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Scheduling delegate's interim decisions and invitation for further comment: ACCS, June 2015

Scheduling medicines and poisons

3 June 2015

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Interim decisions on matters referred to an expert advisory committee: ACCS#13 (1.1-1.3)

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

1.1 2-ethylhexanoic acid and its derivatives

Scheduling proposal

The Chemicals Scheduling Delegate (the delegate) referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):

  • That a new entry be created in Schedule 6 for 2-ethylhexanoic acid and its derivatives, with appropriate low concentration exemption cut-off in cosmetic and/or domestic preparations containing esters that hydrolyse and/or metabolise to 2-ethylhexanoic acid.

In December 2014, the National Industrial Chemicals Notification and Assessment Scheme (NICNAS), under its Inventory Multi-tiered Assessment Prioritisation (IMAP) programme, referred the following proposal to be considered by the chemicals scheduling delegate:

  • That a new entry be created in Schedule 6 for 2-ethylhexanoic acid and its derivatives, with appropriate low concentration exemption cut-off in cosmetic and/or domestic preparations containing esters that hydrolyse and/or metabolise to 2-ethylhexanoic acid.

The reasons for the request were:

  • 2-Ethylhexanoic acid is not directly used in cosmetic or domestic products in Australia. Ester derivatives of the chemical readily hydrolyse to form 2-ethylhexanoic acid via chemical or enzymatic processes, and this was accepted by the Delegate as a basis for scheduling 2-ethylhexyl 2-ethylhexanoate at concentrations above 10% (which is broadly equivalent to 5% 2-ethylhexanoic acid). The Cosmetic Ingredient Review's (CIR) assessment of alkyl ethylhexanoates (CIR, 2013) indicates that alkyl ethylhexanoates have widespread use in cosmetic products overseas. It is expected that these ester derivatives have similar uses in cosmetic products in Australia.
  • Sixteen cosmetic ingredients which metabolise to 2-ethylhexanoic acid are identified from CIR, 2013. These compounds are best scheduled as derivatives of 2-ethylhexanoic acid, which is the toxic species of concern.
  • Scheduling the derivatives based on the percentage that can be metabolized to 2-ethylhexanoic acid will result in uniform treatment.
  • The critical health effects of 2-ethylhexanoic acid include systemic long-term effects (fertility and developmental toxicity) based on observations in laboratory animals. Fertility effects (reduction in sperm motility, abnormal sperm, and dose-dependent delays in mating) were reported in rats. Developmental toxicity effects were noted in the absence of maternal toxicity from several studies in rats following exposure to the chemical via the oral route. The lowest observed adverse effect level (LOAEL) was reported to be 100 mg/kg bw/day based on skeletal variations (wavy ribs) and skeletal malformations (club foot) of the foetuses.
  • There are currently no labelling requirements for products containing the chemical and its derivatives (apart from 2-ethylhexyl 2-ethylhexanoate) in Australia. However, the characterised critical health effects (fertility and developmental toxicity) have the potential to pose an unreasonable risk to the public under the uses identified.
Delegate's reasons for referring this to the committee

The related substance, 2-ethylhexyl 2-ethylhexanoate was considered by the ACCS at the July 2014 meeting. The key toxicological issue was reproductive toxicity associated with the hydrolysis of this ester to known reproductive toxicants, 2-ethylhexanol and 2-ethylhexanoic acid. The current IMAP report recommends making a separate Schedule 6 entry, with appropriate low-level cut-offs to regulate the use of 2-ethylhexanoic acid, but more particularly, esters that hydrolyse to form this known reproductive toxin.

The delegate asked the ACCS the following questions:

  • The NICNAS IMAP report suggests there are likely to be few products where 2-ethylhexanoic acid may be a direct ingredient, but there are potentially more esters used in cosmetic and domestic products. The 2013 US CIR Expert Panel report lists some 16 alkyl esters of 2-ethylhexanoic acid used in cosmetic products that could be hydrolysed to 2-ethylhexanoic acid. Does the ACCS support a Schedule 6 listing that captures all these esters? What wording of the Schedule 6 entry would best capture such a generic listing?
  • The current Schedule 6 entry for 2-ethylhexyl 2-ethylhexanoate is: 2-ETHYLHEXYL 2-ETHYLHEXANOATE except in preparations containing 10 per cent or less of 2-ethylhexyl 2-ethylhexanoate. There are also entries in Appendices E & F. These entries would become redundant in the light of a generic entry. Should they be deleted or retained?
  • The 10% cut-off to exempt has apparently been recommended for consistency with the 10% exemption in the generic S6 entry for ethylene glycol monoalkyl ethers and their acetates (also a reproductive toxicity issue). Is this cut-off suitable for a generic entry for 2-ethyhexanoates? The 10% cut-off recommended for 2-ethylhexyl 2-ethylhexanoate would represent approximately 5% of the hydrolysed acid. Is it possible to word a generic S6 entry so that it only captures the hydrolysis products of esters at a relevant concentration?
  • The CIR report suggest that current uses of alkyl esters of 2-ethylhexanoic acid used in cosmetic products at concentrations up to 77% in rinse-off products and 53% in leave-on products is 'safe'. What impact does this report have on a proposal to develop a generic listing with one or more exemption cut-offs for leave-on or rinse-off cosmetic products?
  • If a generic listing is impractical, would a simple entry for 2-ethylhexanoic acid and its derivatives, with a 5% exemption cut-off, have any regulatory effect? Would such an entry capture any or all of the alkyl esters as 'derivatives'?
Substance summary

Please refer to the NICNAS IMAP human health Tier II assessment report for Hexanoic acid, 2-ethyl-.

In addition, the CIR assessment of alkyl ethylhexanoates (CIR, 2013) is publicly available from:

Repeat-dose toxicity

In a 90-day dietary study in rats, a LOAEL of 917 mg/kg bw/day was reported based on reduced body weight gain in conjunction with reduced feeding (Canada, 2011). A lowest observed effect level (LOEL) of 303 mg/kg bw/day was also reported based on increased relative liver weight and hepatocyte hypertrophy.

In a 90-day dietary study in mice, a LOAEL of 1040 mg/kg bw/day was reported based on reduced body weight (Canada, 2011; REACH). A LOEL of 885 mg/kg bw/day was also reported based on effects including increased relative liver weight, hepatocyte hypertrophy, kidney effects and forestomach lesions.

Reproduction and developmental toxicity

The chemical is classified as hazardous as a Category 3 reproductive toxin with the risk phrase ‘Possible risk of harm to the unborn child’ (Xn; R63) in Safe Work Australia’s Hazardous Substances Information System (HSIS). There is also sufficient evidence to classify the chemical as potentially toxic in relation to fertility.

The chemical was reported to cause developmental toxicity in several studies in rats following exposure via the oral route (Canada, 2011; Pennan et al., 1992; REACH). These effects were noted in the absence of signs of maternal toxicity. The lowest developmental toxicity LOAEL was reported to be 100 mg/kg bw/day.

In a developmental toxicity study, pregnant female Wistar rats were administered the chemical on gestation days 6-19 via drinking water at 0, 100, 300 or 600 mg/kg bw/day (Canada, 2011; Pennan et al., 1992; REACH). Skeletal variations in foetuses were observed at the lowest dose. A dose-dependent increase in club foot was observed in foetuses of the treatment group (statistically significant at the highest and intermediate dose); this anomaly was not observed in any foetuses of the control group. A statistical increase in wavy ribs was also observed in the foetuses of all treatment groups compared to controls. A dose-dependent increase in malformation of the legs, reported as 'flabby legs (external, slightly paralysed)' was also observed in foetuses of all treatment groups; this was not observed in any foetuses of the control group. While a maternal toxicity LOAEL of 600 mg/kg bw/day (highest dose) was reported from this study, based on decreased maternal body weight gain (Canada, 2011; Pennan et al., 1992), a REACH dossier reported maternal toxicity (slightly lower pregnancy rates and reduced body weights) at 300 mg/kg bw/day. A developmental LOAEL of 100 mg/kg bw/day was determined from this study in both reports.

Foetal skeletal variations, malformations, reduced foetal body weights and early foetal deaths have also been reported in several other developmental toxicity studies in rats following oral exposure to the chemical (Canada, 2011; REACH). For each of these studies, developmental effects were observed in the absence of maternal toxicity.

