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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
2. Scheduling proposals referred to the August 2015 ACCS meeting
The chemicals scheduling delegate has referred the following scheduling proposal for consideration by the Advisory Committee on Chemicals Scheduling (ACCS):
- In May 2015, the Office of Chemical Safety (OCS), based on an application made to the Australian Pesticides and Veterinary Medicines Authority (APVMA) to register a new active ingredient, requested that the delegate consider creating a new entry for momfluorothrin in Schedule 6 of the Poisons Standard.
The reasons for the request were:
- An applicant has sought approval for a new active constituent momfluorothrin, a member of the pyrethroid 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.
- While there are no currently proposed products attached to this application, in supporting documents the applicant has foreshadowed that momfluorothrin will be used in household and pest control insecticide products.
Delegate's reasons for referring this to the committee
While the toxicity profile of momfluorothrin is reasonably straightforward, the OCS evaluation report recommends listing in Schedule 6, while the applicant has requested listing in Schedule 5 (with no supporting evidence or argument). The SPF suggests that the delegate refer the submission to the ACCS for advice on resolution of this apparent conflict.
The delegate asked the committee the following questions:
- The scheduling of the synthetic pyrethroids for agricultural use is spread across Schedules 5 to 7, depending primarily on their acute toxicity, and the extent to which product formulation and dilution of their active ingredient reduces the acute poisoning potential. According to the OCS evaluation and SPF guidelines, the acute toxicity of momfluorothrin is consistent with listing in Schedule 6, based on the sex difference in LD50 (>30 - <2000 mg.kg female rats; >2000 mg/kg male rats).
- The insecticidal Mode of Action (MoA) for all pyrethroids is neurotoxic, but the OCS evaluation report notes that neurotoxic symptoms in rodents appear to be devoid of any histopathological changes in nerves. The liver tumours observed in rats appear to be associated with a MoA (constitutive androstane receptor activation) that is similar to phenobarbital and the related compound metofluthrin, and would not be relevant to humans at low exposures. Therefore, neither of these would appear to be an issue that drives scheduling.
- If the ACCS agrees that the LD50 in female rats is the critical factor driving scheduling, then listing in Schedule 6 with no cut-off (no product at this stage) is an appropriate recommendation.
Figure 1: Chemical structure of momfluorothrin
The acute toxicity end-points for this chemical are listed in the below table.
|Acute oral toxicity LD50 (mg/kg bw)||Rat||
300 < LD50 < 2000 mg/kg bw for females
LD50 > 2000 mg/kg bw for males
|Acute dermal toxicity LD50 (mg/kg bw)||Rat||LD50 >2000 mg/kg bw||N/A|
|Acute inhalational toxicity LC50 (mg/m3/4h)||Rat||LC50 >2030 mg/m3, 4-hour exposure, one death||N/A|
|Skin irritation||Rabbit||Not irritating||N/A|
|Eye irritation||Rabbit||Slight irritant||Schedule 5|
|Skin sensitisation (Maximisation test)||Guinea Pig||Not sensitising||N/A|
The systemic toxicity of momfluorothrin in dietary studies consisted primarily of decreased body weight and body weight gain, liver toxicity such as increased liver weight and centrilobular hepatocellular hypertrophy with associated clinical chemistry changes, and thyroid effects (e.g. follicular cell hypertrophy) generally seen at higher dose levels. This systemic toxicity profile was observed in short-term, subchronic and chronic toxicity studies in rats, mice and dogs, with the available data indicating that the rat was the most sensitive species. A short-term inhalational toxicity study identified treatment-related clinical signs suggestive of mild neurotoxic effects (transient tremor, ataxic gait, muscle rigidity and hypersensitivity). No treatment related adverse effects were seen in a short-term dermal toxicity study in the rat at the limit dose.
Momfluorothrin was not genotoxic in a bacterial reverse mutation test, and results from the in vitro gene mutation assay (in Chinese Hamster V79 cells) and micronucleus test (mice bone marrow cells) were negative. Marginal chromosomal aberration in CHL/IU cells was observed in the in vitro chromosomal aberration test performed, though the in vivo Unscheduled DNA Synthesis (UDS) assay was negative. Overall, momfluorothrin is not considered genotoxic.
