Benzovindiflupyr (122305) Hum a n H ea lth Ri sk Assessment 0408961. 04 08960



### UNITED STATES ENV I RONMENTAL PROTECTION AGENCY

WASHINGTON

, O

. C. 20460

MEMORANDUM

Date: Januar y 28

, 20 15 OFFICE OF
CHEMICAL SAFETY AND
POLLU T ION PREVENTION

SUBJECT: Ben zov indiflup yr New Ac ti ve I ng r edient Human H ea lth Ri sk Assessme nt to Support th e Prop osed Uses on Cereals (wheat

, tritical c, b a rle y, r ye, and oa t ),

Blueberrie s (no n-b e aring)

, Co rn ( field

, pop
, and swee t ), P ean ut s
, Turf

, and
Ornamentals; Cro p Group s 

### 8-10

, 9, and 

### 11-1 

### O; Crop S ub g roup s 

### 1 C, 6C, 

### 1 3 -0?F

, 20A, and 20C; and Establishment of Tol e ran ces o n Imported C offee a nd

S u ga r ca n e.

PC Co d e: 1 22305

Decision No.: 4733 8 2, 4733 8 3

P e t i tion No.: 2F812 I & 2E8123

Ri s k Assess m e n t T y pe: S ingl e C h e mi ca l Agg r egate
TXR No.: NA

MRID No.: A DP Barcode: 0408961, 0 40 8960
Reg i stra ti o n No

. : 100-RUTI

, J OO-RUTA. 100-

R UT L

, 100-R UTR, 100-R UTO, IOO-RUTT

, IOORU TU, 1 00 -R UTE

, IOO-R U I N

Re g ulat ory Act i o n : Sectio n 3 R eg i s trati o n

Case No.: N A

C A S No.: 1072957- 7 1-1

40 CFR: NA (New Active In g r e di e nt )



### FROM: 

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D anette Dr ew, Chemist/Risk sscsso 

# W.--.**ll~ ~** **J~** William Ir w in

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## ~d<. Seye d Tadayo n
, Chem i s

P e t e r Savo ia

, C h em i st

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Ri sk Assess m en t Bran c 1 ( B 

### V / VII)

H ea l t h Effec t s Divi s i o n ( H E D ) (750 9P )



### THROUGH: Michael S. Me t zge r
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Page 1 of 82 Fungicide B r anc h

R eg istration Division (7505 P )Benzovindiflupyr (122305) Human Health Risk Assessment 0408961. 0408960

Syngenta ha s requested U.S. registration of the new active ingredient fungicide benzovindiflupyr

for use on cereals (wheat

, triticale, barley

, rye and oat)

, corn, cotton

, cucurbits. fruiting vegetables

, small fruit vines climbing (except fuzzy kiwifruit). legumes

, peanuts

, pome fruit,

canola

, tu berous and corm vegetables

, lowbush blueberries (non-bearing)

, turf and ornamentals.
Syngenta has also requested that tolerances for benzovindiflupyr o n imported coffee and

sugarcane be estab li shed. The Registration Division of the Office of Pesticide Programs ( OPP)

has requested that 

### HED eva luat e ha za rd and exposu re data and conduct dietary

, residential

, occupationa l

, and aggregate exposure assessments, as needed, to estimate the risk to human

health that will result from the proposed uses of benzovindiflupyr.



### HED has eva lu ated the toxicity and exposure databases for benzovindiflupyr

, and has conducted

a human health risk assessment in support of the proposed u ses. A s ummar y of the findings and

an assessment of human he a lth risk re s ultin g from the proposed uses of benzovindi flupyr 

### are provided in this document.

Page 2 of 82

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 3 of 82 Table of Contents

1.0 Executive Summary

................................ ................................ ................................ ......... 5

2.0 HED Recommendations

................................ ................................ ................................ ... 7

2.1 Data Deficiencies/Conditions of Registration

................................ ................................ .. 7

2.2 Tolerance Considerations

................................ ................................ ................................ . 7

2.2.1 Enforcement Analytical Method

................................ ................................ .................. 7

2.2.2 International Harmonization

................................ ................................ ......................... 8

2.2.3 Recommended Tolerances

................................ ................................ ............................ 8

2.2.4 Revisions to Petitioned

- For Tolerances

................................ ................................ ...... 11

2.3 Label Recommendations

................................ ................................ ................................ 11

2.3.1 Recommendations from Residue Reviews

................................ ................................ . 11

2.3.2 Recommendations from Occupational Assessment

................................ ................... 11

3.0 Introduction

................................ ................................ ................................ .................... 12

3.1 Chemical Identity

................................ ................................ ................................ ........... 12

