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Scheduling delegate's final decisions: ACCS, July 2015

23 July 2015

Book pagination

Part A - Final decisions on matters referred to an expert advisory committee 1.1 - 1.3

Scheduling proposals referred to the March 2015 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#13)

SUMMARY OF DELEGATE'S FINAL DECISIONS

Substance Final Decision
2-ethylhexanoic acid and its derivatives Pending
2-hydroxyethyl methacrylate Schedule 5 – New Entry

2-HYDROXYETHYL METHACRYLATE except when in nail preparations labelled 'Avoid contact with skin'

Appendix E, Part 2 – New Entry

2-HYDROXYETHYL METHACRYLATE Standard statements A, E1, S1.

Appendix F, Part 3 – New Entry

2-HYDROXYETHYL METHACRYLATE  - warning statement 28, safety direction 4.

Implementation date – 1 February 2016

4,5-dichloro-2-N-octyl-3(2H)-isothiazolone Pending
4,7-methano-1H-indene-5-acetaldehyde, octahydro- Not to schedule
4-aminopropiophenone

Schedule 7 – New Entry

4-AMINOPROPIOPHENONE

Appendix J, Part 2 – New Entry

4-AMINOPROPIOPHENONE Standard statement 3.

Implementation date – 1 October 2015.

Ammonium cocoyl isethionate

Schedule 6 – New Entry

AMMONIUM COCOYL ISETHIONATE, except in cosmetic rinse-off preparations containing 30 per cent or less and if containing more than 5 per cent of ammonium cocoyl isethionate when labelled with a warning to the following effect:

IF IN EYES WASH OUT IMMEDIATELY WITH WATER

Appendix E, Part 2 – New Entry

AMMONIUM COCOYL ISETHIONATE Standard statement E1.

Implementation date – 1 February 2016

Babassuamidopropyl betaine

Schedule 6 – New Entry

AMIDOPROPYL BETAINES except:
  1. in cosmetic wash-off preparations containing 30 per cent or less of amidopropyl betaines and, if containing more than 5 per cent of amidopropyl betaines when labelled with a warning to the following effect:

    IF IN EYES WASH OUT IMMEDIATELY WITH WATER;

  2. in cosmetic leave-on preparations containing 1.5 per cent or less of amidopropyl betaines.
  3. in other preparations containing 30 per cent or less of amidopropyl betaines  and, if containing more than 5 per cent of amidopropyl betaines, when labelled with warnings to the following effect:

    IF IN EYES WASH OUT IMMEDIATELY WITH WATER; and

    IF SKIN OR HAIR CONTACT OCCURS, REMOVE CONTAMINATED CLOTHING AND FLUSH SKIN AND HAIR WITH RUNNING WATER.

Appendix E, Part 2 – New Entry

AMIDOPROPYL BETAINES

  • in cosmetic wash-off preparations when included in Schedule 6 Standard statement E1
  • in other preparations when included in Schedule 6 Standard statements E1 and S1

Implementation date – 1 February 2016

Flupyradifurone

Schedule 6 – New Entry

FLUPYRADIFURONE

Implementation date – 1 October 2015

Metofluthrin

Schedule 5 – Amendment

METOFLUTHRIN,

  • in impregnated fabric mosquito repellent preparations for use in a vaporizer containing 15 mg or less of metofluthrin per disk; or
  • when impregnated into a polyethylene slow release matrix containing 250 mg or less of metofluthrin for use as a mosquito repellent.

Implementation date – 1 October 2015

1.1 2-HYDROXYETHYL METHACRYLATE

Scheduling proposal

In December 2014, the NICNAS, under the IMAP programme, referred the following proposal to be considered by the delegate:

  • A proposal to create a new entry for 2-hydroxyethyl methacrylate in Schedule 5 for use in cosmetics or domestic products.

The reasons for the request were:

  • Uses of the chemical in Australia at concentrations up to 10 % in cosmetic products and up to 80 % in domestic products have been identified through Safety Data Sheets (SDSs). Overseas information confirms the use of the chemical in cosmetics (25 products in the Compilation of Ingredients Used in Cosmetics in the United States (CIUCUS), 2011) and domestic products (Household Products Database, US Department of Health and Human Services).
  • The main route of public exposure is expected to be through the skin, although the rate of polymerisation would be expected to limit the extent of exposure. When used in nail enhancement products, short-term small volume skin contact in the immediate vicinity of the fingernail may occur. Exposure is considered more probable for home use of the chemicals than in salon use by trained personnel. Dermal exposure to other parts of the body may occur during domestic use. The low volatility of the chemical limits the potential for exposure through vapour inhalation.
  • Skin sensitisation may occur following exposure to the chemical and other structurally related methacrylates (cross–sensitisation). The CIR advised that methacrylate ester monomers 'are safe to use in nail enhancement products when skin contact is avoided. Products containing these ingredients should be accompanied with directions to avoid skin contact, because of the sensitising potential of methacrylates' (CIR, 2005).
  • There are currently no labelling requirements for products containing this chemical in Australia. Therefore, the characterised critical health effects (skin sensitisation) have the potential to pose an unreasonable risk under the uses identified.
  • The chemical may be present in nail enhancement products as a residual monomer (at <1% on the polymer weight) in polymers based on this chemical, and the proposal is not intended to affect the use of such polymers, as the total residual monomer content of the product is expected to be very low in such cases.
Delegate's reasons for referring this to the committee

