public consultation on the proposed amendments to the ......conversion to ghb has not been raised as...

Public Consultation on the Proposed Amendments to the Poisons Standard

Notice under subsections 42ZCZL of the Therapeutic Goods Regulations 1990 (the Regulations)

A delegate of the Secretary to the Department of Health publishes herein all valid public submissions made in response to the invitation for public submission on the proposed amendments to the Poisons Standard. These submissions were considered by the joint committee of the Advisory Committee on Chemicals Scheduling and the Advisory Committee on Medicines Scheduling (ACCS-ACMS) #10 (November 2014 meeting).

In accordance with the requirements of subsection 42ZCZL of the Regulations these submissions have had confidential information removed.

Material claimed to be commercial-in-confidence was considered against the guidelines for the use and release of confidential information set out in Chapter 6 of the Scheduling Policy Framework for Medicines and Chemicals (SPF). The SPF is accessible at www.tga.gov.au/industry/scheduling-spf.htm .

Eight submissions were received.

The Secretary Scheduling Secretariat GPO Box 9848 CANBERRA ACT 2601

I'J accord hygiene, cosmetic & specialty products industry

Email: [email protected]

Dear Sir/Madam

Public Comment Submission to the March 2014

joint meeting of the Advisory Committee on Chemicals Scheduling (ACCS) and the Advisory Committee on Medicines Scheduling (ACMS)

We refer to the notice published on 14 August 2014 inviting public submissions, with respect to certain substances, addressing a matter raised in s.52E of the Therapeutic Goods Act 1989.

Accord Australasia Limited is the peak national industry association that represents the hygiene, cosmetic & specialty products industry.

Accord wishes to provide information on gamma-butyrolactone for consideration at the November 2014 joint meeting of the ACCS and ACMS.

Please see the attached submission for details.

We thank the Committees and the Secretariat for the extension to provide comments. lt is greatly appreciated.

Accord is an interested party and stake holder with regard to the nominated substances and would appreciate being advised of the Committees' considerations and the Delegate's interim decision, with the opportunity for further submission, if appropriate.

We look forward to further advice from the ACCS, ACMS and the Delegate. Should the Committees or the Delegate re�onal information from Accord at this stage please do not hesitate to contact me on -- ·

Yours faithfully

[ lmsigned for electronic submission]

1 1 September 2014

Accord Australasia Limited ACN 111659168 ABN a3 205141 267

Fusion C4.02, 22- 36 Mountain Street, Ultimo NSW 2007 PO Box 290 BROADWAY NSW 2007

Tel: 61 2 9281 2322 Fax: 61 2 9281 0366 Website: www.accord.asn.au

Products for ltealtlty living and a quality lifestyle

ACCS/ACMS joint-meeting: November 2014

Gamma-butyrolactone

While the feedback from our Members suggests that gamma-butyrolactone is either not used in cosmetics in Australia or its use is very low, according to the International Cosmetic Ingredient Dictionary and Handbook, gamma-butyrolactone (INCI name butyrolactone) can be used as a solvent or fragrance ingredient in nail polish and enamel removers. Gamma-butyrolactone is also listed as a solvent and masking agent in the EU Cosmetic Ingredients database with no restrictions. While the reasons behind the scheduling proposal have not been divulged, based on the proposal to consider the addition of gamma-butyrolactone to Schedule 9 we believe that the concern may relate to gamma-butyrolactone being a precursor of gamma-hydroxybutyrate (GHB), a known recreational drug. If the reason for this consideration is in fact due to the potential misuse of gamma-butyrolactone as a precursor to a recreational drug, we believe that the scheduling controls should only apply to the types of products that could be misused i.e. where gamma-butyrolactone is a major ingredient in the product with no other toxic or unpleasant tasting ingredients, or where gamma-butyrolactone can be easily extracted from the product. As far as we are aware, individual ingredients in products like nail polish and enamel removers are difficult to extract from the product. Any scheduling consideration should also restrict the schedule entry to gamma-butyrolactone. As gamma-butyrolactone is a simple molecule, inclusion of derivatives is likely to capture a much wider range of chemicals with unintended consequences (salts of gamma-butyrolactones are not likely to exist). Many lactones occur naturally and are known to give a “creamy” tone to the fragrance of flowers such as jasmine, tuberose and gardenias. It is our understanding that they also occur in fruits such as peaches, apricots and plums. Naturally occurring substances found in these plants such as gamma-undecalactone (also known as peach lactone) and gamma-nonalactone (also known as coconut lactone) as well as synthetic lactones such as gamma-methyl decalactone are used as fragrances. While all of these chemicals are derivatives of gamma-butyrolactone, as far as we are aware, their potential for conversion to GHB has not been raised as a concern. We also understand that many derivatives of gamma-butyrolactone are used as food flavours e.g. gamma-hexalactone (toasted almond, caramel, tomato), gamma-heptalactone (caramel, milk, nut flavours) and gamma-decalactone (cappuccino, custard, beer). Again, as far as we are aware, no concerns have been raised with the potential for these flavours agents to convert to GHB.