Liver tumours were observed in the 104-week oncogenicity study in rats approaching or exceeding the maximum tolerated dose. There was an increased incidence of hepatocellular adenoma and carcinoma in male rats at 73 and 154 mg/kg bw/day, and in hepatocellular adenomas and carcinomas in female rats at 182 mg/kg bw/day respectively. These tumours were associated with increased liver weight, hepatocellular hypertrophy and an increased incidence of eosinophilic foci in the liver. Momfluorothrin was not carcinogenic in mice and was not mutagenic and/or genotoxic in vitro and in vivo.
In a series of investigations on the MOA for the liver tumours in rats, it has been proposed that treatment with momfluorothrin induced cytochrome P450 (CYP) CYP2B isoform, which was shown to involve activation of the constitutive androstane receptor (CAR) in rat hepatocytes. This resulted in increased liver weights which were associated with centrilobular hepatocyte hypertrophy and induction of increased hepatocellular DNA replication leading to tumour formation. This MOA is similar to that of phenobarbital, which is known to be non-genotoxic, a CAR activator and an inducer of liver CYP2B isoforms. The OCS has evaluated the proposed MOA, and notes the data in support of the postulated MOA and the similarities to the MOA identified for the related compounds metofluthrin and phenobarbital. Overall, the OCS considers that the available data supports the proposal that momfluorothrin-induced rat liver tumours occur via a MOA that is similar to phenobarbital and that it is plausible that the MOA is not relevant to humans. Thus, momfluorothrin is not expected to increase hepatocellular proliferation and, thus, pose a carcinogenic risk to humans.
Reproduction and developmental toxicity
Momfluorothrin was not a reproductive or developmental toxicant. However, in the developmental toxicity study in the rat, clinical signs including tremors were noted (suggestive of a neurotoxic effect) in maternal animals, though development was not affected at maternotoxic doses.
While no neurotoxic effects were observed in the sub-chronic 13 week dietary study in rats, the acute oral (gavage) neurotoxicity study identified several neuro-functional changes, including tremors, salivation and straub tail at the highest dose level of 200 mg/kg bw tested in the acute neurotoxicity study, though no treatment-related neuro-histopathological changes were observed. Overall, when considered with the tremors noted in the rat developmental toxicity study and other acute/short term toxicity studies in the rat, the data available suggests that momfluorothrin has mild neurotoxic potential. In this context, it is possible that momfluorothrin has similar neurotoxic effects to other pyrethroids.
Observation in humans
No information provided.
No information was provided.
Momfluorothrin has recently been registered by the US EPA (Attachment B) and Health Canada.
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Momfluorothrinis not scheduled.
Momfluorothrin has not been previously considered for scheduling; therefore, scheduling history is not available.
Pre-meeting public submissions
No public submission was received.
Summary of ACCS advice to the delegate
The committee recommended a new S6 entry be created for momfluorothrin.
The committee recommended an implementation date of 1 February 2016.
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 recommendations comprised the following:
- Meets criteria for Schedule 6 due to acute oral toxicity.
Delegate's interim decision
Schedule 6 - New Entry
The delegate considered the relevant matters under subsection 52E (1) of the Therapeutic Goods Act 1989: c) the toxicity of the substance.
The proposed implementation date is 1 February 2016. An early implementation date is proposed to facilitate registration of momfluothrin as an active ingredient by the APVMA.
The reasons for the interim decision comprised the following:
The toxicological profile of momfluothrin is well characterised in the OCS evaluation report. Much of the toxicity profile is consistent with SPF criteria for listing in Schedule 5. However, the LD50 in female rats is in the Schedule 6 range and the delegate agrees with the ACCS recommendation, that monfluothrin should be listed in Schedule 6 at this time. It may be possible to consider a lower schedule for products with a low percentage content of momfluothrin at a later time.
The delegate considered the following in regards to this proposal:
- Scheduling proposal;
- ACCS advice;
- Section 52E of the Therapeutic Goods Act 1989;
- Scheduling factors8;
- Other relevant information.
Public submissions on the interim decision
No public submissions were received.
Delegate's final decision
The delegate has confirmed the interim decision as no evidence has been received to alter the interim decision. The delegate has confirmed that the reasons for the final decision are in keeping with those for the interim decision.