3.2 Physical/Chemical Characteristics

................................ ................................ ................. 12

3.3 Pesticide Use Pattern

................................ ................................ ................................ ...... 12

3.4 Anticipated Exposure Pathways

................................ ................................ ..................... 18

3.5 Consideration of Environmental Justice

................................ ................................ ........ 18

4.0 Hazard Characterization and Dose

- Response Assessment

................................ ............ 19

4.1 Toxicology Studies Available for Analysis

................................ ................................ ... 19

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

................................ ... 20

4.2.1 Dermal Absorption

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

4.3 Toxicological Effects

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

4.4 Safety factor for Infants and Children (FQPA Safety Factor)

................................ ....... 23

4.4.1 Completeness of the Toxicology Database

................................ ................................ 23

4.4.2 Evidence of Neurotoxicity

................................ ................................ .......................... 23

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Anim al

............. 24

4.4.4 Residual Uncertainty in the Exposure Database

................................ ......................... 24

4.5 Toxicity Endpoint and Point of Departure Selections

................................ .................... 24

4.5.1 Dose

- Response Assessment

................................ ................................ ....................... 24

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

........... 26

4.5.3 Cancer Classification and Risk Assessment Recommendation

................................ .. 27

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

Assessment

................................ ................................ ................................ ................................ 27

5.0 Dietary Exposure and Risk Assessment

................................ ................................ ......... 30

5.1 Metabolite/Degradate Residue Profile

................................ ................................ ........... 30

5.1.1 Summary of Plant and Livestock Metabolism Studies

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

5.1.1.1 Plant Metabolism Studies

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

5.1.1.2 Livestock Metabolism Studies

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

5.1.2 Summary of Environmental Degradation

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

5.1.3 Comparison of Metabolic Pathways

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

5.1.4 Residues of Concern Summary and Rationale

................................ ........................... 32

5.2 Food Residue Profile

................................ ................................ ................................ ...... 33

5.3 Water Residue Profile

................................ ................................ ................................ .... 33

5.4 Dietary Risk Assessment

................................ ................................ ................................ 34

5.4.1 Description of Residue Data Used in Dietary Assessment

................................ ......... 34

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 4 of 82 5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .................... 35

5.4.3 Acute Dietary Risk Assessment

................................ ................................ ................. 35

5.4.4 Chronic Dietary Risk Assessment

................................ ................................ .............. 35

5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ................ 35

5.4.6 Summary Table

................................ ................................ ................................ ........... 35

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

6.1 Residential Handler Exposure

................................ ................................ ........................ 37

6.2 Residential Post

- Application Exposure

................................ ................................ .......... 38

6.3 Residential Risk Estimates for Use in Aggregate Assessment

................................ ...... 39

6.4 Spray Drift

................................ ................................ ................................ ...................... 39

6.5 Residential Bystander Post

- application Inhalation Exposure

................................ ........ 40

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ... 40

7.1 Acute Aggregate Risk

................................ ................................ ................................ .... 41

7.2 Short

- Term Aggregate Risk

................................ ................................ ........................... 41

7.3 Intermediate

- /Long

- Term Aggregate Risk

................................ ................................ ..... 42

7.4 Cancer Aggregate Risk

................................ ................................ ................................ ... 42

8. 0 Cumulative Exposure/Risk Characterization

................................ ................................ . 42

9.0 Occupational Exposure/Risk Characterization

................................ ............................... 42

9.1 Short

- /Intermediate

- Term Handler Risk

................................ ................................ ........ 42

9.2 Short

- /Intermediate

- Term Post

- Application Risk

................................ .......................... 46

9.2.1 Dermal Post

- Application Risk

................................ ................................ .................... 46

9.2.2 Inhalation Post

- Application Risk

................................ ................................ ................ 46

9.2.3 Restricted Entry Interval

................................ ................................ ............................. 47

10.0 References

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

................................ ................... 50 Appendix B. Metabolites

................................ ................................ ................................ .......... 79 Appendix C. Physical/Chemical Properties

................................ ................................ ............. 81 Appendix D. Review of Human Research

................................ ................................ ............... 82

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 5 of 82 

### 1.0 Executive S ummary

The Agency has received a petition (# 2F8121) for a Section 3 registration for the use of the new pyrazole carboxamide fungicide benzovindiflupyr (also known as SolatenolTM and SYN545192) on the following food and non

- food crops: cereals (wheat, triticale, barley, rye, and oat), blueberries (non

- bearing), corn (field, pop, and sweet), cottonseed (subgroup 20C), cucurbit vegetable (group 9), fruiting vegetables (crop group 8

- 10), small fruit vines climbing, except

fuzz y kiwifruit (subgroup 13

- 07F)

, legume vegetables (subgroup 6C), peanuts, pome fruit (crop group 11

- 10), rapeseed (subgroup 20A), tuberous and corm vegetable (subgroup 1C). Uses are also requested on turf grass and ornamentals. In addition to requesting U.S. tolerances for

residues on the above domestic crops , a second petition (#2E8123 ) was submitted requesting

tolerances without U.S. registrations for residues on imported coffee and sugarcane

.