The toxicological issue (sensitisation potential) raised in relation to the use of 2-hydroxyethyl methacrylate in nail hardening preparations is similar to that considered in relation to the existing Schedule 5, 6 and Appendix C entries for ethyl and methyl methacrylate. It also raises similar considerations to hydroxypropyl methacrylate that were considered by the ACCS in July 2014. It would therefore be reasonable to make a delegate-only decision to make a similar listing in Schedule 5 (viz. 2-HYDROXYETHYL METHACRYLATE in nail preparations except when labelled 'avoid contact with skin'). However, the delegate notes that there are potentially products in the domestic market that may contain much higher concentrations of 2-hydroxyethyl methacrylate (up to 70-80% in windshield repair kits; 10-30% in adhesives/sealants). Therefore, referral to the ACCS is indicated to provide advice on the scheduling of products likely to contain such high concentrations.

The delegate asked the committee the following questions:

  • Are there sufficient similarities between the toxicological profiles of the methyl, ethyl, 2-hydroxypropyl and 2-hydroxyethyl esters of methacrylate to use current schedule entries as a template? Methyl methacrylate is currently listed in Schedule 6, with exemptions for preparations containing 1% or less, and for cosmetic use (but note that cosmetic uses of methyl methacrylate are proscribed via listing in Appendix C). Ethyl methacrylate is listed in Schedule 5, but only for cosmetic use and is exempt from scheduling in preparations containing 1% or less. In July 2014, the ACCS recommended a similar Schedule 5 entry for 2- hydroxypropyl methacrylate:

    2-HYDROXYETHYL METHACRYLATE in nail preparations except when labelled 'avoid contact with skin'

  • Noting that the key toxicological issue with the use of 2- hydroxyethyl methacrylate in nail hardeners (sensitisation potential and cross-sensitisation with other methacrylates) is similar to that previously considered; does the ACCS support a similar scheduling approach for 2-hydroxyethyl methacrylate in nail hardener preparations?
  • What scheduling consideration is needed for products potentially containing high concentrations of 2-hydoxyethyl methacrylate (70-80% in windscreen repair kits; 10-30% in adhesives & sealants)?
  • Note that the Minutes of the February 2007 meeting of the National Drugs and Poisons Scheduling Committee (NDPSC) include a detailed discussion of the rationale for setting a 1% exemption for both methyl and ethyl methacrylates. Is such an exemption cut-off also appropriate for 2-hydroxeythyl methacrylate?

Would the ACCS propose suitable entries in Appendices E & F?

Substance summary

Please refer to the NICNAS IMAP human health Tier II assessment report for 2-propenoic acid, 2-methyl-, 2-hydroxyethyl ester. This report is publicly available on the NICNAS website: NICNAS IMAP-assessment ID 1187.

Acute toxicity

The acute toxicity end-points for this chemical are listed in the below table.

Toxicity Species 2-hydroxyethyl methyacrylate SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rats and mice >2000 N/A
Acute dermal toxicity LD50 (mg/kg bw) Rabbits >2000 N/A
Acute inhalational toxicity LC50 (mg/m3/4h) No data - -
Skin irritation Rabbits Slight irritant (limited data) (R38 in HSIS)
Eye irritation Rabbits Moderate irritant (R36 in HSIS)
Skin sensitisation (Magnusson and Kligman maximisation test) Guinea pigs Positive in 9/12 guinea pigs (No LLNA data; R43 in HSIS)
Scheduling status

2-Hydroxyethyl methacrylate is not specifically scheduled.

Scheduling history

2-Hydroxyethyl methacrylate has not been previously considered for scheduling; therefore, scheduling history is not available.

However, this substance belongs to a group of chemicals known as methacrylate esters, and other chemicals in this group have been considered by NDPSC and ACCS, for the same use and due to the same hazardous property of skin sensitisation. Two other chemicals belonging to this group of chemicals, namely ethyl methacrylate and methyl methacrylate are listed in the Poisons Standard. The NDPSC considered these two chemicals several times over the period of 2006-2008. The committee decided to include ethyl methacrylate in Schedule 5 at concentrations above 1% as the low irritancy and skin sensitisation risks of ethyl methacrylate could be appropriately reduced through including a new Schedule 5 entry for cosmetic use and to create an Appendix F entry providing appropriate warning statements and safety directions and that these risks are sufficiently reduced when there is ≤ 1% monomer present as a residue in a polymer as to warrant exclusion from the requirements of scheduling.

The committee decided to include methyl methacrylate in Schedule 6 for non-cosmetic uses at concentrations above 1% and Appendix C for all cosmetic uses. The committee noted that the severe dermal irritancy, moderate respiratory irritancy and evidence of moderate sensitising potential of methyl methacrylate constituted a moderate potential for causing harm (when for non-cosmetic uses), the extent of which could be reduced through the use of appropriate packaging and labelling and that these risks are sufficiently reduced when there is ≤ 1% monomer present as a residue in a polymer as to warrant exclusion from the requirements of scheduling. However, the cosmetic use of MMA posed sufficient danger as to warrant prohibition of sale, supply and use through inclusion in Appendix C

Another methacrylate ester, 2-hydroxypropyl methacrylate, was considered by the ACCS in July 2014. The delegate's decision was to add the substance to Schedule 5 in nail preparations except when labelled 'avoid contact with skin'. The delegate noted the toxicity of 2-hydroxypropyl methacrylate appears to be less severe than the methyl- and ethyl-methacrylates currently listed in Schedule 5, 6 and Appendix C, although there is some potential for cross-sensitisation to occur between these methacrylate derivatives when used in nail preparations. The implementation date for this decision is 1 January 2016.The final decision of 2-hydroxypropyl methacrylate is available at Reasons for scheduling delegate's final decisions, December 2014 (Chemicals).

