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Scheduling delegate's final decisions: ACCS, November 2015
Scheduling medicines and poisons
Part A - Final decisions on matters referred to an expert advisory committee (ACCS#13)
1. Scheduling proposals referred to the March 2015 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#13)
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.
Delegates 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].
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.
Figure 1: Structure of 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone
The acute toxicity end-points for this chemical are listed in the below table.
|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|
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.
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.
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:
- 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.
- Labels and, where provided, instructions for use shall indicate that children shall be kept away until treated surfaces are dry.
- 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.
- 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.
- 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.
4,5-Dichloro-2-n-octyl-3(2H)-isothiazolone is currently listed in Schedule 6.
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 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.
The delegate agrees that the current Schedule 6 entry remains appropriate.
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.
Public submissions on the interim decision
Two submissions were received. One submission did not support the delegate's interim decision, and provided further toxicological data in support of the scheduling proposal. The second submission did not comment on the scheduling proposal specifically rather the submission commented in general terms on the scheduling of biocides used in paint production in Australia.
An edited version of the submission is available on the TGA website at: Public Submissions ACCS#13 March 2015
Delegate's final decision
In response to the interim decision, the applicant submitted additional information. For appropriate consideration of the additional information this matter will be referred back to the ACCS for further advice. Since the interim decision was to make no change to the current schedule 6 listing that decision stands, pending consideration of the additional submitted information by the ACCS and the delegate.
The delegate notes the comments made in a submission relating to the use of industrial biocides. The delegate has made no determination on whether the use of 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone as an industrial biocide is consistent with exemption from scheduling under the provisions of Appendix A. This is a matter for individual State/Territory jurisdictions in interpreting their legislation. However, the delegate notes the points made in the public submission relating to the need for harmonisation of regulatory approaches to industrial biocides and the ACCS recommendation that the relevant entry in Appendix A may need to be reviewed. This matter will also be referred back to the ACCS for consideration at the next available meeting.