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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, February 2016
Scheduling medicines and poisons
Part A - Interim decisions on matters referred to an expert advisory committee
1. Scheduling proposals referred to the November 2015 meeting of the Advisory Committee on Chemicals Scheduling (ACCS#15)
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
- In August 2015, the Office of Chemical Safety (OCS), based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) to approve a new active constituent, recommends that the Delegate consider creating a new entry for oxathiapiprolin Appendix B of the SUSMP.
The reasons for the request are:
- The applicant submitted a data package seeking approval of the new active constituent oxathiapiprolin, a member of the piperidinyl thiazole isoxazoline class of chemical. As a new chemical for AgVet use, it will require consideration by the Delegate/ACCS for SUSMP listing prior to final registration of products containing this active constituent.
- Currently proposed products attached to this application are for agricultural use.
Specific issues/questions raised by the delegate
The delegate asked the committee the following questions:
- Does the ACCS support the OCS proposal that the toxicity profile of oxathiapiprolin is low and that listing in Appendix B is warranted?
- Noting that a GP maximisation test on the active ingredient was negative for sensitisation potential, but that a similar test on the formulated product was positive, does this suggest that oxathiapiprolin should be listed in Schedule 5 or 6? Is there any clear basis for the disparity in the sensitisation test results?
- Do the OCS-recommended safety directions, that include warnings of sensitisation potential, obviate the need to schedule the active ingredient?
Figure 9. Chemical structure of Oxathiapiprolin (DPX-QGU42)
The acute toxicity end-points for oxathiapiprolin are listed in the below table.
|Acute oral toxicity LD50 (mg/kg bw)||SD Rat||>5000 (no deaths)||Appendix B|
|Acute dermal toxicity LD50 (mg/kg bw)||SD Rat||>5000 (no deaths)||Appendix B|
|Acute inhalational toxicity LC50 (mg/m3/4h)||SD Rat||>5100 (no deaths)||Appendix B|
|Skin irritation||NZW rabbit||Non-irritant||Appendix B|
|Eye irritation||NZW rabbit||Non-irritant||Appendix B|
|Skin sensitisation (GPMT method)||Hartley Guinea pigs||Not sensitising||Appendix B|
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
For full summaries and discussion of other endpoints, please see the OCS evaluation report for oxathiapiprolin/the product. An abridged overview is included below.
Short-term and subchronic toxicity studies in rats, mice and dogs reported no systemic toxicity effects of oxathiapiprolin. Chronic dietary studies in mice and rats also reported no systemic toxicity. No treatment related adverse effects were seen in a short-term dermal study in the rat at the limit dose.
There was no evidence of a mutagenic/genotoxic potential of oxathiapiprolin or its primary metabolites in vitro with and without metabolic activation, or a genotoxic potential in vivo. While the metabolite IN-E8S72 was positive in vitro for structural chromosome aberrations in human peripheral blood lymphocytes, the follow-up in vivo micronucleus test with IN-E8S72 was negative at up to the limit dose of 2000 mg/kg bw.
There was no evidence of carcinogenic potential in the long-term rodent tests.
Reproduction and developmental toxicity
In a dietary two generation study in rats, no parental toxicity was seen and no effect was seen on reproductive parameters. However, there was a slight but significant increase in the mean age to achieve preputial separation in these F1 and F2 males at the highest dose of 17000/10000 ppm (equivalent to 1228/1278 mg/kg bw/day). This singular effect of a delay in preputial separation, associated with decreases in pup body weight at 17000/10000 ppm, a dose level exceeding the limit dose of 1000 mg/kg bw/day (as recommended in the OECD TG 416), occurred without other evidence of reproductive/developmental toxicity across the series of Guideline-compliant studies. No evidence of developmental toxicity potential was seen in an oral (gavage) developmental toxicity study in rats or in rabbits, and androgenic potential of oxathiapiprolin was negative in a series of in vivo and in vitro studies). Therefore, while acknowledging the occurrence of the preputial separation finding, the available data suggests that oxathiapiprolin should not being considered a hazard for reproductive or developmental toxicity.
Other toxicology endpoints
In an acute oral (gavage) neurotoxicity study in rats no evidence of an acute neurotoxic effect was seen in functional observation battery or motor activity assessment. Oxathiapiprolin was also not neurotoxic in rats in the combined subchronic toxicity/neurotoxicity study at up to limit dose concentrations.
Oxathiapiprolin is not considered to pose any immunotoxicity risk.
Observation in humans
No information was provided.
At this time, the proposed agricultural use of oxathiapiprolin is not expected to result in general public (i.e. domestic) exposure. Spray drift considerations have not been considered.
Oxathiapiprolin is part of a Global Joint Review (US EPA as lead with Health Canada, Australia and Mexico as partners) and is currently under national assessment for each individual country. The US EPA has notified a proposed registration decision in July 2015.
Oxathiapiprolin is not specifically scheduled.
Oxathiapiprolin has not been previously considered for scheduling; therefore, scheduling history is not available.
Pre-meeting public submissions
No public submissions were received.
ACCS advice to the delegate
The Committee recommended that a new Appendix B listing be created for oxathiapiprolin as follows:
Appendix B - New Entry
The committee recommended an implementation date of 1 June 2016.
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; (c) the toxicity of a substance.
The reasons for the recommendations comprised the following:
- active constituent in pesticide products; and
- very low toxicity
The delegate considered the following in regards to this proposal:
- Scheduling proposal;
- ACCS advice;
- Section 52E of the Therapeutic Goods Act 1989;
- Scheduling factors12;
- Other relevant information.
Delegate's interim decision
The delegate notes, and accepts, ACCS advice that oxathiopiprolin has sufficiently low toxicity that it does not meet any of the SPF criteria for scheduling. Accordingly, listing in Appendix B is considered to be appropriate. The delegate notes that the ACCS was unable to resolve the apparent difference in sensitisation potential between the active ingredient and the tested product, but notes that the Safety Directions provide adequate warning for users of the product and that listing in Schedule 5 is not necessary to flag this unresolved potential toxicity.
The proposed addition to the SUSMP is 1 June 2016.
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the delegate included: c) the toxicity of the substance.
Appendix B - New Entry
Part 1 - Reasons for Entry
a) Low toxicity
Part 2 - Area of Use