Schedule 5

ETHYL METHACRYLATE (excluding its derivatives) for cosmetic use except in preparations containing 1 per cent or less of ethyl methacrylate as residual monomer in a polymer.

Schedule 6

† METHYL METHACRYLATE (excluding its derivatives) except:

  • for cosmetic use; or
  • in preparations containing 1 per cent or less of methyl methacrylate as residual monomer in a polymer.
Schedule 10/Appendix C

METHYL METHACRYLATE for cosmetic use except in preparations containing 1 per cent or less of methyl methacrylate as residual monomer in a polymer.

Appendix F, Part 3
Poison Warning Statements Safety Direction
Ethyl methacrylate 28. (Over) (Repeated) exposure may cause sensitisation. 4. Avoid contact with skin.
9. Use only in well ventilated area.
23. Keep away from heat, sparks and naked flames.
Appendix F, Part 3
Poison Warning Statements Safety Direction
Methyl methacrylate 28. (Over) (Repeated) exposure may cause sensitisation. 4. Avoid contact with skin.
9. Use only in well ventilated area.
23.  Keep away from heat, sparks and naked flames.
Pre-meeting public submissions

One submission was received, which was not in support of scheduling. The submission noted that there are no restrictions on the use of the substance in cosmetics internationally, that a CIR expert review panel concluded that the methacrylate esters considered are safe as used in nail enhancement products when skin contact is avoided, and there has been no demonstration of harm from the use of the substance in Australia or in other economies with comparable safety standards.

Edited versions of these submissions are available at Public submissions on matters referred to the March 2015 meeting .

Summary of ACCS advice to the delegate

The committee recommended that a new Schedule 5 entry be created for 2-hydroxyethyl-methacrylate except when in nail preparations labelled 'Avoid contact with skin'

The committee also recommended appropriate Appendix E statements (standard statements A, E1 and S1) and F statements (warning statement 28, safety direction 4) for 2-hydroxyethyl methacrylate.

The committee recommended an implementation date of 1 February 2016.

The committee also recommended that the delegate consult with the Medicines Scheduling Delegate on dental restorative preparations containing 2-hydroxyethyl methacrylate ethyl.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (b) the purposes for which a substance is to be used and the extent of use of a substance; and (c) the toxicity of the substance.

The reasons for the recommendations comprised the following:

  • Risks associated with the use pattern in nail preparations can be managed with appropriate labelling.
  • Skin sensitisation potential and evidence of eye irritation.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors1;
  • Other relevant information.
Delegate's interim decision

The delegate accepts ACCS advice that a new Schedule 5 entry be created for 2-hydroxyethyl methacrylate. Its toxicological profile is consistent with the SPF criteria for Schedule 5, including relatively low acute toxicity, skin/eye irritancy and sensitization potential. The toxicity of 2-hydroxyethyl methacrylate appears to be less severe than the methyl- and ethyl-methacrylates currently listed in Schedule 5, 6 and Appendix C, although there is some potential for cross-sensitization to occur between these methacrylate derivatives when used in nail preparations. The delegate notes, and accepts, ACCS advice that the entry should not be specific for its use in cosmetic products because of its potential use in other products at high concentrations, but that products  used on the cuticles (nails) could be exempted with appropriate 'reverse scheduling' label warning statement 'avoid contact with skin'. The delegate also notes that the potential for use of 2-hydroxyethyl methacrylate in dental restorative products and has referred the matter to the medicines delegate for consideration.

The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989:  (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 delegate agrees with the proposed implementation date of 1 February 2016. An extended implementation date should allow sufficient time for existing affected products to be re-labelled or withdrawn.  

Public submissions on the interim decision

One submission was received on the delegate's interim decision. That submission did not object to the delegate's interim decision.

An edited version of the submission is available at Public submissions on scheduling matters.

Delegate's Final Decision

The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

The delegate has confirmed the proposed implementation date of 1 February 2016.

Schedule 5 – New Entry

2-HYDROXYETHYL METHACRYLATE except when in nail preparations labelled 'Avoid contact with skin'

Appendix E, Part 2 – New Entry
Poison Standard statements
2-hydroxyethyl methacrylate

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).

E1 – If in eyes wash out immediately with water

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

Appendix F, Part 3 – New Entry
Poison Warning statements Safety direction
2-hydroxyethyl methacrylate 28. (Over) (Repeated) exposure may cause sensitisation. 4. Avoid contact with skin.

1.2 4,7-METHANO-1H-INDENE-5-ACETALDEHYDE, OCTAHYDRO-

Scheduling proposal

In December 2014, the NICNAS, under its New Chemicals assessment programme, referred the following proposal to be considered by the delegate:

  • A proposal to create a  new entry for 4,7-Methano-1H-indene-5-acetaldehyde, octahydro- in Schedule 6 when used in cosmetic and household products, except when used in accordance with the NICNAS recommended usage concentrations.

The reasons for the request were:

  • The chemical has moderate to high acute oral toxicity, consistent with the Schedule 6 factors
  • The chemical is a skin irritant and skin sensitiser, consistent with the Schedule 6 factors

The chemical has been early listed on to the Australian Inventory of Chemical Substances (AICS) at the request of the notifier and is therefore currently available for use by introducers other than the original notifier.

