Fludioxonil Registrant Meeting

– 03

- 1 2

- 2013

- Syngenta

- EPA Meeting Highlights
Syngenta and US Environmental Protection Agency

March 12 , 2013

On March 12, 2013 , at the request of Syngetna , the technical registrant for fludioxonil
, representatives from Syngenta met for 1.5 hours with US Environmental Protection Agency (EPA) to discuss the status of the ongoing regist ration review of fludioxonil

. During the presentation Syngenta discussed the current status of the data requirements listed in the data call

in (DCI) and to seek additional clarification on several o f the ecological effects and fate data requirements. Syngenta also highlighted the 90

- day response was recently submitted and included several data waivers. The Agency plans to review the data waivers and provide Syngenta with a formal written response.

# Fludioxonil Registration Review

March 12, 20132 

### ● Introduction and background



### ● Provide an update for the DCI.

● Testing of solo TEP and premix TEP

- EPA requested a number of mixture Typical End

- use Product 

### (TEP) studies in the DCI.

● Discuss the relative sensitivity of freshwater and marine fish in the 

### context of addressing data gaps.

● Discussion and q uestions for consideration 

# Outline3 

### ● Introduction and background



### ● Provide an update for the DCI.

● Testing of solo TEP and premix TEP

- EPA requested a number of mixture Typical End

- use Product (TEP) studies in the DCI.

● Discuss the relative sensitivity of freshwater and marine fish in the 

### context of addressing data gaps.

● Discussion and questions for c onsideration



# Outline4 

### Class Phenylpyrrole , derived from natural anti

- mycotic compounds isolated from a soil bacterium, Pseudomonas spp

. 

### General Uses Protective contact fungicide for soil

- borne and foliar diseases. Post

- harvest treatment for storage. Seed treatment for various crops. 

### Key diseases Foliar: Botrytis
, Monilinia spp. Soil

- Borne: Rhizoctonia, Sclerotinia, Fusarium Post

- Harvest: Botrytis, Penicillium 

### Key Crops Field and Seed Treatment Uses: Strawberries, Caneberries, Cucurbits, Lettuce, Soy Post Harvest Use: Citrus and Apples



# Introduction: General background

Botrytis Sclerotinia5 

### ● Oct, 1995, Fludioxonil Technical (100

- 759) and the End

- Use Product, Maxim ® 

### 4FS (100

- 758), were approved.

- Maxim 4FS is a 40% solo end

- use product for seed treatment on multiple crops and is the basis for many seed treatment formulations.



### ● Feb, 1997, End

- Use Product, Medallion ® 

### (100

- 769), is approved for use on ornamentals grown in containers.

- Medallion is a 50% solo end

- use product and is the basis for ornamental and turf uses.



### ● Mar, 2001, Turfgrass uses were approved for Medallion ® 

### (100

- 769).

● Aug, 2001, Onion and strawberry foliar uses were approved for Switch ® 

### 62.5 WG (100

- 953).

- Switch ® 62.5 WG is a premix of fludioxonil (25%) and cyprodinil (37.5%) and is used for foliar applications.



### ● Mar, 2002, Onion and strawberry foliar uses were approved for Medallion (100

- 769). 

# Introduction: Key registrations6 

### Seed treatment

- Formulation Types: FS (flowable suspension), WP (wettable powder), RTA (Ready

- to

- Apply), DS (Powder for Dry Seed)

- Mixture Partners: Mefenoxam, Thiamethoxam, Difenoconazole
, Mancozeb
, Azoxystrobin
, Myclobutanil
, Abamectin 

### Foliar (crops)

- Formulation Types: WG ( wettable dispersible granule), solo WP

- Mixture Partners: Cyprodinil


### Turf/Ornamentals

- Formulation Types: WG, SE ( suspo
- emulsion; listed as EC in DCI ), solo WP, WG, SC

- Mixture Partners: Cyprodinil, Chlorothalonil, Propiconazole
, Mefenoxam


### Post

- Harvest

- Formulation Types: SC (suspension concentrate), solo WP and SC

- Mixture Partners: Azoxystrobin, Difenoconazole



# Introduction: Formulations7 

### Example Formulations

Example Formulation Types

● WP ( Wettable Powder) example formulation: “Medallion”

- 50% fludioxonil (solo formulation)