Benzovindiflupyr ( N

- [9

- (dichloromethylene)

- 1,2,3,4

- tetrahydro

- 1,4

- methanonaphthalen

- 5

- yl]

- 3

- (difluoromethyl)

- 1

- methyl

- 1 H

- pyrazole

- 4

- carboxamide ) is currently undergoing global joint review [review partners are the United States Environmental Protection Agency (U.S. EPA), the Pest Management Regulatory Agency (PMRA) of Canada and Mexi c o]. The submitted studies (toxicology, residue chemistry, exposure) provide a complete database for conducting this

aggrega te human health risk assessment for benzovindiflupyr

.

The rat is the most sensitive species tested and the target organs are the liver, thyroid and kidneys. Benzovindiflupyr produced effects in rat fetuses (i.e. decreased fetal weight and

ossification ) in developmental toxicity st udies but only at maternally toxic doses . In the rabbit developmental study, there were no adverse effects in e ither the does or the fetuses at the highest dose tested. In reproduction studies, offspring effects occurred at doses higher than the doses causing parental effects; thus, there was no quantitative increase in sensitivity in rat pups. There

are indication s of reproductive toxicity in rats such as decreased follicle counts, but these effects did not result in reduced fertility.

No evidence of specific neurotoxicity was observ ed in the acute neurotoxicity (ACN) or sub

chronic neurotoxicity (SCN) studies. Benzovindiflupyr caused decreased activity and decreased grip strength in the neurotoxicity studies; however, there were no supportive neuro

histopathology in any toxicological study, even at the highest doses tested. A developmental neurotoxicity study w as not required.

Benzovindiflupyr has low acute toxicity by the dermal and inhalation routes, with moderate toxicity via the oral route. It is not a dermal sensitizer, but causes mild skin irritation and moderate eye irritation

. Benzovindiflupyr did not display systemic effects in the 28

- day dermal study, even at the limit dose of 1000 mg/kg/day. A dermal hazard is not identified and a quantitative dermal exposure assessment is not required. Based on a weight of evidence (WOE) approach, the requirement fo r a subchronic inhalation toxicity study was waived

. There was no

evidence of i mmune system toxicity in a study conducted in the mouse , or in any other toxicity

studies in the database

.

Benzovindiflupyr ca used tumors in the thyroid in the chronic rat study at the highest dose tested

. In mice, no tumor formation was observed

. Benzovindiflupyr was negative in all mutagenicity

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 6 of 82 studies. Benzovindiflupyr is classified as “ Suggestive Evidence of Carcinogenic Potential ”

. T he Agency has d etermined that quantification of risk using a non

- linear approach (i.e., RfD ; reference dose ) will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to benzovindiflupyr.

The toxicological database for benzovindiflupyr is complete with regard to pre

- and postnatal toxicity, neurotoxicity, and immunotoxicity, and there are no residual uncertainties in the exposure database ; in addition, there is no evidence of quantitative or qualitative susceptibility

. T herefore, the 10X F ood Q uality P rotection A ct (FQPA) S afety F actor (SF) was reduced to 1X.

The nature of the residue in primary crops, rotational crops , and livestock has been adequately

delineated , with parent compound benzovindiflupyr defined as the residue of concern for

tolerance enforcement . For the purpose of dietary (food) risk assessment, the residue s of concern are parent compound plus h ydroxylated benzovindiflupyr ( metabolite SYN546039 ) . For drinking water, the residue of concern is benzovindi flupyr.

The crop field trial data and animal feeding studies are adequate to support tolerances and registrations for the proposed domestic uses and for tolerances for the non

- domestic uses. Following a 180

- day plant

- back interval (PBI), no residues are expected in rotational crops. Adequate storage stability, method validation data and processing studies have been submitted. An adequate analytical method is available to enforce the proposed tolerances for benzovindiflupyr in plant and livestock commod ities . Except where precluded by policy differences, international harmonization of recommended tolerance levels was achieved.