Chemicals Scheduling Secretariat GPO Box 9848 CANBERRA ACT 2601

Email: [email protected]

Dear Sir/Madam

I'J accord hygiene, cosmetic & specialty products industry

Public Comment Submission to the November 2014

joint meeting of the Advisory Committee on Chemicals Scheduling (ACCS)

and the Advisory Committee on Medicines Scheduling (ACMS)

We refer to the notice published on 25 September 2014 inviting public submissions, with respect to certain substances, addressing a matter raised in s.52E of the Therapeutic Goods Act 1989.

Accord Australasia Limited is the peak national industry association that represents the hygiene, cosmetic & specialty products industry.

Accord wishes to provide information on:

• 1-butanol;

• 1-propanol; • 2-cyclohexylphenol;

• Lemongrass oil; and

• Soluble oxalates;

for consideration at the November 2014 joint meeting of the ACCS and ACMS.

Please see the attached submission for details.

Accord is an interested party and stakeholder with regard to the nominated substances and would appreciate being advised of the Committees' considerations and the Delegate's interim decision, with the opportunity for further submission, if appropriate.

We look forward to further advice from the ACCS, ACMS and the Delegate. Should the Committees or the Delegate re�onal information from Accord at this stage please do not hesitate to contact me on - ·

Yours faithfully

[ lmsigned for electronic submission]

23 October 2014

Accord Australasia Limited ACN 111659168 ABN a3 205141 267

Fusion C4.02, 22- 36 Mountain Street, Ultimo NSW 2007 PO Box 290 BROADWAY NSW 2007

Tel: 61 2 9281 2322 Fax: 61 2 9281 0366 Website: www.accord.asn.au

Products for ltealtlty living and a quality lifestyle

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1-butanol

Accord had previously questioned the need to schedule 1-butanol based solely on ocular irritancy that is common to most solvents. While we now understand that the concern is raised with the aerosol or spray formats of products containing, we are still unsure whether scheduling of this solvent is necessary. Hydrocarbon aerosol propellants such as butane are also eye irritants (although it appears milder than 1-butanol), especially when they are in their liquid form (liquefied butane can cause burns or frostbites to the eyes). However, it is well known that aerosols are meant to be sprayed away from the eyes, which could explain the reason for the low level of incidents involving propellant eye irritancy. We also note that trigger nozzle sprays are designed in such a way so that the nozzle is aimed away from person using the spray. While we understand that aerosols and sprays can still be aimed at others, we believe this is moving into deliberate misuse scenario. NICNAS IMAP report on 1-butanol notes that 1-butanol is classified as irritating to eyes between 5-10%, and irritant causing irreversible eye damage at concentrations greater than or equal to 10%. It also notes that internationally, 1-butanol is used between 1-10% in domestic products. Given that 1-butanol classified as reversible eye irritant in concentrations < 10%, which is known to be the use concentration based on the US domestic products data, we do not believe that scheduling of 1-butanol is necessary. However, if some controls are deemed necessary, we believe products containing up to 10% should be exempt from scheduling. Further other controls such as safety, warning and first aid statements should be considered for higher concentrations rather than inclusion in schedules i.e. reverse scheduling. Any scheduling controls should also be restricted to products in aerosol or spray formats.

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1-propanol

Accord had previously questioned the need to schedule 1-propanol based solely on ocular irritancy that is common to most solvents. While we now understand that the concern is raised with the aerosol or spray formats of products containing, we are still unsure whether scheduling of this solvent is necessary. As noted in our submission for 1-butanol, aerosols and sprays designed to be held in such a way to spray away from the person using the spray or aerosol. Further, we note that 1-propanol appears to be milder than 1-butanol. NICNAS IMAP report on 1-propanol notes that 1-propanol is classified as irritating to eyes between 5-10%, and irritant causing irreversible eye damage at concentrations greater than or equal to 10%. However, it also notes that internationally, 1-propanol is used at up to 60% in domestic products. As far as we are aware, there has not been any concerns raised with the types of products containing 1-propanol in these concentrations. Accord has previously noted in our submission that 1-propanol can be used as an active ingredient in alcohol based hand rubs in both cosmetic and therapeutic preparations. The active alcohol concentration in these products range between 60 – 95%. We do not believe that any scheduling controls are required for 1-propanol. However, if some controls are deemed necessary, we believe these controls should be restricted to the aerosol or spray format products containing >10% 1-propanol. Further other controls such as safety, warning and first aid statements should be considered for higher concentrations rather than inclusion in schedules i.e. reverse scheduling.

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1-cyclohexylphenol

Accord welcomes the proposal to exempt certain product categories from Schedule 9. We understand that the reason for the initial addition of cyclohexylphenols to Schedule 9 was its use as a recreational drug (“non-classical” cannabinoid). Feedback from members suggests that 1-cyclohexylphenol is an impurity present in quantities < 0.5% in certain preservatives and disinfectants. We believe this level of impurity should be exempt from scheduling as it is unlikely that they can be isolated for use as a recreational drug – the reason they exist as an impurity in the product is because they are not easily isolated. We also welcome the move to include certain uses of 1-cyclohexylphenol in Schedule 6. While we are unsure what cut-off levels would be appropriate, generally speaking, isolation substances like 1-cyclohexylphenol from complex formulated products is quite difficult. Exemption from scheduling could apply if 1-cyclohexylphenol is contained in a formulated product i.e. not a simple solution.

