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Scheduling delegate's final decisions, July 2016

Scheduling medicines and poisons

27 October 2016

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1.1 4,5-Dichloro-2-N-Octyl-3(2H)-Isothiazolone

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

Scheduling proposals deferred from the March 2016 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#16)

1.1 4,5-Dichloro-2-N-Octyl-3(2H)-Isothiazolone

Delegate's scheduling proposal

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

  • To amend the current 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone Schedule 6 entry to exclude water-based, acrylic or silicone paints, jointing compounds and sealants containing 0.1% or less of 4,5-Dichloro-2-N-octyl-3(2H)-isothiazolone. This is a matter that was first considered at the March 2015 ACCS meeting. It is being reconsidered after submission of additional data.
Scheduling application

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

  • A proposal to amend the current 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone 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 delegate's interim decision on this proposal was published on the TGA website on 3 June 2015. Following the June 2015 public consultation on the delegate's interim decision, the applicant provided additional toxicology studies to be considered by the delegate and/or the committee and a revised proposal for the chemical, limiting the proposed exception to water based/acrylic/silicone paints, jointing compounds and sealants containing 0.1% or less of the chemical.

The applicant's reasons for the request are:

  • The applicant proposes that the current entry in Schedule 6 for 4,5-Dichloro-2-N-octyl-3(2H)-isothiazolone be amended to exclude water-based, acrylic or silicone paints, jointing compounds and sealants containing 0.1% per cent or less of 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone from scheduling and consequently excluding products containing this chemical at a concentration of <0.1% from mandatory packaging and labelling requirements for Schedule 6 chemicals.
Specific issues/questions raised by the delegate

The reasons the delegate has referred this substance to the Committee were: The key issue to be considered in relation to this re-scheduling application is whether the proposed Schedule 6 concentration cut-off in a product matrix is protective against the demonstrated sensitizing potential for this isothiazolinone biocide. In support of the re-scheduling application, the applicant has provided additional sensitisation studies for the substance in water-based paints, and proposes a slight alteration to the wording to specify that the exemption be limited to water-based acrylic or silicone paints. The issue of whether the biocidal use pattern falls within the general exemption for biocides in Appendix A was not resolved in the delegate's original decision, and remains unresolved in the current submission.

The delegate has sought advice on the following questions:

  • Does the ACCS support the revised exemption clause proposed by the applicant?
  • What weight should be given to the applicant's contention that the substance is substantially retained in the paint matrix and is therefore not available for absorption into the skin?
  • Can the ACCS resolve the apparently different sensitisation outcomes, where LLNA and Buehler tests on the substance in either a paint matrix or in an acetone vehicle provide positive and negative results at similar concentrations, noting that some of the positive results in a paint matrix are at concentrations well below the proposed Schedule 6 exemption cut-off?
  • What weight should be given to the negative sensitisation shown in the most recent Buehler test study (Hall, 2012) at a concentration of 0.12% in water-based and silicone paint, compared to the clearly positive result at 0.08% in an acetone vehicle.
Substance summary

Text

Figure 1.1: Structure of 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone

Figure 1.1: Structure of 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone

Table 1.1: sensitisation data for 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone
Study Vehicle 4,5-Dichloro-2-N-octyl-3(2H)-isothiazolone
Concentration ppm
(%)
Outcome Test type
O'Hara and Anderson 2002a
Reference 3
Paint

300 (0.03)

500 (0.05)

800 (0.08)

Sensitiser

Sensitiser

Sensitiser

Buehler
(Guinea Pigs)
O'Hara and Anderson 2002b
Reference 4
Paint 1150 (0.12) Sensitiser Buehler
(Guinea Pigs)
Sanders 2007
Reference 5
Paint

300 (0.03)

600 (0.06)

900 (0.09)

1120 (0.11)

Non sensitiser

Non sensitiser

Non sensitiser

Sensitiser

LLNA (mouse)
Acetone

300 (0.03)

600 (0.06)

900 (0.09)

1120 (0.11)

Sensitiser

Sensitiser

Sensitiser

Sensitiser

McMillan 2002
Reference 7
Paint

95 (0.0095)

478 (0.048)

718 (0.072)

947 (0.095)

1094 (0.11)

Non sensitiser

Non sensitiser

Non sensitiser

Non sensitiser

Non sensitiser

LLNA (mouse)
Acetone

95 (0.0095)

478 (0.048)

718 (0.072)

947 (0.095)

1094 (0.11)

Sensitiser

Sensitiser

Sensitiser

Sensitiser

Sensitiser

Sanders 2009
Reference 8
Paint

600 (0.06)

900 (0.09)

1200 (0.12)

Non sensitiser

Non sensitiser

Sensitiser

LLNA (mouse)
Acetone/olive oil (4:1) 1200 (0.12) Sensitiser
Acetone 1200 (0.12) Sensitiser
Hall 2012
Reference 9
Water based paint 1200 (0.12) Non sensitiser Buehler
(Guinea Pigs)
Silicone based paint 1200 (0.12) Non sensitiser
Acetone 800 (0.08) Sensitiser
Sensitisation

See Table 1.1.