In a reproductive toxicity study in Wistar rats, the sodium salt of the chemical was administered via drinking water at 100, 300 or 600 mg/kg bw/day (Pennan et al., 1993; REACH). Males were exposed to the chemicals for 10 weeks prior to mating and for three weeks during mating; females were exposed for two weeks prior to mating and throughout the entire gestation and lactation period. Effects on the male reproductive system (reduction in sperm motility) were observed at 100 mg/kg bw/day, and increases in abnormal sperm were observed at 300 and 600 mg/kg bw/day. Dose-dependent delays in mating at 300 and 600 mg/kg bw/day were also reported, in addition to some animals being reported to be 'totally infertile'.

Public exposure

While use of the chemical in domestic products in Australia is not known, it is reported to be used in domestic products overseas. Limited information with regard to concentration in domestic products is available from the US National Library of Medicine's Household Products Database, which indicated use of the chemical in:

  • liquid form auto products (antifreeze) at up to 8%;
  • a home maintenance product (paint drier) at up to 5%; and
  • an arts and craft stain product at less than 4%.

An approximate margin of exposure (MOE) was calculated by Canada (2011) based on domestic use of the chemical in similar types of products identified in this report (alkyd paints), using similar levels of bioavailability, and LOAELs. The calculations resulted in the determination that the MOE was acceptable, particularly given the expected episodic exposure of the general population to the chemical from normal use of these products.

However, since esters that hydrolyse and/or metabolise to 2-ethylhexanoic acid are widely available to the general public, appropriate restrictions on the chemical and its derivatives are needed.

International regulations

The chemical is listed on the following:

  • European Union Cosmetic Directive 76/768/EEC Annex II: List of Substances which must not form part of the composition of cosmetic products.
  • New Zealand Cosmetic Products Group Standard - Schedule 4: Components cosmetic products must not contain.
Scheduling status

2-Ethylhexanoic acid is not specifically scheduled.

Scheduling history

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

However, a chemical belonging to the same group of chemicals, namely 2-ethylhexyl 2-ethylhexanoate was considered by the ACCS in March 2014. The delegate decided to include this chemical in Schedule 6 due to reproductive/developmental toxicity associated with its ready hydrolysis to the known reproductive toxicants, 2-ethylhexanol and 2-ethylhexanoic acid.

Schedule 6

2-ETHYLHEXYL 2-ETHYLHEXANOATE except in preparations containing 10 per cent or less of 2-ethylhexyl 2-ethylhexanoate.

Appendix E, Part 2
Poisons Standard statements
2-Ethylhexyl 2-ethylhexanoate 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).
Appendix F, Part 3
Poisons Warning statements Safety direction
2-Ethylhexyl 2 ethylhexanoate 53. CAUTION - 2-ethylhexyl 2-ethylhexanoate should not be used by pregnant women.
Pre-meeting public submissions

One public submission was received. The submission proposed that 2-ethylhexanoic acid should be included in Schedule 6, except when in concentrations of 10% or less, to be consistent with the scheduling decision for 2-ethylhexyl-2-ethylhexanoate (2-EHEH) made in August 2014. The submission noted that the Appendix E and F statements used for 2-EHEH are also relevant for 2-ethylhexanoic acid and should be maintained. The following schedule entry for esters of 2-ethylhexanoic acid was also proposed:

  • ALKYL ETHYLHEXANOATES (excluding derivatives) in preparations containing 10 percent or more alkyl ethylhexanoate calculated as 2-ethylhexanoate.
Summary of ACCS advice to the delegate

The committee recommended that a new Schedule 6 entry be created for 2-ethylhexanoic acid with exceptions in preparations containing 5 per cent or less of as calculated as 2-ethylhexanoic acid.

The committee also recommended a new Appendix E, Part 2 entry (standard statement A) and a new Appendix F, Part 3 entry (warning statement 53).

In addition, the committee recommended the current Schedule 6 and Appendices E and F entries for 2-ethylhexyl 2-ethylhexanoate be deleted.

The committee recommended an implementation date of 1 October 2015.

