### Date:

Subject: UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, 

### D.C. 20460



### August 5, 2014 OFFICE OF CHEMICAL SAFETY
AND POLLUTION PREVENTION



### Flupyradifurone: Human Health Risk Assessment for the First Food Use on : Root Vegetables Excep t Sugar Beet (Subgroup 1 B), T ube r ous and Corm Vegetables (Subgroup 1C), Bulb Vegeta bl es (Group 3-07), Leaf y Vegetables (Except Brassica) (Group 4), Taro Leaves, Turnip Tops, Head and Stem Brassica Vegetables (Subgroup SA), Le afy Brassica Greens Vegetables (Subgroup SB),
Edible-Podded Legume Vegetables (Subgroup 6A), Succulent Shelled Pea and

Bean (Subgroup 6B), Died Shelled Pea and Bean (except Soybean) (Subgroup 6C), Foliage of Legume Vegetables (except Soybean) (Subgroup 7A), Soybean (Seed), Fruiting Vegetables Except Cucurbits (Group 8-1 0), Cucurbit Vegetables (Group 9), Citrus Fruits (Group 10-1 0), Po me Fruits (Group 11-1 0), Bushberry (Subgroup 13-07B) except Cranberry, Small Frui t Vine Climbing (Except Fuzzy Kiwifruit) (Subgroup 13-07F), Low Growing Berry (Subgroup 13-07G) except Cranberry, Tree Nuts (Group 14-12), Cereal Grains Except Rice (Crop Group

15

, Except Rice), Forage, F odde r and Straw of Cereal Grains (Crop Group 16)

, Nongrass Animal Feeds (Forage, Fodder, Straw and Ha y) (Group 18)

, Cottonseed (Subgroup 20C), Coffee, Hops, Peanuts, Prickly Pear Cactus, and Pitaya.

PC Code: 122304
Decision No.: 471642
Petition No.: 2F81 0 I DP Barcode: 0407063 Registration Nos.: 264-RRUE, 264-RURR Regulatory Action:
Risk Assessment Type: Aggregate Risk Assessment
TXRNo.:NA
MRIDNo

. :NA Case No.: N A
CAS No.: 951659-40-8
40CFR:NA



### FROM: Kristin Rury, 

### Biologist 

# ¥-**~** Steve Funk, Sen i o r Chemist 

## ,.4

_**~** 

### Meheret Negussie

, Chemist

# ~ LAP

# ~(k{ Whang Phang, Senior Toxicologist 

# A

Vincent Chen, Toxicologist

- ""L.-

_ , ___ _,_ _ 

### Risk Assessment Branch III
Health Effects Division (7509P)



### THROUGH: Christine Olinger, Branch

# Chi~f W ._/ /

.. Risk Assessment Branch III

## ~ Healt h Effects Division (7509



### TO: Jessica Rogala, Risk Manager Reviewer

Insecticide Branch Registration Division (7505P)

Page 1 

### of116

### Table of Contents

1.0 Executive Summary

.............. .. ............. .. ................................ . ................ .. .. .. .. .. ... .. ............ 4
2.0 HED Recommendations

. .. . ......................................... . ... .. .. .. .. .. .................... . .............. . ... .. 7
2.1 Data Deficiencies

................. .. ..... .. ...... ... . .. .. .. ................. .. ................... .. .... . .. .. . ... ............. 7
2

. 2 Tolerance Considerations

.... . .... . ... . ................ .. .. .. .............. .. ................................... .. ... .. 7
2

. 2

. 1 Enforcement Analytical Me t hod

...... ... .. .. .. .. ..................................... ....... .. .. .. ... . ... .. .. ... .. 7
2.2.2 Recommended Tolerances

................. . ....................... . .. .. ... . .. . ... .. ....... . ........................... 8
2

. 2

. 3 Revisions to Petitioned

- For Tolerances

.......................................... .. ................ :

........ . 11


### 2.2.4 International Harmonization

................... . .............................. ... .............. .. ................. 14


### 2.3 Label Recommendations

.. . .................... . ...... .. .. .. .. .. .. .. .. . .... . .. . .......................... . ............ 14


### 2.3.1 Recommendat i ons from Residue Reviews

...................................... . .......... .. ...... .. .. .... 14


### 3.0 Introduction

.. .. .. . .................................... .. ... . ....... . .................... . ....... .. .. .. . . .. ... . ... . .... . ... .. ..... 1 5


### 3.1 Chemical Identity

.................................... .. ...... .. .. .. .. .. .. .. .. .. .. .. ...................................... . 15


### 3.2 Phys i cal/Chemical Characteristics

................................................................. .. .. .. .. .. .. 1 5


### 3.3 Pest i cide Use Pattern

.............................. .. .. .. .. .. .. .. .. .. .. .. .. .. ............................................ 16


### 3

. 4 Anticipated Exposure Pathways

.............................................. .. ................................. 21


### 3.5 Consideration of Environmental Justice

.................................. .. .. .. .. .. .. .. .......... .. ........ 22


### 4

. 0 Hazard Characterization and Dose-Response Assessment

............... . .......................... 22


### 4.1 Toxicology Studies Available for Analysis

.............. .. .. .. .. .. .......... .. .. .. .. .. .. .. ........ .. ...... . 22


### 4.2 Absorption, Distribution

, Metabolism, & 

### Elimination (ADME)

............................. 23
4

. 2

. 1 Dermal Absorption

.. .. ..... . ....... . .. . .................... . . . ............ . .. .. ....... . ... . .. .. .. .. ... . ... . ... .. ... . . . . .. 25
4.3 Tox i cological Effects

. ................................................................................................... 25
4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

............................... 27
4.4

. 1 Completeness of the Toxicology Database

................................................................. 27
4.4.2 Evidence of Neurotoxicity

..... .. .. .. .. .. . ... .. .... ........ .. . .. .. .. .. .. .. .. .. .. .. .. . .. .. .. .... . .. .. .. ... .. .. .. .. .. ... 27
4

. 4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

........... 27
4.4.4 Residual Uncertainty in the Exposure Database

.. .. .. .. .. .. ........................................... 28
4.5 Toxicity Endpo i nt and Point of Departure Selections

...................................... .. ...... 28
4

. 5.1 Dose-Response Assessment

...... .. ..... ... .......................................................................... 28
4.5

. 2 Recommendation for Combining Routes of Exposures for Risk Assessment

. ....... 28
4

. 5.3 Cancer Classification and Risk Assessment Recommendation

................................ 29
4

. 5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

........ . .. . ........................................ . ............................ .. .. .. .. .. .. .. .. .. ... . ...... .. .. .. .... . . .. .... 29

5.0 

### Dietary Exposure and Risk Assessment..

........ .. .................................................... .. .. .. .. . 30
5.1 Metabolite/Degradate Residue Profile

....................................................................... 30
5.1.1 Summary of Plant and Animal Metabolism Studies

.......................... .. ..................... 30
5 .1. 2 Summary of Environmental Degradation

................................................ .. .. .. .. .. .. .. .... 31


### 5

. 1.3 Compar i son of Metabolic Pathways

...................................................................... .. .. . 32
5. 1. 4 Residues of Concern Summary and Rationale

.. .. .. .. .. .. .. ...... .. .................................... 33
5.2 Food Residue Profile

............... .. .. .. ..... .. ......... ... ..................................... ... .. .. .. .. ........ . ... 35
5.3 Water Residue Profile

.. .. ........................................ .. ...... .. .. .. ...................................... .. 35
5.4 Dietary Risk Assessment

.... . .............................................................. ... .. .. ................... . 36
5.4. 1 Description of Residue Data Used in 

### Dietary Assessment..

.. .................................... 36
5.4

. 2 Percent Crop Treated Used in Dietary Assessment

............ .. .................. .. ................ 36

5.4.3 Acute Dietary Risk Assessment..

..................................... . ........................ .. .. .. ... .. .. .. .. .. 3 7

Page 2 of 116

### Page 3 of 116

5.4.4 Chronic Dietary Risk Assessment

................................ ................................ ............... 37
5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ................ 37
5.4.6 Summary Table

................................ ................................ ................................ ............ 37
6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 38
6.1 Residential Bystander Post

- application Inhalation Exposure

................................ . 38
6.2 Spray Drift

................................ ................................ ................................ .................... 39
7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .. 39
8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 39
9.0 Occupational Exposure/Risk Characterization

................................ ............................ 40
9.1 Short

- /Intermediate

- Term Occupational Handler Risk

................................ ........... 40
9.2 Short

- /Intermediate

- Term Post

- Application Risk

................................ .................... 41
9.2.1 Dermal Post

- application Risk

................................ ................................ ..................... 41
9.2.2 Inhalation Post

- application Risk

................................ ................................ ................. 42
10.0 References

................................ ................................ ................................ ......................... 43 Appendix A. Toxicology Profile and Executive Summaries

................................ .................. 45
A.1 Toxicology Data Requirements

................................ ................................ ................... 45
A.2 Toxicity Profiles

................................ ................................ ................................ ............ 46
A.3 Hazard Identification and Endpoint Selection

................................ .......................... 56
A.4 Executive Summaries

................................ ................................ ................................ ... 58
A.5 Flupyradifurone: Summary of NOAEL/LOAEL (with BW 3⁄4 

### scaling for human equivalent dose)

................................ ................................ ................................ ....................... 85 Appendix B. Metabolism Summary Table

................................ ................................ ............... 87 Appendix C. Physical/Chemical Properties and Metabolites

................................ ................ 87 Appendix D. Review of Human Research

................................ ................................ .............. 102 Appendix E. Qualitative Evaluation of DFA

................................ ................................ ......... 103 Appendix F. Occupational Exposure Tables

................................ ................................ ........ 106

### Page 4 of 116

1.0 Executive Summary

Flupyradifurone (BYI 02960) is a new butenolide insecticide currently undergoing global joint review (GJR) with Australia, Brazil, Canada, and Mexico. Butenol ide insecticides, like nicotine
and neonicotinoid insecticides , bind to nicotinic acetylcholine receptors (nAchR) . Once the flupyradifurone binds to the receptor, the receptor is blocked causing insect death.

Proposed Use Profile Bayer CropScience has proposed one technical and two end

- use product (EP) registrations: SivantoTM (EPA Reg. No. 264

- RRUR) and BYI 02960 480 FS (EPA Reg. No. 264

- RRUE)

.

SivantoTM may be applied at single application rates ranging from 7.0

– 28 fl oz/A (0. 091

– 0.365 lb ai/A), with a maximum seasonal application rate of 0.365 lb ai/A to the numerous proposed agricultural crops via ground, aerial, or chemigation equipment. The proposed SivantoTM label requires occupational handlers to wear the following pers onal protective equipment (PPE): long sleeved shirts, long pants, shoes, socks, and chemical resistant gloves. The proposed restricted entry interval (REI) is four hours.

BYI 02960 480 FS may be applied as a single seed treatment application at a rate of 0.045

– 0.068 mg ai/seed (0.00036

- 0.00054 lb ai/lb seed) . The soybean seeds are treated with standard slurry or mist commercial seed treatment equipment

. The proposed seed treatment label requires seed treaters and workers cleaning the treatment fac ilities to wear the following PPE: long sleeved shirts, long pants, shoes, socks, and chemical resistant gloves. Baggers and others involved in the packaging of treated seed are required to wear long sleeved shirts, long pants, shoes, and socks.

There are no proposed residential uses of flupyradifurone.

Exposure Profile There is potential for occupational short

- and intermediate

- term dermal and inhalation exposure

to flupyradifurone during mixing, loading, appl ying , and post

- application activities. There is also potential for acute and chronic exposure through food and drinking water from the proposed uses of flupyradifurone.

Toxicity/Hazard The most sensitive effects seen in the flupyradifurone database were skeletal muscle atrophy/degeneration in dogs. With repeated dosing, reductions in body weight and food consumption were commonly seen in various studies and in all species of test animal s (rats, mice, dogs

, and rabbits). The liver and thyroid were shown to be the common findings of flupyradifurone toxicity. The database appears to suggest that dogs are more sensitive to the effects of flupyradifurone; however, w ith body weight adjustmen ts ( based on a 3⁄4 scaling factor

– shown in Appendix A.5 ), the dog and rat are almost equally as sensitive in response to flupyradifurone toxicity. The skeletal muscle atrophy/degeneration seen in the 90

- day and one

year dog studies formed the basis for ch ronic dietary exposure and short

- and intermediate

- term occupational toxicity endpoints. The points of departure (PODs) were 7.8 mg/kg/day and 12 mg/kg/day for chronic dietary exposure and for short

- and intermediate

- term occupational

### Page 5 of 116

exposure assessments, respectively. The developmental toxicity study in rats demonstrated no evidence of susceptibility in developing animals. In the rabbit developmental toxicity study, there was an increase in the incidence of fetal death at 80 mg/kg/d ay (the highest dose tested), a dose that did not produce adverse effects in the maternal animals. Therefore, a quantitative increase in susceptibility was demonstrated in the rabbit developmental toxicity study. In the 2

- generation reproduction study in rats, decreased parental body weights ( > 10%) were seen at the LOAEL of 137 mg/kg/day (parental NOAEL = 37.8 mg/kg/day). In contrast, body weight
decreases that were considered adverse were seen in F 2 

### pups at 37.8 mg/kg/day (the parental
NOAEL and the of

fspring LOAEL; offspring NOAEL = 7.7 mg/kg/day). These findings suggest quantitative susceptibility for developing young animals. Although flupyradifurone produced quantitative susceptibility in rabbit developmental toxicity study and qualitative suscept ibility in the rat reproductive toxicity study, the PODs selected for risk assessment are protective of the effects seen in the developing fetuses and young animals. Therefore, there are no concerns for reproductive or developmental toxicity of flupyradif urone, and no concerns for increased susceptibility to the developing young. HED presently has sufficient information to evaluate the hazards associated with exposure to flupyradifurone at this time and the Food Quality Protection Act (FQPA) safety factor has been reduced to 1X. Flupyradifurone also produced clinical signs (piloerection and pupillary dilatation) indicative of neurotoxicity in the acute neurotoxicity study, and these clinical signs were used to establish the toxicity endpoint with a point of departure of 35 mg/kg for acute dietary exposure assessment. The exposure databases are complete or are estimated based on data that reasonably account for potential exposures.

Flupyradifurone is classified as “not likely to be carcinogenic to huma ns .” Flupyradifurone exhibits low acute mammalian toxicity via oral, dermal, and inhalation routes of exposure (Category III or IV for acute lethality and irritation studies) and is not a dermal irritant or
sensitizer. HED waived the requirement for the subchronic inhalation toxicity stud y (TXR#0056903).

Dietary Exposure (Food and Water) and Risk Estimates Unrefined acute and chronic dietary analyses were conducted for flupyradifurone; the assessments incorporated recommended tolerance

- level residues a nd default or empirical processing factors, conservative drinking water estimates, and assumed that 100% of the proposed crops were treated. The results of the acute and chronic analyses do not exceed the Agency’s level of concern (LOC) for the general U. S. population and all population subgroups.
At the 95 th 

### percentile of exposure, th e acute dietary (food and drinking water) risk estimates
utilized 24 % of the acute population adjust dose (a PAD ) for the general U.S. population and
utilized 3 8 % of the a PAD for children 1

- 2 years old , the most highly exposed population subgroup. The chronic dietary (food and drinking water) risk estimates utilized 39 % of the chronic population adjusted dose ( cPAD ) for the general U.S. population and utilized 84 % of the
cPAD for children 1

- 2 years old , the most highly exposed population subgroup.

Studies submitted in support of the registration of flupyradifurone indicate that there could be exposure to difluoroacetic acid (DFA) in drinking water and in food ( plants and animals)

. DFA was shown to be a mammalian metabolite with approximately 6% of flupyradifurone administered to rats being converted to DFA , and DFA was a metabolite in the ruminant and poultry metabolism studies. The most sensitive toxic effect s to be used in the risk assessment for

### Page 6 of 116

flupyradifurone would not be expected from DFA, which has a very different chemical structure. A range

- finding and subchronic toxicity study with DFA showed a similar potency to but
different toxic effects (black fo ci in the glandular part of the stomach) than the parent compound (skeletal muscle atrophy and degeneration in dogs, and decreased body weight and food consumption in rats, mice, dogs, and rabbits) , indicating that risk from DFA should be assessed
separate ly from the parent.

The Agency conducted a conservative screening

- level chronic dietary exposure evaluation to estimate risks from DFA. This evaluation assumed conservative drinking water concentrations,
that 100% of the crops contained DFA at median r esidue values . The screening exposure evaluation of DFA showed 5

- 7 X less exposure to DFA than to flupyradifurone. Therefore, since there is similar potency (albeit with different toxic effects) between flupyradifurone and DFA but less exposure expected t o DFA than flupyradifurone , the Agency has no additional risk concerns about exposure to DFA.

Aggregate Exposure Risk Estimates The only relevant aggregate risk assessments for flupyradifurone include acute and chronic exposure to residues in food and dri nking water. The acute and chronic dietary risk assessments for the U.S. population and all population subgroups do not exceed the Agency’s LOC (<100% PAD) , as described above

.

Occupational Risk
A short

- and intermediate

- term occupational risk assessment was performed for flupyradifurone use on the proposed crops and for the proposed seed treatment use. The LOC for occupational handler and post

- application risk is a margin of exposure (MOE) < 100. There are no occupational handler risk estimates of conc ern for the proposed uses of flupyradifurone a ssuming
baseline clothing ( i.e., no PPE) ; for the agricultural uses of flupyradifurone, the short

- and
intermediate

- term combined (dermal + inhalation) occupational handler MOEs ranged from 260 to 95,000 . With the addition of gloves, as required on the flupyradifurone label, the short

- and
intermediate

- term combined (dermal + inhalation) occupational handler MOEs ranged from 800

to 95 ,000. For the proposed seed treatment use of flupyradifurone, the combined (d ermal + inhalation) short

- and intermediate

- term MOEs ranged from 2,000 to 14,000.

The occupational short

- term post

- application risk estimates resulted in dermal MOEs of >170 on the day of application and w ere not of concern. Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation exposure assessment was not performed for flupyradifurone at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitat ive occupational post

- application inhalation exposure
assessment for flupyradifurone.

Review of Human Research This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or o ther chemical. These data, which include studies from Pesticide Handlers Exposure Database ( PHED 1.1 ) ; the Agricultural Handlers Exposure Task Force ( AHETF ) database; ExpoSAC Policy 14 , 15.1 (SOPs for Seed Treatment) and The Reviewer’s Aid to Calculating Occupational Exposure From Activities Related to Agricultural

### Page 7 of 116

Seed Treatment ; and the Agricultural Reentry Task Force ( ARTF ) database; are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applica ble ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. For citations of t hese data, see Appendix D.

Environmental Justice Potential areas of environmental justice concerns, to the e xtent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

2.0 HED Recommendations

Provided revised petition Sections B and F are submitted, there are no deficiencies that would preclude granting a Section 3 registration on the proposed crops. The specific tolerance recommendations are detailed in Section 2.2.2, and revisions to petitioned

- for tolerances are
discussed in Section 2.2.3.

2.1 Data Deficiencies

Guideline 875.2100

– Dislodgeable Foliar Residue D ata

Since the highest estimated occupational post

- application exposure using default dislodgeable foliar residue (DFR) values is not minimal in comparison to the level of concern (i.e., the calculated MOE is not greater than 2 times higher than the level of concern, MOE = 170 compared to the LOC of 100); t herefore, EPA is requiring the 40CFR DFR data requirement to facilitate any necessary exposure assessments refinements and to further EPA’s general understanding of the availability of dislodgeable foliar pesticide residues.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Only parent flupyradifurone is considered a residue of concern for tolerance enforcement of plants and livestock commodities.

An adequate analytical method (Method R V

- 001

- P10

- 03) which uses high performance liquid chromatography with tandem mass spectrometry ( HPLC/MS

- MS ) to quantitate residues of flupyradifurone in various crops is available for enforcement. T he validated limit of quantification ( LOQ ) is 0.01 mg/kg for flupyradifurone in most commodities

.

An HP LC/MS/MS method, Method RV

- 004

- A11

- 05 ( latest revision of the data collection
method RV

- 004

- A11

- 0 4), is adequate as the enforcement method for determination of residues
of flupyradifurone in li vestock commodities The validated LOQ for flupyradifurone is 0.01 mg/kg in all matrices

### Page 8 of 116

FDA multiresidue methods (MRMs) are suitable for flupyradifurone only in non

- fatty matrices

. The methods are not suitable for fatty matrices or matrices that require further clean

- up.

2.2. 2 Recommended Tolerances

HED has reviewed the available residue data and has determined the appropriate tolerance levels for residues of flupyradifurone (Table 2.2.2). The recommended tolerance expression is as
follows:

Tolerances are established for residues of the insecticide flupyradifurone, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only f lupyradifurone,
4

- [[(6

- chloro

- 3

- pyridinyl)methyl](2,2

- difluoroethyl)amino]

- 2(5H)

- furanone.

Table 2.2.2 . Tolerance Summary for Flupyradifurone Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition ) Aspirated grains
fractions 40 40 Grain, aspirated grain fractions

Root vegetables except sugar beets (Crop Subgroup 1B) 1.5 0.9 Vegetable, root, except sugar beet, subgroup 1B

Tuberous and corm vegetables (Crop Sub

Group 1C) 0.5 0.05 Vegetable, tuberous and corm, subgroup 1C

Crop subgroup 3

- 07A, onion, bulb, subgroup 0.3 0.09 Onion, bulb, subgroup 3

- 07A

Crop subgroup 3

- 07B, onion, green, subgroup 3 3.0 Onion, green, subgroup 3

- 07B

Leafy vegetable, except Brassica vegetables (Crop Group 4) 40 none Subgroup tolerances will be
recommended.

Leafy greens, subgroup

4A - 30 The residue range among the representative crops exceeds the suggested 5X (6

– 7 X), but use of the highest representative crop (spinach) tolerance estimate is protective.

Leaf petioles, subgroup

4B - 9.0

Taro, leaves 40 30 Translation from subgroup 4A.

Head and Stem Brassica (Crop Subgroup 5A) 6 6.0 Brassica , head and stem, subgroup 5A

Leafy Brassica Greens (Crop Subgroup 5B) 40 40 Brassica, leafy greens, subgroup
5B Turnip greens 40 40 Translation from leafy Brassica

greens

### Page 9 of 116

Table 2.2.2 . Tolerance Summary for Flupyradifurone Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition )

Edible

- podded legume vegetables (Crop Subgroup 6A) 5 3.0 Vegetable, legume, edible podded, subgroup 6A

Succulent, Shelled Pea and Bean (Crop Subgroup 6B) 4 None The residue range between the representative crops exceeds the suggested 5X by a substantial amount, 13X. Crop

- specific tolerances (pea, bean) are listed
below.
Pea, succulent

- 2.0 See 40CFR§180.1 Bean, succulent

- 0.2 See 40CFR§180.1 Dried, shelled pea and bean (except soybean) (crop subgroups 6c) 6 3.0 Pea and bean, dried shelled, except soybean, subgroup 6C

Foliage of legume vegetables, including soybeans (Crop Group 7, forage, green vines) 40 30 Vegetable, foliage of legume, group 7

Foliage of legume vegetables, including soybeans (Crop Group 7), Hay 50 None Only one tolerance is possible per crop group. The recommended 30 ppm covers vines, forage, and hay from pea, bean, and soybean. Soybean, seed 4 1.5 Fruiting vegetables, except cucurbits (Crop Group 8

- 10), fruit 3 1 .5 Vegetable, fruiting, group 8

- 10

Tomato, paste 4 None Covered by the fruiting vegetable group tolerance. Cucurbit vegetables (Crop Group 9), fruit 2 0.40 Vegetable, cucurbit, group 9

Citrus fruits (Crop Group 10

- 10), fruit 3 3.0 Fruit, citrus, group 10

- 10

Citrus, pulp, dried 15 10 Fruit, Citrus, dried pulp Orange HAFT X P f = 4.6 ppm X 1.77 = 8.14 ppm Pome fruits (Crop Group 11

- 10), fruit 1.5 0.70 Fruit, pome, group 11

- 10

Bushberry group (Crop Subgroup 13

- 07B)

, except cranberry 4 4.0 Bushberry

, except cranberry, subgroup 13

- 07B

Small fruit vine climbing subgroup, except fuzzy kiwifruit (Crop Subgroup 13

- 07F) 3 3.0 Fruit, small vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F

Grapes, raisin 6 5.0 Grape, raisin

Grape HAFT X P f = 1.90 ppm X 2.5 = 4.75 ppm

### Page 10 of 116

Table 2.2.2 . Tolerance Summary for Flupyradifurone Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition ) Low growing berry subgroup (Crop Subgroup 13

- 07G)

, except cranberry 1.5 1.5 Berry, low growing, except cranberry, subgroup 13

- 07G

Tree nuts (Crop Group 14), nutmeat 0.15 0.02 Nut, tree, group 14

- 12

Pistachio 0.15 None Pistachio is included in the tree nut group 14

- 12. Tree nuts (Crop Group 14), hulls 15 15 Almond, hulls

Grain, cereal, group 15, except rice; grain 4 3.0 Grain, cereal, group 15, except
rice and corn Pop corn, grain

- 0.05 Corn, pop, grain Field corn, grain

- 0.05 Corn, field, grain Sweet corn, kernels plus cobs with husks removed (K+CWHR) 0.4 0.05 Corn, sweet, kernel plus cob with
husks removed

Wheat, bran 5 None Wheat bran is covered by the cereal grain group 15 tolerance. Rice, grain (rotational crop) 4 None No supporting data.

Grain, cereal, forage, fodder and straw, Group 16, forage 20 30 Grain, cereal, forage, fodder and straw, group 16

Grain, cereal, forage, fodder and straw, Group 16, hay 40 None Only one tolerance is possible per crop group. The recommended 30 ppm covers hay, forage, fodder, straw, and stover of all cereal grains. The proposed 40 ppm for hay included residues from DFA, not part of the recommended definition. Grain, cereal, forage, fodder and straw, Group 16, straw 30 None

Grain, cereal, forage, fodder and straw, Group 16, stover 15 None

Cotton, undelinted seed, Crop Subgroup
20C 0.9 0.80 Cottonseed subgroup 20C

Cotton, gin by

- products 40 40 Cotton, gin byproducts Nongrass animal feeds, forage, Crop Group 18 20 None Inadequate number of trials for the representative commodity clover. Separate tolerances for clover with regional registration and alfalfa are listed elsewhere in
this table. Alfalfa, forage

- 9.0 Alfalfa, hay

- 20 Nongrass animal feeds, hay, crop group 18 40 None Inadequate number of trials for the representative commodity clover. Separate tolerances for clover with regional registration and alfalfa are listed elsewhere in
this table.

### Page 11 of 116

Table 2.2.2 . Tolerance Summary for Flupyradifurone Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition ) Coffee, bean, green 1 2 1.5 Coffee, green bean
Coffee, bean, roasted;
instant 3 None Covered by the coffee bean
tolerance. Hops 20 10 Hop, dried cones Peanut, hay 30 20
Peanut, nutmeat 0.15 0.04 Peanut Prickly pear cactus,
fruit 0.5 0.30 Cactus, fruit

Pitaya, fruit 0.5 0.30 Pitaya Translation from prickly pear cactus fruit. Prickly pear cactus, pads 0.9 0.70 Cactus, pads

Cattle, fat 0.2 0.20 Cattle, meat 0.2 0.30 Cattle, meat byproducts 0.7 1.0 Goat, fat 0.2 0.20
Goat, meat 0.2 0.30 Goat, meat byproducts 0.7 1.0 Hog, fat 0.2 0.01 Hog, meat 0.2 0.01 Hog, meat byproducts 0.7 0.04 Horse, fat 0.2 0.20
Horse, meat 0.2 0.30 Horse, meat byproducts 0.7 1.0

Milk 0.3 0.15 Poultry, eggs 0.3 0.01 Egg Poultry, meat 0.4 None No reasonable expectation of
residues Poultry, meat byproducts 0.5 None No reasonable expectation of
residues Sheep, fat 0.2 0.20 Sheep, meat 0.2 0.30 Sheep, meat byproducts 0.7 1.0

Tolerance with Regional Registration Clover, forage

- 20 Use limited to Oregon, Idaho, Washington Clover, hay

- 30 Use limited to Oregon, Idaho, Washington

1 There is no US registration.



### 2.2. 3 Revisions to Petitioned

- For Tolerances

The Petitioner requested a definition for enforcement of tolerance as the sum of flupyradifurone
and difluoro acetic acid ( DFA ) and 4

- [(2,2

- difluoroethyl)amino]furan

- 2(5 H )

- one (DFEAF), expressed as flupyradifurone

, which significantly inflated the field trial residue values and resulted in higher tolerance values. EPA, consistent with its global review partners , has selected

### Page 12 of 116

parent fl upyradifurone only as the residue definition for tolerance enforcement. Flupyradifurone is the major portion of the residue in plant commodities and in some livestock commodities. In other livestock commodities, it is present at the same approximate conce ntration as some metabolites. Moreover, the significant metabolite difluoroacetic acid (DFA) is not suitable for enforcement purposes, as its concentration is erratic with time. The harmonized enforcement definition, flupyradifurone only, will facilitat e trade and is predicted to be the residue definition adopted by Codex in the future based on application of their policy. Therefore, EPA is reducing the tolerance values for the petitioned

- for tolerances for the following commodity groups/subgroups or co mmodities: cattle, goat, hog, horse, and sheep meat and meat byproducts; hog fat; milk; poultry eggs; root vegetables subgroup 1B; tuberous and corm vegetables subgroup 1C; bulb onion subgroup 3

- 07A; leafy vegetable group 4; legume vegetables subgroup 6A, 6B,6C; soybean; foliage of legume vegetables group 7; fruiting vegetables group 8

- 10; cucurbit vegetables group 9; citrus pulp; pome fruits group 11

- 10; grape raisins; bushberry subgroup 13B except lowbush blueberry; tree nut group 14; cereal grain group 15 except rice and except corn; sweet corn, cereal grain forage, fodder, and straw group 16; nongrass animal feeds crop group 18; cotton undelinted seed; coffee bean; hops; peanut hay; peanut; prickly pear cactus fruit and pad.

The petition requested a to lerance for root vegetables, except sugar beets subgroup 1B at 1.5 ppm. The ratio of highest average field trials (HAFTs) of the representative commodities (carrot/radish, 0.603/0.046 ppm) was 13, but the ratio of the median residue value was 1.8. The

sma ll median ratio indicates that the central tendency of both carrot and radish residue values are similar and that a single tolerance would be appropriate for the subgroup, represented by carrot and radish. The higher tolerance estimate from carrot (0.90 ppm) will cover all members of the subgroup.

The petition requested a tolerance for the leafy vegetable, except brassica vegetables, group 4 at 40 ppm. Based on the available residue data, EPA is establishing separate tolerances for each of the subgrou ps of group 4, instead of a single tolerance for the whole group. For subgroup 4A (leafy greens), EPA is establishing a tolerance at 30 ppm, based on the highest residues, which were found on the representative crop spinach. For subgroup 4B (leafy petiol es), EPA is establishing a separate tolerance at 9.0 ppm based on the celery residues. The leafy greens subgroup tolerance was translated to cover taro leaves; therefore, EPA is establishing a tolerance for taro leaves at 30 ppm, rather than the 40 ppm req uested.

The petitioned

- for tolerance for the shelled pea and bean subgroup 6B at 4 ppm was not possible because the residues on the garden pea and lima bean were substantially different. Residues differ by more than 5X between succulent peas and succulent beans. In accordance with 40 CFR 180.40(g), a subgroup tolerance is not normally appropriate; rather, EPA may establish individual crop tolerances. Therefore, EPA is establishing individual tolerances for succulent peas and succulent beans.

The petition requ ested a tolerance for cereal grains, grain, group 15 except rice at 4 ppm. The residues on sweet corn and field corn grain were much lower than those on sorghum, wheat, and barley grains; therefore, EPA is excluding corn (field corn, popcorn, and sweet cor n) grain from that group 15 tolerance, as well as rice. Based on available residue data, EPA is establishing

### Page 13 of 116

separate tolerances for popcorn, grain, field corn, grain, and sweet corn (kernels plus cobs with husks removed) at 0. 0 5 ppm. Under 180.40(h), EP A may exclude some commodities from a group tolerance where the residue levels are significantly higher or lower than the other commodities in the group. Corn, unlike the other cereal grains, has a protective husk and this
difference is often reflected in lower residues for late season foliar applications. Therefore, EPA is excluding corn grain and rice from the crop group 15 tolerance and establishing separate tolerances for corn. The remaining cereal grains, represented by grain sorghum, barley, and
whe at, are quite similar.

The petition requested a tolerance on nongrass animal feeds group 18, forage at 20 ppm and hay at 40 ppm. EPA is unable to establish group 18 tolerances at this time for forage and hay because data from only four field trials on cl over (one of the representative crops) were available. Based on the available data, EPA is establishing tolerances for alfa l fa and regional tolerances for clover (since use on clover is restricted to Washington, Oregon, and Idaho, the
area where the field trials were conducted). A group tolerance could be considered if additional field trials for clover from diverse areas of the US were supplied.

The petition requested a tolerance for rice grain at 4 ppm as a rotational crop. EPA cannot
establish this t olerance at this time because no data were provided to support this request. Rice field trial data are required to establish a tolerance.

The proposed wheat bran tolerance of 5 ppm is not necessary. The cereal grain group tolerance
covers wheat bran. The highest average field trial (HAFT) residue for wheat grain was 0.73 ppm and the experimentally determined processing factor for the conversion of grain to bran was 2.4. Therefore, the tolerance estimate for wheat bran is 1.8 ppm (0.73 X 2.4). As 1.8 ppm is less than the 3 ppm cereal group tolerance, a separate tolerance for wheat bran is not needed.

EPA was petitioned for tolerances on tree nut group 14 and pistachio. In the Federal Register of August 22, 2012 (77 FR 50617) (FRL

– 9354

– 3), EPA issue d a final rule that revised the crop grouping regulations. As part of this action, EPA expanded and revised the existing tree nut group 14. Changes to crop group 14 included adding the specialty commodities African nut tree, Brazilian pine, Bunya, Bur oak

, Cajou nut, Candlenut, C oconut, Coquito nut, Dika nut, Ginkgo, Guiana chestnut, Heartnut, Japanese horse

- chestnut, Mongongo nut, Monkey

- pot, Monkey puzzle nut, Okari nut, Pachira nut, Peach palm nut, P equi, Pili nut, Pine nut, Pistachio, Tropical almond and Yellowhorn including cultivars, varieties, and/or hybrids of these; and naming the new crop group tree nut group 14

– 12. EPA indicated in the August 22, 2012 final rule as well as the earlier November 9, 2011 proposed rule (76 FR 69693) (FRL

– 8887

– 8) tha t, for petitions for which a Notice of Filing had been published, the Agency would attempt to conform these petitions to the rule. Therefore, consistent with this rule, EPA has assessed exposure to the, insecticide flupyradifurone, assuming use under the r evised tree nut group 14

- 12. Because revising the requested crop group to the updated crop group did not result in a risk of concern, EPA is establishing tolerances for flupyradifurone residues on tree nut group 14

– 12.

Cranberry was removed from subgroup s 13

- 07B and 13

- 07G at the request of the petitioner as a modification to the original request.

### Page 14 of 116

Tolerances are not needed for the processed commodities tomato paste, roasted coffee, and
instant coffee. The recommended tolerances for the raw agricultural commodities, tomato and green coffee bean cover the respective processed commodities. The highest average field trial (HAFT) result for coffee was 0.55 ppm, and the processing factors for roasted coffee and instant coffee were 0.59 and 1.9, r espectively. Tolerance estimate (HAFT X processing factor; 0.55X0.59 = 0.32 ppm roasted bean; 0.55X1.9=1.0 ppm instant coffee) are less than the recommended green coffee bean tolerance (1.5 ppm). The HAFT for the tomato field trials was 0.57 ppm and the processing factor for conversion to paste was 2.0, and the product (0.57X2.0) is less than the recommended fruiting vegetable group tolerance (1.5 ppm).

