ESTEEM - Polyoxin D zinc salt APP202334 - Category C Reduced Risk - - PowerPoint PPT Presentation

ESTEEM - Polyoxin D zinc salt

APP202334 - Category C Reduced Risk Hearing: 9 December 2015 Applicant Contact - Eurofins Agroscience Services Pty Ltd

Kaken Pharmaceutical Co., Ltd.

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Introduction

To seek approval to import the fungicide ESTEEM, containing 5% w/w Polyoxin D zinc salt, a new active ingredient with an unique non-toxic mode of action, for the control of fungal diseases in apples and grapes.

Benefits:

• 1. Useful in resistance management
• 2. Useful for disease control in the pre-harvest period
• 3. Negligible risk to workers and consumers
• 4. Negligible risk to the environment

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Outline

• 1. Key properties
• 2. International Use History
• 3. Wide Use
• 4. Unique, Non-Toxic Mode of Action
• 5. Mammalian Toxicology
• 6. Hazard to the Environment
• 7. Rapid Degradation in the Environment
• 8. Effect to Māori Culture
• 9. Benefits
• 10. Applicant Conclusion

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Key Properties

Polyoxin D zinc salt (active ingredient) ESTEEM (5 % AI, suspension concentrate)

• 1. Long term international use history for fungicide
• 2. Biochemical pesticide with a naturally occurring characteristics
• 3. Unique, non-toxic mode of action [FRAC CODE19]
• 4. Low toxicity to human health and the environment
• 5. Degrades rapidly in the environment
• 6. Tolerance exemption has been established in the US for

residues on all crops (40 CFR §180.1285)

• 1. Wide Use in the United States
• 2. Designed for the organic crop protection market
• 3. Low toxicity to human health and the environment
• 4. Post-harvest Use approved in the United States

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History of polyoxin D zinc salt

1962: Polyoxins were discovered in a culture broth of Streptomyces cacaoi ver. Asoensis from Kumamoto in Kyushu, southwest of Japan. 1968: Polyoxin D zinc salt; first registration in Japan. Until Now: Polyoxin D Zinc Salt has been produced by fermentation technology with minor chemical modification in Japan, and then, classified as a biochemical pesticide by US EPA.

• Mt. Aso

In general, natural-derived materials are more friendly to the environment

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Japan Taiwan Korea The United States Mexico Over 40 years Over 31 years Over 29 years Over 25 years Over 17 years Over 6 years Over 7 years Over 4 years

No reports of adverse effects on human health and the environment

Sales Volume as Polyoxin D Zinc Salt Technical: Several dozen metric ton per year. * : Tolerance exemption has been established.

Long term international use history

Food use Non food use * * * 6

Use for many crops in the US

Fruit: Berries and Small Fruits, Citrus Fruits, Grapes, Pome Fruits , Stone Fruits , Pomegranate Tree Nuts: Almonds, Pistachios

・・・・・ Post-harvest use approved

PHI: 0 days, tolerance exemption in or on all food commodities 7

Vegetables: Leafy vegetables, Carrots, Cucurbit Vegetables, Fruiting Vegetables

Unique, non-toxic mode of action

Polyoxin D UDP-N-acetyl glucosamine Chitin Chitin Synthetaze Normal germination of spore Germ tube swelling Loss of the ability to infect Untreated Control Polyoxin D Treated

New mode of action in New Zealand Highly fungal specific (FRAC CODE 19)

n

Significant benefits in disease resistance management

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Competitive Inhibition

MIC* (μg/mL) Pathogenic fungi Piricularia oryzae 3.12 Cochliobolus miyabeanus 6.25 Pellicularia sasakii <1.56 Alternaria kikuchiana 50 Yeast 4 strains > 100 Aerobic bacteria 10 strains > 400 Anaerobic bacteria 3 strains > 400 Acid-fast bacteria 1 strains > 400

Not an antibiotic, not a bactericide

No activity on bacteria No activity on chitin synthesis in insects and yeasts

9 * Minimum Inhibitory Concentration

Mammalian Toxicology

Low hazard, but retaining PPE requirements are appropriate.