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Lemongrass oil

Accord notes that this agenda item relates to the recent decision on citral, neral and geranial. We have received no direct feedback to date on the use of lemongrass oil from our Members. However, during our consultation on citral, neral and geranial, it became apparent that our Members well understood that citral, neral and geranial are present in a large number of essential oils including lemongrass oil, and any decision made on citral and its isomers would also affect these essential oils. Accord therefore has no objections to scheduling of lemongrass oil in line with citral, neral and geranial, as we believe this would provide clarity for industry Members that may not be aware that lemongrass oil is 90% citral.

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Soluble oxalates

Accord notes that the ACCS considered whether the current schedule entry for OXALIC ACID except its derivatives and insoluble salts captures soluble oxalate salts. We note that generally, solubility of salts is not specifically mentioned when scheduling or reverse scheduling a substance. The fact that the reverse scheduling specifically mentions insoluble salts only i.e. not soluble salts, has led to the conclusion by most in industry that soluble salts are captured by the oxalic acid schedule 6 entry. If this was not the intent of the scheduling committee, then we would welcome a clarification, which could be provided by removing the word “insoluble” from the current schedule 6 entry. While we note that the intent of the use of soluble oxalates in dental care products is to form insoluble calcium oxalate crystals, products contain soluble oxalate salts, not the insoluble calcium oxalate crystals. Accord has previously supported exempting certain uses and concentrations of soluble oxalates. Our views have not changed since making our last submission made on 20 February 2014 to the ACCS meeting. Our comments to the March 2014 ACCS meeting are reproduced below for ease of consideration:

Accord supports the proposed exemption from scheduling of oxalic acid in domestic cleaning preparations containing 8% or less oxalic acid. We also request that the ACCS and the Delegate consider exemption for dental products including mouthwashes containing 3% or less of soluble salts of oxalic acid. While the exemption could be limited to therapeutic dental products, if the use of up to 3% soluble salts of oxalic acid is considered acceptable in therapeutic dental products, the same should apply to non-therapeutic dental products. Further, if a company markets products to treat tooth sensitivity, the product would automatically become therapeutic. Potassium oxalate is currently in products used to treat dental sensitivity marketed in the UK, and its use for this purpose is also permitted in the United States. The oxalate ion works by combining with calcium ions in the oral cavity to form insoluble calcium oxalate crystals which block the dentinal tubules. According to the SCCS notes of guidance for the testing of cosmetic ingredients and their safety evaluation, 7th revision1, approximately 10% mouthwash is expected to be retained in the oral cavity after use (conservatively estimating). The intended dose of the mouthwash is between 10-20ml. This equates to maximum absorption of approximately 30mg of oxalate ion. Oxalic acid is a naturally occurring substance found in common foods such as coffee, spinach, carrots, lettuce and chocolate. Based on information on average quantities of oxalic acid in foods from the United States Department of Agriculture (USDA)2, more than 10 times the amount of oxalic acid retained from a mouthwash can be consumed from eating one medium sized carrot (carrots contain approximately 0.5g (500mg) oxalic acid per 100g – an average carrot weighs approximately 70g). We therefore request that the following scheduling proposal be considered:

1 http://ec.europa.eu/health/scientific committees/consumer safety/docs/sccs s 004.pdf. 2 http://www.ars.usda.gov/Services/docs htm?docid=9444

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Schedule 6 OXALIC ACID except: a) its derivatives and insoluble salts,

b) in household and domestic cleaning preparations containing 8 per cent or less oxalic acid or its soluble salts, and c) in dental care preparations including mouthwashes containing 3 per cent or less oxalic acid or its soluble salts.

AFGC AUSTRALIAN FOOD& GROCERY COUNCIL

Level 2, 2-4 Brisbane Ave Barton ACT 2600

o • • I • I

100 6

f t1fir ''Sifi?'§ fft'SII'inftga.gov .au and [email protected]

Dear Sir/Madam

p 02 62731466 F 02 62731477

AFGC.ORG.AU

20 October 2014

RE: Response to the Invitation to Comment on the Proposed Amendments Referred by the

Delegate for Scheduling Advice for Consideration by the Joint Committee of the ACCS and the

ACMS: Soluble Oxalates

The AFGC would like to express its support for the following agenda item put forward by the delegate

for consideration at the November meeting:

Soluble oxalates: At the March 2014 meeting of the ACCS, an issue was raised regarding whether

soluble oxalate salts used in therapeutic goods such as mouthwashes would be captured by the

current Schedule 6 entry OXALIC ACID except its derivatives and insoluble salts. This issue needs to

be clarified along with the need for a specific clause exempting soluble oxalates in mouthwashes.