Based on the outcomes of a quantitative risk assessment (sensitisation) the recommended usage concentration in fine fragrances is lower than that initially proposed for use by the notifier. All other concentrations are those proposed by the notifier and found to not pose an unreasonable risk based on the NICNAS assessment. The assessment noted the absence of hazard data to assess the chronic toxicity of the notified chemical. This was deemed important in the context of the acute toxicity of the notified chemical.  In the absence of repeat dose data, the notified chemical was approved for use in cosmetic and household products based on the limited exposure potential, as reflected in the very low use concentrations.

Delegate's reasons for referring this to the committee

The ACCS has now considered a number of fragrance chemicals referred from the NICNAS. For chemicals with a low toxicity profile and likely to be present at quite low concentrations in products in the retail market, the ACCS has advised that there is insufficient public health risk to warrant inclusion in a schedule of the Poisons Standard. At the November 2014 ACCS, there were five fragrance chemicals that generated such advice. At the November 2013 and July 2014 ACCS meetings, similar advice was offered in relation to two other fragrance ingredients. However, at the July 2014 meeting, ACCS advice in relation and one other fragrance chemical (4,4-dimethyl-1-cyclohexene-1 propanal) was to list it is Schedule 6, with exempt cut-offs at 0.1% to 1% for various cosmetic and other product types. The different ACCS advice appears to be related to the severity of the toxicity potential of the pure compound, with 4,4-dimethyl-1-cyclohexene-1 propanal recommended a Schedule 6 listing because of the severity of the skin/eye irritancy potential and sensitization potential.

The delegate asked the ACCS the following questions:

  • Does the ACCS consider that the toxicological profile of of 4,7-Methano-1H-indene-5-acetaldehyde, octahydro- is sufficiently similar to the seven fragrance chemicals where no scheduling action was recommended, or is it more like 4,4-dimethyl-1-cyclohexene-1 propanal, where listing in Schedule 6 was recommended, along with different product-related exemption cut-offs?
  • If scheduling is recommended, is the chemical name (4,7-Methano-1H-indene-5-carboxaldehyde, octahydro-6-methyl-) or the name used in the NICNAS assessment (4,7-Methano-1H-indene-5-acetaldehyde, octahydro) the preferred name for listing (or some other name)?

Does the ACCS support different exempt cut-offs for a Schedule 6 entry for different product types, as proposed in the NICNAS report?

Substance summary

Please refer to the NICNAS New Chemical assessment report for 4,7-Methano-1H-indene-5-acetaldehyde, octahydro- (Word, 122kb).  This report is publicly available on the NICNAS website.

Acute toxicity

The acute toxicity end-points for this chemical are listed in the below table.

Toxicity Species 4,7-Methano-1H-indene-5-acetaldehyde, octahydro- SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Rat 300-2000 Moderate to high toxicity
Acute dermal toxicity LD50 (mg/kg bw) Not provided Not provided -
Acute inhalational toxicity LC50 (mg/m3/4h) Not provided Not provided -
Skin irritation In-vitro Irritant
Eye irritation In-vitro Non-irritant
Skin sensitisation (LLNA) Mouse

Sensitiser

(EC3 = 7.13%)
Skin sensitisation Human Non-sensitiser
Repeat-dose toxicity

No information was provided.

Mutagenicity

This substance was not a mutagenic in bacterial reverse mutation test.

Genotoxicity

This substance was not clastogenic in in vitro test.

Carcinogenicity

No information was provided.

Reproduction and developmental toxicity

No information was provided.

Observation in humans

No information was provided.

Public exposure

There will be widespread and repeated exposure of the public to the notified chemical (at ≤ 0.5% concentration) through the use of a wide range of cosmetic and household products. The principal routes of exposure will be dermal, while ocular and inhalation exposures (e.g. through the use of spray products) are also possible.

International regulations

No information was provided.

Scheduling status

4,7-Methano-1H-indene-5-acetaldehyde, octahydro- is not specifically scheduled.

Scheduling history

4,7-Methano-1H-indene-5-acetaldehyde, octahydro- has not been previously considered for scheduling; therefore, scheduling history is not available.

However, a chemical with a similar toxicological profile, namely 4,4-dimethyl-1-cyclohexene-1-propanol was considered by the ACCS in March 2014 and the Delegate decided in his final decisions to include this chemical in Schedule 6.

Schedule 6 – New Entry

4,4-DIMETHYL-1-CYCLOHEXENE-1-PROPANAL except:

  • in leave-on cosmetic preparations containing 0.1 per cent of less of 4,4-dimethyl-1-cyclohexene-1 propanal;
  • in rinse-off cosmetic preparations containing 0.5 per cent of less of 4,4-dimethyl-1-cyclohexene-1 propanal; or
  • in other preparations containing 1 per cent of less of 4,4-dimethyl-1-cyclohexene-1 propanal.
Appendix E, Part 2 – New Entry
Poisons Standard statements
4,4-Dimethyl- 1-cyclohexene-1-propanal

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).

E2 - If in eyes, hold eyelids apart and flush the eye continuously with running water. Continue flushing until advised to stop by a Poisons Information Centre (e.g. phone Australia 13 11 26; New Zealand 0800 764 766) or a doctor, or for at least 15 minutes.
Appendix F, Part 3 – New Entry
Poisons Warning statements Safety direction
4,4-Dimethyl-1-cyclohexene-1-propanal

5. Irritant.

28. (Over) (Repeated) exposure may cause sensitisation.

