Public Release Summary - on the Evaluation of the new ...



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Public Release Summary

ON THE EVALUATION OF THE NEW ACTIVE AMISULBROM IN THE PRODUCT AMICUS BLUE FUNGICIDE

APVMA Product Number 70161

© Australian Pesticides and Veterinary Medicines Authority 2016

ISBN 978-1-925390-40-7 (electronic)

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Unless otherwise noted, copyright (and any other intellectual property rights, if any) in this publication is owned by the Australian Pesticides and Veterinary Medicines Authority (APVMA).

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With the exception of the Coat of Arms and other elements specifically identified, this publication is licensed under a Creative Commons Attribution 3.0 Australia Licence. This is a standard form agreement that allows you to copy, distribute, transmit and adapt this publication provided that you attribute the work.

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The APVMA’s preference is that you attribute this publication (and any approved material sourced from it) using the following wording:

Source: Licensed from the Australian Pesticides and Veterinary Medicines Authority (APVMA) under a Creative Commons Attribution 3.0 Australia Licence.

In referencing this document the Australian Pesticides and Veterinary Medicines Authority should be cited as the author, publisher and copyright owner.

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The terms under which the Coat of Arms can be used are set out on the Department of the Prime Minister and Cabinet website (see .au/pmc/publication/commonwealth-coat-arms-information-and-guidelines).

Disclaimer

The material in or linking from this report may contain the views or recommendations of third parties. Third party material does not necessarily reflect the views of the APVMA, or indicate a commitment to a particular course of action.

There may be links in this document that will transfer you to external websites. The APVMA does not have responsibility for these websites, nor does linking to or from this document constitute any form of endorsement.

The APVMA is not responsible for any errors, omissions or matters of interpretation in any third-party information contained within this document.

Comments and enquiries regarding copyright:

Director Public Affairs and Communication

Australian Pesticides and Veterinary Medicines Authority

PO Box 6182

KINGSTON ACT 2604 Australia

Telephone: +61 2 6210 4988

Email: communications@.au

This publication is available from the APVMA website: .au.

Contents

PREFACE V

About this document v

Making a submission v

Further information vi

1 Introduction 1

1.1 Purpose of application 1

1.2 Product claims and use pattern 1

1.3 Mode of action 1

1.4 Overseas registrations 1

2 Chemistry and manufacture 2

2.1 Active constituent 2

2.2 Formulated product 4

2.3 Conclusion 5

3 Toxicological assessment 6

3.1 Summary 6

3.2 Evaluation of toxicology 7

3.3 Public health standards 10

3.4 Conclusion 11

4 Residues assessment 12

4.1 Introduction 12

4.2 Analytical methods 13

4.3 Stability of the pesticide in stored analytical samples 14

4.4 Residue definition 14

4.5 Residue trials 14

4.6 Animal commodity MRLs 14

4.7 Estimated dietary intake 15

4.8 Bioaccumulation potential 15

4.9 Spray drift 15

4.10 Residues in rotational crops 15

4.11 Recommendations 15

5 assessment of overseas trade aspects of residues in food 17

5.1 Commodities exported 17

5.2 Destination of exports 17

5.3 Proposed use pattern 17

5.4 Overseas registration and approved label instructions 18

5.5 Comparison of Australian MRLs with Codex and International MRLs 18

5.6 Potential risk to trade 19

6 Occupational health and safety assessment 21

6.1 Summary 21

6.2 Health hazards 21

6.3 Formulation, packaging, transport, storage and retailing 21

6.4 Use pattern 21

6.5 Exposure during use 22

6.6 Exposure during re-entry 22

6.7 Recommendations for safe use 23

6.8 Conclusion 23

7 Environmental assessment 24

7.1 Introduction 24

7.2 Environmental fate 24

7.3 Environmental effects 26

7.4 Risk assessment 28

7.5 Conclusion 28

8 Efficacy and safety assessment 29

8.1 Proposed product use pattern 29

8.2 Assessment of study/trial data 29

8.3 Conclusion 31

9 Labelling requirements 32

abbreviations 38

Glossary 43

References 45

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, Office of Chemical Safety (OCS), Department of Environment (DoE), 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: .au.

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 Australian Pesticides and Veterinary Medicines Authority (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 AMICUS BLUE FUNGICIDE should be granted. Submissions should relate only to matters that are required by the APVMA to be taken into consideration in determining whether the safety, efficacy or trade criteria have been met. Submissions should state the grounds on which they are based.

