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Scheduling delegate's final decisions: ACCS, November 2015
Scheduling medicines and poisons
Part B - Final decisions on matters not referred to an expert advisory committee
3. Agriculture and veterinary chemicals
In September 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 bixafen, recommends that the Delegate consider creating a new entry for bixafen in Schedule 5 of the SUSMP.
The reasons for the request are:
- A data package seeking approval of the new active constituent bixafen, a member of the carboxamide fungicide class of chemicals belonging to the sub-class of the pyrazole-carboxamides, a succinate dehydrogenase inhibitor of fungal pathogens was received. As a new chemical for AgVet use, it will require consideration for SUSMP listing prior to final registration of products. Currently the proposed product attached to this application is for agricultural use.
Figure 1. Structure of Bixafen (BYF 00587)
The acute toxicity end-points for bixafen are listed in the below table.
|Acute oral toxicity LD50 (mg/kg bw)||Wistar Rat||>2000 (no deaths)||Appendix B|
|Acute dermal toxicity LD50 (mg/kg bw)||Wistar Rat||>2000 (no deaths)||Appendix B|
|Acute inhalational toxicity LC50 (mg/m3/4h)||Wistar Rat||>5383 (no deaths)||Appendix B|
|Skin irritation||NZW rabbit||Non-irritant||Appendix B|
|Eye irritation||NZW rabbit||Non-irritant||Appendix B|
|Skin sensitisation (LLNA method)||NMRI mouse||No determination possible not of regulatory quality||Not applicable|
The systemic toxicity of bixafen in dietary studies consisted primarily of decreases in 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 rats and mice were equally sensitive. A mechanistic study indicated that hepatotoxicity may be due to induction of both phase I and II hepatic enzymes.
There was no evidence of a mutagenic/genotoxic potential of bixafen or its primary metabolites in vitro with and without metabolic activation, or a genotoxic potential in vivo.
There was no evidence of carcinogenic potential in the long-term rodent tests.
Reproductive toxicity potential
In a dietary two generation study in rats, parental systemic toxicity was seen at the top (2500 ppm) and mid dose (400 ppm) level. At the top dose decreased body weight (5%-6% decrease seen in dams of both generations throughout gestation), decreased body weight gain (15%-18% decrease in body weight gain in dams of both generations throughout gestation and lactation), and increased liver, spleen, thyroid, thymus (females only) and kidney (males only) weights were noted in both genders. At the mid dose male liver weight was increased (P0 only) while female liver weights were increased in all doses in the P1 generation. Liver hypertrophy was also sharply increased in high dose rats of both generations and sexes. Reproductive findings were not affected by treatment. In offspring, decreased pup body weight (8%-12% decrease seen in pups of both generations on day 21) and pup body-weight gain, and decreased spleen, thymus (F1 only) and brain weights were also seen at the top dose level. However, OCS considers that the observed effects in offspring were a secondary non-specific consequence of maternal toxicity. Bixafen is not considered to be a reproductive toxicant.
Developmental toxicity potential
No evidence of a developmental toxicity potential was seen in an oral (gavage) developmental toxicity study in rats at the mid and high dose levels that produced marked maternal toxicity (e.g. body weight gain was 42% lower during the dosing period compared to controls at the high dose), with foetal weights also decreased at mid and high dose levels. Maternal body weight gains were decreased at the high dose during the treatment period and liver weights were increased in both the mid and high dose dams.
In an oral (gavage) developmental toxicity study in rabbits maternal body weight gains were decreased at the high dose during the treatment period and liver weights were increased in both the mid and high dose dams, along an increased incidence of visceral and skeletal findings at the high dose were seen. While these findings were outside of the historical control range they were seen in the presence of marked maternal toxicity (e.g. body weight gain was reduced (↓74%) at several time intervals between GD 6 and 26 and overall (GD 6 to 29; ↓59%) as well as reduced foetal weights (↓6% combined). Thus, bixafen was not considered to be a developmental toxicant in rabbits as the observed skeletal findings in foetuses were considered a secondary non-specific consequence of marked maternal toxicity.
Other toxicology endpoints
No evidence of neurotoxicity was seen in acute and repeat dose studies however, this was not investigated independently in standard neurotoxicity studies.
Bixafen was not investigated for immunotoxic potential.
Observation in humans
No information was provided.
At this time, the proposed agricultural use of bixafen is not expected to result in general public (i.e. domestic) exposure. Spray drift considerations have not been considered.
The European Food Safety Authority (via the United Kingdom as the rapporteur member state lead for the evaluation) published a peer review of the pesticide risk assessment of the active substance bixafen in November 2012 and products containing bixafen are registered in the United Kingdom.
Bixafen is not specifically scheduled.
Bixafen has not been previously considered for scheduling; therefore, scheduling history is not available.
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 factors18;
- Other relevant information.
Delegate's final decision
Schedule 5 - New Entry
Reasons for delegate's decision
The toxicology profile for bixafen is relatively straightforward, and its low toxicity profile suggests possible listing in Appendix B. However, the OCS evaluation report draws attention to the submitted LLNA sensitisation test was non-compliant. Despite a compliant LLNA test on the combination product with prothioconazole that was negative for sensitisation potential, the OCS evaluation recommends listing in Schedule 5 as a cautionary measure, and the sponsor has accepted that recommendation.
The delegate decided that the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989 include (c) the toxicity of a substance.
he implementation date is 1 February 2016.