● WDG (Water Dispersible Granule) example formulation : “Switch 62.5WG”

- 25% fludioxonil ; 37.5% cyprodinil

● SE ( Suspo

- Emulsion) example formulation: “ Instrata ”

- Listed as “EC” in DCI

- 1.2% fludioxonil ; 4.7% propiconazole ; 29.9% chlorothalonil8 

# Introduction: End

- use product rates

Solo End

- use Product Mixture End

- use Product

Example Trade Names Medallion ® WP/WDG

(Cannonball ® WG ) (100

- 769) Switch ® 62.5 WG (100

- 953) Instrata ® SE

(100

- 1231)

Fludioxonil in End

- use Products 50% 25% 1.2%

Maximum Single Application Rate ( lbs a.i ./A/app) Crops: 0.25 Turf: 0.68 Ornamentals: 0.5 

### * Crop: 0.22 Turf: 0.45

Maximum Annual Application Rate ( lbs a.i ./A/year) Crops: 1.0 Turf: 2.0 Ornamentals: 2.0 

### * Crops: 0.9 Turf: 1.8

* Syngenta appreciates the opportunity to discuss these rates with the Agency9 

# Introduction: Clarification of Fludioxonil Use Rates

Ornamental Rate : (EPA Reg. No. 100

- 769) Maximum single rate = 4 oz /100gals

. = 0.5 lbs. ai /A /app (assuming 400 gal/A) Maximum annual rate = 1.5 oz./1,000 sq.ft / yr (2 lb ai /A/

yr )

Turf Rate: (EPA Reg. No. 100

- 769) Maximum single rate = 0.5 oz /1,000 sq. ft. = 0.68 lbs

. ai /A/app Maximum annual rate = 2 lbs. ai /A/ yr

EPA: HED Risk Assessment Dated, May 21,2012, (D389613) assumed 2.0 lb ai /A/app as the single maximum application rate.10 

### ● Introduction and background



### ● Provide an update for the DCI.

● Testing of solo TEP and premix TEP

- EPA requested a number of mixture Typical End

- use Product (TEP) 

### studies in the DCI.

● Discuss the relative sensitivity of freshwater and marine fish in the 

### context of addressing data gaps.

● Discussion and questions for c onsideration 

# Outline11 Table 1. Studies that Syngenta plans to conduct to address DCI data gaps. 

# Update of study classification for DCI

Guideline Test Type Test substance In DCI

850.2100 Avian acute oral toxicity test (Passerine) TGAI Y

850.4500 Algal toxicity ( Navicula ) TGAI Y

850.4500 Algal toxicity ( Skeletonema ) TGAI Y

850.4550 Algal toxicity ( Anabaena ) TGAI Y

Non

- guideline Life cycle s ediment toxicity test ( Hyalella ) TGAI Y

Non

- guideline Life cycle s ediment toxicity test ( Chironomus ) TGAI Y

Non

- guideline Life cycle s ediment toxicity test ( Leptocheirus ) TGAI Y

835.1300 Daphnid chronic toxicity test ( Daphnia ) A Requesting 24 months TGAI Y
850.1500 850.1075 Fish l ifecycle toxicity

– Freshwater ( Pimephales )

Acute toxicity test

- Freshwater ( Pimephales ) B TGAI Y

850.1350 Mysid Chronic (Marine Invertebrate Life

- Cycle) Requesting 24 months TGAI Y

A = Syngenta requests 24 months: Chronic study and l aboratory capacity issues for high quality contract laboratories. B = DCI states that an acute must be performed with the same species as the life cycle study.12 Table 2. Studies listed on DCI that are classified as acceptable in DERs.

Guideline Test Type Test Substance MRID Updated Classification

850.1010 Aquatic invertebrate acute test

– Freshwater TGAI 43080010 Acceptable DER (10/30/06) A Remove from DCI

850.1025 Oyster acute toxicity test

-

Shell Deposition TGAI 43080011 Acceptable DER (10/30/06) B Remove from DCI

850.1035 Mysid acute toxicity test TGAI 43080012 Acceptable EPA Memo (4/19/2011) C Remove from DCI

850.1075 Fish acute

- Marine TGAI 43080013 Acceptable

- EPA Memo (2/26/2008) D Remove from DCI

850.4500 (formerly 850.5400) Green Algal toxicity TGAI 48526505 Acceptable EPA Memo (1/12/13) E Remove from DCI 