1. Avoid contact with eyes.

2. Avoid contact with skin.
Pre-meeting public submissions

One submission was received, which did not support scheduling. The submission notes the history of not scheduling fragrances and notes that there is an international standard (International Fragrance Association, IFRA) that applies to fragrances that companies internationally comply with.

Summary of ACCS advice to the delegate

The committee recommended that 4,7-Methano-1H-indene-5-acetaldehyde, octahydro- does not require a schedule listing.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the committee included: (a) the risks and benefits of the use of a substance; and (c) the toxicity of a substance.

The reasons for the recommendation comprised the following:

  • Use as a fragrance in low concentrations.
  • Use in low concentrations and alternative controls warrants leaving this product unscheduled.
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors2;
  • Other relevant information.
Delegate's interim decision

The delegate accepts ACCS advice that the fragrance ingredient 4,7-methano-1H-indene-5-acetaldehyde, octahydro-  does not require scheduling. The delegate notes that sensitisation potential is the toxicological finding that could justify inclusion in the schedules, and that the ACCS has made recommendations at this and previous meetings that it is not necessary to use the scheduling process to regulate fragrance chemicals when there is no evidence of a significant public health hazard associated with the low concentrations likely to be found in consumer products in Australia.  There were no other toxicological factors that would justify scheduling.  Accordingly, the interim decision of the delegate is to NOT include this chemical in the Poisons Standard.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (b) the purposes for which a substance is to be used and the extent of use of a substance; and (c) the toxicity of a substance.

Public submissions on the interim decision

One submission was received. The submission supported the delegate's interim decision.

An edited version of the submission is available at Public submissions on scheduling matters.

Delegate's final decision

The delegate notes the submission received in response to publication of the interim decision and confirms the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

1.3 4-AMINOPROPIOPHENONE

Scheduling proposal

In January 2015, the OCS, based on an application made to the APVMA to register a new active constituent and new products for agricultural uses, referred the following proposal to be considered by the chemicals scheduling delegate:

  • That a new entry for 4-aminopropiophenone be created in Schedule 7

The reasons for the request are discussed below.

A toxicological data package has been submitted to support the approval of a new active constituent, 4-aminopropiophenone (also known as para-aminopropiophenone, or PAPP) for agricultural use. A concurrent application by a separate applicant seeks registration of new products relying on the active constituent data submitted. One product (wild dog bait) contains 1.68% PAPP, while another (fox bait) contains 1.14% PAPP. The products are intended for use as vertebrate toxins for the population control of wild dogs and foxes respectively.

The OCS notes that this is the first consideration of PAPP for agricultural use.

Delegate's reasons for referring this to the committee

The delegate asked the committee the following questions:

  • The proposed use pattern of this pesticide is as a wild dog/ fox bait. The OCS report notes that the lethal dose in the dog (30-50 mg/kg) is much lower than in rodents (170-230 mg/kg). While the dog LD50 falls within the range the SPF suggests for listing in Schedule7, the rodent acute lethality is more in the range the SPF suggests for Schedule 6, and this is the basis that the product sponsor has argued for a listing in Schedule 6.
  • The OCS supports its recommendation for listing in Schedule 7 by noting that humans are relatively more susceptible to methaemoglobinaemia, the key toxic effect caused by PAPP, and that the overall toxicity profile is based on relatively old and non-compliant toxicity studies. Furthermore, there is some evidence of PAPP's genotoxicity potential and inadequate evidence to establish its carcinogenicity potential.
  • Does the ACCS support listing 4-aminopropiophenone in Schedule 7 or in Schedule 6, with or without a low-level cut-off? Should this listing include an index cross-reference to PAPP?
  • Does the proposed use pattern suggest listing in Appendix J, noting that such listing is reserved only for substances also listed in Schedule 7?  
Substance summary

PAPP is an anticyanide drug based on its methaemoglobin forming mode of action.

Structure of 4-aminopropiophenone

Structure of 4-aminopropiophenone

Acute toxicity

The acute toxicity end-points for this chemical are listed in the below tables.

Toxicity Species PAPP SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Dog
Rat
Mouse
30-50
177-221
168-223
High to extreme high toxicity
Moderate to high toxicity
Moderate to high toxicity
Acute dermal toxicity LD50 (mg/kg bw) No data No data N/A
Acute inhalational toxicity LC50 (mg/m3/4h) No data No data N/A
Skin irritation No data No data N/A
Eye irritation No data No data N/A
Skin sensitisation No data No data N/A

The acute toxicity end-points for the two products are listed in the below tables.

Toxicity Species Product SPF Classification
Acute oral toxicity LD50 (mg/kg bw) Estimated from available data Low toxicity (LD50 > 1731/1322 mg/kg bw)# N/A
Acute dermal toxicity LD50 (mg/kg bw) Estimated/inferred from data Likely to be low toxicity (dermal pharmacokinetics study with product) N/A
Acute inhalational toxicity LC50 (mg/m3/4h) No data No data N/A
Skin irritation No data No data N/A
Eye irritation No data No data N/A
Skin sensitisation No data No data N/A

# The estimation in this case was by Finney's estimation, assuming PAPP acute oral LD50 of 30 mg/kg bw and assigning an oral LD50 of 5000 mg/kg bw for the balance of non-active constituents in this case for the purposes of the calculation, noting that while no LD50 data were available for the non-active constituents, the non-active constituents are in general use as food and/or food additives).