Submissions must be received by the APVMA by close of business on 26 July 2016 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: enquiries@.au

Further information

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

Copies of full technical evaluation reports covering toxicology, occupational health and safety aspects, residues in food and environmental aspects are available from the APVMA on request.

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

Introduction

1 Purpose of application

Nufarm Australia Limited has applied to the APVMA for registration of the new product AMICUS BLUE FUNGICIDE containing the new active constituent amisulbrom as a suspension concentrate (SC) formulation. Amicus Blue Fungicide contains 32 g/L amisulbrom and 180 g/L copper (Cu) present as tribasic copper sulphate.

This publication provides a summary of the information reviewed and an outline of the regulatory considerations for the proposed registration of Amicus Blue Fungicide, and approval of the new active constituent, amisulbrom.

2 Product claims and use pattern

Amicus Blue Fungicide is intended for the control of downy mildew (Plasmopara viticola) in grapevines and white blister (Albugo candida) and downy mildew (Hyaloperonospora brassicae) in brassica vegetable crops.

The proposed use of Amicus Blue Fungicide on brassica vegetable crops involves up to three foliar applications per crop at the rate of 2 L/ha (64 g amisulbrom/ha) with 7 to 10 day re-treatment intervals for consecutive applications.

Amicus Blue Fungicide is proposed for use in grapevines at a dilute spraying rate of 250 mL/100L (8 g amisulbrom/100L). The product is applied as a protectant spray to grapevines commencing after shoots are 10 cm long. Amicus Blue Fungicide is intended to be applied to grapevines with not more than two consecutive applications and a maximum of four applications per season with consecutive applications to be made 7–10 days apart. Amicus Blue Fungicide is not to be applied after E-L 31 (early bunch closure) on grapes grown for export wine production.

3 Mode of action

Amisulbrom, a new active to the Australian market, is an oomycete-specific fungicide which acts by inhibiting mitochondrial complex III activity through binding to the Qi centre and impairing respiration. The Fungicide Resistance Action Committee (FRAC) has categorised amisulbrom as a Quinine Insider Inhibitor (QII) based upon this mode of action. Amisulbrom has been designated as a Group 21 FUNGICIDE for resistance management purposes.

Copper (Cu) present as tribasic copper sulphate is designated as a Group M1 fungicide and acts as a multi-site activity fungicide.

For resistance management purposes, Amicus Blue Fungicide is a Group 21 and Group M1 fungicide.

4 Overseas registrations

Products containing amisulbrom are currently registered overseas including in Europe, Japan, Korea, Taiwan and Vietnam. These registrations cover a range of crops including potatoes, lettuces, tomatoes, eggplants and grapes. In the USA, amisulbrom has import tolerances established for tomatoes and grapes.

Chemistry and manufacture

1 Active constituent

Amisulbrom is a new active constituent which belongs in the sulfonamide chemical class of fungicides.

Chemical characteristics of the active constituent:

|Common Name (ISO): |Amisulbrom |

|IUPAC NAME: |3-(3-bromo-6-fluoro-2-methylindol-1-ylsulfonyl)-N,N-dimethyl-1H-1,2,4-triazole-1-sulfonamide. |

|CAS Name: |3-[(3-bromo-6-fluoro-2-methyl-1H-indol-1-yl)sulfonyl]-N,N-dimethyl-1H-1,2,4-triazole-1-sulfonamide |

|CAS Registry Number: |348635-87-0 |

|Manufacturer code: |NC-224 |

|Minimum purity: |965 g/kg minimum |

|molecular formula: |C13H13BrFN5O4S2 |

|Molecular Weight: |466.3 |

|Structure: | |

| | |

| | |

| | |

| | |

| | |

| | |

|Chemical family: |Sulfonamide fungicides; triazole fungicides |

|Mode of Action: |Inhibits fungal respiration with binding to the Qi centre site on cytochrome bc1 (ubiquinone |

| |reductase) in Complex III. |

Physical and chemical characteristics of amisulbrom

|Physical Form (99.8% purity): |Very pale yellow, odourless, crystalline solid (99.9%) |