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

The reasons for the recommendation comprised the following:

  • Developmental toxicant.
  • Alkyl esters are used in cosmetic products which in vivo hydrolyse to the acid which is the toxin.
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 factors;
  • Other relevant information.
Delegate's interim decision

The delegate accepts ACCS advice that the recent scheduling decision to include 2-ethylhexyl-2-ethylhexanoate in Schedule 6, because of the reproductive toxicity potential of its hydrolysed acid and alcohol components, needs to be broadened to capture all the alkyl 2-ethylhexanoate esters that can yield 2-ethylhexanoic acid via hydrolysis. The delegate notes the advice from NICNAS and the actions by other regulators to limit the concentrations of such esters in cosmetic products that are applied directly to human skin. The issue considered by the ACCS was how to word a generic entry in Schedule 6 to capture these esters. ACCS advice was that, while 2-ethylhexanoic acid was unlikely to be used in cosmetics or other products as itself, including its alkyl esters in the entry could ensure that all the substances of concern would be captured. The exemption cut-off (5%) could then be based on the amount of 2-ethylhexanoic acid able to be released by complete hydrolysis. It is possible that a simple Schedule 6 entry for 2-ethylhexanoic acid could capture the alky esters as 'derivatives', consistent with guidance in Part 1 of the Poisons Standard, but the proposed wording should be clearer in its coverage and provide a consistent exemption cut-off for substances that contain 2-ethylhexanoic acid in different proportions based on molecular weights.

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

The delegate agrees with the proposed implementation date of 1 October 2015 noting that it balances the need to safeguard public health by early implementation of a more restrictive scheduling decision, and the lag-time associated with the need to re-label or withdraw affected products already in the marketplace.

Schedule entry
Schedule 6 - New entry

2-ETHYLHEXANOIC ACID and its alkyl esters except in preparations containing 5 per cent or less calculated as 2-ethylhexanoic acid.

Appendix E, Part 2 - New entry
Poison Standard statement
2-ethylhexanoic acid and its alkyl esters A - For advice, contact a Poisons Information Centre (e.g. phone Australia 13 1126; New Zealand 0800 764 766) or a doctor (at once).
Appendix F, Part 3 - New entry
Poison Warning statemens Safety directions
2-ethylhexanoic acid and its alkyl esters 53 - CAUTION - (Name of substance) should not be used by pregnant women.
Schedule 6, Appendix E and Appendix F - Delete entries

2-Ethylhexyl 2-ethylhexanoate.

1.2 2-hydroxyethyl methacrylate

Scheduling proposal

The delegate has referred the following scheduling proposal for consideration by the ACCS:

  • A proposal to create a new Schedule 5 entry for 2-hydroxyethyl methacrylate with an appropriate cut-off to exempt. The scheduling proposal will primarily address use in cosmetic products, but may include other product types as well.

In December 2014, 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.

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 1.4 2-hydroxypropyl

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:

  1. for cosmetic use; or
  2. 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.

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 factors;
  • 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.

Schedule entry
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.

1.3 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone

Scheduling proposal

The delegate has referred the following scheduling proposal for consideration by the ACCS:

  • A proposal to amend the current 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone schedule 6 entry to exclude from the scheduling for paints, jointing compounds and sealant preparations containing 0.12% or less of 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone.

In July 2014, the delegate received the following application to be considered for rescheduling:

  • A proposal to amend the 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone current Schedule 6 entry to exclude paints, jointing compounds and sealants containing 0.12% per cent or less of 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone from scheduling.

The applicant's reasons for the request were:

  • 4,5-Dichloro-2-N-octyl-3(2H)-isothiazolone is a film biocide used in paints, jointing compounds and sealants to provide fungicide protection to stop the growth of mould. Given the nature of these products, their packaging and use, oral ingestion of any significant amounts of the formulated product is unlikely. The proposed exemption cut-off concentration of 0.12% is low, exposure would be accidental and based on the pharmacology of the substance, any associated absorption would be minimal with clearance within 2 days and no evidence of accumulation once absorbed.
  • The proposal aims to provide 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone with an exemption from scheduling in the same manner that specified concentrations of carbendazim and octhilinone are exempt. Carbendazim and octhilinone have been extensively considered by scheduling committees over a 40 year period. Hence, there is considerable precedent related to this proposal and the relevant matters under 52E(1): the risks and benefits, potential hazards, extent and patterns of use and dosage and formulation have previously been considered for carbendazim and octhilinone resulting in exemption cut-offs for both substances.
  • On the basis of the toxicological data presented in this submission, 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone is a safer, suitable alternative film biocide to carbendazim (excluded from Schedule 7 at 0.1% or less) and is an isothiazolinone structurally-related to the film biocide octhilinone (excluded from Schedule 6 at 1% or less); however, without an exemption from Schedule 6, 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone is not regulated in the same manner as carbendazim and octhilinone.
Delegate's reasons for referring this to the committee