Toxicokinetics/ADME

In experimental animals including dogs, rats and monkeys,  PAPP is absorbed by gastrointestinal tract more rapidly in rats and dogs (Tmax up to 60 min) than in monkeys (Tmax 1 – 1.5 hour). Urine is the major pathway of excretion (> 70% administered radiolabel), and faeces is the minor elimination route in these species.

The oral bioavailability of PAPP in dogs was reported at 32-52%, while an early study reported information that 65-90% of an orally administered 1.25 mg/kg bw dose of PAPP in humans was accounted for in urine samples.

PAPP is biotransformed by the liver enzymes in vivo into a bioactive form, as the hydroxylamine derivative PHAPP. Once formed, PHAPP is taken up by circulating erythrocytes where a redox cycle, known as kreisprozess, taken place, where PHAPP is converted to p-nitrosopropiophenone (PNPP), which brings about the simultaneous oxidation of haem Fe2+ to Fe3+. Intra-erythrocytic NADPH, generated from glucose-6-phosphate dehydrogenase, participates in the reduction of p-nitrosopropiophenone (PNPP) back to PHAPP, which again can oxidize a haem portion of the haemoglobin (Hb) molecule to methaemoglobin (MetHb).

Repeat-dose toxicity

Two short term toxicology studies for PAPP were presented for evaluation: a 14-day oral study in rats, and a 14-day oral study in monkeys. No observed effect levels (NOELs) were not established in the studies.

In the 14-day rat study, PAPP was administered at 0, 35 / 20, 90 / 50 or 140 / 130 mg/kg bw/d (for M/F respectively). Enlarged spleens associated with erythroid hyperplasia, sinusoidal enlargement and pigment, and raised MetHb were observed in all dose levels, which led to a LOEL of 35 mg/kg bw/d in males and 20 mg/kg bw/d in females. In addition, reduced RBC count along with increased PCV and haemoglobin were evident at ≥90/50 mg/kg bw/d; pigment was also present in Kupffer cells of the liver and renal proximal tubular epithelial cells at the high dose level.

In the 14-day monkey study, PAPP was administered at 0, 17, 50 and 150 mg/kg bw/d, and a LOEL was established at 17 mg/kg bw/d on the basis of raised MetHb concentrations detected before dosing each day, RBC morphology and bone marrow changes and Heinz body formation in all test groups during the dosing period. These changes were not fully reversed after a 2-week recovery period.  In both studies, the haematology data indicated the effects of PAPP on erythropoiesis, along with oxidative damage and haemolysis.

No other repeat-dose studies were provided in the submission.

Mutagenicity/genotoxicity

PAPP was positive for mutagenicity in an Ames test (+S9).  Summary data suggested that PAPP was mutagenic in the presence of S9 metabolic activation in the forward gene mutation assay.

Two in vivo mouse micronucleus tests were provided in the submission. In the first study, PAPP (unpurified; unknown purity/concentration) elicited a negative clastogenicity response, while in the second study, PAPP (>100% purity from the certificate of analysis) was considered to induce micronuclei in bone marrow (i.e. elicited clastogenic potential), as the definition of a negative clastogenic response was not met.

The OCS notes that no primary guideline-compliant in vitro genotoxicity data was provided in the submission, and the available in vivo micronucleus test data raises concerns regarding the in vivo clastogenic potential of the test (supported by the Ames test data). On this basis, the OCS considers that PAPP is likely to be genotoxic.

Carcinogenicity

Overall, from the information available, it is unknown whether PAPP is carcinogenic.  Secondary data of limited reporting and regulatory value suggested that PAPP induced an increased incidence of tumours and carcinomas, while another study indicated that PAPP did not trigger treatment-related changes in neoplastic observations in a methylcholanthrene model of epidermal tumourigenesis.

Reproduction and developmental toxicity

No data on reproduction and developmental toxicity were available.

Other toxicology endpoints

Overall, there is insufficient data to determine whether PAPP has neurotoxic or immunotoxic potential.

Observation in humans

PAPP was well absorbed in the human following ingestion of 1.25 mg/kg bw, and 65 – 90% of the administered dose was accounted for in the urine.

PAPP given orally to human volunteers at 50, 80 or 100 mg (equivalent to 1.1 – 1.8 mg/kg bw PAPP) resulted in a maximum MetHb level of 7% (n = 1), 13.1% (range 0 – 43%, n = 37) and 22% (range 2 – 48%, n = 13) respectively.  MetHb formation began 15–30 minutes after PAPP treatment, and peak levels were reached at 1–2 hours after PAPP treatment. The high variability in the maximum MetHb level within a dose group was likely related to differences in body weights and the contents of the gastric compartments, noting that fasting resulted in higher peak MetHb formation upon PAPP dosing. Other than bluish lips, the study did not note any clinical signs or other adverse effects associated with PAPP-induced methaemoglobinaemia.

Single oral doses of PAPP caused increases of MetHb levels in a dose-related manner in one normal female human subject, i.e. 3.5% and 15% MetHb after 1.14 and 3.4 mg/kg bw PAPP doses respectively (n = 1 only). In addition, two males showed higher responses to PAPP, with 24% and 32% MetHb formation after 1.45 and 1.39 mg/kg bw PAPP doses respectively.