The March 2014 post-meeting comments indicated that further information was needed to consider the

proposal to exclude the soluble salt potassium oxalate, when incorporated in a mouthwash for tooth

sensitivity, from the current scheduling entry for oxalic acid. The AFGC understands that our member

company••••••••••••· in response. forwarded to the Committee Secretariat on 11

July 2014 further specific information on the preclinical toxicity of oxalic acid and the clinical in-use

safety of the potassium oxalate salt in a mouthwash concentration of 1.4%.

Should the Committee agree with the proposal, AFGC supports the request from- that any required

label warnings/precautions statements for mouthwash containing potassium oxalate be in alignment

with the following statements already in use in the European market:

• KEEP OUT OF REACH OF CHILDREN • Do not use this product if you are sensitive or allergic to oxalates • Do not use this product if you have a history of kidney disease, hyperoxaluria, kidney stones

or have a condition that affects your absorption of foods/nutrients, or take high doses of vitamin C (1,000 mg or more per day).

• If you experience discomfort or irritation, stop using the product. • If a significant amount (more than 10 mL) is swallowed, drink a cup of milk or water and

contact your doctor or an Accident and Emergency department.

AUSTRALIAN

FOOD& GROCERY COUNCIL

AFGC Level 2, 2-4 Brisbane Ave

Barton ACT 2600

p 02 62731466

F 02 62731477

AFGC.ORG.AU

In addition although no special handling precautions are required for the formulated product, we

consider a child resistant cap is would be prudent.

-

The Secretary

Australian Government

Department of Health National Industrial Chemicals

otification and Assessment Scheme

Chemicals Scheduling Secretariat Office of Chemical Safety (MDP 88) GPO Box 9848 CANBERRA ACT 260 I

Em ail: chemicals.scheduling@health. gov.au

Dear Secretariat

Public comment on scheduling of 1-butanol and 1-propanol- Joint committee of the Advisory Committee on Chemicals Scheduling (ACCS) and the Advisory Committee on Medicines Scheduling (ACMS), November 2014

As a follow up to the notice published on 25 September 2014 of the Delegate's request for public comments under subsection 42ZCZK of the Therapeutic Goods Regulations 1990,

with respect to chemicals !-butanol (CAS No. 71-36-3) and 1-propanol (CAS No. 71-23-28), addressing a matter raised in section 52E of the Therapeutic Goods Act 1989, I am now forwarding a public submission in supp�rt of listing these chemicals in Schedules 5 and 6.

For both chemicals, NICNAS recommendations for scheduling are based on evidence for a specific use scenario of coarse aerosols in pump and/or spray products at concentrations of concern for severe eye irritation, where there is potential for ocular exposure.

NICNAS therefore recommends to the Committee that these short chain alcohols should be treated separately from other short chain alcohols·such as 1-hexanol (CAS No. 111-27-3) and ethanol (CAS No. 64-17-5) as they are qualitatively distinct due to evidence of irreversible eye irritation with !-butanol and 1-propanol.

NICNAS agrees with the percentage cut-offs discussed in the interim decision for both chemicals. However, our main concern is in aerosol product applications where ocular exposure can lead to irreversible eye damage, which could be controlled through appropriate scheduling of aerosol use of these chemicals as recommended in the NICNAS report.

If you require more information or would like hesitate to call

Yours sincerely

21 October 2014

MDP 147 GPO Box 58 Sydney NSW 2001 Telephone: (02) 8577 8800 Fax: (02) 8577 8888 ABN 31 162 998 046

ASMI requests the joint ACCS/ACMS to carefully consider the possible impact of the above

scheduling proposals on therapeutic goods, and care should be taken to ensure that any

amendments are clearly and carefully drafted to exclude any impact on these products.

The ACCS should also allow sponsors adequate time to make changes to formulations and/or

labelling if needed; adequate transition times are important to industry, as is the need to allow

existing stock in market to be sold through.

As an industry representative, ASMI is a key stakeholder in scheduling matters and we are keen to

provide further input as required. We look forward to the Delegate's interim decisions and greater

detail on the final scheduling proposals.

Please contact me should you require any further clarification relating to this submission.

Page 4 of 4

The Secretary Scheduling Secretariat GPO Box 9848 CANBERRA ACT 2601

Dear Sir/Madam,

21st October 2014

RE: Comments on Proposed amendments referred by the Delegate for scheduling

advice for consideration by the Advisory Committee on Chemicals Scheduling (ACCS) and joint ACCS/ACMS meetings

1-Butanol

Proposal to set aside the interim decision and seek further advice on the specific

range of products containing 1-butanol that would warrant scheduling to protect against eye damage, and whether these should include such products as aerosol or

spray products and/or arts & craft materials, where there may be a greater risk of

being taken into the eye. This may include further consideration of ACCS advice

that 1-butanol in cosmetics and therapeutic goods be exempted from any proposed

schedule entry.

- supports the above proposal to seek clarity on the range of products that warrant SCFi'eduling from a safety perspective.

1-Butanol is used in very low concentrations in a number of - products which include therapeutic and cosmetic products and we are not aware orny issues relating to the ingredient.