# Update of study classification for DCI

A = DER: Acute Toxicity of CGA

- 173506 (Fludioxonil) to Freshwater Invertebrates

- Daphnia magna (EPA guideline 72

- 2 ),10/30/06
B = DER: 72

- 3(B)

- Acute EC50 Test with an Estuarine/Marine Oyster, 10/30/06 C = EPA Memo: Fludioxonil Ecotoxicity Data Reviews and Reclassification of Studies Based on Review for Registration Review Problem Formulation; DP Barcode: 384856, April 19, 2011
D = EPA Memo: Reclassification of Acute Estuarine/Marine fish Toxicity Test (Guideline 72

- 3(A)); MRID 43080013, 2/26/08
E = EPA Memo on Fludioxonil Toxicity Tests. DP Code: 392309, 392311, 392312, PC Code: 071503 . 1/12/1213 Table 3. Studies that are no longer needed based on Agency response to comments on Preliminary Problem Formulation as there is no direct application to water (watercress use; communicated November 11/8/2011)

Guideline Test Type Material In DCI Comment/ Justification

850.4500 Algal toxicity ( Green Alga) TEP Y EPA Memo 11/8/11 A Remove from DCI

850.4500 Algal toxicity ( Navicula ) TEP Y EPA Memo 11/8/11 A Remove from DCI

850.4500 Algal toxicity ( Skeletonema ) TEP Y EPA Memo 11/8/11 A Remove from DCI

850.4550 Algal toxicity ( Anabaena ) TEP Y EPA Memo 11/8/11 A Remove from DCI 

# Update of study classification for DCI

A “Response to initial 60

- d comments on: Preliminary Problem Formulation for Environmental Fate, Ecological Risk, Endangered Species, and Drinking Water Exposure Assessments for Fludioxonil ” indicated that TEP testing is no longer needed (November 11/8/2011).” Page 10 of 24: “No additional studies are requested at this time for aquatic non - vascular plants carried out on the TEP because there is no longer a concern for direct application to water.”14 

### ● Introduction and background



### ● Provide an update for the DCI.

● Testing of solo TEP and premix TEP

- EPA requested a number of mixture Typical End

- use Product 

### (TEP) studies in the DCI.

● Discuss the relative sensitivity of freshwater and marine fish in the 

### context of addressing data gaps.

● Discussion and questions for c onsideration 

# Outline15 

# Ecotox Testing with Typical End

- use Products

EPA has requested an extensive dataset of toxicity studies with premix formulations (i.e., mixture formulations that contain multiple AIs).

Challenges:

• Differences in e

- fate properties of AIs make translation of lab ecotox studies to environmental exposure challenging.

• How ecotox data for premix formulations will be used in the assessment so that future studies can be effectively designed and conducted.16 

### Formulation Types Requested

● WP ( Wettable Powder) example formulation : “Medallion”

- 50 % fludioxonil (solo formulation, highest rate)



### ● WDG (Water Dispersible Granule) example formulation: “ Switch 62.5WG ”

- 25 % fludioxonil ; 37.5% cyprodinil

● SE ( Suspo

- Emulsion) example formulation: “ Instrata ”



### - Listed as “EC” in DCI

- 1.2% fludioxonil ; 4.7% propiconazole ; 29.9% c hlorothalonil Guideline Test Type Material In DCI

850.1025 Oyster acute toxicity test WDG or WP TEP Y

850.1025 Oyster acute toxicity test SE ( Instrata ) Y

850.1035 Mysid acute toxicity test SE ( Instrata ) Y

850.1010 Daphnia acute SE ( Instrata ) Y (Study Available, not yet submitted ) 

# Solo TEP and Mixture TEP: Invertebrates

Table 5. Invertebrate acute study data gaps in DCI for TEPs.17 

### ● Fish TEP studies also identified as data gaps



# Solo TEP and Mixture TEP: Fish
Table 6. Fish acute study data gaps for TEPs

Guideline Test Type Material In DCI

850.1075 Fish acute

- Marine WDG or WP TEP Y

850.1075 Fish acute

- Marine SE Y

850.1075 Fish acute

- Freshwater SE Y (Study Available, not yet submitted )18 

### Calculation of Toxic Units (Generic Example )

● Toxic Units (TUs) can be used to estimate if response to a mixture is additive, greater than additive or less than additive ( Sprague and Ramsay, 1965; also http ://

www.epa.gov/npdes/pubs/owm0264.pdf ).