A number of general clinical review papers discussing methaemoglobinaemia indicated that sustained high MetHb levels ≥ 20% resulted in a range of clinical symptoms/signs with scaling MetHb levels, including headache, dyspnoea, nausea and tachycardia occurring at ≥20% MetHb; lethargy, stupor and deteroriating consciousness occurring at up to 55% MetHb; cardiac arrhythmias, circulatory failure and neurological depression at ≥ 55% MetHb, and death/mortality occurring at ~70% MetHb.

It is noted that the information derived was mostly limited to single dose exposures at low dose levels (0.7 - 1.8 mg/kg bw). Even at this low dose range, PAPP caused a clear dose-related increase in MetHb levels in human subjects (up to 48%), suggesting that humans are sensitive to PAPP-mediated MetHb formation and the likely effects associated with elevated MetHb levels described in clinical reviews discussing methaemoglobinaemia.

Public exposure

Occupational use considerations

The use pattern for the PAPP products is similar to existing registered meat based baits, such as 1080 baits.

Both dog and fox baits are applied at a rate of one bait per 5 – 10 ha (only one bait per site), up to 20 baits per km2 depending on dog and fox densities. One bait is sufficient to kill a wild dog or a fox.

The baits will be applied predominantly into pastoral farming areas to target wild dogs and foxes preying on livestock, and also in national parks and other crown land where wild dogs and foxes require management.

Based on the formulation (a solid bait matrix) and product use pattern, dermal contact with the products baits will be the main route of exposure for users.

The European Union has recently published a HEEG opinion on a harmonised approach for the assessment of rodenticides (EC, 2012) which provides guidance on the use rates and exposure for rodenticides based on an exposure study. This guidance has been used by OCS along with the provided draft product label indications and applicant information in the absence of product specific data. The most appropriate scenario for pre-formed baits would be wax blocks in this case, though it is acknowledged that the wax block scenario described is a slightly conservative estimate.

The relevant endpoint for risk assessment was methaemoglobin formation observed across studies (noted as a toxicodynamic effect of PAPP administration). The LOEL of 0.8 mg/kg bw was selected for the risk assessment, and the MOE applicable to this risk assessment was identified as 100, consisting of a 10-fold intra-species variation, a two-fold safety factor for use of a LOEL, and a 5-fold safety factor for deficiencies in the PAPP database in this case.

Overall exposure to PAPP arising from application of the products is 222.32 mg of product per day (equivalent to 0.2 g of product per day).

Based on a concentration of 1.68% PAPP in the wild dog bait and an average weight of an adult of 70 kg, this would result on a systemic exposure of 0.053 mg PAPP/kg bw/d without gloves, and a systemic exposure of 0.0053 mg PAPP/kg bw/d with gloves. (Given the lower content of PAPP in fox bait, and the identical use pattern, the modelling for fox bait was not conducted in full as the exposure estimate for wild dog bait was considered sufficient).

Comparison of the risk assessment endpoint LOEL with the expected daily exposure to the product, indicates that the MOE for use of the product when wearing a single latery of clothing is 15 without gloves, and 151 with gloves. This indicates that there is an adequate MOE for the product to be used according to the described use pattern with the use of appropriate PPE (use of single-layer of clothing and chemical-resistant gloves).

Public health considerations

From a public exposure viewpoint, in the incidental contact and accidental ingestion scenario, a 10 kg toddler consuming a whole bait would result in a systemic exposure equivalent to 40–100 mg/kg bw PAPP.

In considering the toxicology of PAPP and PAPP-induced methaemoglobin formation, the available toxicity data indicates that relatively low doses of PAPP (approximately 0.8 mg/kg bw) would produce methaemoglobin in humans, albeit at relatively low levels (4.5–12%; see Paulet et al.,1963), with no clinical signs of toxicity observed. The data also shows a steep dose response curve for methaemoglobin formation. In addition, reported acute oral LD50 values after ingestion of PAPP were 30–50 mg/kg bw in dogs, and 177–221 mg/kg bw in rats (though rats are not regarded as adequately predicting the acute oral toxicity potential of PAPP in humans). Therefore, it is noted that the resulting oral exposure to PAPP after accidental ingestion of a bait (40–100 mg/kg bw for a toddler) would not result in a sufficient margin of safety.

In this case, noting that the product is not intended for domestic use, this risk of accidental ingestion of a bait by a toddler may be further mitigated by the addition of label warning statements and restraints limiting access to the products, and warning the general public when baiting operations are taking place, in a similar manner to that for other bait products such as 1080-based products (noting that uneaten bait will also be collected by workers after expiration of the baiting period). The following label restraints/statements are recommended:

  • Not for domesticuse.
  • Keep out of reach of children

In addition, the proposed RLP leaflet from the applicant contains language regarding public notification, poison notices and distance restrictions which are considered appropriate and should be retained.

PUBLIC NOTIFICATION

While fox PAPP baits (400mg PAPP baits) pose a lower risk to dogs, the PAPP dose in wild dog baits (1000mg PAPP) will kill any dog. Neighbours should be notified to allow them to take appropriate action. The notification should advise that steps (e.g. restraint, muzzling) need to be taken to ensure that domestic dogs do not gain access to PAPP baits. The notification should specify the dates between which baiting will occur. This notification should be given to all adjoining landholders at least 72 hours in advance. A record of the notifications should be kept. If baiting is not undertaken within the dates specified an additional notification should be made.