Tolerances are not required for poultry meat and poultry meat byproducts, as the projected diet for po ultry and the results of the poultry feeding study indicate that residues are not likely in poultry meat and poultry meat byproducts.

2.2. 4 International Harmonization

Flupyradifurone has not been considered by the Codex system, and therefore there are n o harmonization issues. The active global review participants, Australia, Canada, and the US, are working together to harmonize MRLs wherever possible. All plant commodity tolerances are harmonized. The livestock commodity tolerances for ruminant commodi ties are not harmonized with Canada, with US tolerance being approximately twice the corresponding Canadian tolerances. This is a direct result of the different diets (exposures) determined by Canada and the US. Canada does not consider forage and fodder crops that are not native to Canada. The US and Canada tolerances for eggs are harmonized. Canada will establish default tolerances for poultry meat and meat by

- products at the LOQ. The US will establish no poultry tolerances as
there is no reasonable expectation of residues. A comparison of specific tolerances/MRLs is provided in HED’s summary of flupyradifurone residue data (S. Funk, 02/17/2014, D415670).

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

The proposed label pre

- harvest interval (PHI) for prickly pear is 14 days, but the crop trials were
conducted with a 21

- day PHI. The label PHI must be changed to 21 days.

The proposed label specifies use on members of the non

- grass animal feeds crop gr oup 18 with use on clover limited to Washington, Idaho, and Oregon. However, clover and alfalfa are the representative commodities of this group, and there are an inadequate number of clover trials. Therefore, the label must be amended to allow use on al falfa (nationally) and clover in Washington, Idaho, and Oregon. Uses on crop group 18 must be removed from the label.

A rotational crop interval of 30 days for rice is not adequately supported. The rotational field trials conducted in Europe at 50% of th e seasonal rate shows no residues on barley grain at a 30 day PBI. However, the residue level at a 100% seasonal rate cannot be predicted. Since the use on rice is not supported by adequate rotational crop data and cereal grain primary trials cannot be

u sed to establish a rice tolerance (see 2.2.3), rice falls under the crops not on the label and for

### Page 15 of 116

which no tolerances exist; therefore, the appropriate interval is 12

- months. The exception for
rice must be removed from the label.

The label must be amend ed to indicate that uses in greenhouses are not allowed because supporting field trial studies for greenhouse uses were not submitted

.

The proposed label specifies use on members of crop subgroup 1B (root vegetables). However, a crop subgroup tolerance c ould not be recommended. Therefore, the label must be amended to indicate use on carrot and radish only.

3.0 Introduction

Flupyradifurone is a member of the butenolide class of chemistry effective against a broad range of sucking insects. It has a simi lar insecticidal mode of action to neonicotinoids. Flupyradifurone is formulated into two systemic insecticide product s : Sivanto 200 SL is for soil and foliar applications intended for the control of aphids, whiteflies, leafhoppers and other
insects infes ting many fruit, vegetable, plantation, row and specialty crops ; and BYI 02960 480
FS is for soybean seed treatment. After uptake into the plant via the roots or translaminarly through leaf tissue, flupyradifurone is translocated acropetally in the xylem, in the direction of the transpiration stream and is distributed into plant cells.

3.1 Chemical Identity

Table 3.1. Flupyradifurone Nomenclature.
Compound

C 12 H 11 ClF 2 N 2 O 2 Chemical Structure

Common name Flupyradifurone Company experimental name BYI 02960

IUPAC name 4

- [(6

- chloro

- 3

- pyridylmethyl)(2,2

- difluoroethyl)amino]furan

- 2(5 H )

- one CAS name 4

- [[(6

- chloro

- 3

- pyridinyl)methyl](2,2

- difluoroethyl)amino]

- 2(5 H )

- furanone

CAS # 951659

- 40

- 8

End

- use product/EP SivantoTM 200SL (1.67 lbs ai /gallon or 200 g ai /l soluble concentrate) BYI 02960 480 FS (4 lbs ai /gallon or 480 g ai /l flowable concentrate for seed treatment)



### 3.2 Physical/Chemical Characteristics

Flupyradifurone has substantial solubility in both organic solvents and water and a low octanol/water partition coefficient, and therefore is predicted to show no strong preference for fat

### Page 16 of 116

versus muscle or for cream versus skim milk/whey. It has a low vap or pressure and not expected
to volatilize.

3.3 Pesticide Use Pattern

Table 3.3.1. Proposed Use Pattern for Flupyradifurone

Applic. Type Applic.

Rate (lb ai /A) Max.

No. Applic.

per Season Max.

Seasonal Applic. Rate (lb ai /A) PHI

(days) Use Directions and

Limitations

BYI 02960 480 FS (4 lbs ai /gallon) Soybean

Seed treatment 0.045

– 0.068

mg ai/seed,
30

– 45 g
ai/100 kg,
or 0.027 1 1 0.365

(from uses,
seed

treatment and foliar) N/A Use only as a commercial

water

- based slurry. All
seeds treated must be
colored with an EPA

approved dye or colorant.
Treated seeds must be
labeled in accordance with the requirements of the
Federal Seed Act. SivantoTM 200 SL (1.67 lbs ai /gallon)

Cereal Grains (except rice)

Foliar 0.183

- 0.365 7 sweet corn 7 forage 21 grain
21 straw
21 stover Minimum retreatment

interval 7 days. Minimum spray volume 10 gallons/acre for ground and 2 gallons/acre for
aerial.

Cotton

Foliar 0.183

- 0.365 14 Minimum retreatment interval 10 days. Minimum spray volume 10 gallons/acre for ground and 2 gallons/acre for
aerial.

Non

- Grass Animal Feeds (Crop Group 18 including alfalfa, clover, crown vetch, kudzu, lespedeza, lupin, milk vetch, sainfoin, trefoil, velvet bean, vetch)

Foliar 0.183

- 0.365 7 forage, silage, hay,
or seed of alfalfa, lespedeza,
sainfoin
14 all other Minimum retreatment

interval 10 days. Minimum spray volume 10 gallons/acre for ground and 2 gallons/acre for
aerial. Use on clover is limited to Idaho, Washington, and Oregon.

Peanut

Foliar 0.183

- 0.365 7 Minimum retreatment interval 10 days. Minimum spray volume 10 gallons/acre for ground

### Page 17 of 116

Table 3.3.1. Proposed Use Pattern for Flupyradifurone

Applic. Type Applic.

Rate (lb ai /A) Max.

No. Applic.

per Season Max.

Seasonal Applic. Rate (lb ai /A) PHI

(days) Use Directions and

Limitations

and 2 gallons/acre for
aerial. Root Vegetables (except sugar beet) (crop group 1B including garden beet, carrot, celeriac, chervil, chicory, ginseng, horseradish , parsley (turnip

- rooted), radish, oriental radish, rutabaga, salsify, skirret, turnip)

Foliar 0.183

- 0.365 7 Minimum retreatment interval 10 days. Minimum spray volume 10 gallons/acre for ground and 2 gallons/acre for
aerial.

Tuberous and Corm Vegetables (crop group 1C including Arracacha, Arrowroot, Artichoke (Chinese and Jerusalem), Canna (edible), Cassava (bitter and sweet), Chayote (root) , Chufa, Dasheen (taro), Ginger, Leren, Potato, Sweet potato, Tanier (cocoyam), Turmeric, Yam bean (jicama, manoic pea), Yam (true)

Foliar 0.183

- 0.365 7 Minimum retreatment interval 7 days. Minimum spray volume 10 gallons/acre for ground and 2 gallons/acre for
aerial. Leafy Vegetables (except Brassica ) (crop group 4 including Amaranth (leafy amarant h, Chinese spinach, tampala), Arugula (Roquette), Cardoon, Celery, Celtuce, Chervil, Chinese celery, Chrysanthemum (edible

leaved and garland), Corn salad, Cress (garden), Cress (upland, yellow rocket, winter cress), Dandelion, Dock (sorrel), Endive, Flore nce fennel (sweet anise, sweet fennel, Finocchio), Lettuce (head and leaf), Orach, Parsley, Purslane (garden and winter), Radicchio (red chicory), Rhubarb, Spinach [including New Zealand and vine (Malabar spinach, Indian spinach)], Swiss chard, Taro leaves

Foliar 0.183

- 0.365 1 Minimum retreatment interval 7 days. Minimum spray volume 10 gallons/acre for ground and 2 gallons/acre for
aerial.

Brassica (Cole) Leafy Vegetables (crop group 5 including Broccoli, Broccoli Raab ( rapini ), Brussels sprouts, Cabbage, Cauliflower, Cavalo broccolo, Chinese broccoli ( gai lon ), Chinese cabbage ( bok choy ), Chinese cabbage ( napa ), Chinese mustard cabbage ( gai choy ), Collards, Kale, Kohlrabi, Mizuna, Mustard greens, Mustard spinach, Rape greens ) and Turnip Greens

Foliar 0.183

- 0.365 1 Minimum retreatment interval 7 days. Minimum spray volume 10 gallons/acre for ground and 2 gallons/acre for
aerial. Legume Vegetables (succulent or dried) (crop group 6 including Edible Podded and Succulent Shelled Pea and
Bean and Dried Shelled Pea and Bean ( Lupinus spp., including grain lupin, sweet lupin, white lupin, and white sweet lupin) Bean ( Phaseolus spp., including field bean, kidney bean, lima bean, navy bean, pinto bean, runner bean, snap bean, tepary bean, wax bean) Bean ( Vigna spp., including adzuki bean, asparagus bean, blackeyed pea, catjang, Chinese longbean, cowpea, Crowder pea, moth bean, mung bean, rice bean, Southern pea, urd bean, yardlong bean) Pea ( Pisum spp. including dwarf pea, edible

- pod pea, English pea, fi eld pea, garden pea, green pea, snow pea, sugar snap pea) Other Beans and Peas (Broad bean (fava bean), Chickpea (garbanzo bean), Guar, Jackbean, Lablab bean (hyacinth bean), Lentil, Pigeon pea, soybean (immature seed), Sword bean , soybean )

### Page 18 of 116

Table 3.3.1. Proposed Use Pattern for Flupyradifurone

Applic. Type Applic.

Rate (lb ai /A) Max.

No. Applic.

per Season Max.

Seasonal Applic. Rate (lb ai /A) PHI

(days) Use Directions and

Limitations

Foliar 0.183

- 0.365 7 forage
7 leaves
7 vines 7 pods 7 hay 7 seed (fresh or dry, except soybean) 21 dry soybean seed Minimum retreatment

interval 7 days. Minimum spray volume 10 gallons/acre for ground and 2 gallons/acre for
aerial.

Fruiting Vegetables (crop group 8

- 10 including Cocona, Eggplant (including: African, Pea and Scarlet eggplants), Garden huckleberry, Goji berry, Groundcherry, Martynia, Naranjilla, Okra, Pepino, Pepper (including all peppers i.e. bell, non

- bell, hot, sweet, etc.), Roselle, Su nberry, Tomatillo, Tomato (including: Bush, Currant, Tree) including cultivars, varieties and/or hybrids of these commodities)

Foliar 0.183

-

0.365 1 Minimum retreatment interval 10 days. Minimum spray volume 10 gallons/acre for ground and 2 gallons/acre for
aerial.

Soil 0.365 1 45 The following methods of application may be used: 1. chemigation into root

zone through low

- pressure drip, trickle, micro

sprinkler or equivalent equipment; 2. injection below the
eventual seed

- line prior to planting. Place pesticide 3

- 4 inches below seed

- line; 3. potting hole drench at transplanting; or 4. post

- transplant drench following setting and covering. Cucurbit Vegetables (crop group 8 including Chayote (fruit), Chinese waxgourd (Chinese preserving melon),
Citron melon, Cucumber, Gherkin, Gourd (edible, includes hyotan, cucuzza, hechima, Chinese okra),
Momordica spp. (includes balsam apple, balsam pear, bitter melon, Chinese cucumber), Muskmelon (hybrids
and/or cultivars of Cucumis melo including true cantaloupe, c antaloupe, casaba, Crenshaw melon, golden pershaw melon, honeydew melon, honey balls, mango melon, Persian melon, pineapple melon, Santa Claus melon, snake melon), Pumpkin, Squash (includes summer squash types such as: crookneck squash, scallop squash, str aightneck squash, vegetable marrow, zucchini, and winter squash types such as acorn squash, butternut squash, calabaza, cushaw, Hubbard squash, spaghetti squash), Watermelon (includes hybrids and/or
varieties of Citrullus lanatus )

Foliar 0.183

- 0.365 1 Minimum retreatment interval 7 days. Minimum spray volume 10 gallons/acre for ground

### Page 19 of 116

Table 3.3.1. Proposed Use Pattern for Flupyradifurone

Applic. Type Applic.

Rate (lb ai /A) Max.

No. Applic.

per Season Max.

Seasonal Applic. Rate (lb ai /A) PHI

(days) Use Directions and

Limitations

and 2 gallons/acre for
aerial.

Soil 0.365 1 21 The following methods of application may be used: 1. chemigation into root

zone through low

- pressure drip, trickle, micr o

sprinkler or equivalent equipment; 2. injection below the
eventual seed

- line prior to planting. Place pesticide 3

- 4 inches below seed

- line; 3. potting hole drench at transplanting; or 4. post

- transplant drench following setting and covering. Hops

Foliar 0.137 1 0.137 21 Minimum spray volume 25gallons/acre for ground and 10gallons/acre for
aerial.

Citrus Fruit (crop group 10

- 10 including Calamondin, Citrus citron, Citrus hybrids ( Citrus spp., Eremocitrus

spp., Fortunella spp. , Microcitrus spp., and Poncirus spp.), Grapefruit (including Japanese summer), Kumquat, Lemon, Lime, Lime (Sweet, Australian desert, Australian finger, Australian round, Brown River finger, Mount White, New Guinea wild, Russell River, Tahiti), Mandarin (Mediterranean, Satsuma), Orange (sour, sweet, Tachibana, Trifoliate), Pummelo, Tangelo, Tangerine [includes Tangerine (mandarin or mandarin orange), Clementine, Mediterranean mandarin, Satsuma mandarin, Tangelo, Tangor, cultivars and varieties], Tangor, Uniq fruit, and cultivars, varieties and/or hybrids of these commodities )

.

Foliar 0.183

-

0.365 1 Minimum retreatment interval 10 days. Minimum spray volume 2.5 gallons/acre for ground and 2 gallons/acre for
aerial. 2

Soil 0.365 1 30 Pesticide may be applied by the following methods:
1. chemigation into root

zone through low

- pressure drip, trickle, micro

sprinkler or equivalent equipment; or
2. basal drench in
sufficient water to move pesticide into root

- zone. Pome Fruit (crop group 11

- 10 including Apple, Azarole, Crabapples (Chinese apple, Chinese crab apple, Chinese flowering apple, Crab apple, Cutleaf crab apple, Florentine crab apple, Hall crab apple, Iowa crab apple, Japanese crab apple, Kai do crab apple, Manchurian crab apple, Paradise apple, Sargent's crab a pple, Siberian

### Page 20 of 116

Table 3.3.1. Proposed Use Pattern for Flupyradifurone

Applic. Type Applic.

Rate (lb ai /A) Max.

No. Applic.

per Season Max.

Seasonal Applic. Rate (lb ai /A) PHI

(days) Use Directions and

Limitations

crab apple, Soulard crab apple, Southern crab apple, Sweetcrab apple, Tea crab apple, Toringa crab apple, Western Crabapple, Yunnan crab apple, and varieties and/or hybrids of these), Loquat, Mayhaw, Medlar, Pear, Asian pear, Quince, Chinese quince, Japanese quince, Tejocote, and cultivars, varieties and/or hybrids of these )

.

Foliar 0.183

- 0.365 14 Minimum retreatment interval 10 days. Minimum spray volume 25 gallons/acre for ground and 10 gallons/acre for
aerial. Bush Berry (crop subgroup 13

- 07B , except cranberry, including Aronia berry, Blueberry ( Vaccinium spp.

– highbush, lowbush and cultivars and/or hybrids of these [= all blueberry species]), Chilean guava, Currant (black, buffalo, native and red), Elderberry, European barberry, Gooseberry ( Ribes spp.), Honeysuckle (edible), Huckleberry, Jostaberry, Juneberry, Lingonberry, Salal, Sea buckthorn, and cultivars, varieties and/or hybrids of
these ).

Foliar 0.183

- 0.365 3 Minimum retreatment interval 7 days. Minimum

spray volume 25 gallons/acre for ground and 2 gallons/acre for
aerial. Low Growing Berry (crop subgroup 13

- 07G , except cranberry, including Bearberry, Bilberry, Blueberry (lowbush), Cloudberry, Lingonberry, Muntries, Partridgeberry, Strawberry, plus cultivars, varieties and/or hybrids of these .)

Foliar 0.183

- 0.365 0 Minimum retreatment interval 10 days. Minimum spray volume 10 gallons/acre for ground and 2 gallons/acre for
aerial. Small Fruit Vine Climbing (except Fuzzy Kiwifruit) (crop subgroup 13

- 07F inclu ding Amur river grape, Gooseberry ( Ribes spp.), Grape, Kiwifruit (hardy, only), Maypop, Schisandra berry, and cultivars, varieties and/or hybrids of these

Foliar 0.183

-

0.365 0 Minimum retreatment interval 10 days. Minimum spray volume 25 gallons/acre for ground and 10 gallons/acre for
aerial.

Soil 0.365 1 30 Pesticide may be applied by the following methods: 1. chemigation into root

zone through low

- pressure drip, trickle, micro

sprinkler or equivalent equipment; or
2. basal drench in
sufficient water to move pesticide into root

- zone.

### Page 21 of 116

Table 3.3.1. Proposed Use Pattern for Flupyradifurone

Applic. Type Applic.

Rate (lb ai /A) Max.

No. Applic.

per Season Max.

Seasonal Applic. Rate (lb ai /A) PHI

(days) Use Directions and

Limitations

Tree Nut (crop group 14 including Beech nut, Brazil nut, Butternut, Cashew, Chestnut, Chinquapin, Hazelnut (filbert), Hickory nut, Macadamia nut (bush nut), Pecan, Pistachio, Walnut [in cluding black and English (Persian) walnuts] ), excluding almond.

Foliar 0.183

- 0.365 7 Minimum retreatment interval 14 days. Minimum spray volume 75 gallons/acre for ground. Do NOT apply by aerial application.

Cotton

Foliar 0.183

- 0.365 14 Minimum retreatment interval 10 days. Minimum spray volume 10 gallons/acre for ground, 2 gallons/acre for aerial. Prickly Pear /Cactus Pear ( opuntia spp .), Pitaya

Foliar 0.183

- 0.365 14 Minimum retreatment interval 7 days. Minimum spray volume 75 gallons/acre for ground. Do NOT apply by aerial application.

Coffee Beans (Import from Central America (Guatemala, Mexico) and Brazil) 3

Drench + Foliar 0.535

+ 0.178 1

+ 3 1.07 0 The minimum retreatment
interval for foliar application is 15 days. Application to soil should be October to February,
when the soil is the

wettest. Rotational Crops Crop Type Rotational Interval (days)

On

- label 0

With tolerance 4 0 Sugarcane (Florida) 14

Rice (white and wild) 30

All others 360

1 For a seeding rate of 60 lbs/acre (ExpoSAC SOP15, 03/02/2004)

2 Minimum application volumes are for control of Asian citrus psyllid control in Florida only. For control or suppression of ot her pests, application volumes should be increased to provide thorough and complete coverage to obtain adequate control.

3 Requisite translated label from Brazil was provided (MRID 48844205)

4 Crop Group 3 has a recommended tolerance, but not a use on the prop osed label.



### 3.4 Anticipated Exposure Pathways

Humans may be exposed to flupyradifurone in food and drinking water since flupyradifurone may be applied directly to growing crops and application may result in flupyradifurone reaching

### Page 22 of 116

surface and ground sou rces of drinking water. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, during seed treatment, as well as during application. There is also a potential for post

- application exposure for workers re

entering treated fields.

This is the first risk assessment prepared for the proposed uses of flupyradifurone. This risk assessment considers all of the exposure pathways based on the proposed new uses of flupyradifurone.

3.5 Consideration of Environm ental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Lo w

- Income Populations," http://www.epa.gov/environmentaljustice/resources/policy/exec_order_12898.pdf

. As a part of every pesticide risk assessment, O PP considers a large variety of consumer subgroups according
to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water

consump tion, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic

group. Additionally, OPP is able to assess dietary exposure t o smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for childr en 1

- 2 years , youths , and adults entering or playing on treated
areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models
th at consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

Flupyradifurone is a member of the butenolide class of chemicals, which the Registrant claims to
have a pesticidal mode of action similar to neonicotinoids , acting on the nicotinic acetylcholine receptor (nAchR). Analogous to neonicotinoids, flupyradifurone is thought to bind and stimulate insect nAchRs, leading to paralysis and death. The effects seen in the acute neurotoxicity study are likely related to stimulation of the nAchRs, however there is limited additional evidence in mammalian studies that the pesticidal mode of action is important to mammals.

4.1 Toxicology Studies Available for Analysis

All the required toxicity studies on f lupyradifurone have been submitted to support proposed
food

- use registrations

. The toxicology database is acceptable for characterizing flupyradifurone
hazard and includes 28

- day oral, 90

- day oral, and 28

- day dermal studies in rats; 28

- day oral and

### Page 23 of 116

90

- d ay oral toxicity studies in mice; 28

- d ay

- oral and 90

- day oral toxicity studies in dogs; a 1

- y ear dietary study in d ogs; a c arcinogenicity study in m ice ; a 2

- year dietary c ombined

c hronic/ c arcinogenicity in r ats ; developmental toxicity studies in rats and ra bbits; a 2

- gene ration

r eproduction study in rats; acute and subchronic neurotoxicity studies in rats; a developmental neurotoxicity study in rats; m utagenicity and g enotoxicity studies in b acterial & m ammalian

m odel s ystems ; 28

- day dietary immunotoxicity studies in r ats ; m etabolism and p harmacokinetic

s tudies in rats with 3 different 14 

### C

- label in g positions on flupyradifurone; and in vivo and in vitro
dermal penetration studies on the formulated flupyradifurone. Of the available studies, some subchronic toxicity studies in rats, mice, and dogs contained data on liver enzymes, thyroid hormones, and plasma concentration of flupyradifurone. Two metabolites (DFA and difluoroethyl

- amino

- furanone) were tested in subchronic oral toxicity studies and in the genotoxicity battery of studies, while two other metabolites ((6

- chloro

- 3

- pyridyl) methanol and

6

- chloronicotinic acid (6

- CNA)) were tested only with bacterial gene mutation assays. Summaries of all toxicology studies are presented in Attachment A

.

4.2 Absorption, Distributi on, Metabolism, & Elimination (ADME)

Absorption, distribution, metabolism and elimination (ADME) of flupyradifurone were investigated using 14 

### C label at three different positions as shown below

.

Pyridinylmethyl

14 

### C Furanone

- 4

- 14 

### C Ethyl

- 1

- 14 

### C



### Regardless of labeling position, t he results showed that following oral administration of a low dose (2 mg/kg) of flupyradifurone to male and female rats, the gastrointestinal absorption of radioactivity was high and accounted for >80 % of the administered dose. In most cases, t he maximum plasma concentration was reached within 1 or 2 hours after dosing. With the high dose (200 mg/kg), the peak plasma concentration was observed between 2 and 4 hours after dosing. After reaching the peak concentration, th e radioactivity levels in plasma declined steadily by several orders of magnitude in all studies independent of sex or labeling position of the test compound. Elimination was very fast, mainly via urine and almost completed after 24
hours

. No radioactivi ty was detected in the expired air after dosing with the pyridinylmethyl

and ethyl

- 1

- labeled compounds. With administration of [furanone

- 4

- 14 

### C] flupyradifurone between 1 and 3% of the administered radioactivity was detected in the expired air.

The absor bed dose was rapidly distribut ed; a t approximately 1 hour after dosing, the concentrations in liver and kidney were significantly higher than in blood, suggesting a preferred clearance from blood and distribution mainly to the organs responsible for metabo lism (liver) and excretion (kidney). Very low levels were found in the brain, spinal cord

, and renal fat.

### Page 24 of 116

These results are similar in male and female rats independent of the labeling position. A fast decline of radioactivity concentrations was observed for all organs and tissues in males and females during the entire test period. Concentrations fell for most organs and tissues below 5% of the maximum tissue radioactivity after one day. After seven days, only very low
concentrations were found in a few organs and tissues of rats. Basically

, male and female rats exhibited very similar absorption, distribution

, and elimination patterns. The quantitative whole body autoradiography studies demonstrated that there was no accumulation of radioactivity in

an y organ of the tested male and female rats.

Flupyradifurone was readily metabolized in the rat. Numerous metabolites were formed, most of them being minor. The parent compound represented the predominant part of the radioactivity in
urine of male and female rats. In feces of male rats, the metabolite BYI 02960

- OH was more prominent than the parent compound. Two metabolites, 6

- chloro

- nicotinic acid ( BYI 0296 0

- 6

- CNA) and BYI 02960

- hippuric acid were also prominent in male but not in female rats.

The organ metabolism study using the ethyl

- 1

- 14 

### C label showed that, in the 24 hours samples of plasma, organs, and tissues, difluoroacetic acid (BYI 02960

- DFA) was by far the major metabolite accounting for more than 50% of the radioactivity in the tissues. However, the BYI
02960

- DFA accounted for approximately 6% of the administered dose.

The metabolic profiles in urine and feces were very similar for both sexes, b ut male rats showed a higher rate of metabolite formation as compared to females.

The figure below schematically shows the sites of the molecule which are involved in the
metabolic reactions:

The principal metabolic reactions of flupyradifurone in rat s could be summarized as follows :

 Hydroxylation followed by conjugation with glucuronic acid or sulfate ;

 C leavage of the difluoroethyl group forming BYI 02960

- des

- difluoroethyl, and BYI 02960

- DFA ;

 Cl eavage of the molecule at the pyridinylmethylene bridge f orming 6

- chlor

- nicotinic acid
BYI 02960

- 6

- CNA, which was further conjugated with glycine to BYI 02960

- hippuric acid
and BYI 02960

- difluoroethyl

- amino

- furanone.

### Page 25 of 116

4.2.1 Dermal Absorption

There is no dermal absorption study available with technical grade flu pyradifurone. However, in

vivo (rat) and in vitro ( h uman and rat skin) dermal penetration studies with the liquid (SC) formulation of flupyradifurone are available. The dermal absorption values from the 24 hour
measurements from in vivo and in vitro dermal absorption studies on the most dilute test formulation (0.1 g/L of 200 g/L SL) were used to estimate the human dermal absorption factor (DAF) with the equation: human DAF = (in vitro human % absorption) x [(in vivo rat % absorption/ (in vitro rat % absorption) ] . The calculated DAF was 7.42% for 24

- hour exposure.

4.3 Toxicological Effects

The most sensitive effects seen in the flupyradifurone database were skeletal muscle atrophy/degeneration in dogs , which appear to be the most sensitive tested animal; however, with 3⁄4 body weight scaling (Appendix A.5) the rat and dogs are equally as sensitive to the effects of flupyradifurone . With dietary administration, r eductions in body weight and food consump tion were commonly seen in all species of the test animals (rats, mice, dogs

, and rabbits). The liver and thyroid were also common targets of flupyradifurone toxicity

. The liver effects often consisted of increased liver weight, hepatocellular hypertroph y, liver enzyme increases (cytochrome p 450 increases), and decreases in total cholesterol. Some of the liver effects were judged to be adaptive responses while some were correlated with vacuolations and changes in clinical chemistry parameters (increases in alkaline phosphatase (ALP) and alanine aminotransph e rase (ALT), and cholesterol level changes indicative of liver effects which were progressed beyond the adaptive stage. The thyroid effects consisted of thyroid follicular cell hypertrophy and were see n mainly in rats. In addition, the thyroid effects were generally found in conjunction with liver effects.

The developmental toxicity data in rats and rabbits showed that flupyradifurone caused delayed
bone ossification in the fetal rats and increase i ncidence of fetal death in rabbits. These effects were seen at the maternal lowest observed adverse effect levels (LOAEL, 150 mg/kg/day) in rat developmental study. No adverse maternal effects was seen at the highest tested dose (80 mg/kg/day) in the comb ined data of rabbit developmental studies (main and range finding studies). The increased incidence of fetal death in rabbits was considered to be both a quantitative increase in susceptibility in the developing fetuses. However, clear no observed
adverse effect levels (NOAELs) were established for both rat and rabbit developmental toxicity
studies.

The results of a 2

- generation reproduction study showed that flupyradifurone reduced the number of estrus cycle s , decreas ing the number of implantation s in P 2 

### dams

, and decreas ing the litter size in the presence of decreased body weight and food consumption in maternal animals

. In addition, the body weight of F 2 

### pups was decreased at a dose (37.8 mg/kg/day) where no effect was seen in the parental animals, and this finding suggested a quantitative increase in susceptibility in the young rat.

### Page 26 of 116

Carcinogenicity studies in rats and mice did not yield a compound

- rel ated increase in tumor incidence, and the genotoxicity battery did not show flupyradifurone to produce any genotoxicity.

The acute neurotoxicity study showed that flupyradifurone caused increases in the incidence of piloerection and dilated pupils at 50 mg/kg. At the next higher dose level (200 mg/kg) and above, it produced a large number of clinical signs, which are indicative of neurotoxicity. These included lower muscle tone, rapid respiration, low arousal, tremors, myoclonic jerks, chewing, repetiti ve licking of lips, gait incoordination, flattened or hunched posture, dilated pupils, impaired (uncoordinated or slow) righting reflex, impaired flexor and tail pinch responses and reduced rectal temperature. However, none of these clinical signs were fo und in the dietary feeding studies, including the 90

- day neurotoxicity study. The effects seen in the acute neurotoxicity study are likely related to stimulation of the nAchRs, however there is limited additional evidence in mammalian studies that the pes ticidal mode of action is important to
mammals. The differences in the findings between the acute neurotoxicity study and other studies using dietary administration might be explained by the rapid absorption and excretion. Flupyradifurone was absorbed ra pidly in the metabolism study where rats were dosed by gavage. Peak plasma levels were reached within 1

- 4 hours of dosing depending on the dose

, and flupyradifurone was almost completely eliminated approximately 24 hours after administration.
With dietar y administration, the rodent test animal consumed the compound mostly during the entire night, and the internal flupyradifurone concentration required to produce the effect was probably seldom reached due to metabolism and rapid elimination from the body. As a result, clinical signs were not reported. N o neurotoxicity or other adverse effects were seen in 90

- day dietary neurotoxicity study in rats at dose levels as high as 174 mg/kg/day.

No immunotoxicity was found in rats tested at the highest dose of 2 30 mg/kg/day.

T he acute toxicity of flupyradifurone was low for all routes (oral, dermal

, and inhalation). The

rat oral LD 50 

### was estimated to be greater than 2

, 000 mg/kg

, with mortalities reported at 2

, 000 mg/kg but none at 300 mg/kg (Tox icity Cat egory III). The acute dermal LD 50 

### for rats was
>2

, 000 mg/kg (Tox icity Cat egory III). The a cute inhalation LC 50 

### for rats was >4

, 671 mg/m 3 

### (4.67 mg/L)

, which was the highest achievable concentration (Tox icity Cat egory IV). Flupyradifurone was not irritating to rabbit skin and caused only slight ocular irritation (redness of the conjunctivae) which was reversed within 48 hours.

Several metabolites were found in plants and rat metabolism studies; some of these metabolites were tested in mutagenicity studies and s ubchronic oral toxicity studies. The results showed that

m ost of the f

lupyradifurone metabolites had l ower toxicity than the parent compound except difluoroacetic acid (DFA) (BCS

- AA56716 see Toxicity Profile Table in Attachment A). The limited data (90

- da y oral feeding study in rats) showed that DFA produced a different effect from the parent compound, black foci in the glandular part of the stomach which correlated with
the histopathology finding of focal glandular erosion/necrosis. In addition, slight d ecreases in hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, and hematocrit were also
found. The stomach effects were seen at a LOAEL of 66 mg/kg/day which was lower than a comparable 90

- day oral toxicity study of the parent compound in rats (LOAEL = 156 mg/kg/day). It should also be noted that when comparing the NOAEL and LOAEL of this study

### Page 27 of 116

to a similar study (90

- day oral study in dogs) with parent compound, on a molar basis, the NOAELs and LOAELs of DFA and the parent are comparable, however, the effects are different. Furthermore, it should be reiterated that in the rat metabolism study with flupyradifurone, DFA was formed and detected as approximately 6% of the administered dose.

4.4 Safety F actor for Infants and Children (FQPA Safety Factor)

Based on the currently available toxicity and exposure data, the risk assessment team recommended the FQPA Safety Factor be reduced to 1X as supported by a complete toxicological database. Although there are clinical signs which indicated neurotoxicity in adult rats and quantitative increases in susceptibility demonstrated by decreased body weights in F 2 

### rat pups and quantitative and qu alitative susceptibility demonstrated by increased incidence of dead rabbit fetuses, there are clear NOAELs for these effects. The NOAEL for offspring toxicity in
the 2

- generation reproduction study is equivalent to the POD selected for risk assessment wh ile the NOAELs for neurotoxicity (clinical signs) and rabbit development toxicity are greater than the NOAEL selected as the POD for risk assessment. Therefore, the POD is protective of the effects which are indicative of neurotoxicity and susceptibility in rats and rabbits. There is no uncertainty in the exposure database. Overall, the data support the determination that an additional safety factor is not needed. The details for reducing the FQPA safety factor are
elaborated below.

4.4.1 Completeness o f the Toxicology Database

The flupyradifurone toxicology database is adequate to characterize any potential for prenatal or postnatal risk for infants and children, and includes acceptable developmental toxicity studies in the rat and rabbit and a rat rep roductive toxicity study , as well as acute and subchronic neurotoxicity studies

. HED waived the required subchronic inhalation toxicity study based on flupyradifurone ’s physical chemical properties, including low vapor pressure; low acute
inhalation toxic ity (Toxicity Category IV); and the use of a conservative, chronic oral POD that results in screening

- level MOEs that do not exceed the target MOE for a waiver of 10X the LOC (TXR# 0056903 ).

4.4.2 Evidence of N eurotoxicity

Although there is evidence that flupyradifurone has neurotoxic effects, EPA has a complete set of neurotoxicity studies (acute, subchronic, and developmental). The effects of those studies are
well

- characterized and indicate neurotoxic effects that occur at levels above the chronic POD that was selected for risk assessment. The NOAEL for the acute neurotoxicity study is being used for the acute POD. Therefore, there is no need to retain the 10X FQPA safety factor to account for any uncertainty concerning these effects.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence that flupyradifurone results in increased susceptibility in in utero rats or rabbits in the prenatal developmental studies or in young ra ts in the 2

- generation reproduction study. There is quantitative susceptibility in rabbit developmental study and in the pup of the reproduction study, but the PoDs are protective of this increased susceptibility.

### Page 28 of 116

4.4.4 Residual Uncertainty in the Exposu re Datab ase

The exposure databases are complete or are estimated based on data that reasonably account for potential exposures. The chronic dietary exposure assessment for flupyradifurone was conservatively based on 100 % crop treated (CT) assumptions, as well as conservative ground
and surface drinking water modeling estimates. All of the exposure and risk estimates are based on conservative assumptions that do not underestimate risk.

4.5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- R esponse Assessment

With oral dosing, ADME of flupyradifurone was rapid. The time of peak plasma concentration
was reached within 1

- 4 hours, depending on the dosage employed. Elimination was almost complete by 24 hours after dosing. The ADME data are co nsistent with the timing and doses causing effects throughout the database as there was little difference in the values of the LOAELs between the chronic study and subchronic study in either rats (90

- day: 156 mg/kg/day; chronic: 120 mg/kg/day) or dogs (90

- day: 33 mg/kg/day; chronic: 28 mg/kg/day). The minor differences were due to differences in dose selection. However, in the 1

- year dog study, the effect seen at the LOAEL (28 mg/kg/day) was more extensive than that in the 90

- day dog study.
The 1

- year do g study was used to establish the toxicity endpoints and POD for the chronic dietary exposure assessment. For short

- term incidental oral exposure assessment and short

- and
intermediate

- term dermal and inhalation assessment, the selection of the POD (12 mg /kg/day) and toxicity endpoint from the 90

- day dog study and the 2

- generation reproduction study as co

critical is appropriate and is protective of any effects seen in the developmental studies in rats and rabbits. In a similar reasoning, the 90

- day dog s tudy is also appropriate for toxicity endpoint
selection for short

- term dermal and inhalation exposure assessments. The duration of a 90

- day dog study also corresponds to the duration of exposure for the intermediate

- term dermal and inhalation exposure. The reason for employing the 2

- generation reproduction study as a co

critical study in selecting the toxicity endpoint for the dermal, and inhalation exposure assessment is that the pup body weight loss occurred at similar LOAEL as the skeletal muscle

atro phy/degeneration in the 90

- day dog study. In addition, the pup body weight loss is a clear effect of flupyradifurone on the young animal.

