ESTEEM -Polyoxin D zinc salt

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

Kaken Pharmaceutical Co., Ltd.

1

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 management2. Useful for disease control in the pre-harvest period3. Negligible risk to workers and consumers4. Negligible risk to the environment

2

Outline1. Key properties2. International Use History3. Wide Use4. Unique, Non-Toxic Mode of Action5. Mammalian Toxicology6. Hazard to the Environment7. Rapid Degradation in the Environment8. Effect to Māori Culture9. Benefits10. Applicant Conclusion

3

Key PropertiesPolyoxin D zinc salt (active ingredient)

ESTEEM (5 % AI, suspension concentrate)

1. Long term international use history for fungicide2. Biochemical pesticide with a naturally occurring characteristics3. Unique, non-toxic mode of action [FRAC CODE19]4. Low toxicity to human health and the environment 5. Degrades rapidly in the environment6. Tolerance exemption has been established in the US for

residues on all crops (40 CFR §180.1285)

1. Wide Use in the United States2. Designed for the organic crop protection market3. Low toxicity to human health and the environment4. Post-harvest Use approved in the United States

4

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 environment5

Japan

Taiwan

Korea

The United States

Mexico

Over 40 yearsOver 31 years

Over 29 years

Over 25 years

Over 17 yearsOver 6 years

Over 7 yearsOver 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 historyFood 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-acetylglucosamine

Chitin

Chitin Synthetaze

Normal germination of spore

Germ tube swellingLoss of the ability to infect

Untreated Control

Polyoxin D Treated

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

n

Significant benefits in disease resistance management 8

CompetitiveInhibition

MIC* (μg/mL)

Pathogenic fungi

Piricularia oryzae 3.12Cochliobolus miyabeanus 6.25Pellicularia sasakii <1.56Alternaria kikuchiana 50

Yeast 4 strains > 100Aerobic bacteria 10 strains > 400Anaerobic bacteria 3 strains > 400Acid-fast bacteria 1 strains > 400

Not an antibiotic, not a bactericide No activity on bacteriaNo activity on chitin synthesis in insects and yeasts

9

* Minimum Inhibitory Concentration

Mammalian Toxicology

Low hazard, but retaining PPE requirements are appropriate.

Acute OralESTEEM: Technical:

Rat LD50 >5000 mg/kg bwRat LD50 (males) >15000 mg/kg bwRat LD50 (females) >10000 <15000 mg/kg bw

Acute Dermal ESTEEM: Technical:

Rat LD50: >5050 mg/kg bwRat LD50: >2000 mg/kg bw

Acute InhalationESTEEM:Technical:

Rat LC50 > 2.20 mg/LRat LC50 (males) >2.44 mg/LRat LC50 (females) >2.17 mg/L

Contact Sensitization

ESTEEM:Technical:

6.5BNo

Mutagenicity NoCarcinogenicity NoReproductive/ 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: 2058.7F: 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: 1063F: 1112 Not Identified No effect 4 M, 4 F

(Beagle)

3 Rat 90 day

M: 119F: 135

M: 1166F: 1333

Slight EffectsLower 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 11

Hazard Classifications, EcotoxESTEEM 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 REPORTGround-based application onlyNot spraying onto or into water 12

Acute risk quotients under controlsApplication ControlsMax 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

ApplesFish

0.00395.1 0.00076

0.1 / No concern0.05 / No concern

for threatened species

Daphnia 1.4 0.0028Algae 7.05 0.00055

GrapesFish

0.00215.1 0.00042

Daphnia 1.4 0.0015Algae 7.05 0.000298

2L Esteem (100 g a.i.) /ha per application6 times in a year7 days0 daysNone

EPA STAFF REPORT

13

Effect of ESTEEM to the environment

The response of Aphelinus malito 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

Mor

talit

y (%

)

14

Sponsor:

No effects of the inert ingredients to Daphnia

Rapid Degradation in the environment

Degradation Route Condition DT50 (days)

Photodegradationin 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 CultureTaha hauora (human health)

Mahinga kai (food resources)

Harmful in the aquatic environment (9.1C)

Limitation : ground-based application onlynot 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.

16

Benefits1. 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 concernsTolerance exemption with 0 days PHI in several countriesOngoing Project (Canada, EU, Korea, etc. )

Much lower hazard profile than many other fungicidesLong term international use history for fungicideBeneficial for both workers and consumers

Lower hazard profile to and rapid degradation in the environment17

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.

18