main points in opposition of the proposed amendments:

• The proposed Schedule 2 entry is unnecessarily restrictive in relation to human external therapeutic and cosmetic use products. In 2015, the SCCS published that they consider β-arbutin to be safe for consumers in cosmetic products in a concentration up to 7% in face creams provided the contamination of hydroquinone remains below 1 ppm. In 2015, the SCCS also published their opinion that α-arbutin is safe for consumers in cosmetic products in a concentration in face creams and up to 0.5% in body lotions.
• Given the above, the following alternative wording was proposed in the public submission:

  Schedule 4 - New Entry

  ARBUTIN in preparations for human therapeutic or cosmetic use except:

  1. when included in Schedule 2; or
  2. in hair preparations containing 0.75 per cent; or
  3. in cosmetic nail preparations containing 0.05 per cent; or
  4. in oral herbal preparations containing 500 mg or less of arbutin per recommended daily dose; or
  5. in preparations for human external therapeutic or cosmetic use for the face containing not more than 2 per cent; or
  6. in preparations for human external therapeutic or cosmetic use for the body containing not more than 0.05 per cent.

  Schedule 2 - New Entry

  ARBUTIN in preparations for human external therapeutic or cosmetic use (excluding hair preparations and cosmetic nail preparations) containing between more than 2 percent and not more than 5 percent of arbutin except:

  1. in hair preparations containing 0.75 percent; or
  2. in cosmetic nail preparations containing 0.05 percent; or
  3. in preparations for human external therapeutic or cosmetic use for the face containing not more than 2 percent; or
  4. in preparations for human external therapeutic or cosmetic use for the body containing not more than 0.05 percent.
• As evidenced by the SCCS reports, topical arbutin at the proposed limits does not pose a risk of harm to public health.
• Benefits of the proposed limit include permitting greater access by consumers. The ability of consumers to manage minor skin imperfections without posing a burden on the public purse through unnecessary medical consultations as well as relieve undue pressure on pharmacists so that they may concentrate on more appropriate health concerns.
• The wording under this proposal is for topical application in human therapeutic or cosmetic goods. The LD₅₀ value via the dermal route showed to be greater than 928 mg/kg bw (the technically applicable maximal dose). The tested animals showed no signs of harm for application via dermal route. It is expected this would likely be similar for humans.
• One of the main issues with arbutin is the presence of hydroquinone, and there is no mention of any residue limits on hydroquinone. This should be added for clarity.

Summary of Joint ACCS-ACMS advice/recommendations to the Delegate

The Committee recommended that a new Schedule 4 entry be created for arbutin in the Poisons Standard as follows:

The Committee also recommended an amendment to the hydroquinone index entry as follows:

The Committee recommended an implementation date of 1 June 2020.

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 and extent of use; (c) the toxicity of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

The reasons for the advice included:

1. risks and benefits of the use of a substance:
   • Benefits:
     • Benefits relate mainly to traditional use. It is in many listed herbal medicines and herbal ingredients available for use to practitioners.
   • Risks:
     • Little risk as <0.6% excreted as free hydroquinone in urine.
     • In common foods and herbs with little toxic effects.
     • The risks of arbutin are associated with potential for hydrolysis to form free hydroquinone, which is regarded as having higher level of risk compared to arbutin.
2. the purpose for which a substance is to be used and the extent of use:
   • Arbutin is commonly found in foods and is a component of 11 herbal ingredients included in the TGA Permitted Ingredients Determination, which are available to sponsors to be included in products listed on the ARTG. There are many listed medicines containing these ingredients that have arbutin as a mandatory component.
   • Arctostaphylos uva-ursi, a major source of arbutin, has a history of traditional use in symptoms of cystitis. The TGA restricts indications for listed medicines to those in the Permitted Indications list. The other 10 herbal ingredients have a traditional use in a variety of other indications.
3. the toxicity of a substance:
   • Consistent with Schedule 4.
   • Toxicity concerns relate mainly to risks associated with conversion to hydroquinone.
4. the dosage, formulation, labelling, packaging and presentation of a substance:
   • Nil.
5. the potential for abuse of a substance:
   • No evidence of abuse or misuse of the affected herbal medicines.
6. any other matters that the Secretary considers necessary to protect public health:
   • Use in men: For Arctostaphylos uva-ursi, community EMA monograph (2018) notes that clinical use in men is not recommended based on risk of complicated UTI in men above age 50 which may be due to benign prostatic hyperplasia and thus require the assessment by a medical practitioner. This may be helped by labelling.

Delegate's considerations

In making this interim decision, I have considered the following material:

• The application to amend the current Poisons Standard with respect to arbutin;
• Joint Meeting of the Advisory Committee on Chemicals Scheduling and the Advisory Committee on Medicines Scheduling's advice;
• The public submissions received before the first closing date;
• Section 52E of the Therapeutic Goods Act 1989, in particular: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health;
• The Australian Health Ministers' Advisory Council's Scheduling Policy Framework (SPF 2018); and
• The Australian Health Ministers' Advisory Council's Scheduling Handbook (V 1.0, January 2018).

Reasons for interim decision

I agree with the Committee's finding that the relevant matters of section 52E of the Therapeutic Goods Act 1989 are: (a) risks and benefits of the use of a substance; (b) the purpose for which a substance is to be used and the and extent of use; (c) the toxicity of a substance; (e) the potential for abuse of a substance; and (f) any other matters that the Secretary considers necessary to protect public health.

In my view, the relevant parts of the Scheduling Policy Framework (SPF) 2018 are the Scheduling Factors for Schedule 4.

I have made the decision to amend the current Poisons Standard to create a new Schedule 4 entry for arbutin and I have set out my reasons below.

I am of the view that arbutin and hydroquinone are separate substances of differing toxicity and molecular make up and as a result, should each have separate entries in the Poisons Standard. I agree with the data presented in the application that arbutin has a significant history of traditional use and is present in many food sources, as well as being a component of eleven herbal ingredients included in the TGA Permitted Ingredients Determination.

I have taken into consideration the toxicological data presented and I find that the proposed cut-off of 500 mg or less of arbutin per recommended daily dose as proposed by the Applicant to be acceptable. The amount of free hydroquinone following absorption of a 500 mg dose of arbutin would result in acceptable amounts of free hydroquinone in accordance with the cut-offs for hydroquinone in the Poisons Standard. I acknowledge that this cut off is well within the safe levels outlined by the European Scientific Cooperative on Phytotherapy (ESCOP), the European Medicines Agency (EMA) monograph and the British Pharmacopoeia (PB) monograph.

I find the Schedule 4 entry for arbutin appropriate, noting that any dosage of arbutin above the cut-off requires medical management by a general practitioner.

I have considered that the scheduling proposal provided limitations on the use of arbutin in cosmetic products and that these limits were a direct conversion of the hydroquinone cut-offs as set out in the Poisons Standard. Several public submissions suggested adopting the cut-offs outlined in the European (Scientific Committee on Consumer Safety) report. However, as the nature of the current scheduling application and associated toxicological data was in reference to the traditional use of arbutin in herbal preparations, I find that on balance, the topical use of arbutin should be considered in a separate consultation. This would allow for specific consideration of toxicity data on the dermal effects of arbutin.

I note that the current decision will affect the Permissible Ingredients Determination, which will require updating to the eleven herbs cross referenced in the list.

---