The POD (35 mg/kg) selected from the acute neurotoxicity study is also protective of any effects
seen in the devel opmental toxicity studies in rats and rabbits.

The toxicity e ndpoints and points of departures are presented in Table 4.5.4.1, and the rationale
for the selections is presented in Appendix A.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

HED combines exposure from different routes for each population if the same toxic effects are seen for that duration of exposure by each route. Since the same endpoint (skeletal muscle atrophy in the dog, co

- critical with the pup body wei ght decrease) was chosen for both dermal and inhalation risk assessment, these exposures should be combined.

### Page 29 of 116

4.5.3 Cancer Classification and Risk Assessment Recommendation

Flupyradifurone is classified as “ Not likely to be Carcinogenic to Humans” based on the absence of increased tumor incidence in acceptable/guideline carcinogenicity studies in rats and mice.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

Table 4.5.4.1: Summary of Toxicity Endpoints and Poin ts of Departure for Use in Dietary
, Non

- Occupational
,

and Occupational Human Health Risk Assessments

.

Exposure/ Scenario Point of Departure Uncertainty/

FQPA Safety
Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Acute Dietary (All populations) NOAEL =

35 mg/kg/day UF A = 10x

UF H =10x

FQPA SF= 1x aRfD =0.35

mg/kg/day Acute neurotoxicity study

– rat

LOAEL = 50 mg/kg/day based on increased incidences of piloerection in both sexes and pupil dilation in females on Day 1. At the next higher dose level (200 mg/kg) or above, lower muscle tone, rapid respiration, low arousal, tremors, myoclonic jerks, chewin g, repetitive licking of lips, gait incoordination, flattened or hunched posture, dilated pupils, impaired (uncoordinated or slow) righting reflex, impaired flexor and tail pinch responses and reduced rectal temperature.
Automated measures of motor activit y were also reduced in both sexes, compared to controls.

Chronic Dietary (All Populations) NOAEL =

7.8 mg/kg/day UF A = 10x

UF H =10x

FQPA SF= 1x cRfD = 0.078

mg/kg/day
cPAD = 0.078 mg/kg/day 1

- year oral toxicity study

- dog

LOAEL= 28 mg/kg/day based on minimal to slight, focal to multifocal areas of skeletal muscle degeneration in gastrocnemius and/or biceps
femoris muscle.

Dermal
Short

- (1

- 30 days)
and I ntermediate

terms (1

- 6 months) NOAEL =

12 mg/kg/day

DAF =
7.42% a UF A = 10x

UF H =10x LOC = 100 90

- day oral toxicity study

- dog
LOAEL= 33 mg/kg/day based skeletal muscle atrophy/ degeneration.

2

- generation reproduction study

- rat as a co

critical study.
NOAEL= 7.7 mg/kg/day Offspring LOAEL=38.7 mg/kg/day based on pup body weight decrease.

Inhalation Short

- (1

- 30 days) and

I ntermediate

- terms (1

- 6 months) NOAEL =

12 mg/kg/day UF A = 10x

UF H =10x LOC = 100 90

- day oral toxicity study

- dog
LOAEL= 33 mg/kg/day based on skeletal muscle atrophy/ degeneration
2

- generation reproduction study

- rat as a co

critical study.
NOAEL= 7.7 mg/kg/day Offspring LOAEL=38.7 mg/kg/day based on pup body weight decrease.

Cancer (oral, dermal, inhalation) Classification: “Not likely to be Carcinogenic to Humans” based on data showing no treatment

- rela ted

increase in tumors incidence in rat and mouse carcinogenicity studies. No mutagenic concern was reported in the genotoxicity studies. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A =

### Page 30 of 1 16

extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (c = chronic). RfD = reference
dose. LOC = l evel of concern. Dermal Absorption Factor = DAF. Toxicity via the inhalation route of exposure is assumed to be equivalent to toxicity via the oral route. a : This DAF was calculated based o n t he dermal absorption values from the 24 hours

measurements o f the most dilute test formulation used in the in vivo rat and in vitro human and rat skin dermal penetration
studies. To estimate the human dermal absorption factor (DAF) , the following equation is used : Hu man DAF = (in vitro human % absorption ) x [(in vivo rat % absorption / (in vitro rat % absorption )]

.



### 5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

Plants The metabolic fate of [ 14 

### C]

- flupyradifurone was investigated in potato, apple, rice, cotton, and tomato using two radiolabeled forms of flupyradifurone (furoanone

- 4

- 14 

### C and pyridinylmethyl

14 

### C) for all crops except tomatoes, where a third radiolabel form was used (ethyl

- 1

- 14 

### C). It is
noted that no meta bolism study was provided for a leafy vegetable. However, the array of studies presented with similar results is adequate to translate to the remaining plant types. The metabolism of flupyradifurone was qualitatively similar in five different metabolic g roup types (root, fruit, cereal grain, oilseed, and fruiting vegetable) regardless of the application type (foliar, soil drench, seed). Moreover, the metabolism was similar for both longer (100 day) and shorter (20 day) PHIs. However, the relative amount s of parent and metabolites varied considerably with the crop and timing of application.

Flupyradifurone was generally a major component of the residue in all instances, although its contribution was significantly greater at the shorter PHIs typical of m ost proposed uses. An exception was noted in the early season only application to apple trees (PHI 98 days), where extensive metabolism/reincorporation of the radiolabel into natural products occurred ( with the [Furanone

- 4

- 14 

### C]

- BYI 02960 label ) and parent was subsequently a minor component.

The soil

- treatment type studies showed some total breakdown of flupyradifurone and re

incorporation of the radiolabel into carbohydrates, especially for rice and tomato. Cleavage of the parent to 6

- chloro

- 3

- pyridine methanol ( CHMP ) and CHMP reaction products, hydroxylation /conjugation of the furanone moiety, cleavage of the pyridinylamine bond with formation of BYI
02960

- difluoroethyl amino furanone and degradation of the furanone moiety with formation of
BYI 02960 a cetic acid and further metabolism products were evident. A radiolabeled study with the difluoroacetic acid moiety was conducted only for the drench application to tomato, where large amounts of radiolabeled DFA were found.

Similar paths of metabolism were observed with the foliar treatments (cotton, apple, rice). Formation of difluoroacetic acid was likely a significant pathway, as evidenced in the
determination of non

- radiolabeled difluoroacetic acid from the various plant extracts.

Livestock Nature of the residue studies with separate radiolabels on the furanone and pyridinyl rings of flupyradifurone were conducted with laying hens and a lactating goat. Adequate amounts of the

### Page 31 of 116

administered doses were recovered in all c ases. Generally, adequate amounts of the radiolabeled residues were released by solvent extraction and subsequently identified or characterized.

Metabolism in poultry was far more extensive than in ruminants. Parent flupyradifurone was generally a minor component in hen matrices, with the exception of fat (15% of the TRR) and eggs (20% of the TRR) for the pyridinyl label only. Fatty acids were the major metabolic product with the furanone label for eggs, fat, and liver, indicating extensive metabolism. With the pyridinylmethyl label, acetyl

- AMCP, from cleavage of both the furanone and difluroethyl groups, was the major residue in eggs, and the major residue in liver was BYI 02960 OH

- SA from hydroxylation of the furanone. Similar extensive hydroxylation to BYI 02960 OH
derivatives was seen in ruminant liver.

Metabolism in ruminants was very limited. BYI 02960 was the major portion of the residue in fat, muscle, and liver. The parent was also the major component in milk with the pyridinyl label,
but la ctose from total breakdown and reincorporation of the radiolabeled carbon was the major component in milk for the furanone label. Significant metabolism was demonstrated only in kidney. The major metabolites were BYI 02960 OH (15%

- 35% of the TRR) and BYI 02960
OH

- glucuonides (26%

- 31% of the TRR) from hydroxylation followed by conjugation with glucuronic acid.

Metabolism in livestock with [Ethyl

- 1

- 14 

### C]

- BYI 02960 was not studied. Therefore, nothing can
be concluded from the metabolism studies about the significance of DFA as a livestock metabolite. However, DFA was measured in the livestock feeding studies and was found is some matrices to be present in significant quantities. It was the major portion of the residue in poultry commodities.

5.1.2 Summa ry of Environmental Degradation

With respect to environmental fate, flupyradifurone is moderately soluble and is classified as mobile to moderately mobile. It is relatively stable to hydrolysis, soil photolysis, anaerobic soil metabolism, and anaerobic a quatic metabolism. It does degrade via aqueous photolysis with a
half

- li f e of approximately three days. Under aerobic aquatic conditions the half live values ranged from 237 to 365 days for parent alone and from 676 to 893 days for parent plus

unextracte d residues. The main transformation products observed were DFA and 6

- CNA in aerobic and anaerobic soil metabolism studies and in field dissipation studies, while BYI 02960

- succinamide and BYI 02960

- azabicyclosuccinamide were present in aqueous photolysis studies. Preliminary information indicates that DFA is highly mobile and 6

- CNA is mobile to moderately mobile; therefore, both have the potential to leach to groundwater.

Based on flupyradifurone’s log K OW 

### value of 0.08, and log octanol

- air partition coe fficient (K OA 

### ) values of 11, it is not likely to bioconcentrate in terrestrial organisms. 1 

### This is supported by the predicted short half

- life in the vapor phase. Compounds with a log K OW 

### of three and above are

1 A recent scientific advisory panel (SAP) reported, “Gobas et al. ( 2003 ) concluded that chemicals with a log K OA > 5 can biomagnify in terrestrial food chains if log K OW >2 and the rate of chemical transformation is low. However, further proof is needed before accepting these limits without reservations” ( USEPA, 2009 ) . This was also supported by Armitage and Gobas’s work completed in 2007 ( Armitage and Gobas, 2007 )

.

### Page 32 of 116

generally considered to have the potential t o bioconcentrate in aquatic organisms. Because flupyradifurone’s log K OW 

### is 0.08, it is not expected to significantly bioconcentrate in aquatic organisms.

Study results indicate that flupyradifurone is persistent to very persistent 2 

### in soil, sediment a nd

water.

The transformation products that are potentially important for human health drinking water exposure include the four major transformation products observed in environmental fate studies at greater than 10% applied radioactivity:

 6

- chloronicotinic acid (6

- CNA),

 difluoroacetic acid (DFA),

 BYI 02960

- succinamide (M48), and

 BYI 02960

- azabicyclosuccinamide (M47).

6

- CNA is degraded rapidly in three aerobic soil systems ( the dissipation half

- life, or DT 50 

### , ranged from 3 to 7 days). The degradate DFA was persistent to very persistent in two aerobic aquatic systems (DT 50 

### ranged from 121 to 951 days).

Dissipation half

- lives for the whole soil profile ranged from 8 to 310 days. Most residues were
observed in the top 15 cm at all sites; however, flupyradifurone was observed up to a depth of 40
cm. Field sites varie d in percent organic carbon (rang ing from 0.8 to 4.4% OM), soil properties, and pH (range from 5.5 to 8.2). Carryover of residues at the end of the sampling period ranged from 8 to 59%, indicating that flupyradifurone does have the potential to accumulate in soil over multiple applications and from year to year. Two of the major degradates observed in laboratory studies, 6

- CNA and DFA, were also obs erved in the field studies. M47 and M48 were not looked for in the field dissipation studies.

Measured aerobic soil DT 50 

### s of 38 to 401 days are uncertain because of high amounts of unextracted residues which may or may not constitute residues of concern. Half

- lives calculated assuming that the unextracted residues do constitute residues of concern range from 79 to 799 days and are approximately double those for parent alone.

5.1.3 Comparison of Metabolic Pathways

The metabolic pathways in the five crop s and application types (soil, foliar, seed) studied are qualitatively similar and well understood based on characterization and identification of the residues. The metabolism from the confined rotational crop study is similar to the primary crop
metaboli sm studies. Parent BYI 02960 is generally the predominant part of the residue ; where it is not predominant

, a natural product (such as glucose) predominates. Difluoroacetic acid is a major metabolite, although it has been directly confirmed in only one m etabolism study. The
metabolites are also rat metabolites.

2 According to the Toxic Release Inventory Classification System, chemicals with half

- lives greater tha n 60

- days are classified as persistent and chemicals with half

- lives greater than 180 days are classified as very persistent ( USEPA,
2012a )

.

### Page 33 of 116

On basis of the metabolites identified, transformation of flupyradifurone ( BYI 02960 ) proceeds by the following pathways:

 oxidative cleavage of the difluoroethylamine bond and formation of difluoroacetic acid

 complete degradation of the furanone moiety and incorporation of carbon atoms into the natural compound pool, e.g. into glucose/carbohydrates

 cleavage of the pyridinylmethylamine bond and formation of BYI 02960

- difluoroethylamino

- furano ne and its corresponding counterpart BYI 02960

- CHMP, which was either conjugated with carbohydrates or oxidised to 6

- chloronicotinic acid (6

- CNA)

 hydroxylation of the furanone moiety or the difluoroethyl moiety followed by conjugation with carbohydrates,

 oxidative degradation of the furanone moiety to an acetic acid group followed either by conjugation with a carbohydrate or further degradation.

The metabolism in ruminants qualitatively mirrors that of plants. Metabolism is limited, with parent BYI 02960 the predominant component of the residue in all commodities. In milk, complete deg radation of the parent (degradation of the furanone moiety) and reincorporation is indicated by the presence of radiolabeled lactose. Other similar metabolic pathways are indicated by the presence of 6

- CNA from the cleavage of the pyridinylmethylamine bond and the presence of BYI 02960

- OH

- gluA from hydroxylation of the furanone moiety.

The metabolism in poultry is much more extensive than in plants or ruminants, as evide nced by the low or no concentrations of parent BYI 02960 in eggs and tissues. The majority of the radiolabeled residue was characterized as fatty acids. The minor metabolites found are
consistent with metabolites found in the ruminant and in the rat. An exception is BYI 02960 acetyl

- AMCP found only in poultry.

5.1.4 Residues of Concern Summary and Rationale

Primary Crops: Parent flupyradifurone, glucose, CHMP

- di

- glyc, 6

- CNA, and DFA were
identified as major residue s in the primary crop metabolism studies and/or crop field trials.
Glucose and CHMP

- di

- glyc are highly soluble and not of toxicological concern. 6

- CNA has been characterized as not of toxicological concern as well, and it is expected to be rapidly
metabolized and conjugated. Parent flupyradifurone and DFA are considered as residues of concern (ROC) for risk assessment due to their comparable NOAELs and LOAELs and their identification as main residues in the metabolism studies and crop field trials. However, for tolerance enforcement, parent flupyradifurone alone is considered an appro priate marker of
misuse.

Rotational Crops: Parent flupyradifurone and DFA were identified as main components in the rotational crops. Other metabolites also observed in the primar y crops were identified in the rotational crops, but were excluded from the ROC definition based on the absence of a toxicity concern. Parent flupyradifurone is recommended as ROC for tolerance enforcement while parent flupyradifurone and DFA are recommen ded as the ROCs for risk assessment.

### Page 34 of 116

Processed commodities: P rocessing studies showed that p arent flupyradifurone is stable upon processing and therefore an adequate marker of misuse and tolerance enforcement in processed commodities. Parent flupyradifu rone and DFA are included as the ROCs for risk assessment.

Livestock: Parent flupyradifurone and DFA are the main residues identified in the ruminant metabolism and feeding studies. Since parent flupyradifurone was observed in the feeding study,
it is considered an appropriate marker of misuse on ruminant commodities and recommended as
the ROC for tolerance enforcement

.

The poultry feeding study showed DFA as the main residue, and parent flupyradifurone and
several metabolites at low concentrations relative to DFA. Parent flupyradifurone is predicted to be at or below the LOQ of the analytical method in poultry commodities at the calculated poultry exposure level. DFA may be slightly above the LOQ in some poultry commodities at the exposure level. The ROCKS suggested that the residue definition for enforcement should include parent and DFA. However, further consultation with the international partners led to the decision to include only parent in the ROC for enforcement. DFA does not have a stron g advantage as a marker for misuse, and the lack of a DFA feeding study does not allow for

accurate determination of the DFA residue contribution from DFA itself. Therefore, p arent flupyradifurone is the ROC for tolerance enforcement and risk assessment i n poultry
commodities

.

Drinking Water: P arent flupyradifurone, DFA, BYI 02960

- succinamide and BYI

- 02960

- azabicyclosuccinamide are included as residues of concern for risk assessment. The aqueous photolysis degradates, BYI 02960

- succinamide (M48) and BYI 02960

- azabicyclosuccinamide (M47) , are recommended for surface water estimates only since these are likely to be formed in
clear and shallow water bodies

. 6

- CNA was a major transformation product in the fate studies, but is excluded as a ROC, since it is not considered of toxicity concern.

Table 5.1.4: Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

. 1 , 2

Matrix Residues I ncluded in Risk
Assessment Residues I ncluded in Tolerance Expression

Plants Primary Crop Flupyradifurone
Diflu o roacetic acid Flupyradifurone

Rotational Crop Flupyradifurone
Difluoroacetic acid Flupyradifurone

Processed Commodities Flupyradifurone
Difluoroacetic acid Flupyradifurone

Livestock Ruminant Flupyradifurone
Difluoroacetic acid Flupyradifurone

Poultry Flupyradifurone
Difluoroacetic acid Flupyradifurone

Drinking Water 2 Flupyradifurone, Difluoroacetic acid, BYI
02960

- succinamide, and BYI
02960

- azabicyclosuccinamide 3 Not Applicable 4

1 Difluoroacetic acid and flupyradifurone may need to be considered in separate risk assessments.

2 Refer to Appendix 1 for the names and/or chemical structures of the metabolites/degradates.

### Page 35 of 116 3 The aqueous photolysis degradates, BYI 02960

- succinamide (M48) and BYI 02960

- azabicyclosuccinamide (M47), are recommended for surface water estimates only.

4 NA

– Not applicable

.



### 5.2 Food Residue Profile

There are adequate residue data on plant food and feed commodities for the purposes of risk
assessment and tolerance assessment. P arent flupyradifurone is the major component of the residue in food commodities, as evidenced by the plant metabolism studies and the crop field trial studies. The parent is quantifiable with the po ssible exception of tree nuts, where both
f l u pyradifurone and DFA are at or below the LOQ (0.01ppm). The crop field trials indicate that
difluoroacetic acid, DFA, can be a significant portion of the residue for some commodities, most notably legume vegeta bles. Residues of parent generally decline with PHI, but DFA often increases with PHI and reaches a plateau around 32

– 35 days after crop treatment. This makes DFA a poor marker for tolerance enforcement purposes.

Flupyradifurone shows only a slight te ndency to concentrate as a surface residue. It tends to distribute throughout the commodity , i.e., is systemic

. Flupyradifurone is taken into the plant via the roots (soil drench treatment) or translaminarly through the leaf tissue (foliar treatment). T he residues are qualitatively similar from both paths. Flupyradifurone is stable to the conditions of processing. It concentrates in dried (raisins) and concentrated (tomato paste) processed commodities, but does not concentrate in juices or oils. It co ncentrates slightly in outer surface
commodities such as cereal bran. Storage stability studies on divergent commodity types demonstrated that flupyradifurone and DFA are stable in commodities stored frozen for intervals that encompass the storage of samp les from the crop field trials.

Confined rotational crop studies indicated the potential for flupyradifurone residues present at very low levels at PBI s up to one year. However, flupyradifurone is proposed for use on almost all food and feed commodities, with the exception of herbs and spices, stone fruit, tropical fruit, grass animal feeds, mushrooms, rice, sugar cane, and some oilseeds. Rotational crop studies with sugarcane show that a PBI of 14 days is acceptable. Limited field rotational crop stud ies from Europe indicate that flupyradifurone will most likely be <0.01 ppm on rotational crop commodities at a one year PBI. For crops without a tolerance and/or a label ed use, except sugarcane, a PBI of one year is necessary.

Livestock feeding studie s show that flupyradifurone does transfer to meat, milk, poultry, and eggs, but overall transfer to poultry commodities is low at the anti ci pated exposure levels. Adequate feeding concentration levels are available to bracket the exposure anticipated from residues of flupyradifurone on livestock feed commodities. Parent is the major component of the residue in ruminant commodities, but DFA is significant in poultry commodities. No DFA feeding studies were available for risk assessment purposes, and DFA l evels in livestock commodities from the feeding of DFA (in crop matrices) were estimated from a mass balance analysis of the flupyradifurone feeding studies.

5.3 Water Residue Profile

### Page 36 of 116

Since f lupyradifurone is a proposed new chemical , t here are no monitoring data currently
available. The estimated drinking water residues used in the dietary risk assessm ent were provided by EFED (K. White, D415166, 02/28/2014) and incorporated directly into th e dietary

exposure assessment. Estimated w ater residues were incorporated in the DEEM

- FCID into the food categories “water, direct, all sources” and “water, indirect, all sources.” Estimated drinking water concentrations ( EDWCs ) were calculated for total toxic residues consisting of parent plus

M 47 plus M48 plus unextracted residues (referred to as “TTR

- UN”). The number of growing seasons per year was not specified on the label and flupyradifurone could be used for multiple seasons per year on one site. Therefore, the estimates incorporated into the dietary assessment conservatively assumed three growing seasons per year , and resulted in the highest EDWC.

The EDWC for the acute and chronic assessment was estimated using PRZM

- GW (ground water). The models used to derive the EDWCs are listed in Table 5.3.1. The models and their descriptions are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/

.

Table 5.3.1 . Tier I EDWCs for residues of flupyradifurone plus M47 plus M48 plus unextracted
residues. 1

Source of Drinking Water (Model) TTR

- UN concentration in drinking water ( μg/L)

Acute Annual Average or Post

Breakthrough Average Surface Water (Modified Tier 1 Rice Model) 112 112

Surface W ater (PRZM/EXAMS) 46.1 ( 1 season) 47.7 (2 seasons) 52.5 (3 seasons) 13.9 ( 1 season) 20.1 (2 seasons) 22.3 (3 seasons)

Ground W ater (PRZM

- GW) 117 (1 season) 23.8 (2 seasons)
352 (3 seasons) 102 (1 season) 208 (2 seasons)
307 (3 seasons )

1 For surface water, all values reflect residues of flupyradifurone plus the aqueous photolysis degradates, M47 and M48, plus unextracted residues. For groundwater, residue values reflect parent only as recommended by ROCKs because photolysis is less likely in groundwater, and because P RZM

- GW models do not include inputs for photolysis. Residues in groundwater also include unextracted residues because it is uncertain whether the unextracted residues are parent or a residue of concern.
Bolded values indicates values used in the acute and chronic assessments. Refinements can be made to get lower EDWCs.



### 5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

For both acute and chronic dietary assessments, HED used recommended tolerance

- level
residues fo r the proposed crops. DEEM default processing factors were used for dried apple, dried beef, and dried pear; empirical processing factors were used for processed commodities of apple (sauce and juice), coffee, citrus oil, cotton (oil), corn (bran, flour, meal, starch, oil), grape (wine, juice), grapefruit (juice), hops (dried cones), limes (juice), lemons (juice), oranges (juice and peel ), peanut (butter, oil), pears (juice), potatoes (chips, flakes, cooked), tomatoes (juice, puree, paste), soybeans (oil, milk, flour), and wheat (bran, germ, flour).

5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary exposure analysis assumed that 100% of the proposed crops were treated with flupyradifurone because there are currently no registered uses.

### Page 37 of 116

5.4.3 Acute Dietary Risk Assessment

The results of the acute analysis indicate tha t acute dietary (food and drinking water) exposure
and risk estimates do not exceed HED’s LOC [ i.e., <100% acute population adjusted dose (aPAD)] for the U.S. population and all population subgroups. At the 95 th 

### percentile of exposure, th e resulting acute dietary risk estimates utilized 24 % of the a PAD for the general U.S. population and utilized 3 8 % of the a PAD for children 1

- 2 years old , the most highly exposed population subgroup. The results of the acute dietary exposure analysis are included in Table
5.4.6.

5.4.4 Chronic Dietary Risk Assessment

The chronic dietary (food and drinking water) exposure and risk estimates do not exceed HED’s LOC [i.e., < 100% chronic population adjusted dose (cPAD)] for the U.S. population or any population subgroups. The resulting chronic dietary risk estimates utilized 39 % of the cPAD for the general U.S. population and utilized 84 % of the cPAD for children 1

- 2 years old , the most highly exposed population subgroup. Based on the lack of refinement in the assessment, actual dietary exposure is expected to be significantly lower.

5.4.5 Cancer Dietary Risk Assessment

Flupyradifurone is classified as “not likely to be carcinogenic to humans”; therefore a cancer dietary exposure assessment was not performed.

5.4.6 Sum mary Table

Table 5.4.6 . Summary of Dietary (Food and Drinking Water) Exposure and Risk for Flupyradifurone. 1

Population Subgroup Acute Dietary ( 95 th Percentile) Chronic Dietary

Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD

General U.S. Population 0.082755 24 0.030629 39
All Infants (<1 year old) 0.100233 29 0.038 123 49

Children 1

- 2 years old * 0.13 3852 3 8 0.065 155 84

Children 3

- 5 years old 0.131183 37 0.055 003 71

Children 6

- 12 years old 0.083856 24 0.035 222 45

Youth 13

- 19 years old 0.063792 18 0.024 110 31

Adults 20

- 49 years old 0.076762 22 0.028 118 36

Adults 50

- 99 years old 0.075170 21 0.02 7976 36

Females 13

- 49 years old 0.080078 23 0.028 251 36

1 The subpopulation with the highest risk estimate is bolded.

### Page 38 of 116

5. 5 Dietary Exposure Evaluation

- DFA

Studies submitted in support of the registration of flupyradifurone indicated that there could be exposure to DFA in food (plant and animal based) and drinking water. DFA was also shown to be a mammalian metabolite; approximately 6% of flupyradifurone adm inistered to rats was converted to DFA, and DFA was a metabolite in the ruminant and poultry metabolism studies. The most sensitive toxic effects to be used in the risk assessment for flupyradifurone would not be expected from DFA, which has a very differ ent chemical structure. A range

- finding and subchronic toxicity study with DFA showed different toxic effects (black foci in the glandular part of the stomach) than the parent compound (skeletal muscle atrophy and degeneration)

, indicating that risk from DFA should be assessed separately from the parent. DFA is much more polar than the parent compound as well; which indicates it may be excreted rapidly. HED conducted a screening

- level evaluation of DFA to determine if there were any residual concerns for exposure to DFA. This evaluation assumed conservative drinking water concentrations, that
100% of the crops contained DFA at median residue values for all crops except when individual median residues were available. For livestock, dietary burdens were ca lculated based on DFA tissue to flupyradifurone feed ratios. Using these conservative inputs , exposure to DFA is 7X less than estimated exposure to flupyradifurone for the general US population, and 5X less than estimated exposure to flupyradifurone for c hildren 1

- 2 years old, the highest exposed population subgroup. Therefore, s ince there is similar potency (albeit with different toxic effects) between flupyradifurone and DFA, but less exposure expected to DFA than the flupyradifurone, the Agency has no additional risk concerns about exposure to DFA.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no proposed residential uses of flupyradifurone; therefore, a residential exposure
assessment has not been conducted. A turf transfer rable residue (TTR) study is not required for flupyradifurone at this time because there are no proposed uses on turf.

6.1 Residential Bystander Post

- application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- applicati on inhalation exposure assessment was not performed for flupyradifurone at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure ( 7.0 x 10

- 9 

### mm Hg at 20 o 

### C), and the low proposed use rate (0.365 lb ai/A) . However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal

Ins ecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 3 

### . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and proce dures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post

- applicat ion inhalation exposure assessment for flupyradifurone.

3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

### Page 39 of 116

6.2 Spray Drift

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for flupyradifurone. The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was d eveloped as a result of a Data
Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information). 4 

### The Agency is also taking means to qualitatively and qualitatively address spray drift as a potential source of exposure in risk assessments for pesticides through existing programs such as Ag Drift and chemical specific properties of pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during
the Registration Review process which ensures that all uses for that pesticide will be considered concurrently.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to qu antitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. There are no residential uses of flupyradi furone; therefore, the aggregate risk includes only exposure from food and drinking water. Acute and chronic dietary risks do not exceed HED’s LOC for the U.S. population or any population subgroups. Refer to Section 5.0 for the dietary exposure estimate s.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to flupyradifurone and any ot her substances and flupyradifurone does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that flupyradifurone has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

4 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm

### Page 40 of 116

9.0 Occupational Exposure /Risk Characterization

9.1 Short

- /Intermediate

- Term Occupational Handler Risk

T here is potential for short

- and intermediate

- term occupational exposure to flupyradifurone during both handler [mixing, loading, and application (via the dermal and inhalatio n routes)] and
post

- application activities (via the dermal route) based on the proposed uses.

Additionally, for both dermal and inhalation exposures, the PODs selected are considered protective of both short

- and intermediate

- term durations.

The quanti tative exposure/risk assessment developed for occupational handlers is based on the following scenarios:

 Mixing/Loading liquid formulations for aerial, airblast, chemigation, and groundboom application;

 Applying sprays with aerial, airblast, and groundboom equipment;

 Flagging for aerial applications;

 Mixing/Loading/Applying using a backpack sprayer and mechanically pressurized handgun;

 Primary handling for seed treatment (loading/applying, sewing, baggi ng treated seed; multiple activities); and

 Secondary handling for seed treatment (planters).

Results are presented for “baseline,” defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective glove s, and no respirator, as well as
baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc). The proposed BYI 02960 480 FS (EPA Reg. No. 264

- RRUE) label requires seed treaters and workers cleaning
the treatment facilities to wear lon g sleeved shirts, long pants, shoes, socks, and chemical resistant gloves. Baggers and others involved in the packaging of treated seed are required to wear long sleeved shirts, long pants, shoes

, and socks. The proposed SivantoTM (EPA Reg. No.

264

- RRUR) label requires occupational handlers to wear long sleeved shirts, long pants, shoes, socks, and chemical resistant gloves.

There are no risk estimates of concern at baseline (no PPE). For the agricultural uses of flupyradifurone, the short

- and interme diate

- term combined (dermal + inhalation) occupational handler MOEs ranged from 260 to 17,000 with baseline PPE. With the addition of chemical
resistant gloves, as required on the flupyradifurone label, the short

- and intermediate

- term combined (dermal + inhalation) occupational handler MOEs ranged from 800 to 57,000. For the proposed seed treatment use of flupyradifurone, the combined (dermal + inhalatio n) short

- and
intermediate

- term MOEs ranged from 2,000 to 14,000. The occupational handler MOE estimates are presented in Appendix F.

### Page 41 of 116

9.2 Short

- /Intermediate

- Term Post

- Application Risk

9.2.1 Dermal Post

- application Risk

HED uses the term post

- applica tion to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. For flupyradifurone , both short

- and intermediate

- term post

- application exposure could occur for the proposed agricultural uses

. It may be applied throughout the growth season, including pre

- bloom, during bloom, or following bloom, increasing the likelihood of exposure during post

- application activities. However, because the POD is the same for dermal short

- and
intermediate

- term exposures, one asse ssment is protective of both durations.

Chemical

- specific dislodgeable foliar residue data have not been submitted for flupyradifurone. Therefore, this assessment uses HED’s default assumption that 25% of the application is
available for transfer on da y 0 following the application and the residues dissipate at a rate of 10% each following day.

The occupational short

- and intermediate

- term dermal post

- application risk estimates ranged from 170 to 15,000 on the day of application. A summary of the antic ipated worst

- case post

application activities and associated transfer coefficients and MOEs for the proposed crops/use sites is provided in Appendix F.

In accordance with 40CFR158, DFR data are required for all occupational (e.g., crop, nursery, greenho use use sites) or residential (e.g., ornamental and vegetable gardens, pick your own farms, retail tree farms) uses that could result in post

- application exposure to foliage. In the
absence of chemical

- specific DFR data, EPA uses default values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment includes an analysis of a number of DFR studies, which resulted in the selection of a revised default values for the fraction of the application rate available for transfer after a foliar application (F AR 

### ). These values are based on an analysis of 19 DFR studies. Since that time, the Agricultural Re

- entry Task Force has submitted information (MRID 49299201) that corrects an application rate error made in the original submission of “ARF039

– Determination of Dermal and Inhalation Exposure to Reentry Workers During Chrysanthemum Pinching in a Greenhouse” (EPA MRID 45344501). As a result, the range of F AR 

### values was revised from 2%

- 89% to 2%

- 47%. In the data, a large range of transferability is observed and this variability can potentially be attributable to many factors such as active ingredient; formulation; field conditions in the studies; weather conditions (e.g., humidity); or many other difficult to quantify factors. Alt hough witnessed across multiple chemicals, this range in F AR 

### values is not expected when considering DFR data for a single chemical. At this time, the ARTF submission did not alter the selection of 25% as the reasonable, high

- end default value. Because D FR data are not available for flupyradifurone, EPA is using the default value of 25%. Although there may be a small degree of uncertainty in the use of the default DFR value for flupyradifurone (i.e., there is a small chance that the F AR 

### value may exceed the applicable default value ), it is likely that the health

- protective aspects of EPA’s occupational post

- application assessment methodology will more than compensate for

### Page 42 of 116

this potential uncertainty. For example, when assessing residential and occupational post

application exposure to gardens and ornamentals, EPA assumes the following: exposures occur

to zero

- day (i.e., day of application) residues every day of the assessed exposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it doesn’t rain, etc); individuals perform
the same post

- application activities performed in the transfer coefficient study day after day (e.g., weeding, harvesting, pruning, etc.); and individuals engage in these post

- application activities for a high

- end a mount of time every day (represented by data reflecting time spent gardening based on survey data).

Given the conservatisms discussed above and the potential compounding nature of these conservatisms, EPA is able to rely upon the calculated exposure estim ates with confidence that exposure is not being underestimated.

However, since the highest estimated occupational post

- application exposure using default DFR values for flupyradifurone is not minimal in comparison to the level of concern (i.e., the calculated MOE is not greater than 2 times higher than the level of concern, MOE = 170 compared to the LOC of 100); EPA i s requiring the 40CFR DFR data. Therefore, EPA is requiring the 40CFR DFR data requirement to facilitate any necessary exposure assessments refinements and to further EPA’s general understanding of the availability of dislodgeable foliar pesticide residue s. The studies should be conducted on three dissimilar crops; however, HED specifically recommends including grapes in the studies.

9.2.2 Inhalation Post

- application Risk

Based on the Agency's current practices, a quantitative post

- application inhalatio n exposure assessment was not performed for flupyradifurone at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), low vapor pressure ( 7.0 x 10

- 9 

### mm Hg at 20 o 

### C ), and the low proposed use rate (0.365 lb ai/A). However, there are multiple potential sources of post

application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and
received t he SAP’s final report on March 2, 2010 5 

### . The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to identify th e need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational po st

- application inhalation exposure assessment for flupyradifurone.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial
handlers . Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler

5 Available: http://www.epa.gov/scipoly/SAP/meetings /2009/120109meeting.html

### Page 43 of 116

inhalation exposure estimates would be protective of most occupationa l post

- application inhalation exposure scenarios.

Furthermore, inhalation exposure during dusty mechanical activities such as shaking and mechanical harvesting of tree crops is another potential source of post

- application inhalation

exposure. However, th e airblast applicator scenario is believed to represent a reasonable worst case surrogate estimate of post

- application inhalation exposure during these dusty mechanical harvesting activities. The non

- cancer inhalation risk estimate for commercial airblast application does not exceed the Agency’s LOC (i.e., MOE < 100).