Observation in humans

No information was provided.

Public exposure

No information was provided.

International regulations

As discussed in the previous OCS advice to the delegate, the European Commission (EC) assessment report for 4,5-Dichloro-2-N-octyl-3(2H)-isothiazolone as a biocide ingredient in wood preservatives found the chemical to be a skin sensitiser at 0.01% (100 ppm; 4.4 g a.i./cm2) based on the study considered in March 2015, and recommended that a lower specific concentration limit (lower than the default cut off for skin sensitisers of 1%) should be considered even for classification, labelling and packaging (CLP) for this chemical based on the Guidance to Regulation (EC) No 1272/2008 on classification, labelling and packaging (CLP) of substances and mixtures (ECHA, 2009). A classification as an extreme sensitizer with a specific concentration of 0.001% was recommended.

The classification, labelling and packaging (CLP) for the chemical based on the Guidance to Regulation (EC) No 1272/2008 applies for occupational use when risk management control measures are expected to be in place at work sites. The extension to use of the products containing the chemical by non-professional painters and possibly the general public would warrant more stringent measures.

Current scheduling status

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

Relevant scheduling history

In February 1995, the NDPSC, considered toxicological data for 4,5-dichloro-2-N-octyl-3(2H)-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(2H)-isothiazolone in Schedule 6.

In June 2008, the NDPSC noted that the toxicology data provided in support of past considerations were very old and that no new data were submitted with the current submission and agreed to defer consideration in order to seek further advice regarding these studies. They agreed however that it was appropriate to proceed with consideration of the applicant's request and decided to broaden the current Schedule 6 exemption of ≤1% in paint by also including ≤1% in jointing compounds and sealants.

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% 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.

In June 2015 the interim decision of the delegate was published noting that the current Schedule 6 entry was appropriate. In response to the delegate's interim decision, the applicant provided additional toxicology studies to be considered by the delegate and/or the committee and a revised proposal for the chemical, limiting the exception to water based/acrylic/silicone paints, jointing compounds and sealants containing 0.1% or less of the chemical.

Pre-meeting public submissions

One public submission was received. The submission supports the proposed amendments and notes skin contact for paints is incidental during use, and do not remain on the skin thus sensitization risks are minimal.

The public submission is available at Public submissions on scheduling matters.

ACCS advice to the delegate

In response to the delegate's request, the committee has advised there is insufficient evidence to support the proposed cut off for exemption. New animal studies indicate that skin sensitisation can occur at levels either around or below the cut off proposed by the applicant. Skin exposure during the use of the paint is highly likely in the domestic setting with a significant risk of skin sensitisation necessitating label warnings and the substance retention in Schedule 6.

On the weight that should be given to the applicant's contention that the substance is substantially retained in the paint matrix and is therefore not available for absorption into the skin, the Committee advised this was most relevant for applied and dried paint. However, it was noted studies provided indicate up to 20% of the substance was available for absorption and, given the very low concentrations that elicited a response in the animal tests, the reduced absorption does not eliminate the risk of skin sensitisation.

On the delegate's question about LLNA and Buehler tests, the Committee advised that positive test results from one method should not automatically be dismissed in favour of negative findings using the other method. The Committee noted no testing results were provided for product types other than paint, such as jointing compounds and sealants.

The committee advised that the current Schedule 6 entry for 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: b) Incidental dermal exposure is likely with inclusion of the substance as a biocide in paints, jointing compounds and sealants, particularly when these products are used by the general public.; c) Animal studies suggest skin sensitisation is possible at very low concentrations and therefore the substance, at all concentrations, continues to meet the criteria for Schedule 6.

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[1];
  • Other relevant information.
Delegate's interim decision

The delegate notes the advice from the ACCS based on evaluation of additional information submitted by the applicant since this matter was considered at the March 2015 ACCS meeting. The delegate agrees that the new studies suggest a reduction in sensitisation potential when 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone is incorporated in a paint matrix, but that they do not resolve the question of where an appropriate exemption cut-off could be applied to such products. Findings that sensitisation reactions have been demonstrated at and below the proposed cut-off concentrations support the ACCS advice that current scheduling remains appropriate, and that the sensitisation warning statements and POISON signal heading on such products provide appropriate advice to product users.

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.

Submissions on the interim decision

One submission was received. The submission disagreed with the assessment made of the sensitisation potential for 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone when incorporated into a water-based paint matrix and requested further consideration of an exemption for concentrations up to 1000 ppm.

Delegate's final decision

The delegate has confirmed the interim decision as the evidence provided in response to the interim decision does not alter the outcome of previous considerations. The delegate's final decision is that the current Schedule 6 entry for 4,5-dichloro-2-N-octyl-3(2H)-isothiazolone remains appropriate. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.


Footnote

  1. Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)

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