### ● Concentrations in the mixture are expressed as fractions of the individual LC50’s: TU = sum of the LC50 fractions in the mixture using the formula: TU mixture 

### = Conc A 

### / LC50 A 

### + Conc B 

### / LC50 B 

### + ...

At LC50 of mixture, if :

- Sum of TU = 1.0 : Predict 50% mortality (Additive)



### - Sum of TU < 1.0 : Predict less than 50% mortality ( > additive; synergy)

- Sum of TU > 1.0 : Predict > 50% mortality ( < additive; antagonism)19 

### Calculation of Toxic Units (TUs)

– “ Switch 62.5WG”



### Mysid Acute Study ( MRID 45734501)

“ Switch 62.5WG”

-- WDG Formulation ( fludioxonil + cyprodinil )

● Formulation toxicity:



### - Switch 96

- h Mysid LC50 = 51 μg formulation/L ( MRID 45734501 )

.
● TGAI Toxicity:

- Fludioxonil mysid 96

- h LC50 = 270 μg AI/L (MRID 43080012)

• 51 ug /L * 0.25 = 12.8 μg fludioxonil /L

• Toxic Units: 12.8 μg / 270 = 0.05 TU

- Cyprodinil mysid 96

- h LC50 = 8.14 μg AI/L ( PPF discrepancy ; MRID 43908409)



### • 51 ug /L * 0.378 = 19.27 μg cyprodinil /L

• Toxic Units: 19.27 μg / 8.14 = 2.36 TU



## - Sum of TUs = 0.05 + 2.36 = 2.42 TU



## ● TU Value is > 1.0, indicating formulation toxicity of Switch 62.5WG is less than additive.20 

### Calculation of Toxic Units (TUs)

– “ Switch 62.5WG ” Example



### Daphnid Acute Study (MRID 45649301)
“Switch 62.5WG”

-- WDG Formulation ( fludioxonil + cyprodinil )

● Formulation toxicity:

- Switch 48

- h daphnid EC50 = 110 μg formulation/L ( MRID 45649301 )

.
● TGAI Toxicity:

• Fludioxonil daphnid 48

- h LC50 = 900 μg AI/L (MRID 43080010)

- 110 ug /L * 0.25 = 27.5 μg fludioxonil /L

- Toxic Units: 27.5 / 900 = 0.03 TU

• Cyprodinil daphnid 96

- h LC50 = 32 μg AI/L (MRID 43709013)



### - 110 ug /L * 0.376 = 41.36 μg cyprodinil /L

- Toxic Units: 41.36 μg / 32 = 1.29 TU



## - Sum of TUs = 0.03 + 1.29 = 1.32 TU

● TU Value is > 1.0, indicating formulation toxicity of Switch 62.5WG is less than additive.21 

### “ Instrata ” Suspo

- Emulsion

● Oyster, mysid , daphnid , marine and freshwater fish studies have been identified as data gaps for an SE ( Suspo

- Emulsion) TEP.



### ● “ Instrata ” SE Formulation contains:

- 1.2% fludioxonil ; 4.7% propiconazole ; 29.9% chlorothalonil

● Daphnia magna ( Borrmann
, 2010) and Rainbow Trout ( Gonsior , 2010) studies exist:

- Static

- Measured single analyte (i.e. chlorothalonil ) to confirm dosing Guideline Test Type Material In DCI

850.1025 Oyster acute toxicity test SE Y

850.1035 Mysid acute toxicity test SE Y

850.1010 Daphnia acute SE Y (Study Available, not yet submitted )
850.1075 Fish acute

- Marine SE Y

850.1075 Fish acute

- Freshwater SE Y (Study Available, not yet submitted )22 

### Summary of Formulation Testing Discussion



## Data exist for 2

- AI and 3

- AI formulations ( fludioxonil
, propiconazole
, chlorothalonil and cyprodinil ):



## - All studies provide evidence that formulation/mixture toxicity is less than additive23 

# Solo TEP and Mixture TEP: Terrestrial plant

Table 7. Terrestrial plant toxicity (veg. vigor) with WDG or WP TEP.