1-Butanol is recognized as safe for use in cosmetic products and no other market restricts the use of 1-Butanol in cosmetic products. In 2008, the CIR Expert Panel assessed the safety profile of the ingredient in concentrations of 1-Butanol from 0.000007% in bath soaps and detergents to 15% in nail care products. The CIR Expert Panel concluded that the ingredient was considered safe in all the cosmetic categories it was used in.

Any future scheduling decision should ensure that current cosmetic and therapeutic products for which no safety issues have been identified are not affected.

1-Propanol Proposal to set aside the interim decision and seek further advice on the specific range of products containing 1-propanol that would warrant scheduling to protect against eye damage, and whether these should include such products as alcoholbased handrubs, and/or arts & craft materials, where the 1-propanol concentrations are likely to be substantively higher than the proposed scheduling cut-offs or spray products where there may be a greater risk of being taken into the eye. This may include further consideration of ACCS advice that 1-propanol in cosmetics and therapeutic goods be exempted from any proposed schedule entry.

• supports the above proposal to seek clarity on the range of products that warrant SCheduling from a safety perspective.

1-Propanol is used in low concentrations in a number of • products which include therapeutic and cosmetic products and we are not aware Ofany issues relating to the ingredient. In our therapeutic products, the ingredient is found in trace amounts as a solvent.

1-Propanol is recognized as safe for use in cosmetic products and no other market restricts the use of 1-Propanol in cosmetic products. In 2012, the CIR Expert Panel assessed the safety profile of the ingredient in concentrations of 1-Propanol from 0.002% to 100%. The CIR Expert Panel concluded that the ingredient was considered safe in all the cosmetic categories it was used in.

Any future scheduling decision should ensure that current cosmetic and therapeutic products for which no safety issues have been identified are not affected.

Alkoxyethanols and their acetates Proposal to develop separate entries for 2-methoxyethanol, 2-ethoxyethanol, 2-(1-methylethoxy)ethanol, 2-butoxyethanol and 2-propoxyethanol, along with their acetates. These proposals may consider changes to the exemption cut-offs for the Schedule 6 entries, and the need for separate entries in Appendices E, F and I.

Methoxyethanol (CAS 109-86-4 ), and ethoxyethanol (CAS 11 0-80-5) are contained in a number of . topical cosmetic products in low concentrations of up to 0.0008%. We are not aware 'OT'any safety issues relating to these ingredients at these low concentrations when used in topical cosmetic products. The ingredients are used as solvents. Any scheduling proposed by the committee should take the cut off limit, route of administration, and use of ingredient in cosmetic goods into consideration.

If a Schedule 6 entry is adopted, we request the Committee and the Delegate exempt cosmetic products containing methoxyethanol and ethoxyethanol in low concentrations from scheduling.

Formaldehyde donor chemicals Proposal to include the specified seven formaldehyde donor chemicals in the index of the SUSMP with a cross-reference to the formaldehyde schedule entries or to develop separate entries in Schedules 2 and 6, and Appendix C, that mirror the formaldehyde entries in those Schedules .

• supports the above proposal to further clarify the schedule entry for formaldehyde to =ude specific formaldehyde donor chemicals in the index, and cross reference them back to the formaldehyde schedule. We assume there will be no changes to the

concentration cut offs currently specified in the SUSMP .• reserves the right to provide

further comment if any changes to current cut offs are proposed.

Oxalic Acid

Proposal to clarify whether soluble oxalate salts used in therapeutic goods such as

mouthwashes would be captured by the current Schedule 6 entry OXALIC ACID

except its derivatives and insoluble salts with the need for a specific clause exempting soluble oxalates in mouthwashes.

-supports the above proposal to seek clarity on the current scheduling of soluble

OxaTate salts and a specific clause exempting soluble oxalates in mouthwashes.

In response to the March 2014 post meeting comments indicating that further information was needed to consider the proposal to exclude the soluble salt potassium oxalate when

incorporated in a mouthwash for tooth sensitivity from the current scheduling entry for

oxalic acid. forwarded to the Committee Secretariat 11 July 2014 further specific

information on the preclinical toxicity of oxalic acid and the clinical in-use safety of the potassium oxalate salt in a mouthwash in a concentration of 1.4%.

Should the Committee agree with the proposal-requests that any required label

warnings/precautions statements for mouthwas"Fi"'Containing potassium oxalate be in

alignment with the following statements already in use in the European market:

• KEEP OUT OF REACH OF CHILDREN

• Do not use this product if you are sensitive or allergic to oxalates

• Do not use this product if you have a history of kidney disease, hyperoxaluria, kidney stones or have a condition that affects your absorption of foods/nutrients, or

take high doses of vitamin C (1 ,000 mg or more per day).

• If you experience discomfort or irritation, stop using the product. • If a significant amount (more than 10 mL) is swallowed, drink a cup of milk or water

and contact your doctor or an Accident and Emergency department.

In addition although no special handling precautions are required for the formulated

product, we consider a child resistant cap is would be prudent.