This application to vary the current Schedule 6 entry for 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone has some elements in common with the scheduling consideration of methylisothiazolinone and methylchloroisothiazolinone. The common element is the potential for skin sensitisation and where to set an appropriate cut-off from the existing Schedule 6 listing. The different element is that the proposed cut-offs relate to products that are not directly applied to the skin in cosmetics. Also, the current S6 schedule entry for octhilinone, a thiazolone preservative with a comparable toxicological profile, may provide a useful template and support for an amended schedule 6 entry for 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone.

The delegate asked the ACCS the following questions:

  • The applicant has provided skin irritancy/sensitisation test data in support of the proposed exemption cut-off, and these test data have been evaluated by the OCS. Does the ACCS agree that these data support the proposed 0.12% cut-off for paints, jointing compounds and sealant preparations? Note that the OCS evaluation report and references to European Commission assessments suggest a much lower threshold for sensitisation.
  • Is it necessary to develop a separate exemption sub-clause for paints, so that the concentration can be specified as calculated on the non-volatile content of the paint?
  • Can the ACCS advise whether the proposed uses of 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone are consistent with the Appendix A exemption for ALGICIDES, BACTERIOCIDES OR SLIMICIDES for industrial use that do not fit the definition of an agvet product? A search of the Australian Pesticide and Veterinary Medicines Authority (APVMA) PUBCRIS database reveals no registered products containing this ingredient. [Note: there are also no APVMA-registered products containing octhilinone on PUBCRIS, although it is registered as an approved active ingredient].
Substance summary

4,5-Dichloro-2-N-octyl-3(2H)-isothiazolone is an industrial biocide. It is a broad spectrum antifungal biocide used in paints, coatings, silicone sealants, plastics and for marine antifouling applications as well as the preservation of wood, masonry and other construction products.

Depending on the concentration used, 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone can act as a fungicide/fungistat, bactericide/bacteristat and/or algaecide/algicstat.

Chemical structure of 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone
Figure 1: Structure of 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone

Acute toxicity

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

Toxicity Species 4,5-Dichloro-2-N-octyl-3(2h)-isothiazolone SPF classification
Acute oral toxicity LD50 (mg/kg bw) Mouse 567 mg/kg Moderate to high toxicity
Acute dermal toxicity LD50 (mg/kg bw) Rabbit > 2000 mg/kg (in xylene) Low toxicity
Acute inhalational toxicity LC50 (mg/L/4h) Rat 0.22 mg/L (in xylene) High to extremely high toxicity
Skin irritation Rabbits Corrosive (in xylene).
Eye irritation Not provided Corrosive (in xylene) based on skin irritation end-point.
Skin sensitisation (Magnusson-Kligman Method) Guinea pigs Skin sensitiser
Toxicity assessment

The Office of Chemical Safety (OCS) conducted an assessment of the information provided by the applicant.

Based on the available studies, OCS concluded that the chemical is a skin sensitiser in guinea pigs even at the lowest concentration tested (<0.12%) and with a small area of exposure at induction and challenge at remote site. The OCS concluded that the new skin sensitisation study submitted with the application confirms that the chemical is a strong sensitiser and therefore warrants a Schedule 6 entry. There was no evidence provided to support a cut-off concentration of 0.12% or lower.

Observation in humans

No information provided.

Public exposure

The wood preservative is to be used for preventative application by industrial techniques (automated spraying, flow coating, automated dipping, vacuum/pressure and double vacuum treatment). The Applicant has indicated that a future use could be in ready to use formulations for professional in situ use. Such future use has not been considered.

Professionals may be exposed when handling or processing treated wood (secondary exposure). The general public may be exposed during handling/contact with treated wood (secondary exposure).

