Public Release Summary - Evaluation of the New Active Metazachlor in the Product Butisan

Public Release Summary

on the evaluation of the new active metazachlor in the product Butisan Herbicide

APVMA Product Number 80664

December 2016

© Australian Pesticides and Veterinary Medicines Authority 2016

ISSN: 1443-1335 (electronic)
ISBN: 978-1-925390-60-5 (electronic)

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Director Public Affairs and Communication

Australian Pesticides and Veterinary Medicines Authority

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KINGSTON ACT 2604 Australia

Telephone: +61 2 6210 4988

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This publication is available from the APVMA website:

December 2016

Contents1

Contents

Preface

About this document

Making a submission

Further information

1Introduction

1.1Applicant

1.2Details of the product

1.3Overseas registration

2Chemistry and manufacture

2.1Active constituent

2.2Formulated product

2.3Summary

3Toxicological assessment

3.1Evaluation of toxicology

3.2Public health standards

4Residues assessment

4.1Introduction

4.2Metabolism

4.3Analytical methods

4.4Stability of the pesticide in stored analytical samples

4.5Residue definition

4.6Residue trials and rotational crops

4.7Animal commodity MRLs

4.8Estimated dietary intake

4.9Bioaccumulation potential

4.10Spray drift

4.11Recommendations

5Assessment of overseas trade aspects of residues in food

5.1Commodities exported

5.2Destination of exports

5.3Overseas registration and approved label instructions

5.4Comparison of Australian MRLs with Codex and International MRLs

5.5Potential risk to trade

6Occupational health and safety assessment

6.1Health hazards

6.2Formulation, packaging, transport, storage and retailing

6.3Use pattern

6.4Exposure during use

6.5Exposure during re-entry

6.6Recommendations for safe use

6.7Conclusion

7Environmental assessment

7.1Environmental fate and behaviour

7.2Environmental effects

7.3Risk assessment

7.4Conclusions

8Efficacy and safety assessment

9Labelling requirements

Abbreviations

Glossary

References

List of tables

Table 1: Nomenclature of metazachlor

Table 2: Key physicochemical properties of metazachlor

Table 3: Key physicochemical properties of Butisan Herbicide

Table 4: Proposed active constituent standard for metazachlor

Table 5: Proposed amendments to MRL Standard for Metazachlor—Table 1

Table 6: Proposed amendments to MRL Standard for Metazachlor—Table 3

Table 7: Proposed amendments to MRL Standard for Metazachlor—Table 4

Table 8: Major destinations for Australian canola grain, oil and seed

Table 9: Current and proposed Australian and overseas MRLs/tolerances for metazachlor

Table 10: Major soil and aquatic system metabolites of metazachlor

Table 11: Toxicity of active constituent metazachlor and the product Butisan Herbicide for various organisms

Preface1

Preface

The Australian Pesticides and Veterinary Medicines Authority (APVMA) is the Australian Government regulator with responsibility for assessing and approving agricultural and veterinary chemical products prior to their sale and use in Australia.

In undertaking this task, the APVMA works in close cooperation with advisory agencies, including the Department of Health and Ageing, Department of Environment and Energy, Department of Agriculture and Water Resources, and State Departments of Primary Industries.

The APVMA has a policy of encouraging openness and transparency in its activities and of seeking community involvement in decision making. Part of that process is the publication of Public Release Summaries for products containing new active constituents.

The information and technical data required by the APVMA to assess the safety of new chemical products, and the methods of assessment, must be consistent with accepted scientific principles and processes. Details are outlined on the APVMA website at.

This Public Release Summary is intended as a brief overview of the assessment that has been conducted by the APVMA and of the specialist advice received from its advisory agencies. It has been deliberately presented in a manner that is likely to be informative to the widest possible audience thereby encouraging public comment.

About this document

This is a Public Release Summary.

It indicates that the APVMA is considering an application for registration of an agricultural or veterinary chemical. It provides a summary of the APVMA’s assessment, which may include details of:

• the toxicology of both the active constituent and product
• the residues and trade assessment
• occupational exposure aspects
• environmental fate, toxicity, potential exposure and hazard
• efficacy and target crop or animal safety.

Comment is sought from interested stakeholders on the information contained within this document.

Making a submission

In accordance with sections 12 and 13 of the Agvet Code, the APVMA invites any person to submit a relevant written submission as to whether the application for registration of Butisan Herbicideshould be granted. Submissions should relate only to matters that the APVMA is required, by legislation, to take into account in deciding whether to grant the application. These matters include aspects of public health, occupational health and safety, chemistry and manufacture, residues in food, environmental safety, trade, and efficacy and target crop or animal safety. Submissions should state the grounds on which they are based. Comments received that address issues outside the relevant matters cannot be considered by the APVMA.

Submissions must be received by the APVMA by close of business on10 January 2017 and be directed to the contact listed below. All submissions to the APVMA will be acknowledged in writing via email or by post.