A post

- application inhalation exposure assessment is not required as exposure is expected to be negligible. Seed treatment assessments provide quantitative inhalation exposure assessments f or seed treaters and secondary handlers (i.e., planters). It is expected that these exposure estimates would be protective of most post

- application inhalation exposure scenarios.

10.0 References

Ideliz Negrón

- Encarnación, D413192, 12/19/2013. Flupyradi furone

. Report of the Residues of
Concern Knowledgebase Subc ommittee (ROCKS)

.

Jessica Kidwell, 03/18/2014. Flupyradifurone

- Summary of Toxicology Science Advisory Council (ToxSAC) Meeting of February 6, 2014.

K. Rury, D413190, 04/08/2014. Flupyrad ifurone: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for Proposed New Uses of the New Active Ingredient, Flupyradifurone on Soybean Seeds and the Following Agricultural Crops: Brassica;

B ushberries, except C ranberry; C ereal G rains; C itrus; C otton; C ucurbits; F ruiting V egetables;

H ops; L eafy V egetables; L egumes; L ow G rowing B erries; Non

- G rass A nimal F eeds; P eanuts;
P ome F ruit; P rickly P ear s; Root V egetables; S mall V ine C limbing F ruit; T ree N uts, except
A lmonds ; and T uberous and Corm Vegetables.

K. Rury, D413494, 04/08/2014. Flupyradifurone

. Occupational and Residential Exposure
Assessment for a New Insecticide Active Ingredient Proposed for Use on Soybean Seeds and the Following Agricultural Crops: Brassica; B ushberries, except C ranberry; C ereal G rains; C itrus;
C otton; C ucurbits; F ruiting V egetables; H ops; L eafy V egetables; L egumes; L ow G rowing

B erries; Non

- G rass A nimal F eeds; P eanuts; P ome F ruit; P rickly P ear s; Root V egetables; S mall

V ine C limbing F ruit; T ree N uts, except A lmonds; and T uberous and Corm Vegetables.

K. White, D415166, 02/18/2014. Drinking Water Exposure Assessment for the Section 3 New Chemical Registration for use of Flupyradifurone on a Variety of Agricultural Crops.

H. Lantum; R. Baggs, D Krenitsky; M Anders, 12/2002. Nephrotoxicity of Chlorofluoroacetic Acid in Rats. Toxicological Science 70(2): 261

- 8.

### Page 44 of 116

Monique Perron, TXR# 0056903 , 03/08/2014. Flypyradifurone : Summary of the Hazard and Science Policy Council (HASPOC) Meetin g of February 20 th 

### : Waiver for a Subchronic Inhalation Study.

S. Funk, D415670, D413191, D415685, 02/17/2014. Flupyradifurone . First Food Use. Petition for the Establishment of Permanent Tolerances and Registration for Use on Root Vegetables Except Su gar Beet (Subgroup 1B), Tuberous and Corm Vegetables (Subgroup 1C), Bulb Vegetables (Group 3

- 07), Leafy Vegetables (Except Brassica ) (Group 4), Taro Leaves, Turnip Tops; Head and Stem Brassica Vegetables (Subgroup 5A), Leafy Brassica Greens Vegetables (Subgroup 5B), Edible

- Podded Legume Vegetables (Subgroup 6A), Succulent Shelled Pea and Bean (Subgroup 6B), Died Shelled Pea and Bean (except Soybean) (Subgroup 6C), Foliage of Legume Vegetables (except Soybean) (Subgroup 7A), Soybean (Seed), Fruiting Vegetables Except Cucurbits (Group 8

- 10), Cucurbit Vegetables (Group 9), Citrus Fruits (Group
10

- 10), Pome Fruits (Group 11

- 10), Bushberry (Subgroup 13

- 07B), Small Fruit Vine Climbing (Except Fuzzy Kiwifruit) (Subgroup 13

- 07F), Low Gro wing Berry (Subgroup 13

- 07G), Tree Nuts (Group 14

- 12), Cereal Grains Except Rice (Crop Group 15, Except Rice), Forage, Fodder and Straw of Cereal Grains (Crop Group 16), Nongrass Animal Feeds (Forage, Fodder, Straw and Hay) (Group 18), Cottonseed (Subgr oup 20C), Coffee, Hops, Peanuts, Prickly Pear Cactus, and Pitaya. Summary of Analytical Chemistry and Residue Data.

### Page 45 of 116

A ppendix A . Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for the pr oposed food uses of flupyradifurone are in Table A. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A .1 : Toxicology Data Requirements of Flupyradifurone.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ..................... yes

yes

yes

yes

yes
yes yes

yes

yes

yes

yes
yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

................................ .......................... yes

yes

yes

no CR yes

yes

yes

no yes*

870.3700a Developmental Toxicity (rodent)

................................ .. 870.3700b Developmental Toxicity (nonrodent)

............................ 870.3800 Reproduction

................................ ................................ . yes
yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ ................... 870.4300 Chronic/Oncogenicity

................................ ................... yes

yes

yes

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870. 5375 Mutagenicity

— Structural Chromosomal Aberrations

... 870. 5550 Mutagenicity

— Other Genotoxic Effects

....................... yes
yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ .......... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

.............. 870.6300 Develop. Neurotoxicity

................................ ................. no

no

yes

yes CR -

- yes

yes
yes

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

yes

yes yes

yes

yes

Special Studies for Ocular Effects

Acute Oral (rat)

................................ ........................... Subchronic Oral (rat)

................................ .................. Six

- month Oral (dog)

................................ .................. no

no

no -

-

- *Study waived by HASPOC (TXR# 0056903).

### Page 46 of 116

A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity Profile

– Flupyradifurone.

OPPTS
Guideline No. Study Type MRID Results Toxicity Category

870.1000 Acute Oral

- rat 48844101 LD 50 cut off ≥ 2000 mg/kg (HDT) 1/3 death In ACN 2/12 test animals died at 800 mg/kg III

870.1200 Acute Dermal

- Rabbit 48844104 LD 50 > 2 000 mg/kg III

870.1300 Acute Inhalation

- Rat 48844105 LC 50 > 4671 mg/m 3 ( 4.67 mg/L) IV

870.2400 Primary Eye Irritation

-

Rabbit 48844106 Redness of the conjunctivae, reversed within 48 hours (score 2) IV

870.2500 Primary Dermal

Irritation

- Rabbit 48844107 Non

- irritating IV

870.2600 Dermal Sensitization

-

mouse 48844108 Non

- sensitizing NA

Table A.2.2. 

### Repeated dosing, neurotoxicity, mutagenicity, and metabolism studies on Flupyradifurone

.

Guideline
No. Study Type MRID No. (Date)/Classification/ Doses Results

Subchronic toxicity studies

870.3100 (28

- day) 28

- day oral

toxicity study in rats (gavage) 48844149 (2012)

Acceptable /non

- guideline 0, 75, 200, 350 mg/kg/day NOAEL= 75 mg/kg/day LOAEL = 200 mg/kg/day based on decreased food consumption in females; increases in ALT, creatinine, & triglycerides in fem ales, enlarged and prominent lobulation of the liver in males, diffused follicular cell hypertrophy of the thyroid in male. Cytochrome P

- 450 was induced.

28

- day oral toxicity study in rats (diet) 48844150 (2012)

Acceptable/non

- guideline 0, 500, 5000 ppm 0, 33.6, 385 mg/kg/day NOAEL= 33.6 mg/kg/day LOAEL = 385 mg/kg/day based on decreases in body weight, and food consumption; decreases in glucose and total bilirubin; and increases in urea nitrogen and total cholesterol; prominent lobulation of the liv er, and diffused follicular cell hypertrophy of the liver.

28

- day oral toxicity in mice (diet0 48844151 (2007)

Acceptable/non

- guideline 0, 300, 600, 1200 ppm M: 0, 40, 78, 166 mg/kg/day F: 0, 47, 98, 192 mg/kg/day NOAEL = 166/199 mg/kg/day (M/F) (HDT)

28

- day oral toxicity in dogs (diet) (2 dogs/sex/dose) 48844152 (2008)

Acceptable/non

- guideline 0, 500, 2000, 4000 ppm M: 16, 62, 118 mg/kg/day F: 0, 19, 77, 131 mg/kg/day NOAEL = 62 mg/kg/day LOAEL = 118 mg/kg/day based on increased thyroid weights, en larged thyroid, diffuse follicular dilatation of the thyroid, and decreased food consumption.

870.3100 (90

- day) 90

- day oral

toxicity

– rats (diet) 48844111 (2012)

Acceptable/Guideline 0, 100, 500, 2500 ppm M: 0, 6.0, 30.2, 156 mg/kg/day F:0, 7.6, 38.3, 186 mg/kg/day NOAEL = 38 mg/kg/day LOAEL = 156 mg/kg/day based on dark colored thyroid associated with follicular cell hypertrophy. Body weight was slightly decreased.

### Page 47 of 116

Table A.2.2. 

### Repeated dosing, neurotoxicity, mutagenicity, and metabolism studies on Flupyradifurone

.

Guideline
No. Study Type MRID No. (Date)/Classification/ Doses Results

90

- day oral toxicity

– mouse (diet) 48844112 (2012)

Acceptable/Guideline 0, 100, 500, 2500 ppm M:0, 15.6, 80.7 407 mg/kg/day F: 0, 18.8, 98.2, 473 mg/kg/day NOAEL = 81 mg/kg/day LOAEL = 407 mg/kg/day based on consistent decreases in body weight (>10%), liver effects (↑ ALP and ALT, ↓ in total cholesterol, ↑ in absolute and relative liver we ights, ↑ in incidence of moderate diffuse hepatocellular hypertrophy ). Kidney effects (changes in clinical chemistry parameters and loss of multifocal/diffuse cortical epithelial cell vacuolation & increases in urea).

870.3150 90

- oral toxicity

dogs (diet) 48844114 (2012)

0, 400, 1200, 3600/2400 ppm (on week 9 reduced from 3600 to 2400 ppm due to toxicity of the legs) M: 0, 12, 33, 102/85 mg/kg/day F: 0, 12, 41, 107/78 mg/kg/day NOAEL = 12 mg/kg/day LOAEL= 33 mg/kg/day based on skeletal muscle myofib er atrophy/degeneration decreases in body weight towards the end of the study (7

- 9%).

870.3200 28

- day dermal

toxicity study in
rabbits. 48844115 (2012)

Acceptable/guideline 0, 50, 150, 500 mg/kg/day NOAEL= 500 mg/kg/day (HDT).
No adverse effect was seen at any test groups.

870.3456 Subchronic

inhalation

toxicity study in

rats. Not available. HASPOC reviewed the data waiver request from the Registrant. A subchronic inhalation study is not required for flupyradifurone at this time (TXR 0056903).

Chronic toxicity studies

870.4100 Chronic oral

toxicity study in dogs. (1

- year; diet) 48844121 (2012)

Acceptable/Guideline 0, 150, 300, 1000 ppm M: 0, 4.6, 7.8, 28.1 mg/kg/day F: 0, 4.1, 7.8, 28.2 mg/kg/day

N NOAEL= 7.8 mg/kg/day

LOAEL= 28 mg/kg/day based on minimal to slight, focal to multifocal areas of skeletal muscle degeneration in gastrocnemius and/or biceps femoris muscle.

870.4300 Combined

chronic/ carcinogenicity study in rats. 48844123 (2012)

Acceptable/guideline 0, 80, 400, 2000 ppm M: 0, 3.2, 15.8, 80.9 mg/kg/day F: 0, 4.5, 22.5, 120 mg/kg/day
Interim sac. at 52 weeks (10/sex/dose) NOAEL = 15.8 / 22.5 mg/kg/day (M/F) LOAEL = 81/ 120 mg/kg/day (M/F) based on decreases on body weight and body weight gains in females, lens opacity in females, liver effects (macrovacuolation, increased liver weight, eosinophilic/tigroid/mixed foci of hepatocellular alterations increased brown pigmentation), thyroid colloidal alteration and follicular hypertrophy, and lung effects (fomay macrophages and chronic interstitial and perivascular inflammation). In addition, iridial Mydriasis
and retinal fundus were also seen.

870.4200 Carcinogenicity

study in mice. 48844122 (2012)

Acceptable/guideline 0, 70, 300, 1500 ppm M: 0, 10, 43, 224 mg/kg/day F: 0, 12, 53, 263 mg/kg/day
Interim sac. at 52 weeks (10/sec/dose) NOAEL = 43 mg/kg/day LOAEL = 224 mg/kg/day based on a combination decreases in terminal body weights (slight) and body weight gains. Liver weight increases with associated fin ding of diffuse hepatocellular vacuolation.

Developmental and reproductive toxicity studies

### Page 48 of 116

Table A.2.2. 

### Repeated dosing, neurotoxicity, mutagenicity, and metabolism studies on Flupyradifurone

.

Guideline
No. Study Type MRID No. (Date)/Classification/ Doses Results

870.3700 Developmental

toxicity

- rabbit. (gavage) 48844117 (2012) (main study)

Acceptable/non

- guideline 0, 7.5, 15, 40 mg/kg/day

49113601 (2013) Range finding study 0, 15, 40, & 80 mg/kg/day Combined data from both the main and the range finding study. Maternal NOAEL = 80 mg/kg/day
Maternal LOAEL could not be established.

Developmental NOAEL = 40 mg/kg/day Developmental LOAEL = 80 mg/kg/day based increases in the number of dead fetuses and dead fetus per litter. Reduced fetal body weight (8%).

870.3700 Developmental

toxicity

– rat (gavage) 48844116 (2012)

Acceptable/guideline 0, 15, 50, 150 mg/kg/day Maternal NOAEL = 50 mg/kg/day
Maternal LOAEL = 150 mg/kg/day based increased incidence of salivation and decreased food consumption.

Developmental NOAEL = 50 mg/kg/day Developmental LOAEL =150 mg/kg/day based on increased incidence of incomplete parietal and hyoid centrum skull
bone ossification.

870.3800 2

- Generation

reproduction study in rats. 48844119 (2011)

Acceptable/Guideline 0, 100, 500, 1800 ppm Premating P 1 M: 0, 6.6, 32.5, 117 mg/kg/day F: 7.7, 38.7, 137 mg/kg/day Parental NOAEL = 38.7 mg/kg/day Parental LOAEL = 137 mg/kg/day based o n decreased body weights

Reproductive NOAEL = 38.7 mg/kg/day Reproductive LOAEL = 137 mg/kg/day based on reduced number of estrus cycles

Offspring NOAEL = 7.7 mg/kg/day Offspring LOAEL = 38.7 mg/kg/day based on decreases in pup body weights and pup body weight gains in F 2 pups. Neurotoxicity studies

870.6200a Acute

neurotoxicity in rats. (gavage) 48844138 (2011)

Acceptable / Guideline 0, 20, 35, 50, 200, 800 mg/kg NOAEL = 35 mg/kg/day LOAEL = 50 mg/kg/day based on increased incidences of pupil dilation in females on Day 1and piloerection in both sexes. At the next higher dose level (200 mg/kg) or above,
the observed effects included lower muscle tone, rapid respiration, low arousal, tr emors, myoclonic jerks, chewing, repetitive licking of lips, gait incoordination, flattened or hunched posture, dilated pupils, impaired (uncoordinated or slow) righting reflex, impaired flexor and tail pinch responses and reduced rectal temperature. Autom ated measures of motor activity were also reduced in both sexes, compared to controls.

870.6200b Subchronic

neurotoxicity study in rats. 48844139 (2011)

Acceptable / Guideline 0, 100, 500, 2500 ppm M: 0, 5.7, 29.4, 143 mg/kg/day F: 0, 6.9, 34.8, 173 mg /kg/day NOAEL = 34.8 mg/kg/day LOAEL = 143 mg/kg/day based on decreased body weight
in both sexes

Neurotoxicity was not observed at the doses tested.

870.6300 Developmental

neurotoxicity study in rats. 434203011 (2012)

Acceptable/guideline 0, 120, 500, 1200 ppm 0, 10.3, 42.4, 102 mg/kg/day Maternal NOAEL = 102 mg/kg/day (HDT)

Offspring NOAEL = 42 mg/kg/day Offspring LOAEL = 102 mg/kg/day based on statistically significant increases in startle response amplitude.

### Page 49 of 116

Table A.2.2. 

### Repeated dosing, neurotoxicity, mutagenicity, and metabolism studies on Flupyradifurone

.

Guideline
No. Study Type MRID No. (Date)/Classification/ Doses Results

Metabolism studies : It should be noted that absorption, distribution, metabolism, and elimination (ADME) of flupyradifurone was conducted using three different labeling positions: 14 C in the pyridinlylmethylene bridge, in the 4

- position of furanone ring and in the 1 positio n of the ethyl side chain as indicated below:

Pyridinylmethyl

14 C Furanone

- 4

- 14 C Ethyl

- 1

- 14 C

870.7485 ADME with

[pyridinylmethyl

14 C] BYI 02960

- male Wistar rats 48844141 (2012)

Acceptable/guideline Single gavage dose at 2 or 200 mg/kg The absorption started immediately after dosing with the peak plasma concentration (C max ) reached approximately 1
hour after administration in the low dose tests and within approximately 2 to 4 hours in the high dose tests.

The distribution of the radioactivity within the body was fast. From the maximum plasma level (C max ), the radioactivity level declined slowly down to approximately
50% of C max after 4

– 8 hours in the low dose tests and after
8

– 24 hours in the high dose test s and down to low values around the LOQ in the low dose tests and to approximately
0.5% of C max in the high dose tests by study termination (72 hours)

.

Elimination was rapid, mainly by the renal route and essentially complete by 72 hours post dosing. Fema le rats exhibited slightly higher renal excretion rates of approximately 86% and 90% of the administered dose compared to approximately 76% of the dose in males.
Faecal e limination accounted for approximately 23

– 26% of
the total administered dose in males, and 7

– 10% in females. At the time of sacrifice, 72 hours after administration, the radioactive residues in organs and tissues were low, and only trace amounts of approx. <0.1

– 0.3% of the total administered dose was detected in the body and in the GIT

.

The principal metabolic reactions of [pyridinylmethyl

14C]BYI 02960 in rats were: (1) hydroxylation followed by conjugation with glucuronic acid to or with sulphate; (2) cleavage of the difluoroethyl group forming BYI 02960

- des

- difluoroethyl; and cleavage of the molecule at the pyridinylmethyl bridge forming BYI 02960

- 6

- CNA, which was further conjugated with glycine to BYI 02960

- hippuric
acid. Parent compound, three major ( BYI 02960

- OH, BYI
02960

- 6

- CNA and BYI 02960

- hippuric acid) and five
minor metabolite s were isolated from urine and four of them identified by spectroscopic methods

.

[ P yridinylmethyl

14 C] wh ole body autoradiography

rat 48844142 (2011a)

Acceptable/guideline

A single gavage dose of 5 mg/kg [pyridinylmethyl

14 C]BYI02960 in 0.5% aqueous Tragacanth®. The data demonstrate that BYI 02960 was readily absorbed from the gastrointestinal tract and distributed throughout the body immediately after administration.

In male and female rats, maximum residue levels were reached for nearly all organs and tissues at one hour after
administration

. At this time, the levels for liver and kidney

### Page 50 of 116

Table A.2.2. 

### Repeated dosing, neurotoxicity, mutagenicity, and metabolism studies on Flupyradifurone

.

Guideline
No. Study Type MRID No. (Date)/Classification/ Doses Results

were significantly higher than in blood, suggesting a preferred clearance from blood and distribution mainly to those organs tha t are responsible for metabolism (liver) and excretion (kidney), along with several glands. Very low
levels were found in the brain, spinal cord and in renal fat. From peak levels , a fast decline of radioactivity concentrations was observed for all organs and tissues in males and females during the whole testing period. In both sexes, concentrations fell for most organs and tissues below 5% of the maximum after one day and below the limit of quantification after seven days post
administration. No significa nt retention of [pyridinylmethyl

14 C] BYI 02960 in male and female rats
was found.

ADME with [furanone

- 4 14 C]

- BYI 02960

- male Wistar rats 48844143 (2011b)

Acceptable/guideline Single gavage dose of 2 mg/kg bw [furanone

- 4

- 14 C]BYI 02960 in 0.5% aqueous Tragacanth® [Furanone

- 4

- 14C]BYI 02960 was nearly completely
absorbed since >79% and >91% of the total dose
administered was detected in the urines and the organs of
male and female rats

, respectively. The absorption started immediately after dosing ; peak plasma concentration (C max ) was reached approximately 1.5 hours after administration in
both sexes

.

The distribution of the radioactivity within the body was
fast. From the maximum plasma level (Cmax)

, the radioactivity level declined slowly down to appro ximately
50% of Cmax after 8 hours in both sexes and <1% of Cmax 72h after dosing.

Excretion was rapid and mainly by the renal route. The major part of the dose was excreted within 24 hours after

treatment

. At 168 hours after administration, approximately 0.5% of the dose administered for males and approximately 0.2% for females was still detected in the body

.

The parent compound was metabolized to approximately 20
metabolites in total , consisting of one major ( BYI 02960

- OH ) and six minor metabolites of an isolated and purified
compound



### . Parent compound represented the predominant part of the radioactivity in urine but in feces the metabolite

, BYI 02960

- OH

, was more prominent.

The principal metabolic reactions of [furanone

- 4

- 14 C]BYI
02960 in rats were: (1) hydroxylation followed by conjugation with glucuronic acid or with sulphate; (2) cleavage of the difluoroethyl group forming BYI 02960

- desdifluoroethyl; (3) cleavage of the molecule at the pyridinylmethyl bridge forming BYI 02960

- difluoroethyl

amino

- fu ranone; and (4) cleavage of molecule at the nitrogen

- carbon bond next to the furanone moiety followed by further conversion to C1 and C2 compounds of the natural pool including complete degradation to carbon
dioxide.

### Page 51 of 116

Table A.2.2. 

### Repeated dosing, neurotoxicity, mutagenicity, and metabolism studies on Flupyradifurone

.

Guideline
No. Study Type MRID No. (Date)/Classification/ Doses Results

[Furanone

- 4

- 14 C] whole body autoradiography

rat 48844144 (2011b)

Acceptable/Guideline a single gavage dose of 5 mg/kg bw [furanone

- 4

- 14 C]BYI
02960 in 0.5% aqueous Tragacanth®. BYI 02960 was readily absorbed from the gastrointestinal tract and distributed throughout the body immedia tely after administration. At 2 days after dosing, the excretion of radioactivity via urine and feces was almost completed with renal excretion as the predominant route. By 168 hours post dosing approximately 81% in males and 88% in females of
the administ ered dose were recovered in urine and approximately 14% in males and 6% in females in the
feces. A pproximately 1 % (females) to 3% (males) of the
dose was exhaled as 14C

- carbon dioxide during a sampling period of 48 hours.

In male and female rats, maximum radioactivity levels were reached for nearly all organs and tissues at one hour after
administration. At this time, the values for liver, kidney, brown fat, myocardium, nearly all glandular and hormonal organs, and the olfactory bulb were hig her than that in the blood. After seven days, low radioactive residues were measured in nearly all organs and tissues. No evidence for accumulation or significant retention of [furanone

- 4

- 14 C]BYI 02960 in male and female rats



### [ Furanone

- 4

- 14 C]

Metabolism in Organs and
Tissues

-- rat 48844145 (2012b)

Acceptable/guideline

A single gavage dose of 3 mg/kg [furanone

- 4

- 14 C]BYI02960 in 0.5% aqueous Tragacanth® and sacrificed by exsanguination under anaesthesia at 6 hours post dosing. Highest radioactivity levels were detected in the liver and kidney which are the main organs responsible for metabolism and urinary excretion. The residue

- values for plasma and the other tissues were comparable for both

sexes. In the 6 h samples of plasma, organs, and tissues, the parent compound (BYI 02960) was by far the largest component accounting for more than 72% of the total radioactive residues (TRR). For all identified metabolites, the values were less than 12% of the TRR. In the respective urine

s ample pools, the parent compound was the largest radioactive component (≈ 22% of the dose in males and 38% in females). The metabolism was qualitatively similar in male and
female rats. The differences occurred however quantitatively. Metabolism of the par ent compound to the different metabolites was significantly higher in males compared to female rats

ADME with [Ethyl

- 1 14 C]

- BYI 02960

- male Wistar rats 48844146 (2011a)

Acceptable/guideline a single gavage dose of 2 mg/kg bw [Ethyl

- 1

- 14 C]BYI02960 in 0.5% aqueous Tragacanth® [Ethyl

- 1

- 14 C]BYI02960 was nearly completely absorbed
since >85% of the total dose administered was detected in the urine and the body without GIT at sacrifice. The absorption started immediately after dosing; the peak plasma concen tration (C max ) was reached approximately 1
hour after administration. The distribution of the radioactivity within the body was fast. From the maximum plasma level (C max ), the radioactivity level declined slowly down to approximately
50% of C max within 8 hours and to approximately 8% of
C max 72h after dosing. Elimination was rapid and mainly by the renal route. The major part of the dose (>87%) was excreted within 24 hours after treatment. Approximately 82% of the total
administered dose was excreted in th e urine and approximately 14% in the faeces. Only a negligible part of 0.2% of the total administered dose was detected in expired air. At the time of sacrifice, 72 hours after administration, a

### Page 52 of 116

Table A.2.2. 

### Repeated dosing, neurotoxicity, mutagenicity, and metabolism studies on Flupyradifurone

.

Guideline
No. Study Type MRID No. (Date)/Classification/ Doses Results

small proportion of approximately 3% of the total dose
admini stered was still detected in the body without GIT. Parent compound, one major ( BYI 02960

- OH) and five
minor metabolites were identified

. The label specific
metabolite BYI 02960

- DFA was additionally identified
(representing ≈5.77% of the administered dose)



### . Parent compound represented the predominant part of the radioactivity in urine but in faeces samples (≈56% of the administered dose) the metabolite BYI 02960

- OH was more prominent.
The principal metabolic reactions of [ethyl

- 1

- 14C]BYI
02960 in rats were: (1) hydroxylation followed by conjugation with glucuronic acid; (2) cleavage of the difluoroethyl group leading to BYI 02960

- DFA; and (3) cleavage of the molecule at the pyridinylmethyl bridge
leading to BYI 02960

- difluoroethyl

- amino

- furanone



### .

[ Ethyl

- 1

- 14 C]

- Metabolism in organs and
tissues

- rat 48844147 (2012a)

Acceptable/guideline a single gavage dose of 3 mg/kg bw [ethyl

- 1

- 14 C]BYI02960 in 0.5% aqueous Tragacanth® The distribution of the radioactivity within the central compartments of the body (e.g. blood, liver, and kidney)
was fast for both sexes

. Radioactivity residues showed a distinctive preference towards the liver and kidney as the main organs responsible for metabolism and urinary
excretion.

Metabolism of BYI02960 was extensive. Metabo lic reactions took place at least at 3 different structural positions of the test compound. The principal metabolic reactions of [ethyl

- 1

- 14C]BYI 02960 in rats were: (1) hydroxylation followed by conjugation with glucuronic acid, (2) cleavage of the difluo roethyl group leading to BYI
02960

- DFA and (3) cleavage of the molecule at the pyridinylmethyl bridge leading to BYI 02960

- difluoroethyl

amino

- furanone.
In the 24 hours samples of plasma, and organs and tissues
BYI 02960

- DFA was the by far largest metabolite accounting for more than 50% of the TRR. For all other identified metabolites, the values were less than 10% of the TRR. The percentage

- values of the parent compound in these samples ranged from 6 to 38% of the TRR. In th e respective urine sample pools, the parent compound was the largest radioactive component (approximately 48% of the dose in males and 77% in females).
The metabolism was qualitatively similar in male and
female rats. The differences occurred however
quant itatively. Metabolism of the parent compound to the different metabolites was significantly higher in males
compared to female rats



### .

### Page 53 of 116

Table A.2.2. 

### Repeated dosing, neurotoxicity, mutagenicity, and metabolism studies on Flupyradifurone

.

Guideline
No. Study Type MRID No. (Date)/Classification/ Doses Results

870.7600 (Triple pack) I

n

- vivo Dermal absorption study
in rats. 200 g/L Soluble

concentrate formulation (SL200) 48844557 (2010)

Acceptable Undiluted 200 g/L SL formulation, 0.625 g/L aqueous dilution, or 0.1 g/L aqueous
dilution. Exposure time: 8
hours. Using the 24 hour measuring values, the potential dermal absorptions were: 19.6%, 8.3% and 10.3% for undiluted 200/L SL formulation, 0.625 g/L aqueous dilution, and 0.1 g/L aqueous dilation, respectively. Based on the 24

– hour measuring
dermal absorpti on values
from the in vivo
and in

- vitro
dermal absorption
studies with 0.1 g/L aqueous dilution , the in

vivo human
dermal absorption factor
was estimated to
be 7.42% In

- vitro dermal penetration
studies with rat
and human skin. 200 g/L Soluble

concentrate formulation (SL200) 48844558 (2010)

Acceptable Undiluted 200 g/L SL formulation, 0.625 g/L aqueous dilution , or 0.1 g/L aqueous dilution. Exposure time: 8
hours. Based on 24

- hour measuring interval, the dermal penetration were:
Rat skin : 0.15 %, 5.67%, and 6.61% for 200 g/L concentrate, 0.625 g/L aqueous dilution, and 0.1 g/L aqueous dilution, respectively.
Human skin : 0.20% 2.01%, and
4.75% for 200 g/L concentrate, 0.625 g/L aqueous dilution, and 0.1 g/L aqueous dilution, respectively

The human DAF was derived as
follows: in vivo human absorption (% absorbed) = ( in vitro human % absorption × in vivo rat % absorbed) ÷

in vi tr o rat % absorption.

Immunotoxicity study

870.7800 28

- Day Dietary

Immunotoxicity Study 48844148 (2011)

Acceptable / Guideline 0, 125, 600, 3000 ppm 0, 10, 50, 230 mg/kg/day Systemic Toxicity NOAEL = 230 mg/kg/day LOAEL > 230 mg/kg/day

Immunotoxicity NOAEL = 230 mg/kg/day LOAEL > 230 mg/kg/day Immunotoxicity was not observed at the doses tested.

Genotoxicity studies

870.5100 (84

- 2 a) Mutagenic

potential of
Salmonella typhimurium 48844124 (2009a)

Acceptable/guideline TA98, TA100, TA102, TA1535, TA1537; (

- /+ S9) ; 0, 16, 50, 158, 500, 1581 and
5000 μg/plate Negative for mutagenic activity in +/

- S9 test systems up to the limit dose (5000 μg/plate).

870.5100 (84

- 2 a) Reverse mutation

in Salmonella typimurium

. 48844125 (2011)

Acceptable/guideline TA98, TA100, TA102, TA1535, TA1537 (+/

- ) S9 0, 3, 10, 33, 10 0, 333, 1000,
2500 and 5000 μg/plate for Experiment1, and 0, 33, 100, 333, 1000, 2500 and 5000 μg/plate for Experiment 2. (DMSO). Negative for mutagenic activity in +/

- S9 test systems up to the limit dose (5000 μg/plate).

### Page 54 of 116

Table A.2.2. 

### Repeated dosing, neurotoxicity, mutagenicity, and metabolism studies on Flupyradifurone

.

Guideline
No. Study Type MRID No. (Date)/Classification/ Doses Results

870.5300 In vitro forward

gene mutation assay in
mammalian cells (hamster V79 Cells) (HPRT mutation assay) 48844128 (2009)

Acceptable/guideline 0, 46, 92, 184, 368, 736, 1472

and 2944  g/mL for 5 hours (±S9) at 37  C. Negative in the in the V79/HPRT mutation assay (+/

- ) S9.

870.5375 (84

- 2) In vitro

Chromosome
Aberration Test
with Chinese

Hamster V79
Cells 48844131 (2009)

Acceptable/guideline Toxicity assay, 0

– 3000  g/mL (the limit dose) with a 4

- hour treatment period. Seven
concentrations from 0

– 3000 μg/mL with an 18

- hour treatment period. Negative for the induction of structural and numerical
chromosome aberrations in cultured Chinese Hamster V79
cells (+/

- ) S9.

870. 5395 In vivo mouse

( Crl:NMRI BR
mice , males )
micronucleus assy (bone

marrow plychromatic erythrycytes) 48844134 (2009b)

Acceptable/guidelline 0, 10, 20 and 40 mg/kg by two
intra

- peritoneal injections 24 hours apart

. Negative for clastogenic and aneugenic activity in the mouse bone marrow micronucleus assay.

In vivo
Micronucleus Assay in Bone
Marrow Cells of
the Mouse (females) 48844135 (2011)

Acceptable/guideline 0, 12.5, 25 and 50 mg/kg by
two intra

- peritoneal injections 24 hours apart

. Negative for clastogenic and aneugenic activity in the mouse bone marrow micronucleus assay.

Toxicity Studies on Metabolites

Difluoroacetic acid

— (BCS

- AA56716)

14

- Day oral toxicity study

- rat (dietary) 48844153 (2011)

0, 500, 2000, & 8000 ppm M: 0, 48, 187 & 745 mg/kg bw/ day F:0. 51, 201 & 800 mg/kg bw/ day NOAEL = 51 mg/kg/day LOAEL = 187 mg/kg/day based on mean glucose concentration reduced by 41% in males and 48% in females (p <0.01), mean urea concentration was 25% higher in
females (not statistically significant) in comparison to the
controls

. 90

- day oral toxicity study

- rat (dietary) 48844113 (2012)

Acceptable/guideline 0, 200, 1000, 6000 ppm M: 0, 12.7, 66.2, 380 mg/kg/day F:0, 15.6, 78.7, 472 mg/kg/day NOAEL = 12.7/15.6 mg/kg/day (M/F) LOAEL = 66.2/78.8 mg/kg/day (M/F) based on a number of findings including reduced body weight approaching 10% on week 13, decreased food consumption, black foci in the glandular part of the stomach with correlated histopathology finding of focal glandular erosion/necrosis. In addition, slight decreases in hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin, and hematocrit.

Bacterial reverse
mutation ( Salmonella typhimurium strains TA98, TA100, TA102, TA1535, TA1537) 48844126 (2010a)

Acceptable/guideline 0, 3, 10, 33, 100, 333, 1000,
2500 and 5000 μg/plate (+/

- ) S9 Negative for mutagenic activity S almonella Typhimurium

. (+/

- ) S9

### Page 55 of 116

Table A.2.2. 

### Repeated dosing, neurotoxicity, mutagenicity, and metabolism studies on Flupyradifurone

.

Guideline
No. Study Type MRID No. (Date)/Classification/ Doses Results

Mammalian cell gene mutation ( Chinese

Hamster V79
cell/HPRT ) 48844129 (2010a)

Acceptable/guideline 0, 30, 60, 120, 240, 480 and

960  g/mL (+/

- ) S9 Negative in (+/

- ) S9 V79/HPRT mutation assay.

In vitro cytogenetics (chromosome aberration assay
in Chinese
hamster V79 cells) 48844133 (2010b)

Acceptable/guideline 0, 240, 480 and 960 μg/mL (+/

- ) S9 Negative for the induction of structural and numerical
chromosome aberrations in cultured Chinese Hamster V79 cells (+/

- ) S9.

BCS

- CC98193 ( BYI 02960

- difluoroethyl

- amino

- furanone)

28

- Day oral toxicity study

– rat (dietary) 48844109 (2012)

Acceptable/Guideline 0, 200, 800, 3000 ppm M:0, 17, 67, 244 mg/kg/day F:0,19, 76, 256 mg/kg/day NOAEL = 244/273 mg/kg/day (M/F) (HDT)
No adverse effect was found at all tested dose levels.

Bacterial reverse
mutation
Salmonella typhimurium strains TA98, TA100, TA102, TA1535, TA1537 48844127 (2010b)

Acceptable/guideline 0, 3, 10, 33, 100, 333, 1000,
2500 and 5000 μg/plate for Experiment1, and 0, 33, 100, 333, 1000, 2500 and 5000 μg/plate for Experiment 2.In
DMSO. Negative tested up to the li mit dose 5000 μg/plate (+/

- ) S9.