POISON NOTICES

Signage is compulsory for all lands where baiting occurs. Do not lay baits until signage is in place. Signage must include – date baits laid, contact numbers, toxin name (PAPP), target animal and a warning that domestic animals and pets can be affected. Users must ensure that signs are put up before baiting with this product commences on the property and are placed according to requirements specified by the relevant State/Territory authority. These notices must remain up for at least 4 weeks after the authorised period of bait lay has expired or after all untaken baits have been collected.

DISTANCE RESTRICTIONS

It is important to reduce risks of accidental poisoning of working and pet dogs. Baits must be placed at least 150m from a dwelling; 20m from permanent or flowing water bodies; 5m from boundary fences; and 5m from the edge of formed public roadways.

International regulations

A risk assessment on PAPP was conducted by New Zealand EPA in 2011, supporting the distribution of PAPP baits for vertebrate pest control.

Scheduling status

4-Aminopropiophenone (para-aminopropiophenone or PAPP) is not specifically scheduled.

Scheduling history

4-Aminopropiophenone has not been previously considered for scheduling; therefore, scheduling history is not available.

Pre-meeting public submissions

Three submissions were received.

One submission supported a Schedule 7 listing of PAPP active constituent and other formulations above 1000 mg total PAPP in a single package. However, the submission proposed a cut-off to Schedule 6 in baits with 1000 mg PAPP or less.

One submission notes that foxes and wild dogs are an increasing problem in Australian and the impact on the goat industry has been catastrophic in some areas; and PAPP is a very viable and much safer alternative to 1080 poison commonly used for baiting. Therefore, the submission notes PAPP must be listed as a schedule 6 not a schedule 7 poison.

One submission supported PAPP technical material being listed in Schedule 7 (i.e. PAPP technical active and pre-formulated PAPP concentrate), but strongly submit that manufactured bait products containing PAPP do not present a significant public health risk and belong in Schedule 6. They noted that PAPP bait products belong in Schedule 6 because:

  • they satisfy the criteria for Schedule 6 and fail the criteria for Schedule 7 set out in the published scheduling factors, and
  • they have an effective antidote to administer in the event of accidental consumption, which is consistent with Schedule 6 and comparable to other poison baits e.g. snail and slug baits that are generally included in a lower Schedule 5 category.

Edited versions of these submissions are available at Public submissions on scheduling matters.

Summary of ACCS advice to the delegate

The committee recommended inclusion of 4-aminopropiophenone in S7 with cross referencing in the index to para-aminopropiophenone (PAPP).

The committee also recommended the following Appendix J, condition 3, Part 1 entry:

4-Aminopropiophenone - Not to be used except by or in accordance with the directions of accredited government vermin control officers

The committee supported the implementation to occur as soon as possible.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (c) the toxicity of a substance; (d) the dosage, formulation, labelling, packaging and presentation of a substance.

The reasons for the recommendation comprised the following:

  • Toxicity consistent with Schedule 7
  • Can be presented in a way that poses a clear risk
Delegate's considerations

The delegate considered the following in regards to this proposal:

  • Scheduling proposal;
  • Public submissions received;
  • ACCS advice;
  • Section 52E of the Therapeutic Goods Act 1989;
  • Scheduling factors3;
  • Other relevant information.
Delegate's interim decision

The Delegate accepts the advice from the ACCS and agrees to include a new entry for 4-aminopropiophenone in Schedule 7, with a cross-reference in the Poisons Standard index to the common name, para-amidopropiophenone (PAPP).

The toxicity profile of the active ingredient is consistent with SPF criteria for listing in Schedule 7, including an LD50 estimate in dogs at 30-50 mg/kg, positive evidence of genotoxicity potential, and indeterminate evidence relating to its potential carcinogenicity.  The delegate notes the submissions that have argued for creating an exception to Schedule 6 for the formulated bait products, but accepts ACCS advice that such an exception is not warranted on grounds of toxicity and the potential for a toddler to be seriously poisoned through consumption of complete bait. The delegate notes that repeated dose studies with PAPP failed to demonstrate a no observed adverse effect level (NOAEL) at the lowest doses tested (17-20 mg/kg/d) and that humans may be even more susceptible to methaemoglobinaemia formation, possibly at doses as low as 0.1-1.8 mg/kg.

The delegate also notes advice from ACCS members that access controls available through listing in Schedule 7 and Appendix J are required for use in jurisdictions where the products are likely to be used. The delegate notes that such controls would also complement the stated intention of the APVMA to regulate the products as Restricted Chemical Products

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; (d) the dosage, formulation, labelling, packaging and presentation of a substance; and (f) other matters that the Secretary considers necessary to protect public health.

The Appendix J entry proposes that the States/Territories impose use controls consistent with other vertebrate pest controls.

The delegate agrees that the earliest date for implementation of the scheduling decision is desirable to allow the States/Territories to exert appropriate controls as soon as the product registration occurs. The proposed implementation date is 1 October 2015.

Public submissions on the interim decision

No public submissions were received before the due date.

Delegate's final decision

The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.

The delegate has confirmed the proposed implementation date of 1 October 2015.

Schedule 7 – New Entry
4-AMINOPROPIOPHENONE
Appendix J, Part 2 – New Entry
Poison Standard statements
4-Aminopropiophenone 3 - Not to be used except by or in accordance with the directions of accredited government vermin control officers

Footnotes

  • 1, 2, 3Australian Health Ministers' Advisory Council (AHMAC): Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015) [Scheduling Policy Framework]

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