Relevant comments will be taken into account by the APVMA in deciding whether the product should be registered and in determining appropriate conditions of registration and product labelling.

When making a submission please include:

• contact name
• company or group name (if relevant)
• email or postal address (if available)
• the date you made the submission.

All personal information, and confidential information judged by the APVMA to be confidential commercial information (CCI)[1]contained in submissions will be treated confidentially.

Written submissions on the APVMA’s proposal to grant the application for registration that relate to the grounds for registration should be addressed in writing to:

Case Management and Administration Unit

Australian Pesticides and Veterinary Medicines Authority

PO Box 6182

Kingston ACT 2604

Phone:+61 2 6210 4701

Fax:+61 2 6210 4721

Email:

Further information

Further information can be obtained via the contact details provided above.

Further information on public release summaries can be found on the APVMA website

Introduction1

1Introduction

1.1Applicant

BASF Australia Ltd

1.2Details of the product

It is proposed to register Butisan Herbicide, a suspension concentrate productcontaining the 500 g/L metazachlor. Butisan Herbicide isintended for pre-emergent control of annual ryegrass, wild oats and wireweed in canola.

It is proposed that one application of Butisan Herbicide be applied to soil and incorporated by sowing at a maximum application rate of 1.8 L product/ha.

Metazachlor belongs to the chemical class of chloroacetamides and acts by a complex mode of action involving disruption of fatty acid syntheses. Butisan Herbicide acts as a pre- and post-emergence herbicide. Butisan Herbicide enters target plants primarily through the roots, the hypocotyl, and the cotyledons of the germinating and emerging weeds. It has, therefore, its best herbicidal effectiveness during early development stages of the weeds.

Butisan Herbicide is active against a broad range of mono and dicotyledonous weeds. Since it acts via both the roots and the developing shoot, it can be used pre-emergence as well as (early) postemergence.

1.3Overseas registration

Herbicides containing metazachlor are currently registered for use in various crops in United Kingdom and other European countries, Taiwan and Chile. Butisan Herbicide is registered in the United Kingdom and some other European countries for use in canola.

This publication provides a summary of the data reviewed and an outline of the regulatory considerations for the proposed registration of Butisan Herbicide, and approval of the new active constituent, metazachlor.

Chemistry and manufacture1

2Chemistry and manufacture

2.1Active constituent

The active constituent metazachlorwill be manufactured overseas and imported into Australia as a fully formulated product. Metazachlor belongs to the chloroacetamide class of compounds. It is a solid at room temperature, slightly soluble in water at neutral pH giving mildly acidic solutions, and highly soluble in polar and aromatic organic solvents. Metazachlor has good safety properties, not being flammable, explosive or oxidising. The nomenclature and physicochemical properties of metazachlor are summarised in the following two tables. The identity of metazachlor was confirmed through infrared, nuclear magnetic resonance and mass spectrometry.

Table 1:Nomenclature of metazachlor

Table 2: Key physicochemical properties of metazachlor

2.2Formulated product

The proposed formulation is a suspension concentrate, containing 500 g/L metazachlor as the only active constituent. Butisan Herbicide will be formulated overseas. The product will be packaged in high density polyethylene containers ranging in size from 1 L to 110 L. The stability data provided showed that the formulation would not be expected to have any adverse effect on the packaging, and vice versa. Key properties of the formulated product are summarised in the table below.

Table 3: Key physicochemical properties of Butisan Herbicide

2.3Summary

The APVMA chemistry and manufacture section has evaluated the chemistry aspects of metazachlor and Butisan Herbicide (spectroscopic identification, manufacturing and formulation processes, quality control procedures, stability data, specifications, batch analysis results, proposed packaging, and analytical methods) for both the technical active constituent and the formulated product and found them to be acceptable.

On the basis of the chemistry and toxicological assessments, it is proposed that the following APVMA active constituent standard be established for metazachlor:

Table 4: Proposed active constituent standard for metazachlor

Toxicological assessment1

3Toxicological assessment

3.1Evaluation of toxicology

The toxicological database provided for metazachlor is extensive and comprises a full suite of acute and repeat dose toxicity studies in mice, rats and dogs as well as in vitro and in vivo genotoxicity studies,reproductive and developmental toxicity studies. Additionally, a series of acute, short-term, developmental and genotoxicity studies on a number of metabolites have also been provided.

In interpreting the data, it should be noted that toxicity tests generally use doses that are high compared with likely human exposures. The use of high doses increases the likelihood that potentially significant toxic effects will be identified. Findings of adverse effects in any one species do not necessarily indicate such effects might be generated in humans. However, from a conservative risk assessment perspective, adverse findings in animal species are assumed to represent potential effects in humans, unless convincing evidence of species specificity is available. Where possible, considerations of the species specific mechanisms of adverse reactions weigh heavily in the extrapolation of animal data to likely human hazard. Equally, consideration of the risks to human health must take into account the likely human exposure levels compared with those, usually many times higher, which produce effects in animal studies. Toxicity tests should also indicate dose levels at which the specific toxic effects are unlikely to occur.