Guideline Test Type Material In DCI

850.4150 Terrestrial plant toxicity

- Vegetative vigor (10 species) WDG or WP TEP Y

850.4150 Terrestrial plant toxicity

- Vegetative vigor (10 species) SE Y

TGAI vegetative vigor study classified as supplemental (MRID 48526504).

- Use of TGAI, not TEP (guideline 850.4250 allowed for testing with TGAI)

- 5 replicates instead of 10.

- “ supplemental, useful for RA”
Low toxicity to most plants tested up to highest rate of 1 lbs. a.i ./acre (NOEC 1 lb a.i ./A, EC 25 > 1 lbs. a.i ./acre)

- Rye grass NOEC = 0.5 lb a.i ./A, EC 25 > 1 lb a.i ./A

• Demonstrates low sensitivity of NTPs / low risk

• Repeat study and conduct with WP formulation (as for seedling emergence study) if needed by Agency to complete data package24 

### ● Introduction and b ackground



### ● Provide an update for the DCI.

● Testing of solo TEP and premix TEP

- EPA requested a number of mixture Typical End

- use Product (TEP) 

### studies in the DCI.

● Discuss the relative sensitivity of freshwater and marine fish in the 

### context of addressing data gaps.

● Discussion and questions for c onsideration 

# Outline25 Table 8. Fish studies that Syngenta desires to discuss with EPA.

Guideline Test Type Material In DCI
850.1500 850.1075 Fish l ifecycle toxicity

– Freshwater

Acute Fish toxicity test

- Freshwater TGAI Y

850.1500 Fish l ifecycle toxicity

– Marine TGAI Y

850.1400 Fish early

- life stage toxicity test

– Marine TGAI N 

# Relative sensitivity of freshwater and marine fish:



# Relevant studies.26 

### Summary: toxicity can be predicted by mortality/growth in ELS studies. Increasing concentration 

# Relative sensitivity of freshwater and marine fish:



# General pattern of endpoints.

General Fish Chronic Dose Response Pattern for Fludioxonil

Hatching Effects

Growth Effects General obs/ Mortality
No Effects27 % Hatch

Sheepshead minnow = ≥ 92% at concentration ≤ 246 μg/L Fathead minnow = ≥ 94% at concentration ≤ 144 μg/L 

# Relative sensitivity of freshwater and marine fish: 

# Fathead minnow versus Sheepshead minnow ELS
Fathead minnow ( Freshwater ) exhibited greater sensitivity than

Sheepshead minnow ( Marine ).28 A vailable data indicate that freshwater fish are more sensitive than saltwater species ; therefore, Syngenta proposes to conduct a freshwater fish full life

- cycle (FLC) study with fathead minnow (FHM), as well as an accompanying acute study.

Syngenta believes that the marine early life

- stage (ELS) toxicity test completed with sheepshead minnow (SHM; MRID 48526502) is useful for the risk assessment (e.g. ACR approach and relative toxicity as compared to freshwater fish).

However, if additional marine toxicity data are needed, Syngenta proposes to repeat the marine ELS study instead of conducting a marine FLC.

Collectively, the information derived from this testing proposed will be adequate to provide effect data to complete the risk assessment for freshwater and marine fish. 

# Relative sensitivity of freshwater and marine fish:



# Addressing DCI data gaps.29 

### ● Introduction and background



### ● Provide an update for the DCI.

● Testing of solo TEP and premix TEP

- EPA requested a number of mixture Typical End

- use Product (TEP) 

### studies in the DCI.

● Discuss the relative sensitivity of freshwater and marine fish in the 

### context of addressing data gaps.

● Discussion and questions for c onsideration 

# Outline30 

# Discussion and q uestions for c onsideration

● Clarification of fludioxonil use rates.

● Can studies listed in Tables 2 and 3 be removed as data gaps?

● Formulation testing (Solo versus mixture formulations)

- Formulation studies demonstrate less than additive toxicity, therefore Syngenta suggests that extensive additional formulation testing will not be of value.

• If necessary, Syngenta proposes testing with Medallion 50WP only:

- highest concentration and rate TEP; solo formulation



### ● Addressing chronic data gaps for fish?

- Given the greater sensitivity of freshwater fish, would completing the fish full life cycle study with a freshwater species (and associated acute test) satisfy data requirements?31 

# Thank you!