Yours faithfully,

23 October 2014 The Secretary Chemicals Scheduling Secretariat Office of Chemical Safety (MDP 88) GPO Box 9848 CANBERRA ACT 2601 The Secretary Medicines Scheduling Secretariat Therapeutic Goods Administration PO Box 100 (MDP122) WODEN ACT 2606 Dear Sir/Madam, Re: Invitation for public submissions on proposed amendments referred to the joint ACCS/ACMS meetings, November 2014

after conferring with Accord, would like to provide further suggestions to Accord’s proposed wording for the scheduling amendment of oxalate as follows:

Schedule 6 OXALIC ACID except: a) its derivatives and insoluble salts,

b) in household and domestic cleaning preparations containing 8 per cent or less oxalic acid or its soluble salts, and c) in dental care preparations including mouthwashes containing 3 per cent or less oxalic acid or its soluble salts.

1. We would like to be more specific to say “oral care preparations” instead

of “dental care preparations” to avoid reference to products used in the dental clinic setting.

2. We would like to suggest removing "mouthwashes" as the general category of "oral care preparations" can cover all other product forms.

3. We would like to suggest a clearer wording on the concentration guidance as follows: "containing 3 per cent or less of oxalic acid or its equivalent soluble salts."

Net, the proposed wording would be as follows:

Schedule 6

OXALIC ACID except: a) its derivatives and insoluble salts,

b) in household and domestic cleaning preparations containing 8 per cent or less oxalic acid or its soluble salts, and c) in oral care preparations containing 3 per cent or less oxalic acid or its equivalent soluble salts.

11 also be providing a separate submission on the for the joint ACCS/ACMS committee's consideration.

Yours sincerely,

23 October 2014 The Secretary Chemicals Scheduling Secretariat Office of Chemical Safety (MDP 88) GPO Box 9848 CANBERRA ACT 2601 The Secretary Medicines Scheduling Secretariat Therapeutic Goods Administration PO Box 100 (MDP122) WODEN ACT 2606 Dear Sir/Madam, Re: Invitation for public submissions on proposed amendments referred to the joint ACCS/ACMS meetings, November 2014

refer to the notice inviting public comments under subsection 42ZCZK of the Therapeutic Goods Regulations and would like to provide comments on the scheduling proposal for “soluble oxalates” referred by the Delegate to the joint ACCS/ACMS, for consideration on November, 2014. The comments submitted below are relevant to the proposed amendment, and address matters raised in section 52E of the Therapeutic Goods Act 1989. Proposed scheduling amendment: Substance Proposal Soluble oxalates

At the March 2014 meeting of the ACCS, an issue was raised regarding whether soluble oxalate salts used in therapeutic goods such as mouthwashes would be captured by the current Schedule 6 entry OXALIC ACID except its derivatives and insoluble salts. This issue needs to be clarified along with the need for a specific clause exempting soluble oxalates in mouthwashes.

supports previous proposals in public submissions to exempt soluble oxalate salts from current schedule 6 entry, and welcome ACCS/ACMS’ consideration of exempting soluble salts of oxalic acid used in therapeutic oral care preparations (e.g. sensitivity strips, trays, mouthwashes and swabs).

We propose the following scheduling change for oxalic acid; From: Schedule 6: OXALIC ACID except its derivatives and insoluble salts To: Schedule 6: OXALIC ACID except a. its derivatives and insoluble salts b. its soluble salts in therapeutic oral care preparations which provide less than 20

milligrams of oxalic acid per day. Below we provide information as well as our reasoning for this proposed change.

1. Soluble salts of oxalic acid play a key role in the treatment of dentinal

hypersensitivity. Soluble salts of oxalic acid (also known as oxalate) play an important role in the treatment of dentinal hypersensitivity. Therapeutic oral care goods containing soluble salts of oxalic acid are currently approved and marketed in Europe and the United States for the treatment of dentinal hypersensitivity. As many as 57 percent of adults may be living with sensitive teeth [1]. Soluble oxalate salts provide immediate relief and lasting relief of dentinal hypersensitivity when applied to the affected area. Soluble oxalate salts provide relief of dentinal hypersensitivity via deposition of insoluble oxalate crystals in the fluid filled tubules of the dentin. These tubules act as channels which lead to mechanoreceptor nerves within the teeth. Stimuli (typically hot and cold) cause the fluid in the tubules to move thereby causing a sharp shooting pain described as tooth sensitivity. Blocking these channels with oxalate crystals blocks fluid movement preventing the activation of these nerves by common sensitivity triggers such as hot and cold foods.

2. There is considerable exposure to soluble salts of oxalic acid through the diet. Oxalate occurs naturally, both endogenously in the body and exogenously in the diet. The presence of oxalate is ubiquitous throughout the diet, and the main sources of dietary oxalate are plants and plant products [2]. Dietary oxalate consists of both soluble and insoluble salts of oxalic acid, and the ratio of soluble to insoluble oxalate salt varies amongst foods [3]. Spinach consists mostly of soluble oxalate, whereas rhubarb seems to consist mostly of insoluble oxalate