Mammalian gene
mutation (Chinese
Hamster V79 Cells/HPRT) 48844130 (2011)

Acceptable/guideline 0, 51.3, 102.5, 205, 410, 820

and 1640  g/mL (+/

- ) S9. Negative in the V79/HPRT mutation assay (+/

- ) S9

In vitro cytogenetics (chromosome aberration assay
in Chinese
hamster V79 cells) 48844133 (2011a)

Acceptable/guideline

0

– 1636  g/mL (the limit dose) Positiv e (

- S9) Negative (+S9)

In vivo mouse
bone marrow
micronucleus

assay 48844136 (2011b)

Acceptable/guideline 0, 125, 250 and 500 mg/kg by
two intra

- peritoneal injections 24 hours apart Negative for clastogenic or aneugenic activity in the mouse bone marrow micronucleus assay.

In vivo UDS with rat hepatocytes 48844137 (2011c)

Acceptable/gu ideline 0, 1000 and 2000 mg/kg by a single oral gavage dose. Negative in unscheduled DNA synthesis at up to the limit dose of 2000 mg/kg bw.

( 6

- chloro

- 3

- pyridyl)methanol (IM

- 0)

### Page 56 of 116

Table A.2.2. 

### Repeated dosing, neurotoxicity, mutagenicity, and metabolism studies on Flupyradifurone

.

Guideline
No. Study Type MRID No. (Date)/Classification/ Doses Results

Bacterial reverse gene mutation

assay Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537, and
Escherichia coli
strain WP2 uvrA 44988432 (1997)

Acceptable/guideline 0, 313, 625, 1250, 2500 and
5000 μg/plate. (in DMSO) Negative up to the limit dose (5000 μg/plate) with (+/

- ) S9

.

6

- chloronicotinic acid ( IC

- 0)

Bacterial reverse gene mutation

assay Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537, and
Escherichia coli
strain WP2 uvrA 44988502 (1997b)

Acceptable/guideline 0, 313, 625, 1250, 2500 and
5000 μg/plate. ( in DMSO). (+/

- ) S9 Negative up to the limit dose (5000 μg/plate) with (+/

- ) S9

.



### A.3 Hazard Identification and Endpoint Selection

A. 3.1 Acute Reference Dose (aRfD)

– General population including female 13+ Study Selected : Acute neurotoxicity study in rats

MRID No.: 48844138 Dose and Endpoint for Establishing aRfD: NOAEL = 35 mg/kg/day. LOAEL = 50 mg/kg/day based on increased incidences of piloerection in both sexes and pupil dilation in females on Day 1. At the next higher dose level (200 mg/kg) or above, the observed effect s included lower muscle tone, rapid respiration, low arousal, tremors, myoclonic jerks, chewing, repetitive licking of lips, gait incoordination, flattened or hunched posture, dilated pupils, impaired (uncoordinated or slow) righting reflex, impaired flexo r and tail pinch responses and reduced rectal temperature. Automated measures of motor activity were also reduced in both sexes, compared to controls. Uncertainty Factor (UF) : 100 (10x intraspecies, 10x interspecies); FQPA SF = 1x Comments about Study/Endp oint/Uncertainty Factor : The acute neu rotoxicity study is appropriate; the clinical sign, pupil dilatation, is one of the classical signs produced by activation of nicotinic acetylcholine receptor (nAchR) and is a single dose effect. The selected NOAEL is also protective of the effects seen in the rabbit developmental toxicity study, where increased number of dead fetuses and dead fetuses per litter were seen at 80 mg/kg/day.

aRfD = 35 mg/kg/day = 0.35 mg/kg/day

100

aPAD = 0. 35 mg/kg/day = 0.35 mg/kg/day

1

### Page 57 of 116

A.3.2 Chronic Reference Dose (cRfD ) Study Selected : One year Oral Toxicity Study in Dogs

MRID No.: 48844121 Dose and Endpoint for Establishing cRfD: NOAEL = 7.8 mg/kg/day. LOAEL = 28 mg/kg/day based on skeletal muscle degeneratio n. Uncertainty Factor (UF) : 100 (10x intraspecies, 10x interspecies); FQPA SF = 1x Comments about Study/Endpoint/Uncertainty Factor : The one year dog study is appropriate for both the duration and population of concern. The effect (skeletal muscle degener ation) found at the LOAEL or above is rather serious and may relate to mode of the pesticidal action (activation of nicotinic acetylcholine receptions at the neuromuscular junction) of the chemical. In addition the NOAEL (7.8 mg//kg/day) is protective of t he offspring effect (decrease in F2 pup body weight) observed in the 2

- generation reproduction study.

cRfD = 7.8 mg/kg/day = 0.078 mg/kg/day

100

cPAD = 0.0 78 mg/kg/day = 0.078 mg/kg/day

A.3.3 Incidental Oral Exposure (Short

- Term) Selected Study: 90

- Day Oral Toxicity Study in Dogs
Co

- critical study: 2

- Generation reproduction study in rats

MRID No.: 48844114 Dose and Endpoint for Risk Assessment: NOAEL = 12 mg/kg/day. LOAEL = 3 3 mg/kg/day
based on skeletal muscle atrophy/degenera tion

Uncertainty Factor (UF) : Residential Level of Concern for MOE = 100

Comments about Study/Endpoint/Margins of Exposure: This study is appropriate for the duration of exposure. In addition, the toxicity endpoint (skeletal muscle degeneration) is ra ther serious and may relate to mode of the pesticidal action (activation of nicotinic acetylcholine receptions at the neuromuscular junction) of the chemical and the dog is the most sensitive species. In addition the NOAEL (12 mg//kg/day) is protective of the offspring effect (decrease in F2 pup body weight) observed in the 2

- generation at 38.7 mg/kg/day in the 2

- generation reproduction study. The 2

- generation reproduction study is selected as a co

- critical study in
selection.

A.3.4 Dermal Exposure (Shor t

- term; 1

- 30 Days ) Selected Study : 90

- day oral toxicity study in dogs
Co

- critical study: 2

- Generation reproduction study in rats

MRID No .: 48844114 Dose and Endpoint for Risk Assessment: NOAEL = 12 mg/kg/day. LOAEL = 3 3 mg/kg/day
based on skeletal muscle atrophy/degeneration decreases in body weight towards the end of the study (7

- 9%)

.

Uncertainty Factor (UF) : MOE = 100

### Page 58 of 116

Comments about Study/Endpoint/Margins of Exposure : This study is appropriate for the duration of exposure. In addition, the tox icity endpoint (skeletal muscle degeneration) is rather serious and may relate to mode of the pesticidal action (activation of nicotinic acetylcholine receptions at the neuromuscular junction) of the chemical and the dog is the most sensitive species. In a ddition the NOAEL (12 mg//kg/day) is protective of the offspring effect (decrease in F2 pup body weight) observed in the 2

- generation at 38.7 mg/kg/day in the 2

- generation reproduction study.

Inhalation Exposure (Short

- and Intermediate

- Term)
Selected Study: 90

- day oral toxicity study in dogs
Co

- critical study: 2

- generation reproduction study in rats.

MRID No.: 48844114 Dose and Endpoint for Risk Assessment: NOAEL = 12 mg/kg/day. LOAEL = 3 3 mg/kg/day
based on skeletal muscl e atrophy/degeneration

.

Uncertainty Factor (UF) : MOE =100

Comments about Study/Endpoint/Margins of Exposure: No route specific (inhalation) study is available. This dog oral toxicity study is appropriate for the duration of exposure. In addition, the toxicity endpoint (skeleta l muscle degeneration) is rather serious and may relate to mode of the pesticidal action (activation of nicotinic acetylcholine receptions at the neuromuscular junction) of the chemical and the dog is the most sensitive species. In addition the NOAEL (12

m g//kg/day) is protective of the offspring effect (decrease in F2 pup body weight) observed in
the 2

- generation at 38.7 mg/kg/day in the 2

- generation reproduction study.

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90

- Day Oral Toxicity

- R at In a subchronic dietary study ( MRID 48844111) , BYI 02960 (99.5%; NLL 7780

- 44

- 6 ) was
administered to six to seven week

- old Wistar Rj:WI (IOPS HAN) rats in groups of
10 rats/sex/dose at 0, 100, 500, or 2500 ppm daily for 95 to 97 days (0/0, 6.0/7.6, 30.2/38.3, and 156/186 mg/kg bw/d for M/F, respectively). Two additional groups (10 rats/sex/dose) received 0 or 2500 ppm for the same treatment period, then received diet free of the test substance for an additional 30 or 31 day recovery period.

There we re no test substance related effects on clinical signs or FOB parameters, unscheduled mortality, ophthalmology, or urinalysis parameters. The study also examined test substance concentrations in plasma during the last week of the study; the results indicat ed a linear increasing trend between plasma concentration vs. dose level administered between 100 and 500 ppm, but a sub

- linear increasing trend between 100 and 2500 ppm plasma concentrations of test substance. A slight sex

- specific difference in test subs tance plasma concentrations was noted, with higher levels observed in females (1.3

– 1.7× higher than males).

At 2500 ppm, decrease s in mean absolute body weight and body weight gain s were observed in both sexes during the treatment period . During day 8 measuring interval, the absolute body weight decrement in females reached 10%, and at day 14 the decrease was 8%. Thereafter, the

### Page 59 of 116

decrease in body weight was below 8% and persisted until the end of the study. The slight body changes were not considered adverse in males; for females, the decrease (↓10%) reached the magnitude of being adverse at the beginning of the study. The adverse body weight effect in females might reflect higher concentrations of the test compound in females relative t o males. The food consumption was consistently decreased in both males and females (↓9% to ↓29%).
The increased incidence of gross and histopathological changes in the thyroid (dark color thyroid and thyroid follicular cell hypertrophy) combined with incre ased absolute and relative thyroid weight s are considered to be adverse

.

No adverse effects were found at 100 and 500 ppm.

Therefore, the NOAEL in both sexes was 500 ppm (38 mg/kg bw/day); LOAEL was 2500 ppm (156 mg/kg bw/day) based on increased incidence of thyroid f ollicular cell hypertrophy with associated increases of absolute and relative thyroid weights
, decreased body weights in females , and decreased food consumption in both sexes

.

This study is classified as fully reliable (acceptable/guideline) a nd satisfies guideline requirements for a subchronic oral toxicity in rats [ OPPTS 870.3100; OECD 408 (1998)].

870.3100 90

- Day Oral Toxicity

- Mouse
In a 90

- day dietary study ( MRID 48844112) , BYI 02960 (99.5%; NLL 7780

- 44

- 6 ) was administered to six week old C57BL/6J mice in groups of 10/sex/dose at 0, 100, 500, or 2500 ppm (equivalent to 0/0, 15.6/18.8, 80.7/98.2, or 407/473 mg/kg bw/d). Analysis of the plasma concentration of the test substance was conducted on blood sample s of 5/sex/dose group.

Under the conditions of this study BYI 02960 did not affect mortality or produce clinical signs of toxicity. In addition, the test chemical did not produce adverse effects at 100 and 500 ppm.

In males at 2500 ppm, lower body weight gain led to terminal body weight s being 10% lower
than controls. While decreases in body weight gain in males may be associated with decreased absolute food consumption, particularly in study weeks 1 to 2, where up to 11% lower consumption was observed Te rminal body weights were unaffected in 2500 ppm females when accounting for differences in starting body weight s

.

A t 2500 ppm

, clinical chemistry examinations showed a 30/24% (M/F, p < 0.01) decrease in serum cholesterol, 38% (p<0.01) increase in alkaline p hosphatase (ALP) activity in male serum,
and 106% increase in alanine aminotransferase (ALT) activity in female serum

. Absolute and relative liver weights were increased in females at 2500 ppm. When the clinical chemistry parameter changes were considered in the context of an increased severity of diffuse centrilobular hepatocellular hypertrophy in both sexes, these findings we re consistent with toxicologically adverse hepatocellular toxicity in both sexes.

Additionally at 2500 ppm , in clinical chemistry examinations there were increases of 51% in serum urea (p < 0.05) in males and a 5% decrease (p < 0.05) in serum protein in both sexes . When considered in the context of an 11% (p< 0.01) decrease in absolute and relative (to brain weight) kidney weight, along with the absence of multifocal/diffuse cortical epithelial cell vacuolation,

### Page 60 of 116

collectively, these changes suggest test substance related, toxicologically adverse renal toxicity
i n males at 2500 ppm.

The NOAEL was 500 ppm (81 mg/kg/day) for both sexes. The LOAEL was 2500 ppm (407 mg/kg/day) based on based on consistent decreases in body weight (>10%) with associated reduction in body weight gains in male, liver effects (↑ ALP and ALT, ↓ in total cholesterol, ↑ in absolute and relative liver weights, increased incidence of moderate diffuse hepatocellular hypertrophy ). Kidney effects (changes in clinical chemistry parameters and loss of multifocal/diffuse cortical epithelial cell v acuolation & increases in urea)

.


### The results of the plasma analysis showed that t est substance concentrations in plasma at 90

- days

were higher in males than in females at all dose levels. I n both sexes, a generally linear
correlation between administered concentrations of test substance and plasma concentrations was
observed.

This study is classified as fully reliable (acceptable/guideline) and satisfies guideline requirements for a subchronic oral toxicity in mice [ OPPTS 870.3100; OECD 408].

870.3150 90

- Day Oral Toxicity

- Dog
In a 90

- day dietary study ( MRID 48844114) , BYI 02960 was administered to seven to eight month old beagle dogs in groups of 4/sex/dose at dietary concentrations of 0, 4 00, 1200, or
3600/ 2400ppm (high dose reduced from 3600 ppm sta rting on study week 9). Dose levels were equivalent to 0/0, 12/12, 33/41, and 102[85]/107[78] mg/kg bw/d respectively.

BYI 02960 did not affect mortality, ophthalmology, or urinalysis parameters in this study.

Clinical signs were confined to the 3600 ppm dose groups, where one male and one female experienced unsteady/stiff back legs and lower back on study days 44 (both sexes) and 53 and 54 (for the male only). These findings led to reduction of the dose to 2400 ppm from study week 9 (day 56) onwards.

O ver study days 0 to 14, both sexes at 3600 ppm experienced group mean body weight loss of 4/6% (M/F), respectively. Mean body weight s at 3600/2400 ppm were over 10% lower than controls by study week 7 (11/14% decrease in M/F, statistically insignificant), reached a maximum difference of 14/16% (p < 0.05 in M only) lower than controls at study week 8, and partially recovered thereafter, resulting in terminal body weight s 11/13% lower than controls at study week 13. Group mean body weight gains in both sexes at 1200 ppm gradually decreased from controls from study week 3 onwards, resulting in 9/7% lower body weights compared with controls at study week 13. The decreases in body weight gain as well as instances of body weight loss were at least partially accounte d for decreased food consumption.

In haematology, dose

- and time point

- related trends were observed for decreases in RBC count, plasma haemoglobin and haematocrit compared with controls, and the findings are consistent
with a treatment

- related effect at 3600/2400 ppm.

In clinical chemistry, both sexes at ≥ 1200 ppm had marked increases in group mean creatine
kinase (CK) , aspartate aminotransferase (AST) , and alanine aminotransferase activities (ALT)

,

### Page 61 of 116

and at 3600/2400 ppm there were decreased serum creati nine levels and increased serum
cholesterol in both sexes , and increased glucose in females . However, all findings but ALT activity in males at ≥1200 ppm had resolved by study day 84.

In terminal findings, organ weight changes were observed in 3600/2400 ppm males, with relative (to body weight ) kidney weights increased by 31% (p < 0.05), absolute prostate weights increased by 67% (p < 0.05) and relative prostate weights by 88% (p < 0.05).Increased relative kidney weights (16%; not statistically significant) wer e also observed in females at 3600/2400 ppm, and increased absolute (14/11% in M/F, p < 0.05 in M only) and relative (28/24% in M/F, p < 0.05) liver weights were also seen at 3600/2400 ppm.

Pathology examinations reported skeletal muscle myofiber atrophy/degen eration in 2/4 males (both minimal severity) and all four females (3 minimal, 1 slight severity) at 1200 ppm, with an increase in severity at 3600/2400 ppm in males only (1 minimal, 1 slight). All four females at 3600/2400 ppm reported skeletal muscle myof iber atrophy/degeneration of minimal severity. Accumulation of brown pigment to a minimal severity was seen in hepatic Kupffer cells of 2/4 females at 3600/2400 ppm, but was absent from all other groups.

The no

- observed

- adverse

- effect level (NOAEL) for bot h sexes was 400 ppm (12 mg/kg/day)

. The LOAEL was 1200 ppm (33 mg/kg/day)

, based on increased incidence of skeletal muscle myofiber atrophy/degeneration with associated increases in CK. AST, and ALT levels.

This study is classified as fully reliable (acce ptable/guideline) and satisfies guideline requirements for a subchronic oral toxicity in dogs [ OPPTS 870.3150; OECD 409].

870.3200 21/28

- Day Dermal Toxicity

– Rat

In a 28

- day dermal toxicity study ( MRID 48844115) , BYI 02960 (96.2%) was applied to the shaved, intact dorsal skin of male and female Wistar: Crl:WI(Han) rats (10/sex/dose). The test
material was moistened with d eionized water and applied onto approximately 58 cm 2 

### shave skin for 28 daily (consecutive) applica tions. The rats were exposed to the test material for a minimum of 6 hours per day at 0, 50, 150 and 500 mg/kg bw/day. Parameters evaluated included body weight, body weight gain, food consumption, clinical signs, clinical pathology, ophthalmology, organ weights, and gross and microscopic pathology.

Under the conditions of this study, no effects attributable to exposure to BYI02960 were observed in body weight, body weight gain, food consumption, clinical signs, clinical pathology, ophthalmology, or gros s and microscopic pathology data

.

The absolute and relative liver weights at 500 mg/kg/day males were decreased by 6% and 9%, respectively, compared to control rats, with only the relative decrease obtaining statistical significance. There were no test material related clinical or gross or microscopic pathology changes to correlate this finding. Consequently, based on the results of this study, the no

observed

- adverse

- effect

- level (NOAEL) was 500 mg/kg bw/day (HDT) for both male and
female rats. The stu dy report stated that the highest dose, 500 mg/kg bw, was selected after consideration of the amount of test material that could be reliably applied to the skin.

### Page 62 of 116

This study is considered to be fully reliable (acceptable/guideline) and to meet the data

req uirements for a 28

- day dermal toxicity study ( OPPTS 870.3200; OECD 410).

870.3465 90

- Day Inhalation

– Rat The inhalation study was waived (HASPOC, 2/20/2014, TXR# 0056903 )

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study

- Rat In a developmental toxicity study (MRID 48 844 116), groups of mated Crl:CD  

### (SD) female rats ( 23/dose group ) received BYI 02960 (96.2% purity) in 0.5% aqueous methylcellulose 400 vehicle at doses of 0, 15, 50, or 150 mg/kg bw/day (10 mL/kg bw dosing volume) on gestation days (GD) 6 to 20. For dams, parameters evaluated were: body weight

, body weight gain, food consumption, survival, clinical signs, reproductive outcomes, and gross pathology. Fetal parameters evaluated were: fetal body weight , incidences of dead fetuses and/or fetal resorptions,
and incidences of external, visceral, head, and skeletal malformations and variations.

For dams, there were no test substance

- related effects on survival, reproductive outcomes, or

gross nec ropsy findings. The mean number of corpora lutea, implantation sites, resorptions, live fetuses, fetal weight and sex ratio were comparable across all groups and controls. An increased
incidence of salivation (20/23) in 150 mg/kg bw/day animals was noted a nd considered a

treatment

- related effect. Additionally, a lower gestational body weight gain in females was noted

as a treatment

- related effect, with a 16% lower corrected body weight gain at 150 mg/kg b w /d ay compared with controls, and statistically signi ficant decreased food consumption in the same dose group over GD 6 to 12 compared with controls. No adverse maternal effects were observed in the 50 and 15 mg/kg bw/day groups.

In fetuses , there were no test substance

- related effects on the incidence of m alformations or external variations. However, at 150 mg/kg b w /d ay , the incidence of the variations “parietal (unilateral/bilateral): incomplete ossification” and “hyoid centrum: incomplete ossification” were higher than in the control group and were outsid e the in

- house historical control at both litter and fetal levels. These findings were indicative of a slightly delayed fetal development and
considered to be test substance related. No adverse developmental effects were found in 50 and 15 mg/kg bw/day fe tuses.

The maternal NOAEL w as 50 mg/kg bw/day, and matern al LOAEL was 150 mg/kg bw/day , based on salivation, lower gestational body weight gain and decreased food consumption during the treatment period

.

The developmental NOAEL was 50 mg/kg bw/day; deve lopmental LOAEL was 150 mg/kg
bw/d ay , based on increased incidence s of incomplete parietal and hyoid centrum skull bone ossification indicative of delayed fetal development.

This study is fully reliable (acceptable/guideline) and satisfies the requirements for a developmental toxicity study in rats ( OPPTS 870.3700; OECD 414; Directive 87/302/EEC Part B; MAFF 12 Nousan 8147).

### Page 63 of 116

870.3700b Prenatal Developmental Toxicity Study

- Rabbit In a developmental toxicity study (MRID 48844117) by oral gav age dosing, time

- mated female NZW (Crl: KBL) rabbits in groups of 23/dose received BYI02960 (96.2% purity) in 0.5% aqueous methylcellulose 400 vehicle at doses of 0, 7.5, 15, or 40 mg/kg bw/d in dosing volumes of 4 mL/kg bw/d between gestation days (GD) 6

– 28. For the dams, the following parameters
were evaluated: body weight

, body weight gain, food consumption, survival, clinical signs, reproductive outcomes, liver weight and gross pathology. Foetal parameters evaluated were the following: foetal body weig ht , incidences of dead fetuses, and external, visceral, head, and
skeletal malformations and variations.

There were no test substance

- related effects on maternal clinical signs, reproductive parameters litter data endpoints, or gross necropsy findings. However, d uring GD 6

– 8, decreased corrected body weight gain and decreased food consumption w ere observed in 40 mg/kg bw/d maternal
animals. However, the absolute body weights of the treated and the controls groups were comparable. The decreases in body weight gain and in the food consumption were marginal;

t hese observations were considered not to be toxicologically adverse in this case. Therefore, the maternal NOAEL was established at 40 mg/kg bw/d, based on no adverse effects wer e seen at the highest dose tested. When the data of this main study were considered in combination with those of the range finding study (MRID 49113601) (Attachment: Abbreviated Review of the Range Finding study), a maternal LOAEL was established at 80 mg/ kg bw/d based on the markedly decrease in food consumption starting GD 6

- 10 and persisted at lower magnitude to the end of the study and clinical signs (no feces or few feces over several days).

As no evidence of developmental toxicity was observed, and no evidence of an increased frequency of treatment

- related, toxicologically adverse external, visceral or skeletal
malformations and variations were found; the developmental toxicity, NOAEL is 40 mg/kg bw/d, the highest dose tes ted in this study

. However, at 80 mg/kg bw/d in the range finding study, there was an increase in the number of dead fetuses (7 fetuses in 4 litters) relative to the controls (2 fetuses in 1 litter). This finding demonstrated an increase in the percent of dead fetuses per litter (80 mg/kg/d: 7.8% vs. Control: 1.9%). This increase was reported to be outside of the historical control range of the performing laboratory (0.74

– 6.58%). Therefore the LOAEL for developmental toxicity could be established as 80 mg /kg bw/d.

This study is fully reliable (acceptable/guideline) and satisfies the requirements for a developmental toxicity study in rabbits when considered with the results from the range

finding study ( OPPTS 870.3700; OECD 414; Directive 87/302/EEC B.31 ; MAFF 12 Nousan 8147).

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

- Rat
In a two

- generation reproduction study (MRID 48844119) , groups of Wistar [(Crl:WI) Han] rats (30/sex/group) received BYI 02960 in the diet (96.2%; BY I 02960

- 01

- 03) at concentrations of 0, 100, 500, or 1800 ppm (equivalent to 0, 6.6/7.7, 32.5/38.7, and 117/137 mg/kg bw/day for P 1



### – M/F premating intakes; and 0/0, 6.4/7.8, 32.0/39.6, and 122.1/143.4 mg/kg bw/d ay for P 2



### – M/F

### Page 64 of 116

premating intakes). The test substance was solvated in acetone prior to incorporation into the diet. Parental animals received the test diet for at least 70 days before the two week mating period. Confirmed pregnant dams then continued to receive admixed diet during gestation (22 days ) and lactation to weaning (21 days). During lactation, test substance concentrations were reduced by 50% to account for the corresponding increases in feed intakes of dams during this period. At weaning on LD 21, F 1 

### pups (30/sex/group) were randomly selec ted to comprise the P 2 

### generation and treated in the same manner as their respective P 1 

### generation sires and dams.

Excess F 1 

### pups were necropsied. P 2 

### maternal animals were retained until weaning of the subsequent F 2 

### generation at LD 21.

Under the conditi ons of the study, BYI 02960 produced no effects on clinical signs, gross necropsy findings, reproductive organs, sperm parameters, or gestation length in both reproductive generations.

In parental observations, clear treatment

- related decreases in mean body weight (↓10%) with associated reduction in body weight gain were observed at 1800 ppm in P 2 

### fe males during premating period. Decreased food consumption was noted at 1800 ppm females in both generations during the pre

- mating period.

While reproductiv e parameters were unaffected by treatment in P 1 

### females , a slight decrease (

- 17%) in the number of estrus cycles and a slight decrease (

- 8%) in the total number of implantation sites were noted in 1800 ppm P 2 

### females, which may be associated with the
decr eased body weight s observed at the same dose. In addition, a slight reduction in epididymal sperm count in P 1 

### and P 2 

### males and in testicular sperm count in P 2 

### males was observed at 1800

ppm.

In terminal observations, treatment

- related histopathological c hanges were noted in the liver (centrilobular hepatocellular hypertrophy) in P 1 

### males, and accompanied by slight (+9%) increases in the absolute and relative liver weights

, though these changes were considered an adaptive effect in the context of this stud y. While statistically significant increases in absolute and relative liver weights were also noted in other 1800 ppm animals across both generations, no
other treatment

- related liver histopathological findings were observed. An increase in the relative

t hyroid weight in both P 1 

### and P 2 

### males was not accompanied by gross or histopathological change, and the toxicological significance is uncertain.

Ovarian follicle counts in F 1 

### females selected as P 2 

### maternal animals were unaffected by
treatment with the t est substance.

In fetal observations, general survival parameters were unaffected by treatment in both generations. A slight decrease (

- 15%) in overall litter size in F 2 

### pups at 1800 ppm was noted, and when considered along with decreased (

- 8%) overall i mplantations in P 2 

### dams, suggests a slight effect on reproductive function at 1800 ppm.

Pup body weights were unaffected by treatment at 100 ppm in both generations. Treatment

related and statistically significant decreases in mean body weight (

- 7 to

- 14%) and body weight gain (

- 8 to

- 14%) were observed during the weaning period in both generations at 1800 ppm, and

### Page 65 of 116

in the F 2 

### generation at 500 ppm. T erminal findings (necropsy, histopathology and organ weight analyses) did not report treatment

- related ef fects in both generations.

Treatment

- related changes in sexual maturation were limited to slight delays in vaginal patency and preputial separation at 1800 ppm in F 1 

### pups; these effects were considered secondary to
decreased mean body weight s in these a nimals during weaning.

The NOAEL for parental toxi city was 500 ppm ( 38.7 mg/kg bw/d) ; the LOAEL was 1800 ppm (137 mg/kg/day) based on decreased body weight ( ↓10 %) with associated reduced body weight gains in P 1 

### females during the pre

- mating period

.

The NOAEL for offspring toxicity was 100 ppm (7.7 mg/kg bw/d ay ) ; LOAEL was 500 ppm (38.7) based on decreased body weight (

- 7%) in the F 2 

### male and female pups.

The NOAEL for reproductive toxicity was 500 ppm ( 38.7 m g/kg bw/d ay ) ; LOAEL was 1800 ppm (137 mg/kg/d ay) based on a 17% lower (p < 0.05) number of estrus cycles, In addition, a slight reduction in epididymal sperm count in P 1 

### and P 2 

### males and in testicular sperm count in P 2 

### males was observed.

This study was classified as reliable ( acceptable/guideline ) and satisfied the guideline requirements (O PPTS 870.3800; OECD N0. 416; MAFF 12 Nousan 8147) for a reproduction and fertility study.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity

– Rat In a combined chronic/carcinogenicity study (MRID 488 44123) , Wistar Rj:WI (IOPS HAN) rats in groups of 70/sex/concentration received BYI 02960 (96.2%; 2009

- 000239 ) in the diet at concentrations of 0, 80, 400, or 2000 ppm daily for 52 weeks (10/sex/concentration ; interim
sacrifice ) or 104 weeks (60/sex/concen tration). Achieved group mean daily intakes over the entire study duration were 0/0, 3.17/4.48, 15.8/22.5, and 80.9/120 mg/kg bw/d for M/F, respectively. Following overnight fasts on study days 369 to 371 for interim sacrifice groups or study days 739 to 7 53 for carcinogenicity phase groups, all surviving animals were sacrificed by
isoflurane inhalation.

Parameters evaluated included clinical signs, body weight, body weight gain, food consumption, test compound intakes, haematology, clinical chemistry, coa gulation, urinalysis, ophthalmology, organ weights, and gross and microscopic pathology. In addition, blood samples were collected from five randomly selected animals from each group on study weeks 52 and 105, and analysed for levels of parent compound in plasma.

There was no evidence of carcinogenic potential for the test substance at the doses tested in this study. The incidence of premature mortality was unaffected by dosing.

During the first year of dosing, clinical signs were confined to the 2000 pp m dose level in the form of increased incidences of soiled fur for both sexes, alopecia (females only), and in males

### Page 66 of 116

only, external stimuli hyper

- reactivity (7% vs. 0 to 1.4% in other groups), and handling resistance (approx. 2 to 4

- old increased incidence ). All clinical signs had resolved by the second year of dosing with the exception of slight increased incidences of alopecia and soiled fur in males at 2000 ppm. In the absence of other clinical signs of toxicity, the increased incidences of alopecia and soiled fur were not considered toxicologically adverse findings.

Statistically significant differences in mean body weights were confined to the 2000 ppm groups in both sexes, In males, a peak decrease of

- 7% body weight (p < 0.01) at 2000 ppm compared with controls was noted at study week 14, with a final week 106 difference in body weight of

- 6% between 2000 ppm and control animals (not statistically significant). In females at 2000 ppm,

mean body weight s were 8% lower than c ontrols by study week 14 (p < 0.01), with peak body weight differences of

- 17% between 2000 ppm and control animals at week 78 and final body weight differences of

- 13% terminal body weight at 2000 ppm compared with controls at study week 106 (p < 0.01). It is likely that the decreased body weight gain may be secondary to the decreased food consumption observed at 2000 ppm in females.

Ophthalmological findings at the one year examination showed an increased incidence of lens opacity in females at 2000 ppm rela tive to controls (14.3% vs. 4.3%)

. A small consistent increase in serum cholesterol in females at 2000 ppm relative to controls throughout the study was observed, but this change was not considered to be adverse. Plasma concentration analyses after
both on e and two years of treatment indicated a consistent relationship between increasing test substance administration and plasma levels of the test substance for both sexes, with a sub

- linear relationship observed in males and an approximately linear relations hip observed in females.

At both the 52

- week and 104

- week scheduled sacrifices, treatment

- related changes in organ weights were confined to increased relative (to body weight ) liver weight (p < 0.01 in both sexes) at 2000 ppm that were accompanied by liver gross and histopathological changes, including centrilobular hypertrophy and macrovacuolation in both sexes; eosinophilic/tigroid/mixed foci of hepatocellular alteration in males, and increased brown pigmentation of Kupffer cells, general hepatocellular b rown pigmentation and interstitial mononuclear cell infiltrate in females.

Other treatment

- related terminal findings reported in the study included lung findings at 104 weeks in 2000 ppm females, comprising of increased incidence of white foci visible at necropsy. Lung histopathology at 2000 ppm identified lesions comprised of foamy macrophages and chronic interstitial and perivascular inflammation. Additionally, increased thyroid colloid alteration in 2000 ppm males, slightly increased frequency of follic ular cell hypertrophy at 2000 ppm in both sexes, and increased brown pigmentation of follicular cells in 2000 ppm females
were considered treatment

- related and toxicologically adverse.

Adverse effects were not found in 400 and 80 ppm test groups.

The n o
- observed adverse

- effect level (NOAEL) in this study was 400 ppm (15.8/22.5 mg/kg bw/d for M/F respectively). The LOAEL was 2000 ppm (80.9/120 mg/kg bw/d for M/F respectively) , based on a range of in

- life and terminal changes in both sexes. In

- life change s included decreased mean body weight with associated reduction in body weight gain (both sexes), a slightly decreased mean food consumption rate (females only), and a slightly earlier onset of lens opacity (females only) during the first year of treatment . Terminal findings

### Page 67 of 116

considered included increased relative (to body weight ) liver weights at study termination (both sexes), which were accompanied by histopathological changes in the liver (centrilobular hypertrophy and macrovacuolation in both sexes; eo sinophilic/tigroid/mixed foci of hepatocellular alteration in males; increased brown pigmentation of Kupffer cells, general hepatocellular brown pigmentation and interstitial mononuclear cell infiltrate in females). Additional histopathological changes at 2000 ppm included an increased frequency in a range of effects in the thyroid (colloidal alteration in males, follicular hypertrophy in both sexes) and lungs (fomay macrophages and chronic interstitial and perivascular inflammation).

This study is clas sified as fully reliable ( acceptable/guideline ) and satisfies guideline requirements for a combined chronic oral toxicity/carcinogenicity study in rats [ OPPTS 870.4300; OECD 453 (1981].

870.4100b Chronic Toxicity

- Dog
In a 1

- year dietary study (MRID 48844121), BYI 02960 (96.2%; batch 2009

- 000239) was
administered to 5 to 6

- month old beagle dogs (4/sex/dose) at concentrations of 0, 150, 300, or 1000 ppm (0/0, 4.6/4.1, 7.8/7.8, and 28.1/28.2 mg/kg bw/d for M/F, respective ly) for one year.
Parameters evaluated included body weight

, body weight gain, food consumption, test compound intakes, clinical signs, haematology, coagulation, clinical chemistry, urinalysis, ophthalmology, organ weights, and gross and microscopic patho logy. In addition, after an overnight fast blood samples were collected from 1/sex at 0 and 300 ppm animals on study day 141 and analysed for test substance concentrations in plasma.

Under the conditions of this study, there were no test substance

- related effects on clinical signs, survival, haematology, coagulation, clinical chemistry, urinalysis, ophthalmology, general macroscopic findings and organ weight parameters.

Changes in body weight gain were confined to females at 1000 ppm, with an 86% lower body weight gain relative to controls in study week 1, and 17 to 66% lower relative gains over the first
two 13

- week intervals and the final 26 week interval of the study. This decreased body weight gain resulted in terminal body weight s being 9% lower in fema les at this dose relative to
controls. The decreased body weight gain in females at 1000 ppm during week 1 may partially be linked to a 26% lower food consumption relative to controls over the same period. The decease decrease in absolute body weight was s light and showed no statistical significance. Therefore, the changes in body weight were not considered to be adverse. In addition, group mean food consumption was unaffected when averaged across the whole one year treatment period.

Blood plasma levels of BYI 02960 in animals in the 300 ppm dosing group on study day 141 peaked at 3 hours after withdrawal of food. A slightly elevated blood plasma concentration of test substance was observed in males compared with females.

Test

- substance related histopathol ogical findings were confined to myofiber degeneration in skeletal muscle, particularly in gastrocnemius muscle at a 50% incidence and in bicep muscle at 75% incidence in both sexes receiving 1000 ppm diets. These lesions were of either minimal or slight s everity (each at 1 or 2 out of a maximum severity of 5). All animals presenting with gastrocnemius muscle degeneration also presented with biceps femoris muscle lesions, giving a

### Page 68 of 116

total incidence for muscle histopathology of 75% in both sexes at 1000 ppm. D egeneration of the myofiber comprised of one or more of the following changes: atrophy, necrosis, and/or presence of inflammatory cells around the affected myofiber. In addition, there was a slight increase in
ALT level.

