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

Kaken Pharmaceutical Co., Ltd. ESTEEM - Polyoxin D zinc salt APP202334 - Category C Reduced Risk Hearing: 9 December 2015 Applicant Contact - Eurofins Agroscience Services Pty 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 management 2. Useful for disease control in the pre-harvest period 3. Negligible risk to workers and consumers 4. Negligible risk to the environment 2

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 M ā ori Culture 9. Benefits 10. Applicant Conclusion 3

Key Properties Polyoxin D zinc salt (active ingredient) 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) ESTEEM (5 % AI, suspension concentrate) 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 4

History of polyoxin D zinc salt Mt. Aso 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. In general, natural-derived materials are more friendly to the environment 5

Long term international use history Food use Non food use Japan Over 40 years Over 31 years Taiwan Over 29 years * Korea Over 25 years The United States Over 17 years * Over 6 years Mexico Over 7 years * Over 4 years Sales Volume as Polyoxin D Zinc Salt Technical: Several dozen metric ton per year. * : Tolerance exemption has been established. No reports of adverse effects on human health and the environment 6

Use for many crops in the US Tree Nuts: Almonds, Pistachios Vegetables: Leafy vegetables, Carrots, Cucurbit Vegetables, Fruiting Vegetables Fruit: Berries and Small Fruits, Citrus Fruits, Grapes , Pome Fruits , Stone Fruits , Pomegranate ・・・・・ Post-harvest use approved PHI: 0 days, tolerance exemption in or on all food commodities 7

Unique, non-toxic mode of action New mode of action in New Zealand Untreated Control Highly fungal specific (FRAC CODE 19) Chitin Synthetaze n Normal germination of spore Competitive UDP-N-acetyl Chitin Inhibition Polyoxin D Treated glucosamine Germ tube swelling Polyoxin D Loss of the ability to infect Significant benefits in disease resistance management 8

Not an antibiotic, not a bactericide No activity on bacteria No activity on chitin synthesis in insects and yeasts MIC* ( μ g/mL) 3.12 Piricularia oryzae 6.25 Cochliobolus miyabeanus Pathogenic fungi <1.56 Pellicularia sasakii 50 Alternaria kikuchiana Yeast 4 strains > 100 Aerobic bacteria 10 strains > 400 Anaerobic bacteria 3 strains > 400 Acid-fast bacteria 1 strains > 400 * Minimum Inhibitory Concentration 9

Mammalian Toxicology ESTEEM: Rat LD 50 >5000 mg/kg bw Acute Oral Technical: Rat LD 50 (males) >15000 mg/kg bw Rat LD 50 (females) >10000 <15000 mg/kg bw ESTEEM: Rat LD 50: >5050 mg/kg bw Acute Dermal Technical: Rat LD 50: >2000 mg/kg bw ESTEEM: Rat LC 50 > 2.20 mg/L Acute Inhalation Technical: Rat LC 50 (males) >2.44 mg/L Rat LC 50 (females) >2.17 mg/L Contact ESTEEM: 6.5B Sensitization Technical: No Mutagenicity No Carcinogenicity No Reproductive/ developmental No toxicity EPA STAFF REPORT Low hazard, but retaining PPE requirements are appropriate . 10

Key Studies for ADE, PDE, AOEL EPA STAFF REPORT No/Sex NOAEL LOAEL Study type Key effect /Group (mg/kg bw/day) (mg/kg bw/day) Rat M: 2058.7 36 M, 36 F 1 Not Identified No effect 2 year F: 2469.8 (Wister) NO ADE or PDE values are proposed. Dog M: 1063 4 M, 4 F 2 No effect Not Identified 1 year F: 1112 (Beagle) Slight Effects Lower liver weight 10 M, 10 F M: Rel 97% F: Rel 96% Rat M: 119 M: 1166 3 (Fischer) 90 day F: 135 F: 1333 Lower spleen weight M: Rel 95% F: Rel 96% P <=0.05 AOEL are proposed as 1.19 mg/kg bw/day . Very low chronic toxicity to mammals 11

Hazard Classifications, Ecotox ESTEEM Polyoxin D zinc salt Aquatic ecotoxicity 9.1C 9.1B Soil ecotoxicity No No Terrestrial vertebrate No No ecotoxicity Terrestrial invertebrate No No ecotoxicity Ground-based application only EPA STAFF REPORT Not spraying onto or into water 12

Acute risk quotients under controls Application Controls Max application rate: 2L Esteem (100 g a.i.) /ha per application Max number of application: 6 times in a year Min application interval: 7 days Pre-harvest interval : 0 days Re-entry control: None Peak EEC LC 50 or EC 50 Trigger value Crops Species Acute RQ (mg/L) (mg/L) / Presumption Fish 5.1 0.00076 Apples Daphnia 0.0039 1.4 0.0028 0.1 / No concern Algae 7.05 0.00055 0.05 / No concern Fish 5.1 0.00042 for threatened species Grapes Daphnia 0.0021 1.4 0.0015 Algae 7.05 0.000298 EPA STAFF REPORT No concerns for species exposed 13

Effect of ESTEEM to the environment Acute toxicity to Daphnia, The response of Aphelinus mali ESTEEM to residues of ESTEEM EC 50 Test Substance (mg / L) 7.8 – 31.3 Mortality (%) ESTEEM (*) (1.6 – 6.6 as Technical) Polyoxin D Zinc 1.4 Salt Technical (*) Preliminary dose range finding test No effects of the inert Control ESTEEM Carbaryl Diazinon ingredients to Daphnia Sponsor: 14

Rapid Degradation in the environment Degradation Route Condition DT 50 (days) Natural Water 0.4 pH 5.0 buffer 4.0 Photodegradation in water pH 7.0 buffer 2.3 pH 9.0 buffer 1.3 Aerobic soil Aerobic Soil 15.9 metabolism EPA STAFF REPORT 15

Effects to M ā ori Culture Taha hauora (human health) 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. 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 16

Benefits 1. Provide a new opportunity for resistant management Unique, non-toxic, fungal specific mode of action [FRAC CODE 19] 2. Available for use with very short pre-harvest interval Few pesticides available due to residue concerns Tolerance exemption with 0 days PHI in several countries Ongoing Project (Canada, EU, Korea, etc. ) 3. Negligible risk to human health Much lower hazard profile than many other fungicides Long term international use history for fungicide Beneficial for both workers and consumers 4. Negligible risk to the environment Lower hazard profile to and rapid degradation in the environment 17

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