Chemical class

Metazachlor belongs to thechloroacetamide chemical class of herbicides. It acts primarily by inhibition of the formation of very-long chain fatty acids in lipid biosynthesis, through interaction with the condensing elongase enzyme system. This leads to inhibited cell division and tissue differentiation, resulting in stunted and deformed seedlings. The uptake of metazachlor in germinating grass and dicotyledonous plants occurs predominantly via the roots and the developing shoot, and halts the germination process. Plants slowly die off as a result of abnormal growth.

Toxicokinetics and metabolism

Oral absorption, assessed in bile duct-cannulated rats as the sum of radioactivity excreted in urine and bile over 48 hours, was 92% (males) and 105% (females) after a 60 mg/kg bw gavage dose in tylose (cellulose), or 51% (males) and 79% (females) after a 600 mg/kg bw dose. Considerably higher concentrations of radioactivity were found in blood than plasma (blood:plasma ratios were approximately 25–71:1 at 60 mg/kg, and 200–350:1 at 600 mg/kg), indicating radioactivity probably binds more extensively to cellular blood constituents than to plasma proteins.

Terminal half-lives of radioactivity in plasma were comparable for both 600 mg/kg bw (29–39 hrs) and 60mg/kg bw oral dose (28–31 hrs) and in both sexes). Time to reach plasma Cmax was longer after the high dose (24 hrs) than the low dose (4–8 hrs). The rapid excretion (~80% in urine and faeces within 48 hours after single or repeat doses of 60 mg/kg bw; ~90% in urine and faeces 48 hours after single dose of 600mg/kg bw) observed in the balance/excretion experiments is not consistent with a plasma half-life of approximately 30–40 hours, which may be due to binding of radioactivity not only to blood cells but also to plasma proteins, as well as enterohepatic circulation of radioactivity.

Metazachlor was well distributed after absorption, with mean tissue and organ concentrations generally peaking 4–8 hours after a single low oral dose. Concentrations of 14C-metazachlor-derived radioactivity in blood, lung, heart, spleen, adrenals and brain remained relatively constant from 4–120 hours post-dosing.
At 144 hours post-dosing, the mean proportion of the administered dose retained in tissues was highest in blood, liver, skin, and the gut. Considerably higher concentrations of radioactivity were found in blood than plasma, indicating radioactivity probably binds more extensively to cellular blood constituents than to plasma proteins. After 5 daily doses of 300 mg/kg bw/d in Sprague-Dawley rats, there was no evidence of accumulation of radioactivity in tissues, with only small amounts (<1% of total dose) measured in tissues 72hours after the last (fifth) administration.

Metazachlor is rapidly and extensively metabolised. Phase 1 biotransformation comprised of hydroxylation and glucuronide conjugation. The main metabolic route was substitution of chlorine by glutathione, followed by successive degradation of the glutathione group by oxidation and hydrolytic cleavage reactions. Glutathione conjugates formed the majority of the non-extractable metabolites in tissues and blood cells in this study. Oxidation of the methyl groups of the phenyl ring and further conjugation by glucuronic acid was also observed.

Metazachlor and its metabolites are rapidly excreted via urine and bile. The excretion balance did not indicate significant differences in total excretion between single oral high dose, single oral low dose or multiple low dose administration. However, biliary excretion was clearly higher at the low dose (approximately 50–60%) than at the high dose (21–25 %). The bioavailability was 100% at the low dose level but absorption was saturated at the high dose level.

Percutaneous absorption

In vitro dermal absorption studies were conducted with 14C-metazachlor applied to split-thickness dermatomed human skin as a formulation concentrate containing a nominal concentration of 500 g/L metazachlor (undiluted concentrate) and a representative aqueous spray dilution for field use
(1/100 aqueous dilution containing about 5 mg/mL of the formulated concentrate). Actual applied nominal doses to 5 skin preparations per test material were 45.4 ± 0.6 µg/cm2 (low dose) and 5,100 ± 76 µg/cm2 (high dose).

The sum of the mean total absorbable and the mean amount absorbed was 0.31% for the high dose (undiluted concentrate), equating to 15.8 µg/cm2 of absorbed/absorbable mass, and 3.54% for the low dose, equating to 1.6 µg/cm2 absorbed/ absorbable mass.

Acute toxicity

In acute toxicity studies in rodents, metazachlor TGAC 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 >34500 mg/m³, 4–hour exposure, no deaths). It was a slight skin irritant but not an eye irritant in rabbits. Different results were obtained in skin sensitisation studies. In an open cutaneous skin sensitisation study (i.e. non-adjuvant, topical open application), metazachlor was negative while a positive result was obtained in a guinea pig maximization test. Noting that theopen cutaneous skin sensitisation test is no longer a validated skin sensitisation assay, metazachlor is considered to have skin sensitisation potential based on the GPMT (Guinea Pig Maximization Test) results.