The no

- observed

- adverse

- effect leve l (NOAEL) was 300 ppm (7.8 mg kg bw/d for both M/F) for both sexes. The LOAEL was 1000 ppm (28.1/28.2 mg kg bw/d for M/F) for both

sexes, based on increased incidence of minimal

- to

- slight, focal to multifocal areas of skeletal muscle degeneration in gastro cnemius and biceps femoris (75% combined incidence) in both

sexes with associated slight increase in ALT level

.

This study is fully reliable (acceptable/guideline) and satisfies the data requirements for a chronic toxicity study in dogs ( OPPTS 870.4100; O ECD 452).

870.4200b Carcinogenicity (feeding)

- Mouse In a carcinogenicity study (MRID 48844122) , C57BL/6J mice received BYI 02960 (96.2%) in
the diet at concentrations of 0, 70, 300, or 1500 ppm for 52 weeks (10/sex/concentration) or 78 weeks (50/sex/c oncentration). Achieved group mean daily intakes over the entire study duration were 0/0, 10.0/12.2, 43/53, and 224/263 mg/kg bw/d for M/F, respectively. Parameters evaluated included clinical signs, body weight

, body weight gain, food consumption, test compound intakes, haematology, ophthalmology, organ weights, gross pathology (all groups) and histopathology (78

- week group only). In addition, blood samples were collected and analysed for levels of parent compound at weeks 5 2 and 78.

There were no treatment

- related effects on survival or clinical signs of toxicity across all dose
levels tested. No adverse effects were observed at 70 and 300 ppm.

At 1500 ppm, treatment

- related decreased mean body weights (

- 6%/

- 7% for M/F) a nd body weight gain (

- 19%/

- 13% for M/F) were observed compared with controls at statistically significantly levels. While food consumption in 1500 ppm animals was similar to controls, with only marginal decreases observed in females (

- 2

– 3% vs. controls), t he decreased mean body weight and body weight gain suggest decreased food use efficiency, and in this context, the changes in body weight and body weight gain are considered toxicologically adverse. However, the US EPA secondary reviewer considered the ch anges in the body weight parameters not approaching a magnitude of being adverse. In terminal findings at 1500 ppm, increased absolute and relative liver weights in males were observed and correlated to a toxicologically adverse change in liver histopathol ogy (increased frequency and severity of diffuse hepatocellular vacuolation). Increased incidence of small/atrophic kidneys and decreased kidney weights were seen in 1500 ppm males.

Based on the study findings, the NOAEL was 300 ppm (43/53 mg/kg bw/d for males/females respectively). The LOAEL was 1500 ppm (224/263 mg/kg bw/d for males/females respectively), based on statistically significant increases in absolute and relative liver weights, with correlative liver histopathology (diffuse hepatocellular

vac uolation) and decreased kidney weights and alterations in kidney pathology in males (small/atrophic kidneys).

Under the conditions of this study, no treatment

- related increases in tumor incidence were

### Page 69 of 116

observed at all dose levels tested.

Blood plasma anal yses indicated that the concentration of test substance in plasma scaled in an approximately linear manner with increasing dietary dose at both 52 and 78 week time points. There were minor sex differences in test substance concentrations at both time point s, with males presenting with slightly elevated concentrations compared with females. However, no accumulation of test substance was noted during the study.

This study is classified as fully reliable ( acceptable/guideline ) and satisfies guideline requirements for a carcinogenicity toxicity in mice [ OPPTS 870.4200; OECD 451 (1981)].

A.4.6 Mutagenicity

Gene Mutation

Guideline #: 870.5100. Bacteria reverse mutation test., MRID 48844124

Acceptable/guideline Bacteria reverse gene mutation assay using Salmonella typhimurium strains TA98, TA100, TA102, TA1535, TA1537 with and without an exogenous metabolic activation system (S9) with dose levels of 0, 3, 10, 33, 100, 333, 1000, 2500 and
5000 μg/plate for Experim ent1, and 0, 33, 100, 333, 1000, 2500 and 5000 μg/plate for Experiment 2. The test substance was administered to the test system as a solution in dimethyl sulfoxide (DMSO). Under the conditions of this study, BYI 02960 was tested up to the limit dose (500 0 μg/plate) and was negative



### In vitro mammalian cell assay

Guideline #: 870 5300. study type: Test In
Vitro Forward Mutation assay (V79/HPRT)

MRID 48844128 Accetable/guideline In a Chinese Hamster V79 cell/HPRT mutation assay, BYI 02960 (96.2% purity) was tested in the presence and absence of an exogenous metabolic activation system (S9) at concentrations of 0, 46, 92, 184, 368, 736, 1472 and 2944  g/mL for 5 hours (±S9) at 37  C . The highest concentration level was set based on the lack of test substance precipitation at a concentration greater than the limit dose of 10 mM. Cells were then independently subcultured for assessment of cytotoxicity (cloning efficiency) and for exp ression and selection of the 6

- thioguanine (2

- amino

- 6

- mercaptopurine)

- resistant phenotype. The test substance was dissolved in d imethyl sulfoxide (DMSO) at a maximum concentration of 300 mg/mL. Ethyl methanesulfonate (EMS) and dimethylbenzanthracene (DMB A) were used as positive controls for the non

- activated and activated test systems, respectively.

In the mutagenesis assay, visible precipitate was observed at the limit dose of 2944 μg/mL. However, no excessive cytotoxicity was observed at any concen tration tested,
and no concentration

- and treatment

- related increases in mutant frequency were
observed.

BYI 02960 was negative in the non

- activated and S9

- activated test systems in the V79/HPRT mutation assay.



### In vivo cytogenetic

### Page 70 of 116

Guideline 8705385. In Vivo micronucleus assay in mouse bone

marrow
MRID MRID 48844134 Acceptable /guideline In the mouse micronucleus assay, male Crl:NMRI BR mice (5/dose level) were
administered BYI 02960 at d oses of 0, 10, 20 and 40 mg/kg by two intra

- peritoneal injecti ons 24 hours apart, Concurrent control groups were administered corn oil (the vehicle (negative) control), or 20 mg/kg of cyclophosphamide (positive control). All animals were sacrificed 24 hours after the second i.p. injection. Bone marrow

smears were p repared immediately after the sacrifices. In

- life observations included clinical signs. Two thousand PCEs per animal were evaluated for
micronuclei.

In the main study, there were no deaths, though treatment

- related toxicity was observed, including apat hy, roughened fur, weight loss, sternal recumbency, spasm, periodic stretching of the body and difficulty breathing . No evidence of a cytotoxic effect on the bone marrow cells was observed, while t he positive and vehicle controls induced the expected respo nse. No statistically significant increases in micronucleated PCE frequency were observed in any evaluated test substance

treated group of animals.

Under the conditions of this study, BYI 02960 was neither clastogenic nor aneugenic in the mouse bone marrow micronucleus assay.



### A.4.7 Neurotoxicity

870.6200 Acute Neurotoxicity Screening Battery In an acute neurotoxicity study (MRID 48844138 ), Wistar (Rj:WI (IOPS HAN)) rats in groups
of 12/sex/dose received BYI 02960 (96.2%; 2009

- 000239) at 0, 50, 200, or 800 mg/kg bw/day as single oral gavage dose in methylcellulose 400 (0.5% v/v) at 10 mL/kg bw final dosing volumes. A follow up cohort of 12 females/dose received 0, 20, or 35 mg/kg bw/da y oral gavage doses.

Neurobehavioral parameters examined in the first cohort consisted of motor activity and functional observational battery (FOB) assessments at 2 hours post dosing and on Days 7 and 14 after treatment, along with neuropathological exami nations of the peripheral and central nervous systems at study termination.

There were two instances of unscheduled mortality in females at 800 mg/kg bw/day , with animals found dead on study Days 1 (day of dosing) and Day 5, respectively. Both mortalities
were test substance related. C linical signs prior to death in the animal found dead on study day 1 consisted of piloerection, low muscle tone and arousal, rapid respiration, tremors, myoclonic jerks, convulsions, dilated pupils, absence of pupil and flexor reflexes and uncoordinated or slow surface righting reflex.

Effects on body weight gain were con fined to 40 /46% (M/F) lower mean body weight gains at
800 mg/kg bw/day in study week 1 relative to controls that subsequently resolved such that by study day 14 there were no differences in group mean body weight

.

Changes in FOB and activity parameters wer e confined to study day 1 only, with no treatment

related findings being present on study days 7 or 14.

### Page 71 of 116

At 50 mg/kg bw/day

, increased incidences of piloerection in males and females ( 8/12 for M and 7/12 for F, vs. 4/12 for both M and F controls) and of dil ated pupils in females (6/12, vs. 1/12 for controls) were observed on study day 1.

At 200 mg/kg bw/day/day , piloerection, dilated pupils, rapid respiration, lower muscle tone, low arousal, repetitive licking of lips, decreased rearing, exaggerated flexo r reflexes, gait incoordination and flattened body posture, and higher incidence of tremors were seen in both

sexes. In addition, males from the 200 mg/kg bw/day/day dose group exhibited myoclonic jerks and absence of movement, and were also cold to touch, while a higher incidence of walking on tiptoes was observed in females at this dose. Automated measures of motor activity were reduced during the first 10

- min interval of the session in both sexes

.

At 800 mg/kg bw/day/day , piloerection, lower muscle ton e, rapid respiration, low arousal, tremors, myoclonic jerks, chewing, repetitive licking of lips, gait incoordination, flattened or hunched posture, dilated pupils, impaired (uncoordinated or slow) righting reflex, impaired flexor and tail pinch responses and reduced rectal temperature were observed. Automated measures of motor activity were also reduced in both sexes.

In the follow

- up study, the animals at 20 and 35 mg/kg showed no treatment

- related effects in all the parameters examined.

N o gross or microscopic test substance

- related morphological changes were seen in the nervous system tissues

.

The NOAEL in this acute neurotoxicity study is 35 mg/kg bw/day /day; LOAEL is 50 mg/kg bw/day /day based on increased incidences of piloerection in both sexes and increased incidence of pupil dilation in females on study day 1

.

This study is fully reliable (acceptable/guideline) and satisfies the data requirements for an acute neurotoxicity study ( OPPTS 870.6200; OECD 424).

870.6200 Subchronic Neurotoxicity Sc reening Battery In a subchronic neurotoxicity feeding study (MRID 48844139) , seven

- to

- eight week old Wistar Rj:WI (IOPS HAN) rats in groups of 12/sex/dose received BYI 02960 (96.2%; 2009

- 000239) in the diet at concentrations of 0, 100, 500, and 2500 ppm (0 /0, 5.7/6.9, 29.4/34.8, or 143/173 mg/kg bw/day for M/F) for 90 days. The following parameters were evaluated: body weights, body weight gain, food consumption, clinical signs, detailed physical examination, ophthalmology, and gross pathology. A neurobehav ioral test battery consisting of motor activity and functional observational battery (FOB) assessments was conducted on all animals prior to

BYI 02960 dosing (baseline) and during study weeks 2, 4, 8, and 13 or 14, depending on
sacrifice schedule. On test days 92 and 93, 6 rats/sex/group were perfused in situ with fixative. The peripheral and central nervous systems and selected muscle tissues from perfused control and high dose groups were prepared for histological evaluation.

Under the conditions of the study, there were no test substance

- related effects on the following parameters: mortality, ophthalmology, neurobehavioral parameters (FOB and motor activity), or gross and microscopic morphology of the nervous system in either male or female rats of any

### Page 72 of 116

dose groups.

There was a decrease in absolute body weight in males and females at 2500 ppm reaching 9% at week 1 for females and at weeks 4 and 8 for males. The magnitude of reduced body weight did not persist or approach the lev el of being adverse. Associated m ean body weight gain s were also
decreased for both sexes at 2500 ppm relative to controls from study week 1 onwards

.
There were decreases in food consumptions in 2500 ppm males and female (↓1 8/29% (M/F )

p < 0.01) over study week 1, which partially recovered over the study to reach a 9/4% (M/F) lower consumption relative to controls on study week 13.

In this 90

- day neurotoxicity study with dietary administration
, flupyradifurone did not produce neurotoxicity at any dose level s tested. The no

- observed

- adverse

- effect level ( NOAEL) was 500 ppm (29.4/34.8 mg/kg bw/day; M/F); LOAEL was 2500 ppm (143/147 mg/kg bw/day; M/F) based on decreased food consumption with associated slight decrease in absolute body weight.

This study is clas sified as fully reliable (acceptable/guideline) and meets the guideline requirements of subchronic neurotoxicity study ( U.S. EPA OPPTS 870.6200; OECD 424; and MAFF Japan Nousan 8147).

870.6300 Developmental Neurotoxicity Study In a developmental neurotoxicity study (MRID 48844140 ), groups of time

- mated 12

- week old female Wistar Han CRL:WI (HAN) (30/dose group) received acetone

- solvated BYI 02960 (96.2%; 2009

- 000239 ) in the diet at concentrations of 0, 120, 500, or 1200 ppm (0, 10.3, 42.4, or
102 m g/kg bw/d ay ) from gestation day (GD) 6 to lactation day (LD) 21. For dams, the following parameters were evaluated: body weight, body weight gain, food consumption, mortality, clinical signs, detailed physical examination, FOB examination ( GD 13 and 20 and LD 11 and 21 ) , and reproductive outcomes. For pups, neurobehavioral evaluations including learning tasks (passive avoidance and the water maze test), motor activities, and FOB parameters were evaluated throughout the post

- natal period. Additional pup para meters evaluated included body weight

, food consumption, ophthalmology, sexual maturation, brain weights, gross necropsy, and neural and muscle tissue histopathological and morphometric analyses.

Under the conditions of this study, for dams, there were no test substance

- related effects on maternal clinical signs, FOB parameters, mortality, or reproductive outcomes. For offspring, there were no test substance related effects on clinical signs, mortality, acquisition and retention parameters for the passive avoidance and water maze tasks, sexual maturation, surface righting, pupil reflex or other ophthalmology parameters, necropsy findings, organ weights, macroscopic or histological brain morphometry, or brain or peripheral nerve histopathology.

During ge station, a decrease in body weight was seen (↓7%) in 1200 ppm dams and associated decreases in body weight gain were present. At lactation period a decrease of (4% to 6 %) in body weight was also found in1200 ppm dams. A slight decrease in food consumption was found in the dames at various times during the gestation and lactation periods (ranging from 1% to 8%). However, these changes were slight and not considered as adverse.

### Page 73 of 116

For pups, a non

- statistically significant increase in both motor and locomotor activity was seen in males at 1200 ppm on PND 13 relative to concurrent controls. On PND 60, startle amplitude for all 50 trials was statistically significantly (p < 0.05) increased by approx. 2

- fold in females at 1200 ppm relative to controls.

There was n o evidence of treatment

- related changes in brain morphometry or peripheral nerve histopathology.

Under the conditions of this study, the maternal NOAEL was established at 1200 ppm (102 mg/kg/day) based on no adverse effects were found in the dams at the h ighest dose tested.

The offspring NOAEL was 500 ppm (42.4 mg/kg/day); LOAEL was 1200 ppm (102 mg/kg/day) based on statistically significant persistent increased in startle response amplitude.

This study is reliable (acceptable/guideline) and satisfies th e requirements for a developmental neurotoxicity study in rats ( OPPTS 870.6300; OECD 426).

A.4.8 Metabolism

870.7485 Metabolism

– Rat

A

. Pyridinyl methyl

14 

### C In a toxicokinetic and metabolism study ( MRID 48844141 )

, group s of 4 Wistar rats per sex per dose were administered by oral gavage a single dose of 2 or 200 mg/kg bw [Pyridinylmethyl

14 

### C]BYI02960 in 0.5% aqueous Tragacanth® and sacrificed by exsanguination under anaesthesia at 72 hours post dosing. An additional group of 4 male Wistar rats were administered by i.v. a single dose of [Pyridinylmethyl

14 

### C]BYI02960 (2 mg/kg bw) in the same vehicle and sacrificed at the same time post dosing. The test compound was radiolabeled with 14 

### C in the pyridinylmethyl bridge of the molecule . The metab olism and radioactivity which included the test compound and metabolites was determined in urine and faecal samples collected for the time range between dosing and sacrifice. Additionally, radioactivity in plasma micro samples was determined over the study period ( 17 time points). Total radioactivity was determined in excreta and in organs and tissues collected at sacrifice. Samples were analysed, and parent compound and metabolites identified, by radiochromatographic (HPLC, TLC) and spectroscopic (LC / MS)

m ethods.

Mean tot a l radioactivity was nearly quantitative since approx imately 91 to 103% of the
administered dose w as found in the excreta and in the bodies of animals at sacrifice.

[Pyridinylmethyl

14 

### C]BYI 02960 was nearly completely absorbed after oral administration, which was demonstrated by the high factor of bioavailability (F = 0.93) calculated from the plasma data of low dose tests after oral and i.v. administration, and that approximately 76 to 90% of the administered radioactivity were detected i n the urine and in the bodies without GIT at sacrifice of male and female rats. The absorption started immediately after dosing as could be seen from the quick increase of radioactivity in plasma micro samples, with the peak plasma

### Page 74 of 116

concentration (C max 

### ) rea ched approximately 1 hour after administration in the low dose tests and within approximately 2 to 4 hours in the high dose tests.

The distribution of the radioactivity within the body was fast. From the maximum plasma level (C max 

### ), the radioactivity lev el declined slowly down to approximately 50% of C max 

### after 4

– 8
hours in the low dose tests and after 8

– 24 hours in the high dose tests and down to low values around the LOQ in the low dose tests and to approximately 0.5% of C max 

### in the high dose tests by study termination (72 hours)

.

Excretion was rapid , mainly by the renal route and essentially complete by 72 hours post dosing

. Female rats exhibited slightly higher renal excretion rates of approximately 8 6% and 90% of the administered dose compared t o approximately 76% of the dose in males. The major part of the dose detected in urine (>84%) was excreted within 24 hours after treatment and was ongoing up
to 72 hours. Faecal excretion accounted for approximately 23

– 26% of the total administered in males, and 7

– 10% in females. At the time of sacrifice, 72 hours after administration, the radioactive residues in organs and tissues were low, and only trace amounts of ap prox. <0.1

– 0.3% of the total administered dose was detected in the body and in the GIT. Most of the residues of the low dose tests were lower than 0.01 mg/kg sample. The highest concentrations of the low dose tests, but also at a low level of approximate ly ≤0.018 mg/kg sample were detected in blood cells, the GIT and in the eyes of female rats. The residues of the low and high dose tests were nearly proportional to the dose.

Parent compound, three major ( BYI 02960

- OH, BYI 02960

- 6

- CNA and BYI 02960

- hippu ric acid) and five minor metabolites were isolated from urine and four of them identified by spectroscopic methods (LC

- MS and 1H

- NMR and 2D

- NMR), HPLC and/or TLC co

chromatography or comparison. Identification rates were high in excreta, and amounted to 83 %
to 94% of the total administered radioactivity. P arent compound represented the predominant part of the radioactivity in urine of male and female rats. In faeces samples of male rats, the
metabolite BYI 02960

- OH was more prominent than the parent compoun d. Two metabolites,
BYI 02960

- 6

- CNA and BYI 02960

- hippuric acid were also prominent metabolites in male rats
but not in females. In total further 19 unknown metabolites were characterised by their chromatographic behaviour. All of them were detected at tra ce amounts of approximately <0.1%
to 0.9% of the dose. The metabolic profiles in urine and faeces were very similar for both sexes but male rats exhibited a higher rate of metabolite formation compared to female animals. The
metabolic transformation of BYI 02960 was principally oxidative and took place at least at 3 different structural positions of the test compound.

The principal metabolic reactions of [pyridinylmethyl

- 14C]BYI 02960 in rats were: (1) hydroxylation followed by conjugation with glucuronic acid to or with sulphate; (2) cleavage of the difluoroethyl group forming BYI 02960

- des

- difluoroethyl; and cleavage of the molecule at the pyridinylmethyl bridge forming BYI 02960

- 6

- CNA, which was further conjugated with glycine to BYI 02960

- hippuric acid.

The results of the toxicokinetic and metabolism study were in good accordance with those obtained in other studies performed with different radiolabels: [Ethyl

- 1

- 14 

### C]BYI 02960 (Weber,
2011 a ; Study No. M1824567

- 3, Koester, 201 2a ; Study No. M1824575

- 2) and [Furanone

- 4

-

### Page 75 of 116

14 

### C]BYI 02960 (Weber, 2011 b ; Study No.M1824560

- 6, Koester, 201 2a ; Study No. M182457 4

- 1 , Koester, 2011 b , Study No. M1821760

- 5).

This study is fully reliable (acceptable/guideline) and satisfies the study requirements of a metabolism study ( U.S. EPA 870.7485; OECD Section 4 Part 417 and Annex to Directive 87/302/EEC, Part B, Toxicokinetic; JMAFF 12 Nousan 8147).

B. furanone

- 4

- 14 

### C
In a toxicokinetic and metabolism study ( MRID 48844143) , a group of 4 male and 4 female
Wistar rats were admini stered by oral gavage a single dose of 2 mg/kg bw [furanone

- 4

- 14 

### C]BYI 02960 in 0.5% aqueous Tragacanth® and sacrificed by exsanguination under anaesthesia at 168 hours post dosing. The test compound was radiolabeled with 14 

### C in the C4

- position of the
furan one ring of the molecule. The metabolism and radioactivity which included the test compound and metabolites was determined in urine and faecal samples collected for the time range between dosing and sacrifice. Additionally, radioactivity in plasma micro sa mples was determined over the study period (23 time points). Total radioactivity was determined in excreta and in organs and tissues collected at sacrifice. Samples were analysed, and parent compound and metabolites identified, by radiochromatographic (HPL C, TLC) and spectroscopic (LCMS)
methods.

Mean total radioactivity recovery was nearly quantitative since approximately 96% and 102% of the administered dose were found in the excreta and bodies of males and females respectively at
sacrifice.

[Furanone

- 4

- 14C]BYI 02960 was nearly completely absorbed since >79% and >91% of the total
dose administered was detected in the urines and the bodies without GIT at sacrifice of male and female rats respectively. The absorption started immediately after dosing as coul d be seen from the quick increase of radioactivity in plasma micro samples, with the peak plasma concentration (C max 

### ) was reached approximately 1.5 hours after administration in both sexes

.

The distribution of the radioactivity within the body was fast. From the maximum plasma level (C max 

### )

, the radioactivity level declined slowly down to approximately 50% of C max 

### after 8 hours
in both sexes and <1% of C max 

### 72h after dosing.

Excretion was rapid and mainly by the renal route. Approximately 79% of the total dose administered was found the urine of male rats and approximately 91% in the urine of female rats. The major part of the dose was excreted within 24 hours after treatment, for male and female rats. At the time of sacrifice, 168 hours after administrati on, a small proportion of approximately 0.5% of the dose administered for males and approximately 0.2% for females were still detected in the body without GIT.

The parent compound was moderately metabolised to approximately 20 metabolites in total

, consisting of one major ( BYI 02960

- OH ) and six minor metabolites of an isolated and purified compound. Identification rates were >84% of the total dose administered in male rats and >95%
in females. Another approximate 8% of the dose in males and 4% in fem ales were characterised by their chromatographic behaviour but not identified. All metabolites accounting for >1% of the dose administered were identified except a polar metabolite fraction accounting for 5.30% in

### Page 76 of 116

males and 2.45% in females. It is consider ed that this polar fraction is most likely represented by
biomolecules. Parent compound represented the predominant part of the radioactivity in urine but in faeces samples the metabolite BYI 02960

- OH was more prominent.

Overall, male rats showed a highe r rate of metabolism with only approximately 55% of unchanged parent compound found in excreta whereas 76% of unchanged BYI 02960 was found in the excreta of female rats, though the metabolic patterns were very similar in males and
females.

The principal metabolic reactions of [furanone

- 4

- 14 

### C]BYI 02960 in rats were: (1) hydroxylation followed by conjugation with glucuronic acid or with sulphate; (2) cleavage of the difluoroethyl group forming BYI 02960

- desdifluoroethyl; (3) cleavage of the molecule at the pyridinylmethyl bridge forming BYI 02960

- difluoroethyl

- amino

- furanone; and (4) cleavage of molecule at the nitrogen

- carbon bond next to the furanone moiety followed by further conversion to C1 and C2 compounds of the natural pool including complete degrada tion to carbon dioxide.

Male rats exhibited a higher proportion of the polar metabolite fraction and higher residues in the body at the time of sacrifice, and also exhibited a higher proportion of radioactivity in exhaled air in a study with [pyridinylmet hyl

14 

### C]BYI 02960 (Koester 2011 a ). All these observations taken together suggest that the furanone

- 4

- 14 

### C radiolabel is not completely stable and that a small part of the dose obviously underwent extensive biotransformation to C1

- and C2

- fragments that

resu lted in an incorporation of radioactivity into biomolecules, in particular in male rats.

The results of these metabolism investigations are in good accordance with those obtained from the corresponding organ metabolism rat study with [furanone

- 4

- 14 

### C]BYI 0 2960 (Koester,
201 2b ).

This study is fully reliable (acceptable/guideline) and satisfies the study requirements of a metabolism study ( U.S. EPA 870.7485; OECD Section 4 Part 417 and Annex to Directive 87/302/EEC, Part B, Toxicokinetic; JMAFF 12 Nousan 8 147).

C. Ethyl

- 1

- 14 

### C
In a toxicokinetic and metabolism study ( MRID 48844146 ) , a group of 4 male Wistar rats were administered by oral gavage a single dose of 2 mg/kg bw [Ethyl

- 1

- 14 

### C]BYI02960 in 0.5% aqueous Tragacanth® and sacrificed by exsanguination under anaesthesia at 72 hours post dosing. The test compound was radiolabeled with 14 

### C in the C1

- position of the ethyl side chain of the molecule. The metabolism and radioactivity which included the test compound and metabolites was determined in urine and faecal samples collected for the time range between dosing and sacrifice. Additionally, radioactivity in plasma micro samples was determined over the study period (23 time points). Total radioac tivity was determined in excreta (including expired air) and in organs and tissues collected at sacrifice. Samples were analysed, and parent compound and metabolites identified, by radiochromatographic (HPLC, TLC) and spectroscopic (LCMS) methods.

Mean tot al radioactivity recovery was nearly quantitative since approximately 100% of the
administered dose was found in the excreta and bodies of males at sacrifice.

### Page 77 of 116

[Ethyl

- 1

- 14 

### C]BYI02960 was nearly completely absorbed since > 85% of the total dose administered was detected in the urine and the body without GIT at sacrifice. The absorption started immediately after dosing as could be seen from the quick increase of radioactivity in plasma micro samples, with the peak plasma conc entration (C max 

### ) was reached approximately 1
hour after administration.

The distribution of the radioactivity within the body was fast. From the maximum plasma level (C max 

### ), the radioactivity level declined slowly down to approximately 50% of C max 

### within 8 hours and to approximately 8% of C max 

### 72h after dosing.

Excretion was rapid and mainly by the renal route. Approximately 82% of the total administered dose was excreted in the urine and approximately 14% in the faeces. Only a negligible part of
0.2% of the total administered dose was detected in expired air. The major part of the dose (>87%) was excreted within 24 hours after treatment, though excretion was ongoing in the time range between 24 and 72 hours the time of sacrifice. In particular, the major part of the
metabolite BYI 02960

- DFA was excreted on day 2 and day 3. At the time of sacrifice, 72 hours after administration, a small proportion of approximately 3% of the total dose administered was still detected in the body without GIT. The residue wa s highest in plasma with 0.158 mg/kg sample. For most other organs and tissues, levels were in the range between 0.05 and 0.1 mg/kg sample.

Parent compound, one major ( BYI 02960

- OH) and five minor metabolites were identified by
HPLC and/or TLC co

- chromato graphy or comparison. The label specific metabolite BYI 02960

- DFA was additionally identified by high resolution LC/MS of the isolated compound. Identification rates were >95% of the total radioactivity in urine and >85% of the total radioactivity in faece s. Parent compound represented the predominant part of the radioactivity in urine but in faeces samples the metabolite BYI 02960

- OH was more prominent. Approximately 92% of the total dose administered was identified in excreta. Another approximate 3% of th e dose corresponding to 6 unknown metabolites were characterised by their chromatographic behaviour. All metabolites representing >1% of the dose administered have been identified.

The principal metabolic reactions of [ethyl

- 1

- 14C]BYI 02960 in rats were: (1) hydroxylation followed by conjugation with glucuronic acid; (2) cleavage of the difluoroethyl group leading to
BYI 02960

- DFA; and (3) cleavage of the molecule at the pyridinylmethyl bridge leading to BYI
02960

- difluoroethyl

- amino

- furanone.

The results of the metabolism investigations are in good accordance with those obtained from the corresponding organ metabolism rat study with [ethyl

- 1

- 14C]BYI 02960 (Koester, 2012a).

This study is fully reliable (acceptable/guideline) and satisfies the study requirements of a metabolism study ( U.S. EPA 870.7485; OECD Section 4 Part 417 and Annex to Directive 87/302/EEC, Part B, Toxicokinetic; JMAFF 12 Nousan 8147).

870.7600 Dermal Absorption

– Rat Dermal absorption study with technical grade active ingred ient was not conducted. Triple pack dermal penetration studies were conducted with the SL formulation.

### Page 78 of 116

A. In vivo dermal absorption with SL formulation

In an in vivo dermal absorption study with a [pyridinylmethyl

14 

### C]

- BYI02960 200g/L soluble

concentra te (SL) formulation, 7 to 9 week

- old male Wistar Rj: WI (IOPS HAN) rats in groups of 4/concentration/timepoint (MRID 48844557) over four sacrifice timepoints of 8, 24, 72, or 168 hours received either the undiluted 200 g/L SL formulation, or 0.625 g/L or 0 .1 g/L aqueous dilutions for eight hours. Absorption was followed using [ 14 

### C]

- BYI02960, which was uniformly blended into the formulations prior to application. Animals were lightly anaesthetised by an unspecified method and two plastic ‘protective saddles’ were secured to define the application site for the test substance The formulated products were then applied dose to a 2 x 6 cm 2 

### shaved area of dorsal skin as two aliquots of 60  L (total of 120  L) to each animal in the 12 groups (N = 4/group), and the exposed skin area and protective saddles were covered in perforated plastic
as a semi

- occluded cover not touching the skin, and held in place over the saddles with surgical tape (~3 x 4 cm). After eight hours, covers, saddles, and tape were removed and wip ed down by swabs and distilled water. The application sites were swabbed with 1% v/v Tween 80 in PBS until no more radioactivity was detected. If necessary, the treated skin was shaved with the shavings being retained for analysis. The skin was then tape stripped until the epidermis appeared shiny. The 8 hour sampling group animals were sacrificed, while animals retained for the subsequent timepoints received new protective saddles and covers.

Urine, feces, and cage wash samples were collected individuall y at 0 to 8, 8 to 24, and 24

- hour intervals thereafter up to the time of final sacrifice. At sacrifice, animals were subjected to terminal anesthesia by isoflurane, and exsanguinated via cardiac puncture. Application site skin, surrounding skin (within 1 cm perimeter, distant skin, and cardiac blood were collected, and along with skin swabs, tape strips, covers, saddle, and tape were retained for analysis of radioactivity by LSC using a Packard 1900 TR counter.

Non

- absorbed dose was regarded to consist of radiolabel in dressings, surface tape strips (first two strips), and fur. Radiolabel in urine, feces, cage washes, non

- treated skin and carcass was regarded as being directly absorbed. Radiolabel in stratum corn eum, and skin, including surrounding skin were regarded as being potentially absorbable.

For the 200 g/L neat product, the mean total absorbable fractions were 21.78, 19.63, 17.00, and 19.18% of the applied dose for the 8, 24, 72, and 168 hour groups, re spectively. Of these totals, the directly absorbed component was 2.27, 3.88, 4.39, and 8.14% of total applied dose, respectively. The test substance readily distributed to the surrounding skin, reaching 15.16% of total applied dose at 8 hours, and steadily falling to reach 7.69% of total applied dose by 168
hours. The fraction in the non

- treated skin reached a maximum of 2.71% of applied dose at 72 hours, falling to 2.3% of applied dose at 168 hours. The proportion in the stratum corneum varied over time, b eing 1.05% at 8 hours, reaching a maximum of 4.14% of total applied dose at 24 hours, falling to 0.71% of applied dose at 72 hours, and increasing to 1.34% at 168 hours. The urine was the predominant route of excretion, containing a mean total of 2.18% of applied dose at 168 hours, while faeces contained a mean total of 0.94%. Mean total radiolabel recovery ranged from 101.1 to 113.4% of that applied dose for the 8, 24, 72, and 168 hour sacrifice groups respectively.

### Page 79 of 116

For the 0.625 g/L diluted product, the m ean total absorbable fractions were 9.26, 8.28, 9.66, and 5.53% for the 8, 24, 72, and 168 hour exposure groups, respectively. Of these totals, the directly absorbed component was 2.21, 1.31, 2.18, and 2.24% of total applied dose, respectively.

In contrast to the 200 g/L undiluted formulation, distribution to the surrounding skin was minimal, being only 0.307% of total applied dose at 8 hours, 0.345% at 24 hours and rising to 0.577% at 72 hours, and falling to reach 0.154% of total applied dose by 168 hours . The proportion in the non

- treated skin was also far lower than that obtained with the 200 g/L formulation, reaching a maximum of 0.473% of applied dose at 72 hours, and falling to 0.198% of applied dose at 168 hours. The proportion in the stratum corneum was 4.86% at 8 hours and 5.96% at 24 hours, reaching a maximum at 72 hours of 6.41% of applied dose, and falling to 2.71% at 168 hours. The urine was the predominant route of excretion, containing a mean total of 1.10% of applied dose at 168 hours, while faeces contained a mean total of 0.3%. Mean total radiolabel recovery was 99.84, 99.36, 92.30, and 95.59% of total applied dose at the 8, 24, 72, and 168 hour sacrifice groups, respectively.

For the 0.1 g/L diluted product , the mean total absorbable fracti ons were 16.64, 10.32, 18.20, and 20.57% for the 8, 24, 72, and 168 hour exposure groups, respectively. Of these totals, the directly absorbed component was 4.32, 2.78, 5.28, and 8.12% of total applied dose, respectively. Similar to the 0.625 g/L formulati on and in contrast to the 200 g/L formulation, distribution to the surrounding skin was low, being 1.53% of total applied dose at 8 hours, 0.410% at 24 hours, 0.400% at 72 hours, and rising slightly to 0.734% of total applied dose by 168 hours. The
proport ion in the non

- treated skin was between the relatively low levels for the 0.625 g/L formulation and the high levels of the 200 g/L formulations, with a maximum of 1.551% at 8 hours, and falling to 0.794% of applied dose at 168 hours. The proportion in the stratum corneum was 8.74% at 8 hours and 6.26% at 24 hours, and as with the other concentrations, maximum levels were reached at 72 hours, at 11.69% of applied dose, and falling to slightly to 10.37% at 168 hours. The relative level of total applied dose i n the stratum corneum at 168 hours was
therefore 3.8

- fold and 7.7

- fold higher than those obtained with the 0.625 g/L and 200 g/L formulations, respectively. The urine was again the predominant route of excretion, containing a mean total of 3.00% of applied dose at 168 hours, while faeces contained a mean total of 0.443% for this timepoint. Mean total radiolabel recovery was 100.5, 95.8, 102.9, and 95.6% of total applied dose at the 8, 24, 72, and 168 hour sacrifice groups, respectively.

The last available l ayers of stratum corneum (tape strips 12 or 9) for the animals with the highest absorption values in each of the three 168 hour concentration groups all contained radiolabel, albeit at levels 32 to 64% lower than that on the first (surface) tape strips. Wh en considered with the observed urinary excretion of radiolabel at 168 hour study termination, this finding demonstrated that dermal absorption of applied test material was potentially continuing up to and including the 168 hour timepoint.

The study author s stated that as a conservative estimate, the amount of BYI 02960 potentially absorbable following an 8

- hour exposure ranged from 17.0 to 21.8% for the 200 g/L neat product, 5.54% to 9.66% for the 0.625 g/L intermediate dilution, and from 10.3% to 20.6% fo r the highly diluted 0.1 g/L formulation, based on group mean values.

