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Scheduling delegate's interim decisions and invitation for further comment: ACCS/ACMS, July 2016
Scheduling medicines and poisons
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Referred scheduling proposal
An application was submitted to create a new Schedule 5 entry for metazachlor with an appropriate exemption cut-off concentration.
Metazachlor is not specifically scheduled and has not been previously considered for scheduling.
The application's proposed amendments to the SUSMP are as follows:
Schedule 5 - New Entry
METAZACHLOR except in preparations containing 50 per cent or less of metazachlor.
The applicant's reasons for the request are:
- BASF Australia Ltd have submitted a data package seeking approval of the new active constituent metazachlor and registration of the new product containing 500 g/L metazachlor in a suspension concentrate formulation;
- Metazachlor belongs to the chloroacetamide chemical class and acts by inhibition of lipid biosynthesis. As a new chemical it will require scheduling consideration for SUSMP listing prior to final registration of products containing this active constituent;
- BASF Australia Ltd have proposed that metazachlor be listed in Schedule 5 of the SUSMP; and
- Metazachlor is a skin sensitiser in a guinea pig maximisation test and a slight skin irritant in rabbits.
Metazachlor (Figure 3.3) belongs to the chloroacetamide chemical class and acts by inhibition of lipid biosynthesis.
Figure 3.3: Structure of metazachlor
The acute toxicity end-points for metazachlor are listed in Table 3.3A. Briefly, in acute toxicity studies in rodents, metazachlor was of low acute oral toxicity in rats (LD50 = 2160/2140 mg/kg (M/F)) and mice (LD50 = 2010 mg/kg bw); low acute dermal toxicity in rats (LD50 > 6810 mg/kg bw; no deaths) and low acute inhalational toxicity in rats (LC50 >3450 mg/m3, 4 hour exposure, no deaths). Regarding irritation, metazachlor was found to be a slight irritant to the skin, and non-irritating to the eye in rabbits. Metazachlor was found to be a sensitiser in a Guinea Pig Maximisation Test (GPMT).
Metazachlor displays no evidence of mutagenic/genotoxic potential in vitro (with and without metabolic activation), or a genotoxic potential in vivo. Furthermore, there was no evidence of a reproductive toxicity potential in a two-generation reproductive (dietary) toxicity study in rats and shows no evidence of a developmental toxicity potential in developmental toxicity studies conducted with rats and rabbits. No neurotoxicity or immunotoxicity studies were submitted. Regarding carcinogenicity, the OCS considers the evidence for potential carcinogenicity arising from metazachlor administration in mice and rats to be weak and that the overall lack of treatment-related neoplastic findings in long term mouse and rat studies and the lack of genotoxicity in a battery of tests conducted with metazachlor and its metabolites supports the conclusion that metazachlor is unlikely to be a carcinogen. For more information see the OCS human health risk assessment report for metazachlor.
|Toxicity endpoint||Species||Results||SPF (2015) Classification|
|Acute oral toxicity LD50 (mg/kg bw)||Rats, Mice||LD50 > 2000||Appendix B|
|Acute dermal toxicity LD50 (mg/kg bw)||Rat||LD50 > 6810||Appendix B|
|Acute inhalational toxicity LC50 (mg/m3/4h)||Rat||LC50 > 34500||Appendix B|
|Skin irritation||Rabbit||Slight irritant||Schedule 5|
|Eye irritation||Rabbit||Non-irritant||Appendix B|
|Skin sensitisation (GPMT)||Guinea Pig||Sensitiser||Schedule 5|
|Carcinogenicity||Mice, Rats||Carcinogenicity unlikely||N/A|
|Reproduction and developmental toxicity||Rats, Rabbits||Negative||N/A|
The primary target organs for toxicity in short-term, sub-chronic and chronic toxicity studies with metazachlor were the liver, kidney and red blood cells. Effects observed in these studies also included non-specific toxicity (i.e. decreases in food consumption, body weight, or body weight gain), clinical signs (e.g. piloerection, ataxia, salivation, vomiting) and effects on the liver or kidney (e.g. serum liver enzyme changes, increased liver and/or kidney weights, or fatty degeneration of hepatocytes, renal parenchymal cell damage).
Toxicity of metazachlor metabolites
A large number of metabolites were identified and subjected to further investigations in a variety of studies, including acute oral toxicity, 13-week (dietary) repeat-dose and developmental studies, as well as a battery of genotoxicity studies including: in vitro mammalian chromosome aberration test; in vitro mammalian cell gene mutation test (HPRT), in vitro bacterial reverse mutation and in vivo mouse (erythrocyte) micronucleus test. Six metabolites were tested in genotoxicity assays and were found to be negative. In acute oral studies, all metabolites were of low acute oral toxicity (oral LD50 > 500 mg/kg bw) and clinical signs observed in some of these studies were similar to those observed with the parent compound. No toxicologically significant findings were noted in oral sub-chronic or developmental studies in rats on the metabolites.
Toxicity of Butisan Herbicide (containing 50% w/v metazachlor)
The acute toxicity end-points for Butisan Herbicide, based on data for the proposed formulation and a reference formulation (containing 500 g/L metazachlor), are listed in Table 3.3B. Comparison of the findings for the formulation with results for the active constituent suggest that the increased acute oral toxicity and change in eye irritation potential are not due to the toxicity of metazachlor, but rather the product excipients.
|Acute oral toxicity LD50 (mg/kg bw)||Rat||500 < LD50 < 2000|
|Acute dermal toxicity LD50 (mg/kg bw)||Rat||LD50 > 4000|
|Acute inhalational toxicity LC50 (mg/m3/4h)||Rat||LC50 > 6200 (no deaths)|
|Eye irritation||Rabbit||Slight irritant|
|Skin sensitisation (GPMT)||Guinea Pig||Non-sensitiser|
Pre-meeting public submissions
No pre-meeting submissions were received for metazachlor.
Summary of ACCS advice to the delegate
The committee advised that a new Schedule 5 entry be created in the SUSMP for metazachlor.
The committee advised an implementation date of 1 February 2017.
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 advice included:
- Metazachlor exhibits low acute toxicity by all routes. It is not an eye irritant but is a slight skin irritant and a skin sensitiser; and
- The European Food Safety Authority (EFSA) considered that any carcinogenic effects were non-genotoxic, only observed at high doses and within the historical control range, therefore the relevant human risk is low.
The delegate considered the following in regards to this proposal:
- Scheduling proposal;
- ACCS advice;
- Section 52E of the Therapeutic Goods Act 1989;
- Scheduling Policy Framework (SPF 2015); and
- Other relevant information.
Delegate's interim decision
The delegate notes and accepts the advice of the ACCS to create a new Schedule 5 entry for metazachlor. Metazachlor exhibits low acute toxicity by all routes. It is not an eye irritant, but is a slight skin irritant and a skin sensitiser. The European Food Safety Authority (EFSA) considered that any carcinogenic effects were non-genotoxic, only observed at high doses and within the historical control range, therefore the relevant risk of metazachlor to humans is low.
An early implementation date of 1 February 2017 is proposed in order to bring the regulation of this ingredient in products sold in Australia into alignment with international regulations.
The delegate considered the relevant matters under section 52E (1) of the Therapeutic Goods Act 1989: (c) the toxicity of a substance.
Schedule 5 - New Entry