Acute Oral ESTEEM: Technical: Rat LD50 >5000 mg/kg bw Rat LD50 (males) >15000 mg/kg bw Rat LD50 (females) >10000 <15000 mg/kg bw Acute Dermal ESTEEM: Technical: Rat LD50: >5050 mg/kg bw Rat LD50: >2000 mg/kg bw Acute Inhalation ESTEEM: Technical: Rat LC50 > 2.20 mg/L Rat LC50 (males) >2.44 mg/L Rat LC50 (females) >2.17 mg/L Contact Sensitization ESTEEM: Technical: 6.5B No Mutagenicity No Carcinogenicity No Reproductive/ developmental toxicity No

EPA STAFF REPORT 10

Key Studies for ADE, PDE, AOEL

Study type NOAEL

(mg/kg bw/day)

LOAEL

(mg/kg bw/day)

Key effect No/Sex /Group 1 Rat 2 year M: 2058.7 F: 2469.8

Not Identified

No effect 36 M, 36 F (Wister)

NO ADE or PDE values are proposed.

EPA STAFF REPORT

2 Dog 1 year M: 1063 F: 1112

Not Identified

No effect 4 M, 4 F (Beagle) 3 Rat 90 day M: 119 F: 135 M: 1166 F: 1333 Slight Effects

Lower liver weight

M: Rel 97% F: Rel 96%

Lower spleen weight

M: Rel 95% F: Rel 96%

10 M, 10 F (Fischer)

AOEL are proposed as 1.19 mg/kg bw/day.

P <=0.05

Very low chronic toxicity to mammals

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Hazard Classifications, Ecotox

ESTEEM Polyoxin D zinc salt Aquatic ecotoxicity 9.1C 9.1B Soil ecotoxicity No No Terrestrial vertebrate ecotoxicity No No Terrestrial invertebrate ecotoxicity No No

EPA STAFF REPORT

Ground-based application only Not spraying onto or into water

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Acute risk quotients under controls

Application Controls

Max application rate: Max number of application: Min application interval: Pre-harvest interval : Re-entry control:

No concerns for species exposed

Crops Species Peak EEC (mg/L) LC50 or EC50 (mg/L) Acute RQ Trigger value / Presumption Apples Fish 0.0039 5.1 0.00076 0.1 / No concern 0.05 / No concern for threatened species Daphnia 1.4 0.0028 Algae 7.05 0.00055 Grapes Fish 0.0021 5.1 0.00042 Daphnia 1.4 0.0015 Algae 7.05 0.000298

2L Esteem (100 g a.i.) /ha per application 6 times in a year 7 days 0 days None

EPA STAFF REPORT 13

Effect of ESTEEM to the environment

The response of Aphelinus mali to residues of ESTEEM Acute toxicity to Daphnia, ESTEEM

Test Substance EC 50 (mg / L) ESTEEM (*) 7.8 – 31.3

(1.6 – 6.6 as Technical)

Polyoxin D Zinc Salt Technical 1.4

(*) Preliminary dose range finding test

Control ESTEEM Carbaryl Diazinon Mortality (%)

14 Sponsor:

No effects of the inert ingredients to Daphnia

Rapid Degradation in the environment

Degradation Route Condition DT50 (days) Photodegradation in water Natural Water 0.4 pH 5.0 buffer 4.0 pH 7.0 buffer 2.3 pH 9.0 buffer 1.3 Aerobic soil metabolism Aerobic Soil 15.9

EPA STAFF REPORT 15

Effects to Māori Culture

Taha hauora (human health) Mahinga kai (food resources)

Harmful in the aquatic environment (9.1C) Limitation : ground-based application only not spraying onto or into water, etc. No significant concerns regarding birds, insects, and plants Limitation: Controls requiring the use of PPE, etc. Workers and owners of orchards or vineyards have a chance to replace more harmful products with a lower risk product.

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Benefits

• 1. Provide a new opportunity for resistant management
• 4. Negligible risk to the environment
• 2. Available for use with very short pre-harvest interval
• 3. Negligible risk to human health

Unique, non-toxic, fungal specific mode of action [FRAC CODE 19] Few pesticides available due to residue concerns Tolerance exemption with 0 days PHI in several countries Ongoing Project (Canada, EU, Korea, etc. ) Much lower hazard profile than many other fungicides Long term international use history for fungicide Beneficial for both workers and consumers Lower hazard profile to and rapid degradation in the environment

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Applicant Conclusion

The applicant requests the Decision-making Committee to approve the application to import ESTEEM for disease control in apples and grapes, with appropriate controls and an exemption from ADE setting. ESTEEM will provide New Zealand with significant benefits in resistant management, reducing adverse effects to human health and the environment, and for disease control in the pre-harvest period.

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