The evaluator has considered that, due to the basis of high intragroup variability (standard deviation exceeding 25% of the mean), individuals in each group with the highest levels of

### Page 80 of 116

de rmal absorption were considered to be more representative of potential intraspecies variation compared to group means. On an individual animal basis, the highest absorptions of test substance were 29.9, 9.38, and 23.9% for the concentrate, 0.625 g/L, and 0 .1 g/L dilutions, respectively.

In summary, following a n 8

- hour in vivo dermal exposure to [pyridinylmethyl

14 

### C]

- BYI02960 200g/L SL formulation and dilutions, the maximal absorbable dose was 29.9, 9.38, and 23.9% for 200 g/L (neat), 0.625 g/L, and 0.1 g/L dilutions, respectively. The dermal absorption data from both in vivo and in vitro dermal absorption studies were used
to estimate the in vivo dermal absorption factor for humans; the estimated factors were 42.1, 3.32 and 17.2% for BYI02960 200g/L SL conce ntrate, 0.625 g/L, and 0.1 g/L dilutions, respectively.

This study is reliable (acceptable) and meets the data requirements for an in vivo dermal absorption study (OECD TG 427 [2004]).

B. In vitro dermal penetration study with rat and human skin

The dermal penetration of a BYI02960 200g/L soluble concentrate (SL) formulation was tested

in vitro using rat (dorsal) and human (abdominal) skin mounted in a glass flow

- through diffusion cell system with an exposure area of 1 cm2 maintained at 32 + 2oC (MR ID 48844558). The test substance was applied as either the undiluted 200 g/L SL formulation, or as 0.625 g/L or 0.1 g/L aqueous dilutions. Penetration and absorption were followed using [pyridinylmethyl

14 

### C]

- BYI02960, which was uniformly blended into the formulations prior to application.
The formulated products were applied at a rate of 10 μL/cm2 to 2 groups of 6 skins per dose level per species with the exception of the 0.625 g/L groups which had only 5 skins for humans and 4
for rats. The achieved co ncentrations of BYI02960 applied per area of skin was approximately 1800 to 2000, 4.5 to 5.0, and 0.9 to 1.1 μg/cm2 for the 200, 0.625 and 0.1 g/L formulations, respectively. The formulation concentrations and application rates were designed to mimic
pote ntial field

- use exposures. The applied formulation remained in contact with the skins for 8 hours. Serial receptor fluid samples (2×50 μL) were collected hourly for the 24 hour duration of the study. The volume of receptor fluid was maintained by the re placement with a volume of fresh receptor fluid, equal to the total aliquot volume. At 8 hours, the skin surfaces of all groups
were washed with sponge swabs and freshly prepared 1% v/v Tween 80 in phosphate buffered saline. At 24 hours, the skin samples were swabbed again, and stripped using Monaderm adhesive tape to remove non

- absorbed surface test material (first two strips) and stratum corneum (strips three until a shiny appearance had been reached, indicating complete removal). Stripping involved appl ying the tape for five seconds before removing the strip against the direction of hair growth.

For the 200 g/L formulation, mean total recovery was 106.1 and 105.5% of that applied for humans and rats, respectively. As a percentage of total applied dose, t he potentially absorbable fraction (receptor fluid plus tape

- stripped skin) over 24 hours was 0.204 and 0.145% for human and rat skin, respectively. The total absorbable dose was therefore approx. 1.4

- fold greater for human skin than for rat skin. Of the p otentially absorbable fraction, directly absorbed dose (receptor fluid and receptor fluid terminal) only comprised 0.016±0.029% and 0.071±0.071% of the total applied for human and rat skin, respectively. Stratum corneum contained just over half

### Page 81 of 11 6

(0.103±0.12 0%) of the total absorbable fraction in humans, and just over a third (0.055±0.075%) of the total absorbable for rats. Washing the skin at eight hours removed >105% of the applied dose for both species, while tape strips one and two at 24 hours removed 0.1 28 and 0.132% of the applied dose for human and rat skin, respectively.

For the 0.625 g/L formulation, mean total recovery was 100.3 and 96.4% of that applied for humans and rats, respectively. As a percentage of total applied dose, the potentially absorba ble fraction (receptor fluid plus tape

- stripped skin) over 24 hours was 2.008 and 5.667% for human and rat skin, respectively. The total absorbable dose was therefore approx. 2.5

- fold greater for rat
skin than for human skin. As was found for the concentra te formulation, directly absorbed dose (receptor fluid and receptor fluid terminal) was a minor contributor to the potentially absorbable total, being 0.392±0.344% and 1.075±0.330% for human and rat skin, respectively. Stratum corneum again contained just over half of the total absorbable fraction for both humans (1.149±0.534%) and rats (2.852±3.832%). Washing the skin at eight hours removed a mean of 97% and 85.5% of the applied dose for human and rat skin samples, respectively. Tape strips one
and two at 24 hours removed 0.492 and 2.137% of the applied dose for human and rat skin, respectively.

For the 0.1 g/L formulation, mean total recovery was 106.1 and 105.5% of that applied for humans and rats, respectively. As a percentage of total applied dose, the potentially absorbable fraction (receptor fluid plus tape

- stripped skin) over 24 hours was 4.753±2.963% and 6.607±2.796% for human and rat skin, respectively. The extent of interspecies difference at this concentration was therefore similar in magnitude to that for the concentrate, but in reverse direction, being only 1.4

- fold higher for rat skin than for human skin. As was found for the two higher concentration levels, directly absorbed dose (receptor fluid and receptor fluid terminal)
was a minor contribu tor to the potentially absorbable total, being 0.646±0.482% and 1.105±0.436% for human and rat skin, respectively. Stratum corneum again contained just over half of the total absorbable fraction for humans (2.998±1.828%) but was even higher for rats,

compr ising approx. two

- thirds (4.409±2.893%) of the total. Washing the skin at eight hours removed a mean of 89.4% and 85.5% of the applied dose for human and rat skin samples, respectively. Tape strips one and two at 24 hours removed 0.99% and 5.86% of the app lied dose for human and rat skin, respectively.

As penetration into the receptor chamber remained ongoing at the 24 hour termination point of the study for the majority of rat and human skin samples for the three formulation concentrations, test substance remaining in the stratum corneum were considered to be potentially absorbable.

Group mean values were used in the calculations of absorbable dose. Although standard deviations for the potentially absorbable fractions in all groups ranged from 42% (rat 0.1 g/L sample) to 106% (human 200 g/L sample) of the means, the variations were considered likely to be outliers arising from experimental variation/errors rather than representations of true biological variation.

Under the conditions of this in vitro derma l absorption study, the study author calculated the mean total potentially absorbable values in humans/rat skin samples, respectively, over 24 hours

### Page 82 of 116

to be 0.20/0.15% for the 200 g/L formulation, 2.0/5.7% for the 0.625 g/L formulation, and
4.8/6.6% for the 0.1 g/L formulation. The evaluator agreed with the study author’s conclusions.

The results obtained in this study, using an in vitro flow

- through diffusion cell system, demonstrate that penetration and absorption of BYI02960 from the 200 g/L SL formulation was relatively equivalent to within 30 to 40% ranges in rat and human skin when applied as the undiluted concentrate or highly dilu ted (0.1 g/L) formulations, but that dermal absorption was nearly 3

- fold higher in rats for the intermediate dilution (0.625 g/L).

The in vitro dermal absorption data on isolated rat and human skin in combination with
the in vivo rat dermal absorption dat a were used by the primary study evaluator to
estimate the in vivo human dermal absorption factor; the factors were 42.1 % , 3.32 % , and 17.2% for the concentrate, intermediate, and highly diluted formulation, respectively. However, US EPA secondary re v iewer does not agree with th

e conclusion concerning the human dermal absorption factor because there are no data for the exposure duration beyond 24 hours in the in

- vitro human and rat skin studies. Therefore, the US EPA determines that the appropriate estimate for the potential human dermal absorption factor

to be 7.42 % based on the data on the 24

- hour exposure period and most dilute
administered con

c entration (0.1 g/l).

This study is reliable (Acceptable) and fulfils the requirements of the OECD guideline fo r in vitro dermal absorption studies in rats and humans ( OECD 428 (2004)).

A.4.9 Immunotoxicity

870.7800 Immunotoxicity In an immunotoxicity study (MRID 48844148 ), BY I 0 2960 (96.2% a.i. batch# 2009

- 000239)
was administered to seven week old female Wistar, Rj:WI (IOPS HAN) rats in groups of 10/dose at concentrations of 0, 125, 600, or 3000 ppm (0, 10, 50, or 230 mg/kg bw/d) for 30 days. A positive control group consisting of 10 female Wistar, Rj:WI (IOPS HAN) rats received oral gavage doses of 3.5 m g/kg bw/d cyclophosphamide at 5 mL/kg bw dosing volumes for 28 days.

On Day 26, the test animals were immunized with an injection of sheep red blood cells (SRBC). On study Day 30, blood samples were collected from the test animals and serum samples were assayed for their concentration of SRBC

- specific IgM antibodies to provide a quantitative assessment of humoral immune response by ELISA. Additional parameters that were evaluated include mortality, clinical signs of toxicity, body weight

, body weight gai n, food consumption, selected organ weights ( i.e . spleen, and thymus), and macroscopic examination of all major organs, tissues and body cavities.

There were no observable test substance related clinical signs, and premature mortality was
confined to eutha nasia of one animal at 600 ppm due to forelimb automutilation on study day 8. As this was unaccompanied by other necropsy findings, it was considered unrelated to the test
substance.

Overall group mean body weight gains at 3000 ppm over study days 1 to 29 were 23% lower than that in controls (p<0.05), resulting in 6% lower mean terminal body weight than controls

### Page 83 of 116

without statistical significance (p > 0.05). Decreases in food consumption of ≤ 34% (week 1) relative to controls were seen at 3000 ppm throughout the study period and were likely linked to changes observed in body weight gain.

Necropsy findings in negative control and test substance groups were unremarkable, whereas atrophied and/or small ( 5 or 6/10 animals) spleens were observed in cyclophospham ide

- dosed positive control animals.

While there was a dose

- related decreasing trend in absolute spleen weights relative to controls in treated animals (2%, 4% and 6% decreases at 125, 600 and 3000 ppm respectively), relative (to body weight ) spleen weights were essentially unchanged at 3000 ppm (+1% increase). Similarly, absolute thymus weights at 3000 ppm were decreased by 4% relative to controls, but relative (to body weight ) thyroid weights were unaffected. Positive control animals had 32 to 34% (p≤0.01) decreases in mean absolute and relative spleen weights, and 27 to 28% (p≤0.01) decreases in absolute and relative thymus weights, respectively.

The SRBC

- specific IgM ELISA data showed a 55% increase from controls at 125 ppm, 15%
decrease at 600 ppm, and an 18% decrease at 3000 ppm, with no findings being statistically significant (p>0.05). Based on the lack of dose dependency and absence of statistical significance, overall there were no indications of test substance immunosuppressive pote ntial up to and including the highest dose tested of 3000 ppm (~230 mg/kg bw/d). The positive control performed as expected, with a 93% decrease (p < 0.01) in anti

- SRBC IgM antibody
concentrations.

The immunotoxicity NOAEL is the highest dose tested of 300 0 ppm (230 mg/kg bw/d), based on an absence of test substance related immunotoxicity findings at this dose.

This study is fully reliable (acceptable/guideline) and satisfies the guideline requirements (OPPTS 870.7800) for an immunotoxicity study in rats.

A.4.9 Special/Other Studies

90

- day oral toxicity with DFA (metabolite)

In a 90

- day dietary study ( MRID 48844113) , BCS

- AA56716 (97.1%; batch BCOO5984

- 5

- 8) was administered to Wistar [Rj:WI (IOPS HAN)] rats (10/sex/dose) at concentrations of 0, 200, 1000, or 6000 ppm (0/0, 12.7/15.6, 66.2/78.7, or 380/472 mg/kg bw/d, respectively). BCS

AA56716 (difluoroacetic acid) is a plant and soil metabolite of BYI02960.

Parameters evaluated included body weight

, body weight gain, food consumption, clinical signs,

Fu nctional Observational Battery parameters, exploratory locomotor activity, haematology, clinical chemistry, urinalysis, ophthalmology, organ weights, gross and microscopic pathology.

Under the conditions of this study BCS

- AA56716 did not produced test substance

- related effects on survival, clinical signs of toxicity, functional observational battery observations, ophthalmological observations, or organ weights.

### Page 84 of 116

In males at 1000 ppm, mean body weight by study day 8 was 4% lower than controls, 9% (p≤0.01 ) lower than controls by study day 29, and terminal body weight s were 12% (p≤0.01) lower than controls at study day 92. Lower mean body weight and decreased body weight gain were also noted at 6000 ppm, with a mean body weight 4% lower than controls by stu dy day 29, 6% lower by study day 57, with no further decreases through to study termination (all values were not statistically significant).

In females at 1000 ppm, mean body weight was 5% lower than controls at study day 57, and were 4% lower than controls by study day 92 (no statistical significance observed). Lower mean body weight s during the treatment period were also observed at 6000 ppm in females, with a

mean body weight 6% ( p < 0.05) lower than controls at study day 29, 7% (p≤0.05) lower at study day 57 (p≤0.05), and 9% (p≤0.01) lower at study day 92.

Decreased body weight gains in both sexes at 1000 and 6000 ppm was accompanied by corresponding decreases in absolute (g/d) food consumption from study day 4 onwards (earliest time point examined).

In hematology observations, a 9% lower hemoglobin, 6% lower mean corpuscular volume, and 8% lower mean corpuscular hemoglobin were noted in 1000 ppm females relative to controls,.
These findings all displayed poor dose dependency, with similar decreases reported at 6000 ppm.

.

In clinical chemistry observations, Serum glucose concentrations and serum bilirubin were decreased across all dose levels compared with controls; however, notin g the direction of change for the reported effects (decreases, rather than increases), the effects were not considered toxicologically adverse.

A range of urinalysis parameters at ≥ 1000 ppm (including urinary volume, ketone levels and urinary pH) were considered to be treatment

- related, but unlikely to be toxicologically significant given the lack of histopathology and clinical pathology changes.

Test substance related findings at gross necropsy were confined to black foci in the stomach gland of both sexes at 1000 ppm (10/20% incidence for M/F) and 6000 ppm (30%/20% incidence for M/F). The finding was associated at the histopathological level with focal glandular erosion/necrosis in the stomach, and considered to be toxicologically adverse.

The NOAEL was 200 ppm for both sexes (12.7/15.6 mg/kg bw/d for M/F). The LOAEL was 1000 ppm (66.2/78.7 mg/kg bw/d for M/F), based on decreased body weight gains in males, resulting in 12% lower terminal body weight s relative to controls (p < 0.01), associated decreas es in food consumption, black foci in the glandular part of the stomach (10/20% incidence for M/F) for both sexes that correlated histopathologically with focal glandular erosion/necrosis, and (in females only) statistically significant (p≤0.01) decreases in plasma haemoglobin (

- 9%), mean corpuscular volume (

- 6%), mean corpuscular haemoglobin (

- 8%) and hematocrit (

- 7%).

This study is classified as fully reliable (acceptable/guideline) and satisfies guideline requirements for a subchronic oral toxicity in r ats [ OPPTS 870.3100; OECD 408 (1998)].

### Page 85 of 116

A.5 Flupyradifurone: Summary of NOAEL/LOAEL (with BW 3⁄4 

### scaling for human equivalent dose)

With the initial glance, the toxicity data on flupyradifurone appear to indicate that the dog is
more sensitive than the othe r testing animals. However, with BW 3⁄4 scaling for human equivalent dose calculation, the results reveal that the dog and rat have similar sensitivity to the effects of flupyradifurone as indicated in the table below.

Table A.5: Flupyradifurone Summary of NOAEL/LOAEL (with BW 3⁄4 scaling for human equivalent dose)

NOAEL (mg/kg) LOAEL (mg/kg)

Study Test Animal Human Equiva le nt Dose Test Animal Human Equiva le nt Dose

28

- day oral

– rats (gavage) 75 18 200 48

28

- day oral tox.

- rats (dietary) 36 385

28

- day oral tox.

- mice (dietary) 166/199 (M/F) (HDT

28

- day oral tox. dogs (diet) (2 dogs/sex/dose) 62 40 118 75.52

90

- day oral tox.

— dogs 12 7.68 33 21.12

90

- day oral toxicity

– rats (diet) 38 9.12 156 37.44

90

- day oral toxicity

– mouse (diet) 81 407

28

- day Dermal tox.

- rats 500 (HDT) Chronic oral toxicity study in dogs. (1

- year; diet) 7.8 4.00 28 17.92

Combined chronic/ carcinogenicity study in rats. 15.8 / 22.5 (M/F) 3.8/5.4 81/ 120 (M/F)
(No compound related ↑tumor incidence) 19.44/28.8

Carcinogenicity study in
mice 43 224
( No compound related ↑tumor incidence) Developmental toxicity

- rabbit. (gavage) Mat

- 40 Mat 80

Dev

- 40 Dev

- 80 Developmental toxicity

– rat (gavage) Mat

- 50

Dev

- 150 Mat

- 1 50

Dev

- 150 36
36

2

- Generation reproduction study in rats Parental

- 38.7 (HDT) Reprod

- 38.7 Offspring 7.7 Offspring:

1.85 Parental 137

Reprod

- 137

Offspring

- 38.7 Offspring: 9.29

Acute neurotoxicity in rats. (gavage) 35 50

Subchronic neurotoxicity study in rats. 34.8 143

### Page 86 of 116

Table A.5: Flupyradifurone Summary of NOAEL/LOAEL (with BW 3⁄4 scaling for human equivalent dose)

NOAEL (mg/kg) LOAEL (mg/kg)

Study Test Animal Human Equiva le nt Dose Test Animal Human Equiva le nt Dose

Developmental neurotoxicity study in rats. Maternal

- 102 (HDT) Offspring

- 42 Offspring

- 102

28

- Day Dietary Immunotoxicity Study 230 (HDT) No systemic or Immunotoxicity was

see

### Page 87 of 116

A ppendix B. Metabolism Summary Table
Table B. Overall Summary of Characterization and Identification of Radioactive Residues in Tomato,

Potato, Apple, Cotton, and Rice Following Application of [Furanone

- 4

- 14C] BYI 02960 and [Pyridinylmethyl

14 C] BYI 02960 at Rat es and PHIs Reflective of the Proposed Uses Compound 1 Tomato

(drench) Potato

(seed treatment) Apple (foliar) Cotton

Lint (foliar) Rice

(foliar)

TRRs = 0.130P /0.096F ppm TRRs =0.076P

/0.078F ppm TRRs = 0.545P

/1.286F ppm TRRs=8.846P/4.99 3F ppm TRRs=0.620P/0.65
9F

%
TRR ppm %

TRR ppm %

TRR ppm %TRR Ppm %TR
R ppm

BYI 02960 24/36 0.031/0.0
34 40/40 0.031/0.0

31 86/74 0.467/0.9

46 73/70 6.46/3.51 75/57 0.467/0.3
73

6

- CNA 13.2/ 0.017/ 22/ 0.016/ 1.5/ 0.008/ 0.4/ 0.031/ 3.1/ 0.019/

CHMP

- di

glyc 37.1/ 0.048/ 4.4/ 0.003/

CHMP

- glyc 5.1/ 0.007/ 3.7/0.0
03 0.9/ 0.005/

CHMP 3.3/ 0.004/ 3.9/ 0.003/ 0.8/ 0.004/

OH

- glyc 3.4/5.

5 0.004/0.0

05 6.7/6.6 0.005/0.0

05 1.7/1.

1 0.009/0.0

14

Glucose/ carbohydrat

e /28 /0.026 /14 /0.182 /3.6 /0.023

Difluoroethy
l

- amino

furanone /10 /0.01 /4.2 /0.003 /0.2 /0.003

Acetic acid

glyc 0.8/0.
5 0.004/0.0

07 0.6/0.4 0.003/0.0
03

Acetic acid 1.1/0.

7 0.006/0.0

09 7.8/6.1 0.048/0.0
40

AMCP

difluroethan
amine 4.1/ 0.023

OH 1.0/0.
8 0.005/0.0

1 0.4/ 0.002/

Glyoxylic
acid 0.2/0.2 0.015/0.0
09 0.4/ 0.003/

OH

glyc/acetic
acid 14.6/13
.9 1.30/0.69

4

Bromo/chlor

o 1.6/1.6 0.140/0.0
78 1.5/1.7 0.009/0.0

11

Total
identified 86/79 0.111/0.0
75 80/50 0.061/0.0

39 98/91 0.53/1.17 90/86 7.94/4.29 89/68 0.552/0.4
50

Total
characterize
d 12/4.

3 0.016/0.0

04 9.3/12.

4 0.007/0.0

1 0.5/0.

1 0.002/0.0

02 9.5/11 0.837/0.5

30 7.4/17.

2 0.045/0.1

13

Total
extractable 98/85 93/67 99/92 99/97 8.77/4.82 96/86 0.597/0.5
64

Unextractabl

e (PES) 1.5/1

5 6.6/33 1.3/8.
1 0.8/3.4 0.073/0.1
70 2.7/12.

8 0.017/0.0

85 [Difluoroace tic acid] [87 2 ] [0.175 1 ]

1 See Table C.1 for names and structures.

2 [1

- ethyl

14 C] BYI 02960. Conducted only with tomato



### . - Appendix C. Physical/Chemical Properties and Metabolites

### Page 88 of 116

Table C. 1. Physicochemical Properties of the Flupyradifurone (99.4% Purity)

Parameter Value Reference (MRID/BCS Study) Molecular weight (g/mole) 288.68 MRID 48843601

M

- 434475

- 01

- 1 Melting point/range (°C) 69.0 MRID 48843630

M

- 367370

- 01

- 2 pH 6.6 at 24 o C MRID 488436626

M

- 412128

- 01

- 2 Density (g/cm 3 ) 1.43 g/ml at 20 o C MRID 48843642

M

- 412635

- 01

- 2 Water solubility (g/L at 20 °C) 3.2 MRID 48843643

M

- 204285

- 01

- 2 Solvent solubility (g/L at 20 °C) Methanol

n

- Heptane
Toluene
Dichloromethane
Acetone Ethyl acetate Dimethyl sulfoxide >250
0.0005
3.7
>250>25
0
>250
>250 MRID 48843656

M

- 414064

- 01

- 2

Vapor pressure (Pa) 9.1 x 10

- 7 at 20 o C
1.7 x 10

- 7 at 25 o C
2.6 x 10

- 7 at 50 o C MRID 48843650

M

- 309853

- 01

- 3

Dissociation constant (pK
a ) No dissociation occurs in aqueous solutions in the pH range between
1 and 12. MRID 48843636

M

- 418626

- 091

- 2

Octanol/water partition coefficient Log(K OW ) 1.2 (pH 4

– 9) MRID 48843639

M

- 414485

- 01

- 2



### Table C.2. Tabular Summary of Flupyradifurone and Its Metabolites and Degradates. Chemical Name (other names in parenthesis) and Structure Matrix Percent TRR (PPM)

Matrices

- Major Residue (>10%TRR) Matrices

-

Minor Residue (<10%TRR)

Parent Flupyradifurone
BYI 02960

4

- [[(6

- chloropyridin

- 3

- yl)methyl] (2,2

- difluoroethyl) amino]furan

- 2(5H)

- one (IUPAC) 2(5H)

- furanone, 4

- [[(6

- chloro

- 3

- pyridinyl)methyl](2,2

- difluoroethyl) amino]

- (CAS)
CAS

- No.: 951659

- 40

- 8 Tomato 24P (0.031) 36F (0.034)

Potato 40P (0.031)

40F (0.031) Apple 86P (0.47)

74F (0. 95)

Cotton 73P (6.5)

70 F (3.5) Rice grain 75P (0.47)

57F (0.37)

CRC Wheat Grain (29 d) 8.3P (0.02) 0.4F (0.004)

CRC Swiss Chard (29 d) 46P (0.69)

43 F (0.37)

### Page 89 of 116 CRC Turnip Leaf (29 d) 62P (0.51)

64 F (0.44) CRC Turnip Root (29 d) 58P (0.04)

56F (0.04)

Ruminant milk 89P (0.16)

24F (0.25)

Ruminant
muscle 98P(0.35)

88F (0.48)

Ruminant fat 99P (0.10)

80F (0.21)

Ruminant kidney 35P (0.65)

50F (0.74)

Ruminant liver 85 P (1.0)

60F (1.0) Poultry egg 20P (0.017)

2.3F (0.013) Poultry muscle 14F (0.005) 9.8P (0.007) Poultry fat 15P (0.003) Poultry liver 0.9P (0.004) 0.5F (0.01)

Rat Excreta 40

- 77 TDA

BYI 02960 Chloro (Co

- elutes with Bromo)
3

- chloro

- 4

- {[(6

- chloropyridin

- 3

- yl) methyl](2,2

- difluoroethyl)amino}
furan

- 2(5 H

)

- one Cotton 1.6P (0.14) 1.6F (0.078)

Rice 0.4P (0.003) CRC Turnip root (29

- 296 d) 1.4

- 2.5P (0.001)
1.3

- 2.5F (0.06

- 0.001)

CRC Swiss chard (29

- 296 d) 0.4P (0.04)
0.4

- 0.6F (0.003

- 0.001 CRC Turnip leaves (29

- 296 ) 1.3

- 1.6P (0.001

- 0.004)
1.1

- 1.8F (0.007

- 0.002)

Water

BYI 02960 bromo (co

- elutes with chloro)

3

- bromo

- 4

- {[(6

- chloropyridin

- 3

- yl) methyl](2,2

- difluoroethyl)amino}
furan

- 2(5 H

)

- one

### Page 90 of 116

BYI 02960 OH

4

- {[(6

- chloropyridin

- 3

- yl)methyl] (2,2

- difluoroethyl)amino}

- 5

- hydroxyfuran

- 2(5 H

)

- one Apple 1.0P (0.005) 0.8F (0.01)

Rice 0.4P (0.002)

CFC Wheat grain (29d) 10P (0.018) 2.3F (0.011)

CFC Swiss chard (29d) 1.6 P(0.023) 1.9F (0.02) CFC Turnip root (29d) 0.5P (0.001) 0.4F (0.001) CFC Turnip top(29d) 1.4P (0.011) 1.7F (0.012)

Ruminant liver 16P (0.30)

15F (0.22)

Ruminant
muscle 1.8F (0.01)

Ruminant kidney 2.9F (0.008)

Poultry eggs 18P (0.015) 2.3F (0.013)

Poultry muscle 8.1P (0.006) 2.4F (0.004) Poultry fat 5.5P (0.001)

Poultry liver 1.5 (0.007) 0.8F (0.018)

Rat excreta 13

- 29 TDA BYI 02960 OH glyc
3

- {[(6

- chloropyridin

- 3

- yl)methyl] (2,2

- difluoroethyl)amino}

- 5

- oxo

- 2,5

- dihydrofuran

- 2

- yl beta

D

- glucopyranoside Tomato 3.4P (0.004) 5.5F (0.005)

Potato 6.7P (0.005) 6.6F (0.005) Apple 1.7P (0.0090 1.1F (0.014)

CFC Wheat grain (29

- 296d) 5.0P (0.009) 2.1F (0.002)

CFC Swiss chard (29

- 296d) 11

- 28P (0.16

- 0.036)

13

- 21F (0.12

- 0.033)

CFC Turnip leaf (29

- 296d) 10

- 12F (0.02

- 0.09) 9.4

- 11P (0.02

- 0.08)

CFC Turnip root (29

- 296d) 2.5

- 3.8P (0.001

- 0.002)
2.1

- 3.1F (0.001)

BYI 02960

- OH

- glyc

- SA (isomer 1)
And
BYI 02960

- OH

- glyc

- SA (isomer 2) CRC Swiss chard (29

- 296d) 1.7

- 9.2P (0.02

- 0.04)
4.8

- 6.7F (0.01

- 0.05)

CRC Turnip leaf (29d) 2.3P (0.02)

### Page 91 of 116

BYI 02960 acetic acid

N

- [(6

- chloropyridin

- 3

- yl)methyl]

- N

- (2,2

- difluoroethyl)glycine Apple 1.1P (0.006) 0.7F ((0.009)

Rice 7.8P (0.048) 6.1F (0.040)

CRC Wheat grain (29

- 296d) 1.8P (0.002) 1.0F (0.002)

CRC Swiss chard (29

- 296d) 0.6

- 0.9F (0.001

- 0.005)

CRC Turnip leaf (29

- 296d) 1.1

- 1.3F (0.001

- 0.008) CRC Turnip root (29

- 296d) 0.2

- 0.3F (0.001)

Rat

Water

BYI 02960

- acetic acid

- glyc Apple 0.8P (0.004) 0.5F (0.007)

Rice 0.6P (0.003) 0.4F (0.003)

CRC Swiss
chard (29

- 296d) 3.0P (0.013)
0.2

- 1.6F (0.001

- 0.01) CRC Turnip leaf (29d) 0.4P (0.003)
0.5

- 3.5F (0.001

- 0.02)

### Page 92 of 116

BYI 02960 glyoxylic acid

N

- (6

- chloropyridin

- 3

- ylmethyl)

- N

- (2,2

- difluoroethyl)oxamic acid Cotton 0.2P (0.015) 0.2F (0.009)

Rice 0.4P (0.002)

CRC Wheat grain (29d) (15% wheat straw, forage, hay) 6.0P (0.011)

CRC Swiss chard (29d) 2.6P (0.039) 4.7F (0.041) CRC Turnip leaf (29d) 2.6P (0.021) 6.6F (0.045) CRC Turnip root (29d) 12F (0.009) 8.6P (0.006)

BYI 02960 CHMP
6

- chloropyridin

- 3

- ylmethanol (IUPAC)
3

- pyridinemethanol, 6

- chloro

- (CAS)
CAS

- No.: 21543

- 49

- 7 Tomato 3.3P (0.004)

Potato 3.9P (0.003) Apple 0.8P (0.004) CRC Turnip root (29d) 4.1P (0.003)

BYI 02960 CHMP glyc Tomato 5.1P (0.007) )

Potato 3.7P,(0.003) Apple 0.9P (0.005)

CRC Swiss chard (29d) 5.4P (0.080)

CRC Turnip leaf (29

- 296d) 4.5

- 5.9P (0.01

- 0.04)

### Page 93 of 116 CRC Turnip root (135d) 2.0P (0.001)

BYI CHMP di

- glyc Tomato 37P (0.048)

Potato 4.4P (0.003)

BYI 02960 CHMP glyc di

- SA
And BYI 02960 CHMP glyc tri

- SA

Or trisulfate CRC Swiss chard (29

- 296d) 3.2

- 5.3P (0.02

- 0.08)

6

- CNA 4

6

- chloronicotinic acid (IUPAC)
CAS

- No.: 5326

- 23

- 8 Tomato 2 13.2P (0.017)

Potato 3 22P (0.016) Apple 1.5P (0.008)

Cotton 0.4P (0.031)

Rice 3.1P (0.019)

CRC Wheat grain 3.8P (0.007)

CRC Swiss
chard 7.0P (0.10)

CRC Turnip
leaf 1.0P (0.008)

CRC Turnip

root 8.5P (0.006)

Poultry eggs 7.2P (0.006) Poultry muscle 8.8P (0.;006) Poultry fat 1.8P (<0.001) Poultry liver 6.4P (0.028)

Rat excreta 0.4

- 6.3 TDA

Potato 2.3P (0.003)

### Page 94 of 116

BYI 02960

- 6

- CNA

- glycerol

- gluA (isomers 1, 2 & 3) CRC Wheat grain (14

- 29% wheat forage, straw, hay) 22P (0.16)

BYI 02960

- difluoroethyl

- amino

- furanone (DFEAF)
4

- [(2,2

- difluoroethyl)amino]furan

- 2(5 H )

- one Tomato 10F (0.01)

Potato 4.2F (0.003) Apple 0.2F (0.003)

CRC Swiss chard (29d) 17F (0.14)

CRC Turnip
leaf 1.0F (0.007)

Rat excreta 0.96

- 3.5

BYI 02960

- difluoroethyl

- amino

- furanone

OH

- glyc CRC Swiss chard (29d) 1.2F (0.01)

BYI 02960

- AMCP

- difluoroethanamine

N

- [(6

- chloropyridin

- 3

- yl)methyl]

- 2,2

- difluoroethanamine Apple 4.1P (0.023)

Ruminant liver 1.2P (0.02)

Ruminant kidney 1.1P (0.02)

### Page 95 of 116

BYI 02960

- N

- formyl

- AMCP

difluoroethanamine

N

- [(6

- chloropyridin

- 3

- yl)methyl]

- N

- (2,2

- difluoroethyl)formamide

And/Or
BYI 02960

- N

- acetyl

- AMCP

difluoroethanamine

N

- [(6

- chloropyridin

- 3

- yl)methyl]

- N

- (2,2

- difluoroethyl)acetamide CRC Swiss
chard 2.9P (0.043)

CRC Turnip
leaf 3.6P (0.030)

CRC Turnip

root 3.5P (0.003)

BYI 02960

- mercapto

- lactic acid
3

- ({4

- [(2,2

- difluoroethyl)amino]

- 2

- oxo

- 2,5

- dihydrofuran

- 3

- yl}sulfanyl)

- 2

- hydroxypropanoic acid CRC Wheat forage, hay , straw (NOT grain) 1

- 10F (0.003

- 0.07)

BYI 02960

- amino

- furanone
4

- aminofuran

- 2(5 H

)

- one CRC Wheat grain 0.5F (0.002)

CRC Swiss
chard 3.1F (0.02)

### Page 96 of 116 CRC Turnip
leaf 0.9F (0.006)

CRC Turnip

root 4.1 ,(0.003)

BYI 02960

- bromo

- amino

- furanone
4

- amino

- 3

- bromofuran

- 2(5 H )

- one CRC Wheat

Forage, Straw, Hay (NOT grain) 2

- 10F (0.01

- 0.22)

DFA difluoroacetic acid (IUPAC) Acetic acid, 2,2

- difluoro

- (CAS)
CAS

- No.: 381

- 73

- 7 Tomato 87 (0.18)

Rice*
Potato*
Cotton* Apple*
CRC Wheat* CRC Turnip*
CRC Swiss
chard*
Ruminant* Poultry* *Shown to be present in significant amounts by analysis for

non

- labeled compound in the metabolism studies and by analyses of crop field trial studies commodity samples and livestock feeding studies commodity samples.