| |Pale brown, odourless, fine powder (98.9%) |

|Melting Point: |128 ºC-130 ºC |

|relative Density: |D420 = 1.72 (99.8% purity) |

| |D420 = 1.61 (99.1% purity) |

|N-OCTANOL/WATER |LOG POW = 4.4 PH 6.4 AND 25OC |

|PARTITION COEFFICIENT: | |

|VAPOUR PRESSURE AT 25OC: |1.8 X 10-8 PA |

|SOLUBILITY IN WATER AT 20ºC: |0.11 MG/L |

|SOLUBILITY IN VARIOUS SOLVENTS AT 20ºC: |ACETONE: >250 G/L |

| |Methanol: 10.01 g/L |

| |Dichloromethane: >250 g/L |

| |Toluene: 88.63 g/L |

| |Hexane: 0.264 g/L |

| |Ethyl acetate: >250 g/L |

| |n-Octanol: 2.6 g/L |

|HENRY’S LAW CONSTANT: |2.8 x 10-5 Pa m3 mol-1 |

|UV/VIS ABSORPTION (MAX): |Neutral pH = λmax 254 nm |

| |pH acidic methanol = λmax 254 nm |

| |pH basic methanol = λmax 222 nm |

| |pH>12 = λmax 265 nm |

|flammability: |Not flammable |

|Quantum Yield: |0.19 molecules photon-1 at pH 4 and 25°C. |

| |Irradiation over the 48 hour test period was calculated to be equivalent to 106 hours of natural |

| |sunlight at latitude 40 °N |

|explosive properties: |Not explosive |

|oxidising properties: |Not oxidizing |

|Stability: |Stable for two years under ambient conditions. Stable when stored at 54°C for 14 days. Stable when |

| |stored in contact with aluminium, iron, zinc and the corresponding metal acetate salts at 54°C for |

| |14 days |

The APVMA has evaluated the chemistry aspects of amisulbrom active constituent including the manufacturing process, quality control procedures, batch analysis results and analytical methods and found them to be acceptable.

On the basis of the data provided, and the toxicological assessment, it is proposed that the following APVMA active constituent standard be established for amisulbrom:

APVMA CONSTITUENT STANDARD

|CONSTITUENT |SPECIFICATION |LEVEL |

|Amisulbrom |Amisulbrom |Not less than 965 g/kg |

Based on a review of the data provided by the applicant, the APVMA proposes to be satisfied that the chemistry and manufacturing details of amisulbrom are acceptable.

2 Formulated product

The chemistry aspects of the product, Amicus Blue Fungicide (manufacturing process, quality control procedures, batch analysis results and analytical methods) have been evaluated by the APVMA.

The product Amicus Blue Fungicide will be packaged and marketed in 5–1000 L high density polyethylene (HDPE) containers.

Amicus blue fungicide

|distinguishing Name: |AMICUS BLUE FUNGICIDE |

|FORMULATION type: |Suspension Concentrate (SC) |

|Active constituent concentrations: |32 g/L Amisulbrom |

| |180 g/L Copper (Cu) present as tribasic copper sulphate |

Physical and chemical properties of formulated product

|Physical form |Smooth blue-green homogenous suspension |

|ph value (1% aqueous): |7.15 |

|density: |1.24–1.27 g/mL |

|viscosity: |1500–2500 cps |

|persistant foam: |15 mL after 1 min |

|suspensibility: |102.2% |

|dispersion: |2 inversions |

|wet sieve test: |0.0016% retained on a 75µm sieve |

|particle size distribution: |0.33 µm at d(0.1) |

| |1.35 µm at d(0.5) |

| |4.06 µm at d(0.9) |

|Pourability: |0.24% for rinsed residue |

|Flash point: |Not flammable |

|oxidising properties: |No oxidising properties |

|explosive properties: |No explosive properties |

|Pack sizes: |5–1000 L |

|packaging material: |HDPE containers with plastic lids |

|Product stability: |Product is expected to remain stable over the proposed 2–year shelf life |

3 Conclusion

The APVMA is satisfied that the chemistry and manufacture data requirements for the registration of the product Amicus Blue Fungicide and approval of the active constituent amisulbrom have been met.

Toxicological assessment

1 Summary

The proposed use of Amicus Blue Fungicide containing 32 g/L amisulbrom and 180 g/L copper (Cu) present as tribasic copper sulphate is for the control of downy mildew in grapes and downy mildew and white blister in brassicas.

In toxicokinetic studies in rats, amisulbrom oral absorption was approximately 50% at low doses

(10 mg/kg bw) but much lower with high doses (5% at 1000 mg/kg bw). Amisulbrom does not accumulate in the body. It is readily excreted after single or repeat administrations to rats, with >90% eliminated primarily in faeces within 72 hours. Patterns of excretion are similar between sexes. Only small proportions (90%) was eliminated in faeces and urine within 72 hrs, and there were no differences in the pattern of excretion between sexes. During observations after dosing for 120 hrs, mean urinary excretion was lower (11.5–13%) than faecal excretion (82.5–84% of dose).