Dermal exposure and exposure by inhalation are the main exposure routes.

International regulations

In September 2007, the US Environmental Protection Authority (US EPA) determined that 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone is eligible for reregistration provided that additional required data confirm this decision, the risk mitigation measures outlined in the document are adopted, and label amendments are made to reflect these measures.

In April 2014, the European Union (EU) released an approval notice for 4,5-dichloro-2-octyl-2H-isothiazol-3-one with the approval date for the substance of 1 January 2016. The approval of the substance has the following specific conditions:

  • The product assessment shall pay particular attention to the exposures, the risks and the efficacy linked to any uses covered by an application for authorisation, but not addressed in the Union level risk assessment of the active substance.
  • Persons making products containing 4,5-Dichloro-2-octyl-2H-isothiazol-3-one available on the market for non-professional users shall make sure that the products are supplied with appropriate gloves.

Authorisations are subject to the following conditions:

  1. For industrial or professional users, safe operational procedures and appropriate organizational measures shall be established. Where exposure cannot be reduced to an acceptable level by other means, products shall be used with appropriate personal protective equipment.
  2. Labels and, where provided, instructions for use shall indicate that children shall be kept away until treated surfaces are dry.
  3. Labels and, where provided, safety data sheets of products authorised shall indicate that application, maintenance and repair activities shall be conducted within a contained area, on impermeable hard standing with bunding or on soil covered with an impermeable material to prevent losses and minimize emissions to the environment, and that any losses or waste containing 4,5-Dichloro-2-octyl-2H-isothiazol-3-one shall be collected for reuse or disposal.
  4. For products that may lead to residues in food or feed, the need to set new or to amend existing maximum residue levels (MRLs) in accordance with Regulation (EC) No 470/2009 of the European Parliament and of the Council (3) or Regulation (EC) No 396/2005 of the European Parliament and of the Council (4) shall be verified, and any appropriate risk mitigation measures shall be taken to ensure that the applicable MRLs are not exceeded.
  5. Where an article has been treated with or intentionally incorporates one or more biocidal products containing 4,5-dichloro-2-octyl-2H-isothiazol-3-one and where necessary due to the possibility of skin contact as well as the release of 4,5-dichloro-2-octyl-2H-isothiazol-3-one under normal conditions of use of the article, the person responsible for placing the article on the market shall ensure that the label provides information on the risk of skin sensitisation, as well as the information referred to in the second subparagraph of Article 58(3) of Regulation (EU) No 528/2012.
Scheduling status

4,5-Dichloro-2-n-octyl-3(2H)-isothiazolone is currently listed in Schedule 6.

Schedule 6

4,5-DICHLORO-2-N-OCTYL-3(2H)-ISOTHIAZOLONE.

Scheduling history

In February 1995, the NDPSC, considered toxicological data for 4,5-dichloro-2-N-octyl-3(2N)-isothiazolone. No metabolic, sub-chronic or chronic animal data was provided. In a 28-day repeat dose study, gastrointestinal irritation was the major toxic effect. Developmental and genotoxicity studies did not show evidence of teratogenicity or genotoxicity. The committee considered that based on its skin and eye corrosion and skin sensitisation potential, it was appropriate to include 4,5-dichloro-2-N-octyl-3(2N)-isothiazolone in Schedule 6.

Pre-meeting public submissions

No public submissions were received.

Summary of ACCS advice to the delegate

The committee recommends that the proposal is not supported and the current scheduling of 4,5-Dichloro-2-N-octyl-3(2H)-isothiazolone remains appropriate.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: (c) the toxicity of a substance.

The reasons for the recommendation comprised the following:

  • Severe potential for skin sensitisation
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 factors;
  • Other relevant information.
Delegate's interim decision

The delegate accepts the advice of the ACCS that the current Schedule 6 entry for 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone (DCIT) remains appropriate.

The key issues driving the scheduling of 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone are its potential for skin/eye corrosivity and skin sensitisation. An evaluation of submitted test data suggested that skin irritation and sensitisation can be demonstrated to occur at concentrations much lower than the 0.12% in the products under consideration. Accordingly, the delegate is unable to determine a concentration at which a product could be exempted to a lower schedule.

The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: (c) the toxicity of the substance.

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