Rat excreta 5.3 urine TDA
0.49 feces TDA Glucose (hexose) Tomato 28F (0.026) Apple 14F (0.18)

Rice 3.6F (0.023)

CRC Wheat grain 71F (0.34)

CRC Turnip

root 3.4F (0.003)



## ANIMAL METABOLITES ONLY

Lactose Ruminant milk 67F (0.70)

### Page 97 of 116

BYI 02960

- acetyl

- AMCP Poultry eggs 23P (0.019) Poultry muscle 40P (0.028) Poultry fat 28P (0.006) Poultry liver 6.3P (0.027)

BYI 02960

- AMCP

- difluoroethanamine

- SA Poultry liver 0.3P (0.001)

BYI 02960

- acetyl

- cysteinyl

- nicotinic acid Poultry liver 0.3P (0.001)

BYI 02960

- cysteinyl

- nicotinic acid

6

- [(2

- amino

- 2

- carboxyethyl)sulfanyl]nicotinic
acid Ruminant liver 4.8P (0.058)

Ruminant kidney 6.1P (0.11)

### Page 98 of 116

BYI 02960

- hippuric acid

N

- [(6

- chloropyridin

- 3

- yl)carbonyl]glycine Ruminant milk 9.1P (0.017)

Ruminant
muscle 1.3P (0.005)

Ruminant kidney 9.5P (0.18)

Ruminant liver 0.8 (0.01)

Rat excreta 1.1

– 10.5 TDA

BYI 02960

- CHMP

- serinate Poultry excreta

- -

BYI 02960

- des

- difluoroethyl

- OH

- SA Poultry muscle 2.1P (0.001) 0.5F (0.001)

Poultry fat 5.6P (0.001) Poultry liver 3.1P (0.014) 0.2F (0.004) Poultry eggs 0.1F (0.001)

BYI 02960

- des

- difluoroethyl
4

- [(6

- chloropyridin

- 3

- ylmethyl)amino]furan

2(5 H )

- one Poultry eggs 8.9P (0.007) 1.2F (0.006) Poultry muscle 9.9P (0.007) 2.6F (0.005)

Poultry fat 5.0P (0.001)

Poultry liver 1.8P (0.008) 0.8F (0.017)

Ruminant kidney 1.3F (0.019)

### Page 99 of 116 Rat excreta 1.7

- 3.4 TDA

BYI 02960

- methylthio

- glyoxylic acid ({[6

- (methylsulfanyl)pyridin

- 3

- yl]methyl}amino)(oxo)acetic acid Ruminant milk 1.5P (0.003)

Ruminant
muscle 1.3P (0.005)

BYI 02960

- OH

- SA
3

- {[(6

- chloropyridin

- 3

- yl)methyl](2,2

- difluoroethyl)amino}

- 5

- oxo

- 2,5

- dihydrofuran

2

- yl hydrogen sulfate Poultry eggs 5.1P (0.004) 0.6F (0.003) Poultry muscle 1.8P (0.00) Poultry fat 16P (0.003) Poultry liver 22P (0.098) 5.1F (0.11)

Rat excreta 0.2

– 0.5 TDA

BYI 02960

- OH

- gluA (isomer 4) Ruminant kidney 7.5P (0.14) 3.5F (0.052)

BYI 02960

- OH

- gluA (isomer 3); (isomer2)
3

- {[(6

- chloropyridin

- 3

- yl) methyl](2,2

- difluoroethyl) amino}

- 5

- oxo

- 2,5

- dihydrofuran

2

- yl beta

- D

- glucopyranosiduronic acid Ruminant kidney 18P (0.33) 6.9F (0.10)

Ruminant liver 1.4P (0.016)

Rat excreta 0.4

– 2.4 TDA

BYI 02960

- OH

- gluA (isomer 1) Ruminant kidney 6.0P (0.11) 2.2F (0.03)

Rat excreta 0.5

– 1.8 TDA

### Page 100 of 116 Environment Metabolites Only

BYI 02960

- azabicyclosuccinamide (M47)

4

- {(2,2

- difluoroethyl)[(3

- oxo

- 2

- azabicyclo[2.2.0]hex

- 5

- en

- 6

- yl)methyl ]amino}

- 4

- oxobutanoic acid water

– aquatic photolysis (major)

BYI 02960

- succinamide (M48)

4

- {[(6

- chloropyridin

- 3

- yl)methyl](2,2

- difluoroethyl)a mino}

- 4

- oxobutanoic acid water

– aquatic photolysis (major)

### Page 101 of 116

BYI 02960

- deschlorohydroxysuccinamide (M49)

4

- {(2,2

- difluoroethyl)[(6

- hydroxypyridin

- 3

- yl)methyl ]amino}

- 4

- oxobutanoic acid water

– aquatic photolysis (minor)

Tomato: 0.535 lb ai/acre soil drench, 1.5X, at first bud, 69

- 73 day PHI. Potato: 0.25 lb ai/acre seed piece treatment. No label except soybean seed treatment. Apple: 0.155 lb ai/acre foliar, 0.42 X, 14 day PHI Cotton: 0.344 lb ai/acre foliar, 0.94X, 90% bolls open Paddy Rice 1: 0.38 lb ai/acre as GR to soil at transplant Paddy Rice 2: 0.37 lb ai/acre foliar to rice plants, 30 day PHI. No label, but 1X numerous other crop foliar uses

. Hen: 1.0 mg ai/ kg bw X 14 days, or 16

- 17 mg a i/kg feed/day Goat: 1.0 mg ai/kg bw X 5 days, or 24 mg ai/kg feed/day Rat: 2 mg/kg bw and 200 mg/kg bw. Confined Rotational: 0.387 lb ai/acre to soil (1.1X)

### Page 102 of 116

Appendix D. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Han dler Exposure Task Force (AHETF) database; and ExpoSAC Policy 14 and 15.1 (SOPs for Seed Treatment)

, are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For cert ain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 6



### .

6 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

### Page 103 of 116

Appendix E. Qualitative Evaluation of DFA

Studies submitte d in support of the registration of flupyradifurone indicate that there could be significant exposure to difluoroacetic acid (DFA) in drinking water and in food (plants and animals); DFA was shown to be a mammalian metabolite with approximately 6% of flupy radifurone administered to rats being converted to DFA.

Hazard Considerations

The most sensitive flupyradifurone effects seen in the database were skeletal muscle myofiber atrophy/degeneration, decreases in body weight, and decreases in body weight gai n at the LOAEL of 33 mg/kg/day in the 90

- day dog oral toxicity study (NOAEL = 12 mg/kg/day). However, these effects would not be expected from DFA, which has a very different chemical structure. DFA is also much more polar than the parent compound, which may indicate it can be excreted more rapidly.

The Registrant submitted a genotoxicity study, a range

- finding rat toxicity (14

- day) study, and a
sub

- chronic rat (90

- day) toxicity study with DFA. DFA produced black foci in the glandular part
of the stom ach with correlated histopathology findings of focal glandular erosion/necrosis at 66.2/78.8 mg/kg/day (M/F). These dose levels and effects confirm that DFA and flupyradifurone produce different effects on target different tissues . Although these effects occurred at similar potencies (similar comparable NOAELs and LOAELs on a molar basis 7 

### ) , the effects are
different. Therefore, the toxicity to DFA should be evaluated separately from flupyradifurone

. DFA was found in tissues (up to 50%) when flupyradifurone was administered to rats in the subchronic toxicity studies, so the toxicity of DFA has already been considered somewhat in the flupyradifurone toxicity studies and risk assessment. A qualitative S tructure

- Activity Relationship Analysis using DEREK Nexus 2.0 did not identify any toxicity endpoints of concern and the structure of DFA does not cause any specific toxicity concerns. One study in the literature identified kidney toxicity when administer ed intra

- peritoneally at doses approximately 10X the NOAEL. However, kidney toxicity was not observed in the sub

- chronic rat (dietary) toxicity study at doses up to 380 mg/kg/day.

Therefore, although flupyradifurone and DFA produce toxicity at similar dose levels, the effects are not the same, so parent and metabolite cannot be evaluated together. Th ere are no additional toxicity concerns based on DFA’s chemical structure or based on any additional literature
studies.

Exposure Considerations

Exposure to DFA as a result of flupyradifurone application is expected in food (plant

- and
animal

- based) and drinking water. DFA was not a major metabolite in most plant commodities

,

7 Calculation of Equivalent Dose Between DFA and the Parent Compound: MW flupyradifurone = 289 g/mol MW DFA = 97 g/mol. 289 g/mol ÷ 97 g/mol = ~ 3 g/mol. NOAEL in 90 day rat oral to xicity study with flupyradifurone = 30/38 (M/F) mg/kg/day. NOAEL in 14 day rat oral toxicity study with DFA = 12.7/15.6 (M/F) mg/kg/day. 30 mg/kg/day ÷ 3 = ~10 mg/kg/day (which is similar on a molar basis to the DFA NOAEL of 12.7 mg/kg/day.

### Page 104 of 116

but was very significant for the following uses : seed treatment (soybea n), soil drench (tomato), and foliar (succulent legume vegetables, especially green beans and lima beans, and cucurbits). DFA was a major degradate on a relative basis in poultry commodities; but on an absolute basis, only very small concentrations of DFA and parent are anticipated at the calculated livestock feeding (exposure) levels. DFA is a major environmental degradate depending upon the soil type and environmental conditions. DFA is expected to be more mobile than the parent compound. Therefore, e xposure to DFA is still expected to be relatively low compared to exposure to parent flupyradifurone.

The Agency conducted an exposure assessment using conservative drinking water estimates (see table below) and residue data from crop field trials. (Th e inputs are presented at the end of this appendix.) When conducting a screening evaluation of DFA, exposure to DFA is 7X less than estimated exposure to flupyradifurone for the general US population, and 5X less than estimated exposure to flupyradifurone for children 1

- 2 years old, the highest exposed population subgroup.

Table E. Tier I EDWCs for residues of Difluoroacetic acid (DFA). 1

Source of Drinking Water (Model) DFA concentration in drinking water (μg/L)

Acute Annual Average or Post

Breakthrough Average Surface Water (Modified Tier 1 Rice Model) 43 43

Surface water (PRZM/EXAMS) 7.35 ( 1 season) 8.18 (2 seasons) 9.71 (3 seasons) 4.34 ( 1 season) 5.12 (2 seasons) 7.74 (3 seasons)

Groundwater (PRZM

- GW) 51.7 (1 season) 105 (2 seasons) 152 (3 seasons) 36.0 (1 season) 76.2 (2 seasons)
114 (3 seasons)

1 Refinements can be made to get lower EDWCs. Tier II modeling could be conducted to determine EDWC in groundwater.



### Exposure Considerations

While DFA produces toxicity at a similar potency to the parent compound (similar NOAELs and LOAELs on a molar basis), DFA has already been evaluated somewhat in available subchronic toxicity studies; is polar and likely to be excreted more rapidly than the parent compound in mammals; and its chemical structure does not trigger any specific toxicity concerns. Additionally, a screening evaluation of exposure to DFA showed at least 5X less exposure to DFA than to flupyradifurone using conservative screening e valuation inputs (noted below). Since there is similar potency (albeit with different toxic effects) between flupyradifurone and DFA, and a highly conservative assessment indicates exposure to DFA is at least five times less than the parent compound, the Agency has no additional risk concerns about exposure to DFA.

Inputs for the Screening Evaluation of DFA The chronic dietary exposure analysis of flupyradifurone is conservative, incorporating
recommended tolerance

- level values, conservative processing factors based on empirical data, and drinking water estimates that assume 3 growing seasons per year. The a ssessment also assumed that 100% of the proposed crops were treated with flupyradifurone.

### Page 105 of 116

U.S. EPA Ver. 3.16, 03

- 08

- d

DEEM

- FCID Chronic analysis for DFA

- FLUPYRADIFURONE METABOLITE

NHANES 2003

- 2008 2

- day

Residue file name: C: \ Users \ KRURY \ Documents \ My Work Files \ BYI
02960 \ Dietary \ DFAEstimateMedian of Highest Rep Crops with individual Medians and 10X without cranberry.R08 Adjustment factor #2 NOT used. Analysis Date 07

- 15

- 2014/13:11:53 Residue file dated: 07

- 15

- 2014/13:11:29 Reference dose (RfD, Chronic) = .0127 mg/kg bw/day

================================================================= ============== Total exposure by population subgroup

-------------------------------------------------------------------------------

Total Exposure

----------------------------------- Population mg/kg Percent of Subgroup body wt/day Rfd

-------------------------------------- ------------- ---------------- Total US Population 0.003989 31.4% Hispanic 0.004098 32.3%

Non

- Hisp

- White 0.004037 31.8%

Non

- Hisp

- Black 0.003395 26.7%

Non

- Hisp

- Other 0.004485 35.3% Nursing Infants 0.003389 26.7%

Non

- Nursing Infants 0.011014 86.7%

Female 13+ PREG 0.003566 28.1%

Children 1

- 6 0.008134 64.0%

Children 7

- 12 0.004445 35.0%

Male 13

- 19 0.003185 25.1%

Female 13

- 19/NP 0.003068 24.2%

Male 20+ 0.003411 26.9% Female 20+/NP 0.003560 28.0%

Seniors 55+ 0.003372 26.6%

All Infants 0.008660 68.2%

Female 13

- 50 0.003482 27.4 %

Children 1

- 2 0.010061 79.2%

Children 3

- 5 0.007325 57.7%

Children 6

- 12 0.004730 37.2%

Youth 13

- 19 0.003125 24.6%

Adults 20

- 49 0.003543 27.9%

Adults 50

- 99 0.003418 26.9%

Female 13

- 49 0.003484 27.4%

-------------------------------------------------------------------------------

### Page 106 of 116

Appendix F. Occupational Exposure Tables

Table F. 1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flupyradifurone with Baseline Attire

.

Exposure Scenario Crop or Target Level of
Concern Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application
Rate 2 Area

Treated or
Amount
Handled Daily 3 Dermal Inhalation Total

Baseline Baseline Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Mixer/Loader

Mixing/Loading Liquids for Aerial Application Crop Group 10

- 10

(Citrus), Crop Group
11

- 10 (Pome Fruit), Crop Group 13

- 07B (Bushberries, Highbush), Crop Group 14 (Tree Nuts, Except Almonds) 100 220 0.219 0.18 lb ai/A 350 acres 0.0129 930 0.000173 69,000 920

Hops 100 220 0.219 0.14 lb ai/A 350 acres 0.010 1,200 0.000134 90,000 1,200

Field crop, typical 9 100 220 0.219 0.18 lb ai/A 350 acres 0.0129 930 0.000173 69,000 920

Crop Group 15 (Cereal Grains), Cotton, Crop Group 18 (Alfalfa & Forage Crops), Peanuts, Crop Subgroup 1C, Crop Group 6 (Legume Vegetables) 100 220 0.219 0.18 lb ai/A 1200 acres 0.0441 270 0.000591 20,000 270

Mixing/Loading for Airblast Application Crop Group 10

- 10

(Citrus), Crop Group
11

- 10 (Pome Fruit), Crop Group 13

- 07B (Bushberries, Highbush), Crop Group 14 (Tree Nuts, Except Almonds) 100 220 0.219 0.18 lb ai/A 40 acres 0.00147 8,200 0.0000198 610,000 8,100

Hops 100 220 0.219 0.14 lb ai/A 40 acres 0.00114 11,000 0.0000154 780,000 11,000

Mixing/Loading for Chemigation Application Soil Directed: Crop

Group 10

- 10 (Citrus), Crop Group 11

- 10 (Pome Fruit), Crop Group 13

- 07B (Bushberries, Highbush), Crop Group 14 (Tree Nuts, Except Almonds) 100 220 0.219 0.365 lb ai/A 350 acres 0.0261 460 0.000350 34,000 450

### Page 107 of 116

Table F. 1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flupyradifurone with Baseline Attire

.

Exposure Scenario Crop or Target Level of
Concern Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application
Rate 2 Area

Treated or
Amount
Handled Daily 3 Dermal Inhalation Total

Baseline Baseline Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Broadcast: Field crop, typical 9 100 220 0.219 0.18 lb ai/A 350 acres 0.0129 930 0.000173 69,000 920

Soil Directed: Field Crop Typical 9 100 220 0.219 0.365 lb ai/A 350 acres 0.0261 460 0.000350 34,000 450

Broadcast: Crop Group 15 (Cereal Grains), Cotton, Crop Group 18 (Alfalfa & Forage Crops), Peanuts, Crop Subgroup 1C, Crop Group 6 (Legume Vegetables) 100 220 0.219 0.18 lb ai/A 350 acres 0.0129 930 0.000173 69,000 920

Mixing/Loading for
Groundboom Application Broadcast: Field Crop

Typical 9 100 220 0.219 0.18 lb ai/A 80 acres 0.00294 4,100 0.0000394 300,000 4,000

Soil Directed: Field Crop Typical 9 100 220 0.219 0.365 lb ai/A 80 acres 0.00595 2,000 0.0000799 150,000 2,000

Broadcast: Crop Group 15 (Cereal Grains), Cotton, Crop Group 18 (Alfalfa & Forage Crops), Peanuts, Crop Subgroup 1C, Crop Group 6 (Legume Vegetables) 100 220 0.219 0.18 lb ai/A 200 acres 0.00735 1,600 0.0000985 120,000 1,600

Applicator

Aerial Application Crop Group 10

- 10

(Citrus), Crop Group

11

- 10 (Pome Fruit), Crop Group 13

- 07B (Bushberries, Highbush), Crop Group 14 (Tree Nuts, Except Almonds) 100 2.08 0.0049 0.18 lb ai/A 350 acres 0.000122 98,000 0.00000386 3,100,000 95,000

Hops 100 2.08 0.0049 0.14 lb ai/A 350 acres 0.0000946 130,000 0.0000030 4,000,000 130,000

Broadcast: Field crop, typical 9 100 2.08 0.0049 0.18 lb ai/A 350 acres 0.000122 98,000 0.00000386 3,100,000 95,000

### Page 108 of 116

Table F. 1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flupyradifurone with Baseline Attire

.

Exposure Scenario Crop or Target Level of
Concern Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application
Rate 2 Area

Treated or
Amount
Handled Daily 3 Dermal Inhalation Total

Baseline Baseline Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Crop Group 15 (Cereal Grains), Cotton, Crop Group 18 (Alfalfa & Forage Crops), Peanuts, Crop Subgroup 1C, Crop Group 6 (Legume Vegetables) 100 2.08 0.0049 0.18 lb ai/A 1200 acres 0.000416 29,000 0.0000133 900,000 28,000

Airblast Application Crop Group 10

- 10

(Citrus), Crop Group

11

- 10 (Pome Fruit), Crop Group 13

- 07B (Bushberries, Highbush), Crop Group 14 (Tree Nuts, Except Almonds) 100 1,770 4.71 0.18 lb ai/A 40 acres 0.0118 1,000 0.000424 28,000 970

Hops 100 1,770 4.71 0.14 lb ai/A 40 acres 0.00919 1,300 0.00033 36,000 1,300

Groundboom Application Broadcast: Field crop, typical 9 100 78.6 0.34 0.18 lb ai/A 80 acres 0.00105 11,000 0.0000613 200,000 10,000

Soil Directed: Field crop, typical 9 100 78.6 0.34 0.365 lb ai/A 80 acres 0.00213 5,600 0.000124 97,000 5,300

Crop Group 15 (Cereal Grains), Cotton, Crop Group 18 (Alfalfa & Forage Crops), Peanuts, Crop Subgroup 1C, Crop Group 6 (Legume Vegetables) 100 78.6 0.34 0.18 lb ai/A 200 acres 0.00262 4,600 0.000153 78,000 4,300

Flagger

Flagger for Aerial Hops 100 11 0.35 0.14 lb ai/A 350 acres 0.00050 24,000 0.000215 56,000 17,000

### Page 109 of 116

Table F. 1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flupyradifurone with Baseline Attire

.

Exposure Scenario Crop or Target Level of
Concern Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application
Rate 2 Area

Treated or
Amount
Handled Daily 3 Dermal Inhalation Total

Baseline Baseline Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Application Crop Group 10

- 10

(Citrus), Crop Group
11

- 10 (Pome Fruit), Crop Group 13

- 07B (Bushberries, Highbush), Crop Group 14 (Tree Nuts, Except Almonds)

, Field crop, typical 9

, Crop Group 15 (Cereal Grains), Cotton, Crop Group 18 (Alfalfa & Forage Crops), Peanuts, Crop Subgroup 1C, Crop Group 6 (Legume Vegetables) 100 11 0.35 0.18 lb ai/A 350 acres 0.00643 19,000 0.000276 43,000 13,000

Mixer/loader/Applicator

Backpack Sprayer Ground/Soil Directed:

Crop Group 10

- 10 (Citrus) 100 8,260 2.58 0.0365 lb ai/gal 40 gallons 0.0112 1,100 0.0000471 250,000 1,100

Mechanically Pressurized Handgun Broadcast: Crop Group

10

- 10 (Citrus), Crop Group 11

- 10 (Pome Fruit), Crop Group 13

- 07B (Bushberries, Highbush), Crop Group 14 (Tree Nuts, Except Almonds) 100 1,300 3.9 0.0365 lb ai/gal 1,000 gallons 0.0441 270 0.00178 6,700 260

Ground/Soil Directed: Crop Group 10

- 10 (Citrus) 100 1,300 3.9 0.0365 lb ai/gal 1,000 gallons 0.0441 270 0.00178 6,700 260

Broadcast: Field crop, typical 9 100 1,300 3.9 0.0365 lb ai/gal 1,000 gallons 0.0441 270 0.00178 6,700 260

Soil Application: Field crop, typical 9 100 1,300 3.9 0.0365 lb ai/gal 1,000 gallons 0.0441 270 0.00178 6,700 260

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( May 2013 ); Level of mitigation: Baseline. *Aerial Application is assessed assuming a closed cockpit (engineering controls).

2 Based on proposed label (Reg. No. SivantoTM (EPA Reg. No. 264

- RRUR ) )

. 3 Exposure Science Advisory Council Policy #9.1.

### Page 110 of 116

4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF ( 7.42 %) ÷ BW ( 80 kg).
5 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb a i/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW ( 80 kg).

7 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).
8 Total MOE = NOAEL ( 12 mg/kg/day) ÷ ( Dermal Dose + Inhalation Dose )

. 9 Crop Subgroup 1B (except sugarbeet), Crop Group 4 (Leafy Vegetables, except Brassica ), Crop Group 5 ( Brassica Cole Leafy Vegetables), Foliar Application to Crop Group 8

- 10 (Fruiting Vegetables), Foliar Application Crop Group 9 (Cucurbit Vegetables), Crop G roup 13

- 07B (Bushberries, lowbush), Crop Subgroup 13

- 07G (Low Growing Berries)

.

Table F

. 2 . Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flupyradifurone with Label

- Specified PPE (Gloves)

.

Exposure Scenario Crop or Target Level of
Concern Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application
Rate 2 Area

Treated or
Amount
Handled Daily 3 Dermal Inhalation Total

Gloves Baseline Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Mixer/Loader

Mixing/Loading Liquids for Aerial Application Crop Group 10

- 10

(Citrus), Crop Group

11

- 10 (Pome Fruit), Crop Group 13

- 07B (Bushberries, Highbush), Crop Group 14 (Tree Nuts, Except Almonds) 100 37.6 0.219 0.18 lb ai/A 350 acres 0.0022 5,500 0.000173 69,000 5,100

Hops 100 37.6 0.219 0.14 lb ai/A 350 acres 0.00177 7,000 0.000134 90,000 6,500

Field crop, typical 9 100 37.6 0.219 0.18 lb ai/A 350 acres 0.00220 5,500 0.000173 69,000 5,100

Crop Group 15 (Cereal Grains), Cotton, Crop Group 18 (Alfalfa & Forage Crops), Peanuts, Crop Subgroup 1C, Crop Group 6 (Legume Vegetables) 100 37.6 0.219 0.18 lb ai/A 1200 acres 0.00753 1,600 0.000591 20,000 1,500

Mixing/Loading for Airblast Application Crop Group 10

- 10

(Citrus), Crop Group

11

- 10 (Pome Fruit), Crop Group 13

- 07B (Bushberries, Highbush), Crop Group 14 (Tree Nuts, Except Almonds) 100 37.6 0.219 0.18 lb ai/A 40 acres 0.000251 48,000 0.0000198 610,000 44,000

Hops 100 37.6 0.219 0.14 lb ai/A 40 acres 0.000196 61,000 0.0000154 780,000 57,000

Mixing/Loading for Chemigation Soil Directed: Crop

Group 10

- 10 (Citrus), 100 37.6 0.219 0.365 lb ai/A 350 acres 0.00445 2,700 0. 000350 34,000 2,500

### Page 111 of 116

Table F

. 2 . Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flupyradifurone with Label

- Specified PPE (Gloves)

.

Exposure Scenario Crop or Target Level of
Concern Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application
Rate 2 Area

Treated or
Amount
Handled Daily 3 Dermal Inhalation Total

Gloves Baseline Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Application Crop Group 11

- 10

(Pome Fruit), Crop Group 13

- 07B (Bushberries, Highbush), Crop Group 14 (Tree Nuts, Except Almonds)

Broadcast: Field crop, typical 9 100 37.6 0.219 0.18 lb ai/A 350 acres 0.00220 5,500 0.000173 69,000 5,100

Soil Directed: Field Crop Typical 9 100 37.6 0.219 0.365 lb ai/A 350 acres 0.00445 2,700 0.000350 34,000 2,500

Broadcast: Crop Group 15 (Cereal Grains), Cotton, Crop Group 18 (Alfalfa & Forage Crops), Peanuts, Crop Subgroup 1C, Crop Group 6 (Legume Vegetables) 100 37.6 0.219 0.18 lb ai/A 350 acres 0.00220 5,500 0.000173 69,000 5,100

Mixing/Loading for
Groundboom Application Broadcast: Field Crop

Typical 9 100 37.6 0.219 0.18 lb ai/A 80 acres 0.000502 24,000 0.0000394 300,000 22,000

Soil Directed: Field Crop Typical 9 100 37.6 0.219 0.365 lb ai/A 80 acres 0.00102 12,000 0.0000799 150,000 11,000

Broadcast: Crop Group
15 (Cereal Grains), Cotton, Crop Group 18 (Alfalfa & Forage Crops), Peanuts, Crop Subgroup 1C, Crop Group 6 (Legume Vegetables) 100 37.6 0.219 0.18 lb ai/A 200 acres 0.00125 9,600 0.0000985 120,000 8,900

Applicator

Aerial Application Crop Group 10

- 10

(Citrus), Crop Group
11

- 10 (Pome Fruit), Crop Group 13

- 07B (Bushberries, Highbush), Crop Group 14 (Tree Nuts, 100 2.08 0.0049 0.18 lb ai/A 350 acres 0.000122 98,000 0.00000386 3,100,000 95,000

### Page 112 of 116

Table F

. 2 . Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flupyradifurone with Label

- Specified PPE (Gloves)

.

Exposure Scenario Crop or Target Level of
Concern Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application
Rate 2 Area

Treated or
Amount
Handled Daily 3 Dermal Inhalation Total

Gloves Baseline Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Except Almonds)

Hops 100 2.08 0.0049 0.14 lb ai/A 350 acres 0.0000946 130,000 0.0000030 4,000,000 130,000

Broadcast: Field crop, typical 9 100 2.08 0.0049 0.18 lb ai/A 350 acres 0.000122 98,000 0.00000386 3,100,000 95,000

Crop Group 15 (Cereal Grains), Cotton, Crop Group 18 (Alfalfa & Forage Crops), Peanuts, Crop Subgroup 1C, Crop Group 6 (Legume Vegetables) 100 2.08 0.0049 0.18 lb ai/A 1200 acres 0.000416 29,000 0.0000133 900,000 28,000

Airblast Application Crop Group 10

- 10

(Citrus), Crop Group

11

- 10 (Pome Fruit), Crop Group 13

- 07B (Bushberries, Highbush), Crop Group 14 (Tree Nuts, Except Almonds) 100 1,590 4.71 0.18 lb ai/A 40 acres 0.0106 1,100 0.000424 28,000 1,100

Hops 100 1,590 4.71 0.14 lb ai/A 40 acres 0.00825 1,500 0.00033 36,000 1,400

Groundboom Application Broadcast: Field crop, typical 9 100 16.1 0.34 0.18 lb ai/A 80 acres 0.000215 56,000 0.0000613 200,000 44,000

Soil Directed: Field crop, typical 9 100 16.1 0.34 0.365 lb ai/A 80 acres 0.000436 28,000 0.000124 97,000 22,000

Crop Group 15 (Cereal Grains), Cotton, Crop Group 18 (Alfalfa & Forage Crops), Peanuts, Crop Subgroup 1C, Crop Group 6 (Legume Vegetables) 100 16.1 0.34 0.18 lb ai/A 200 acres 0.000538 22,000 0.000153 78,000 17,000

Flagger

Flagger for Aerial Hops 100 12 0.35 0.14 lb ai/A 350 acres 0.000545 22,000 0.000215 56,000 16,000

### Page 113 of 116

Table F

. 2 . Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flupyradifurone with Label

- Specified PPE (Gloves)

.

Exposure Scenario Crop or Target Level of
Concern Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application
Rate 2 Area

Treated or
Amount
Handled Daily 3 Dermal Inhalation Total

Gloves Baseline Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8

Application Crop Group 10

- 10

(Citrus), Crop Group
11

- 10 (Pome Fruit), Crop Group 13

- 07B (Bushberries, Highbush), Crop Group 14 (Tree Nuts, Except Almonds)

, Field crop, typical 9

, Crop Group 15 (Cereal Grains), Cotton, Crop Group 18 (Alfalfa & Forage Crops), Peanuts, Crop Subgroup 1C, Crop Group 6 (Legume Vegetables) 100 12 0.35 0.18 lb ai/A 350 acres 0.000701 17,000 0.000276 43,000 12,000

Mixer/loader/Applicator

Backpack Sprayer Ground/Soil Directed:

Crop Group 10

- 10 (Citrus) 100 8,260 2.58 0.0365 lb ai/gal 40 gallons 0.0112 1,100 0.0000471 250,000 1,100

Mechanically Pressurized Handgun Broadcast: Crop Group

10

- 10 (Citrus), Crop Group 11

- 10 (Pome Fruit), Crop Group 13

- 07B (Bushberries, Highbush), Crop Group 14 (Tree Nuts, Except Almonds) 100 1,300 3.9 0.0365 lb ai/gal 1,000 gallons 0.0132 910 0.00178 6,700 800

Ground/Soil Directed: Crop Group 10

- 10 (Citrus) 100 1,300 3.9 0.0365 lb ai/gal 1,000 gallons 0.0132 910 0.00178 6,700 800

Broadcast: Field crop, typical 9 100 1,300 3.9 0.0365 lb ai/gal 1,000 gallons 0.0132 910 0.00178 6,700 800

Soil Application: Field crop, typical 9 100 1,300 3.9 0.0365 lb ai/gal 1,000 gallons 0.0132 910 0.00178 6,700 800

1 Based on the “Occupational Pesticide

### Page 114 of 116

Handler Unit Exposure Surrogate Reference Table” ( May 2013 ); Level of mitigation: Gloves

. *Aerial Application is assessed assuming a closed cockpit (engineering controls).
2 Based on proposed label (Reg. No. SivantoTM (EPA Reg. No. 264

- RRUR ) )

. 3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF ( 7.42 %) ÷ BW ( 80 kg).
5 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW ( 80 kg).

7 Inhalation MOE = Inhalat ion NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day).
8 Total MOE = NOAEL ( 12 mg/kg/day) ÷ ( Dermal Dose + Inhalation Dose )

. 9 Crop Subgroup 1B (except sugarbeet), Crop Group 4 (Leafy Vegetables, except Brassica ), Crop Group 5 ( Brassica Cole Leafy Vegetables ), Foliar Application to Crop Group 8

- 10 (Fruiting Vegetables), Foliar Application Crop Group 9 (Cucurbit Vegetables), Crop Group 13

- 07B (Bushberries, lowbush), Crop Subgroup 13

- 07G (Low Growing Berries)

.

### Flupyradifurone Human Health Risk Assessment DP No. D407063

Page 115 of 116 Table F .3. Summary of Short

- and Interm ediate

- Term Handler Exposures and Risks for Flupyradifurone Seed Treatment of Soybean
Seeds 1

.

Maximum Application Rate 2 Dermal

Unit Exposure 3 Inhalation

Unit Exposure 3 Amount of

Seed
Treated
or Planted Per Day 4 Dermal

Dose 5 Inhalation Dose 6 Dermal
MOE 7 Inhalation

MOE 8 Combined

MOE 9

lb ai/lb seed mg/lb ai mg/lb ai lb seed/day mg/kg/day mg/kg/day LOC =
100 LOC = 100 LOC =
100
Loader/Applicator

0.00054 0.023 0.00034 281,250 0.00323 0.00000000032 3,700 38,000,000,000 3,700

Sewer

0.00054 0.0062 0.00023 281,250 0.000873 0.000000000016 14,000 770,000,000,000 14,000
Bagger

0.00054 0.0091 0.00016 281,250 0.00128 0.000000000023 9,400 510,000,000,000 9,400
Multiple Activities

0.00054 0.042 0.0016 281,250 0.00591 0.0000000050 2,000 2,400,000,000 2,000

Planters

0.00054 0.25 0.0034 26,667 0.0033 0.000000035 3,600 340,000,000 3,600

1 Seed treatment rate calculations are based on the following assumptions: Soybean Seeds: 1,500 to 3,600 seeds per lb.

2 Application Rate based on proposed label for flupyradifurone ( EPA Reg. No. 264

- RRUE ).
3 Unit Exposures from HED Exposure Science Advisory Council Policy 14 : Standard Operating Procedures for Seed Treatment (baseline inhalation = no respirator).

4 HED default for lb seed treated/planted per day from HED Exposure Science Advisory Council Interim Policy 15.1 and the BEAD memo “Acres Planted Per Day and Seeding Rates of Crops Grown in the United States ” (J. Becker, March 2011).
5 Daily Dermal Dose (mg/kg/day) = daily inhalation unit exposure ( m g/ lb ai) × a pplication rate (lb ai/lb seed) × amount planted (lb seed/day) × dermal absorption factor (7.42%) ÷ body weight (8 0 kg adult).

6 Daily Inhalation Dose (mg/kg/day) = daily inhalation unit exposure ( m g/ lb ai) × a pplication rate (lb ai/lb seed) × amount planted (lb seed/day)

÷ body weight (8 0 kg adult).

7 Dermal MOE = NOAEL ( 12 mg/kg/day for short

- and intermediate

- term exposure ) ÷ Dermal Dose (mg/kg/day) . Level of concern = 100.
8 Inhalation MOE = NOAEL ( 12 mg/kg/day for short

- and intermediate

- term exposure ) ÷ Inhalation Dose (mg/kg/day) . Short

- term level of
concern = 100.
9 Total MOE = NOAEL ( 12 mg/kg/day) ÷ ( Dermal Dose + Inhalation Dose )

.

### Flupyradifurone Human Health Risk Assessment DP No. D407063

Page 116 of 116 Table F.4. Worst

- Case Short

- and Intermediate

- Term Occupational Post

- application Non

- Cancer Exposure and Risk
Estimates for Flupyradifurone

.

Crop/Site Activities Application Rate (lb ai/A) Transfer Coefficient (cm 2 /hr) DFR 1 Dermal Dose (mg/kg/day) 2 MOE 3

Crop Group 1B and Crop Group 1C (Beet, Potato, Turnip) Hand Set Irrigation 0.18 1900 0.50 0.0071 1,700

Crop Group 4 (Leafy Vegetables Except

Brassica ) Hand Set Irrigation 0.18 1900 0.50 0.0071 1,700

Crop Group 5 ( Brassica Leafy Vegetables) Scouting, Hand

Harvesting, Hand Weeding 0.18 4200 0.50 0.0157 760

Crop Group 6 (Legume Vegetables) Hand Set Irrigation 0.18 1900 0.50 0.0071 1,700

Crop Group 8

- 10 (Fruiting Vegetables) Hand Set Irrigation 0.18 1900 0.50 0.0071 1,700

Crop Group 9 (Cucurbit Vegetables) Hand Harvesting, Mechanically Assisted Harvesting, Training, Turning, 0.18 550 0.50 0.0021 5,800

Crop Group 10

- 10 ( Citrus ) Hand Harvesting 0.18 1400 0.50 0.0052 2,300

Crop Group 11

- 10 (Pome Fruit) Thinning Fruit 0.18 3600 0.50 0.0135 890

Crop Subgroup 13

- 07B (Bushberries, except cranberry) Hand Harvesting 0.18 1400 0.50 0.0052 2,300

Crop Subgroup 13

- 07G ( Low Growing Berries ) Hand Harvesting 0.18 1100 0.50 0.0041 2,900

Crop Subgroup 13

- 07F (Small Fruit Vine Climbing, E xcept
F uzzy K iwifruit) Girdling/Turning 0.18 19300 0.50 0723 170

Crop Group 14 (Tree Nuts, E xcept Almonds) Hand Harvesting (Net) 0.18 1400 0.50 0.0052 2,300

Crop Group 15 (Cereal Grains, Except Rice) Detasseling/Hand

Harvesting (Sweet Corn Only) 0.18 8800 0.50 0.0330 360

Hand Set Irrigation 0.18 1900 0.50 0.0071 1,700

Crop Group 18 [Non

Grass Animal Feeds (Forage, Fodder, Straw, Hay)] Hand Set Irrigation 0.18 1900 0.50 0.0071 1,700

Cotton Scouting 0.18 210 0.50 0.00079 15,000

Hop Harvesting,

Mechanically
Assisted 0.14 19300 0.39 0.0562 210

Peanut Hand Set Irrigation 0.18 1900 0.50 0.0071 1,700

1 DFR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.25 and D = 0.10 per day

2 Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption ( 7.42 %)]  BW (kg).
3 MOE = POD ( 12 mg/kg/day) / Daily Dermal Dose

.