[3]. On a weight by weight basis, foods such as spinach and rhubarb contain some of the highest levels of oxalate [2, 3]. Other foods such as okra and chocolate also contain high levels of oxalate, whereas foods such as tomatoes and apples contain low levels of oxalate [2, 4]. Dietary oxalate intake has been evaluated by several groups of investigators and has generally been reported to be ≥ 100 milligrams per day, and it has been noted that there is considerable variability in dietary oxalate intake between individuals [2, 3, 5, 6]. In a robust evaluation, Taylor et al. (2007) prospectively examined dietary oxalate intake in approximately 240,000 health care professionals with and without kidney stones, and found mean oxalate intakes to be 214, 185 and 183 milligrams per day in men, older women and younger women, respectively [6]. The overall mean for this population is 194 milligrams oxalate per day. Together these reported data show that the exposure to soluble and insoluble oxalate salts from the diet is a common occurrence and that the total dietary exposure can be substantial. This supports the proposal to exempt soluble oxalate salts from the current schedule 6 entry as there is already considerable exposure to these salts through the diet.

3. Toxicity profile of oxalic acid.

Oxalic acid is considered to be of moderate acute toxicity through the oral route and of low acute toxicity through the dermal route [7-11]. As evidenced from irritation studies in rabbits, undiluted oxalic acid is considered to be severely irritating to both skin and eyes [12]. However, it did not show any evidence of skin sensitization when tested in a Mouse Local Lymph Node assay (LLNA) at concentrations of 12.5−50% in dimethyl sufoxide [12]. Repeated dietary administration of oxalic acid at 5% of the total diet (equivalent to 2,500-3,000 mg/kg bw/day) for 70-days in Long Evans rats produced decreased body weight, restricted growth in both sexes, reduced estrous cycle at both the doses and thyroid dysfunction (i.e., reduced thyroid weight, changes in iodine and hormone levels). According to the European Agency for the Evaluation of Medicinal Products (EMEA), the observed endocrine effects in this study could possibly be a consequence of the poor health conditions of the treated rats and not a treatment-related effect [10]. With regard to genotoxicity, there was no mutagenic, clastogenic or DNA damaging response observed with oxalic acid in various short term in vitro bacterial mutagenicity, chromosomal aberration assays [7, 8, 10-12]. Due to the absence of tumorigenic response in a limited 2-year carcinogenicity study in rats as well as the absence of structural alerts and negative QSAR predictions for carcinogenicity according to the OECD QSAR tool box, oxalic acid is not expected to have carcinogenic potential [7, 10]. The reproductive toxicity was

assessed on the basis of a two-generation drinking water study at doses ranging from 89−275 mg/kg bw/day in CD-1 mice. At the highest tested dose, general toxicity as well as some reproductive effects indicated by decreased prostate gland weights and changes in kidney weights in parents, abnormal sperm in F2 males, reduced body weight gain in dams accompanied by decreased pup weights, number and size of litters and number of live pups per litter were observed. As a result, the NOAEL for reproductive toxicity in both the generations was established at the next lower dose level of 162 mg/kg bw/day for both parental and neonates [8, 10-12]. With regards to human exposure to oxalic acid, the most common and pertinent adverse effect associated with this constituent is the development of nephrolithiasis, also known as kidney stones [13]. The published literature suggest that exogenous oxalate intake is not the key risk factor for the development of kidney stones, however, it is believed to have a mild to moderate impact on the development of nephrolithiasis [14].

4. Limiting exposure to less than 20 milligrams oxalic acid per day is protective of sensitive subpopulations (i.e. individuals with nephrolithiasis). The aforementioned study conducted by Taylor et al. (2007) found no difference in dietary oxalate intake between those with nephrolithiasis and those without nephrolithiasis [6]. Given that no difference in oxalate intake was found between those with kidney stones and those without, the investigators of this study concluded that dietary oxalate was not a major risk factor for nephrolithiasis [6]. This conclusion is further supported by a study by Siener et al. [15]. In this study, investigators evaluated the efficacy of dietary intervention on urinary risk factors for stone formation in patients with severe nephrolithiasis. On their self-selected diets, patients (N=107) had an average dietary oxalate intake of 76 (± 77) milligrams per day. When placed on a nutritionally balanced diet their oxalate intake was 99 mg/day [15]. The shift to the nutritionally balanced diet was reported to significantly reduce the stone forming potential in these patients. This reduced stone forming potential was not attributed to a change in dietary oxalate intake, but rather to other dietary factors including increased fluid intake and a decrease in the intake of protein and alcohol [15].

Together these data support the conclusion that dietary oxalate intake is not the driving risk factor for the development of kidney stones. However, clinicians still generally recommend that patients with kidney stones limit their exposure to oxalate-rich foods [16]. As previously mentioned, oxalate-rich foods include spinach and rhubarb, whereas foods such as apples and tomatoes are relatively oxalate-poor [2-4]. A comprehensive guidance on the oxalate content of foods lists apples and tomatoes as providing less than 26 milligrams of oxalate per serving [4].

Given that relatively poor sources of oxalate provide less than 26 milligrams per serving, that dietary oxalate intake plays a limited role in the development of kidney stones, and that a robust prospective study showed daily oxalate intake to approximate 200 milligrams without adverse effects; we propose that therapeutic oral care goods providing less than 20 milligrams per day be exempt from Schedule 6. This value falls within the 26 milligram range and can be approximately one tenth the daily intake of oxalate. As such, an exposure of less than 20 milligrams oxalate per day represents a relatively small contribution to daily oxalate intake. This approach will be protective of sensitive subpopulations such as those with a history of kidney stones.

