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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, March 2016
Scheduling medicines and poisons
Part A - Interim decisions on scheduling proposals referred to an advisory committee (March 2016)
1. Advisory Committee on Chemicals Scheduling (ACCS#16)
Referred scheduling proposal
- To consider whether fluopicolide requires listing in the Schedules.
In December 2015, the Australian Pesticides and Veterinary Medicines Authority (APVMA) referred the following proposal to be considered by the delegate:
- A proposal to create a new entry in Appendix B for fluopicolide.
The reasons for the request are:
- Fluopicolide has very low acute oral, dermal and inhalational toxicity;
- Fluopicolide is not irritant to skin or a skin sensitiser
- Fluopicolide is a slight eye irritant;
- Fluopicolide is not a teratogen, neurotoxin, reproductive toxin or genotoxin; and
- Benign liver tumours observed in an 18-month mouse study, were demonstrated in a supplementary studies to be most likely mouse specific, the mechanism of which was shown to be related to the induction of specific cytochrome P450s, which lead to liver tumours in mice specifically, and therefore these tumours were not relevant to the human risk assessment.
Specific issues/questions raised by the delegate
The Delegate referred the substance to the Committee for advice on the following issues:
- Does the ACCS support the proposal that fluopicolide has sufficiently low toxicity that it does not require listing in the Schedules and could be added to Appendix B?
- Does the ACCS have any concerns that the evaluator of the toxicology submission has not been identified, or that evidence of peer review is lacking?
Figure 9. Chemicals structure of fluopicolide.
The acute toxicity end-points for fluopicolide are listed in the following table.
|Acute oral toxicity LD50 (mg/kg bw)||Rat||> 5000||Low toxicity|
|Acute dermal toxicity LD50 (mg/kg bw)||Rat||> 5000||Low toxicity|
|Acute inhalational toxicity LC50 (mg/m3/4h)||Rat||5160||Low toxicity|
|Eye irritation||Rabbit||Slight irritant||Slight irritant|
|Skin sensitisation||Guinea pig||Non-sensitiser||Non-sensitiser|
*Scheduling Policy Framework for Medicines and Chemicals (SPF, 2015)
In the short-term toxicity studies, the target/critical effect was liver pathology, which was observed in a 28-day dietary mouse study. The NOEL was set at 10.4 mg/kg bw/d based on increased liver weights associated with centrilobular hepatocellular hypertrophy at a LOEL (640 ppm).
In sub-chronic toxicity studies, critical effects were seen in the liver of rats. Histopathological effects observed in the 3-month rat dietary study included centrilobular hepatocellular hypertrophy in males at the LOEL (1400 ppm). An increase in the severity and incidence of trabecular hyperostosis of the bone joint was observed in females at the same dose level. A NOEL was set at 7.4 mg/kg bw/day (100 ppm).
Consistent with the liver pathology seen in the short-term and sub-chronic toxicity studies, liver pathology was the target organ in a chronic toxicity study in rats. A NOEL was set at 7.9 mg/kg bw/d (50 ppm) based on the increased absolute and relative liver weights associated with hepatocellular hypertrophy at the LOEL and highest does (400 and 3200 ppm, respectively). A markedly increased incidence of hepatocellular adenoma was observed at 3200 ppm.
Fluopicolide was not genotoxic based on a battery of in vivo and in vitro genotoxicity assays.
Carcinogenicity studies showed an increased incidence of hepatocellular adenoma at the highest dose level (3200 ppm) in a 78-week mouse dietary study and a NOEL was set at 400 ppm. The incidence of hepatocellular carcinoma was unaffected by the treatment. Mechanistic studies demonstrated a mouse specific mechanism for the liver adenoma. It was concluded that the benign liver tumours observed in mice were not relevant to humans.
Reproduction and developmental toxicity
Fluopicolide was not a reproductive toxicant. A NOEL of 25.5 mg/kg bw/d for males and 32.9 mg/kg bw/d for females (500 ppm) was set based on increased liver and kidney weights, adverse kidney histopathology findings and reduced weight gains at the next highest dose tested. A reproduction NOEL of 103.4 mg/kg b/d (2000 ppm) was set at the highest dose tested in a 2-generation dietary study in rats.
Fluopicolide was not a teratogen in developmental studies in rats and rabbits. In rats, a NOEL for maternal and foetal toxicity was set at 60 mg/kg bw/d. This was based on reduced weight gain in dams and delayed development in foetuses observed at the dose level of 700 mg/kg bw/d. A NOEL for teratogenesis was set at the highest dose level 1000 mg/kg bw/day. In rabbits, fluopicolide killed the majority of the dams and their pups at the highest dose tested (60 mg/kg bw/d). At this dose level, a high level of premature delivery, body weight loss and decreases in food consumption were observed. The NOEL for maternal and foetal toxicity was 20 mg/kg bw/d and the NOEL for foetal development was 60 mg/kg bw/d.
Neurotoxicity studies conducted in rats demonstrated that fluopicolide was not neurotoxic.
Not explored by the APVMA in this report. Fluopicolide has been approved for use in the European Union since 2006.
Current scheduling status
Fluopicolide is not specifically scheduled.
Relevant scheduling history
Fluopicolide 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
In response to the Delegate's request the Committee has advised that the toxicity profile of fluopicolide is sufficiently low to support it being included in Appendix B. The Committee noted the slight and transient eye irritation effects of the substance.
The committee advised the following amendments to the Poisons Standard:
Appendix B, Part 3 - New entry
Part 1 – Reasons for Entry
a) low toxicity
Part 2 - Area of Use
The matters under subsection 52E (1) of the Therapeutic Goods Act 1989 considered relevant by the Committee included: c) Toxicity of the substance - Slight and transient eye irritation effects.
The delegate considered the following in regards to this proposal:
- Scheduling proposal;
- APVMA Human Health Risk Assessment Report;
- ACCS advice;
- Section 52E of the Therapeutic Goods Act 1989;
- Scheduling factors10;
- Other relevant information.
Delegate's interim decision
The delegate notes, and accepts, the ACCS advice that the toxicity profile of fluopicolide is not consistent with SPF criteria for listing in any of the schedules. Accordingly, the delegate proposes to list fluopicolide in Appendix B, to designate that it has at least been considered for scheduling.
The proposed implementation date is 1 October 2016. Since listing in Appendix B is not equivalent to a decision to list a substance in a schedule, an implementation date is not strictly relevant. However, early advice to the APVMA of this decision will facilitate prompt registration of products under consideration by the APVMA. Accordingly, amendment of Appendix B at the earliest revision of the Poisons Standard is recommended.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (c) the toxicity of a substance.
Appendix B, Part 3 - New entry
Part 1 – Reasons for Entry - a) low toxicity
Part 2 - Area of Use - 1.3