Percutaneous absorption

Both in vitro (human and rat) and in vivo (human) dermal absorption studies were evaluated. Utilising the triple-pack approach, the estimated human dermal absorption factor (DAF) for a 200 g/L SC formulation of amisulbrom and a 0.067 g/L aqueous dilution were 0.62% and 11.66%, respectively.

Acute toxicity

Amisulbrom had low acute oral (LD50 >5000 mg/kg bw), dermal (LD50 >5000 mg/kg bw) and inhalational (LC50 >2850 mg/m3) toxicity in rats. Amisulbrom was not a skin irritant in rabbits or a skin sensitiser in guinea pigs (maximisation test). Amisulbrom was considered to be a slight but persistent eye irritant in rabbits, noting the extended observation of low-level conjunctival effects in a single animal up to 22 days after treatment.

Amicus Blue Fungicide had low acute oral, dermal and inhalational toxicity. It was not a skin irritant in rabbits or a skin sensitiser in guinea pigs (maximisation method), but slight eye irritation was seen in rabbits.

Systemic toxicity

Repeat dose studies with amisulbrom have been conducted in rats, mice and dogs. Observations common to all species include test substance related and dose dependent reductions in food consumption, lower body weight (and decreased body weight gain), increases in liver organ weight, changes in clinical chemistry parameters (Alkaline phosphatase, Alanine aminotransferase, Gamma-glutamyl transpeptidase, triglycerides), and increased incidence and/or severity of histopathological changes (hepatocellular hypertrophy) in the liver. The liver as a main target organ is consistent with the findings in toxicokinetics studies, where high radiolabel levels were identified in the liver. The most sensitive species in repeat-dose toxicity studies was the rat, with the lowest NOEL in this species being 11.1/14.3 mg/kg bw/day

(M/F; 200 ppm), established in the 2-year chronic/carcinogenicity study.

In addition to the liver, the kidney was another target organ identified. Similar to the liver changes, a dose-dependent and time-related increase in kidney weight and incidence of histopathological changes (cortical tubular pigment, increased cortical tubular basophilia and perivascular lymphoid aggregations) were detected in repeat dose studies.

Genotoxicity and Carcinogenicity

Amisulbrom was not genotoxic in several in vitro and in vivo studies.

In the 2–year combined chronic and carcinogenic study in rats, neoplastic changes, including a higher incidence of liver hepatocellular adenoma and carcinoma, were seen at ≥ 10000 ppm

(496/697 mg/kg bw/d M/F): these were considered to be above the maximum tolerated dose (MTD).

The increased incidence of forestomach tumours in female rats were not considered relevant to humans and caused by local irritation of the stomach mucosa.

In mice an increased incidence in hepatocellular adenoma was observed in males which exhibited dose response. These neoplastic changes were noted at levels below the MTD of 8000 ppm (1035 mg/kg bw/d).

Mechanistic studies submitted suggesting a carcinogenicity mode of action for amisulbrom similar to phenobarbital, a mechanism which is generally not considered relevant to humans, did not provide comprehensive evidence to eliminate the possibility of other modes of action. However, noting that the hepatocellular carcinoma findings only occurred at doses above the MTD, hepatocellular adenomas were only observed below the MTD in male mice, and there was a lack of pre-neoplastic lesions and negative genotoxicity results, on a broader weight of evidence consideration it is unlikely that amisulbrom poses a significant carcinogenic risk.

Reproductive and Development Toxicity

No effect on fertility was observed in the F0 generation in a 2–generation reproductive study in rats. However, prolonged or irregular oestrous cycles, impaired fertility and ovarian atrophy were evident in F1 females. Fertility in F1 males was unaffected by treatment. Mechanistic data (including an anti-oestrogenic uterotrophic assay, an anti-aromatase assay and reproductive hormone level analysis) submitted by the applicant provided evidence that impaired fertility in F1 females was likely secondary to reduced food intake and impaired body weight gain associated with poor palatability of amisulbrom, rather than a direct amisulbrom-related effect. Therefore amisulbrom is not considered to be a reproductive toxicant.

There was no evidence of embryofoetal toxicity in developmental studies in rats and rabbits. Amisulbrom is not considered to be a developmental toxicant.

Neurotoxicity

Acute and subchronic neurotoxicity studies indicated that amisulbrom was not neurotoxic in rats.

Toxicity of metabolites

The metabolite, IT-4 was moderately acutely toxic by the oral route in rats (LD50 >50 mg/kg bw but ................
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