5. An exemption based on milligrams of oxalic acid is appropriate for therapeutic oral care goods.

A concentration based exemption for therapeutic goods containing soluble salts of oxalic acid is not appropriate because such a guidance does not take into account the mass of the administered dose. The actual exposure for a consumer is a function of both the concentration of oxalate in the therapeutic good and the amount of said good that is ingested. Currently therapeutic goods used for the treatment of dentinal hypersensitivity consist of various product forms including strips, trays, mouthwashes and swab applications. The mass of the administered dose for each of these product forms will vary and can impact the exposure to oxalate.

Hence we propose a guidance based on the milligrams of oxalic acid provided and not the concentration of oxalic acid in the product. We feel that this is an appropriate approach for limiting exposure to oxalic acid from various product forms, and hence protects consumers from overexposure to oxalate. A milligram approach is used by globally recognized scientific bodies such as JECFA (Joint Evaluation Committee on Food Additives), SCF (Scientific Committee on Food), EPA (Environmental Protection Agency) and IOM (Institute of Medicine) when applying a limit on daily exposure that is not specific to a product form.

In summary, soluble salts of oxalic acid play an important role in the treatment of dentinal hypersensitivity, an affliction that impacts much of the adult population. Oxalates are ubiquitous throughout the diet and we are currently exposed to substantial amounts of oxalate through food. Exogenous oxalate may have a limited role in the development of kidney stones, however, to be conservative we propose a scheduling change for oxalic acid to

Schedule 6: OXALIC ACID except a. its derivatives and insoluble salts b. its soluble salts in therapeutic oral care goods which provide less than 20

milligrams of oxalic acid per day.

Thank you for this opportunity to make comments. We understand that an interim decision will be published and will be open for further public submission from applicants and those persons who made a submission in response to the original invitation and which were received on or before the closing date for public submission of 23 October 2014. Therefore, we reserve the right to make a further submission at that time.

Yours sincerely,

References: 1. Irwin, C. and P. McCusker, Prevalence of dentine hypersensitivity in a general dental

population. Journal of the Irish Dental Association, 1996. 43(1): p. 7-9. 2. Holmes, R.P. and M. Kennedy, Estimation of the oxalate content of foods and daily

oxalate intake. Kidney Int, 2000. 57(4): p. 1662-7. 3. Holmes, R.P. and D.G. Assimos, The impact of dietary oxalate on kidney stone

formation. Urol Res, 2004. 32(5): p. 311-6. 4. The Oxalate Content of Food. 2008 [cited 2014; Available from:

http://www.ohf.org/docs/Oxalate2008.pdf. 5. Siener, R., et al., Dietary risk factors for hyperoxaluria in calcium oxalate stone

formers. Kidney Int, 2003. 63(3): p. 1037-43. 6. Taylor, E.N. and G.C. Curhan, Oxalate Intake and the Risk for Nephrolithiasis. Journal

of the American Society of Nephrology, 2007. 18(7): p. 2198-2204. 7. Oxalic acid and its common inorganic salts. 1987, The British Industrial Biological

Research Association (BIBRA). 8. EPA R.E.D. facts: Oxalic acid. 1992, United States Environmental Protection Agency

(US EPA). 9. Substance ID: 144-62-7; EINECS name: Oxalic acid, in IUCLID Dataset. 2000,

European Commission - European Chemicals Bureau. 10. Committee for Veterinary Medicinal Products: Oxalic acid, summary report. 2003,

European Agency for the Evaluation of Medicinal Products (EMEA). 11. Wagner, P., EPA Action Memorandum: Inert Reassessment - Oxalic Acid (CAS Reg.

No. 144-62-7). 2005, United States Environmental Protection Agency (US EPA). 12. Information on Registered substances. Oxalic acid, EC No. 205-634-3; CAS No. 144-

62-7. [cited 2011; Available from: http://apps.echa.europa.eu/registered/data/dossiers/DISS-9d952f55-7514-4c7f-e044-00144f67d249/AGGR-d99f041e-7a6a-49fa-a41c-a3c6d00f91b4 DISS-9d952f55-7514-4c7f-e044-00144f67d249.html#section 1.1.

13. Von Burg, R., Toxicology update. Journal of Applied Toxicology, 1994. 14(3): p. 233-237.

14. Moe, O.W., Kidney stones: pathophysiology and medical management. The lancet, 2006. 367(9507): p. 333-344.

15. Siener, R., et al., THE EFFICACY OF DIETARY INTERVENTION ON URINARY RISK FACTORS FOR STONE FORMATION IN RECURRENT CALCIUM OXALATE STONE PATIENTS. The Journal of Urology, 2005. 173(5): p. 1601-1605.

16. Pearle, M.S., et al., Medical Management of Kidney Stones: AUA Guideline. The Journal of urology, 2014.

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