C onservative acute and chronic dietary risk assessments were conducted which used the

recommended tolerance level residues for food, anticipated residues ( based on maximum

theoretical diets ) for livestock commodities

, assumed 100% crop treated for all commodities and screening level model

- estimated drinking water concentrations (EDWCs). A cute and chr onic dietary (food and drinking water combined) risk estimates for the proposed uses of

b enzovindiflupy r did not exceed HED’s level of concern (LOC) for the general U.S. population or any population subgroup , including infants and children (i.e., acute and chronic dietary exposure estimates were less than 100% of the acute population adjusted dose (aPAD) and the chronic population adjusted dose (cPAD)).

There is the potential for residential exposures from the proposed uses of benzovindiflupyr on

turf and ornamentals. Adult (handler and post

- application inhalation ) and children (post

application incidental oral ) exposure estimates are not of risk concern [i.e., margins of exposure (MOEs) are > 100]. While t here is the potential for post

- application dermal e xposure s from residential uses, no dermal hazard was identified in the toxicity database for benzovindif l upyr

. Therefore, a quantitative post

- application dermal risk assessment is not required and was not completed. Residential dermal exposures are not of risk concern.

In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. Based on the proposed uses of benzov indiflupyr

, combined (or aggregate) exposures can occur from dietary sources (food and water) and following use in residential settings. There are no aggregate ( acute, chronic, or

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 7 of 82 short

- term) risk estimates of concern for adults or children expos ed to ben zovindiflupyr as a result of the proposed uses.

Occupational exposures (handler and post

- application) are anticipated from the proposed uses of

benzovindif

l upyr . All occupational handler exposure scenarios assessed using baseline clothing

and default non

- chemical specific assumptions resulted in estimated short

- and intermediate

- term
inhalation MOEs well above the LOC (100) and are therefore n ot of concern

. While t here is the potential for post

- application exposure to workers

, no dermal hazard was identified. Therefore, a quantitative occupational post

- application dermal risk assessment is not required and was not completed; there are no risk concerns for dermal exposur es.

The Worker Protection Statement interim R estricted E ntry Interval ( REI ) of 12 hours is adequate to protect agricultural workers from post

- application exposures to b enzovindifl u pyr

.

T here are no human health risk concerns that would preclude gra nting the requested registrations

for benzovindiflupyr and establishing tolerances for residues at the recommended levels.

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment (S ection 3.5), in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations.”

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. See Appendix D. Review of Human

Research.



### 2.0 HED Recommendations

Pending submission of a revised Section F as described in Section 2.2.4

, submission of a revised Section B as described in Section 2.3.1, and submission of analytical reference standard as described in Section 2.2.1, HED recommends granting the req uested Section 3 registration for benzovindiflupyr and establishing the recommen ded U.S. tolerances for the commodities as

listed in Table 2.2.3.



### 2.1 Data Deficiencies/Conditions of Registration

None.



### 2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate analytical method is available to enforce the proposed tolerances for benzovindiflupyr in plant and livestock commodities. A Quick, Easy, Cheap, Effective, Rugged,

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 8 of 82 and Safe ( QuEChERS ) multi

- residue method ( EN15662:2009 ) was developed for the

determination of residues of benzovindiflupyr via LC

- MS/MS

. The validated limit of quantitation (LOQ) reported in the method is 0.01 ppm

. The method has undergone successful independent laboratory validation (ILV). Radiovalidation of the method was not needed since the solvent system in the proposed QuEChERS enforcement method was used in the metabolism study and adequately demonstrates extraction efficiency.

Benzovindiflupyr has also been subjected to analysis by the Food and Drug Administration (FDA) multi

- residue method protocols. Benzovindiflupyr is no t recovered by the FDA multi

residue methods.

A supply of benzovindiflupyr analytical standard is not available in the National Pesticides Standards Repository.



### 2.2.2 International Harmonization

Benzovindiflupyr is a new active ingredient and no max imum residue levels ( MRLs ) or U.S.

tolerances have yet been established by Codex, Canada, or Mexico. The participating countries

agre e that th e residue definition for tolerance enforcement is benzovindiflupyr only.

The majority of the recommended MRLs ar e harmonized between Canada and the U.S. Mexico typically adopts the U.S. recommendations . In the cases where MRLs are not being harmonized, it is because of policy differences in the way the two countries establish MRLs. Canada does not

establish MRLs for livestock feed items, whereas the U.S. does. Conversely , the U.S. generally does not establish MRLs for livestock commodities when there is no reasonable expectation of finite residues, whereas Canada establishes LOQ

- level MRLs in these situations (e. g., benzovindiflupyr in poultry and swine).



### 2. 2.3 Recommended Tolerances

HED recommends that U.S. tolerances be established in the 40 CFR for benzovindiflupyr on the plant and livestock commodities listed in the Table 2.2.3 . As the residue definitions for plant and livestock commodities are the same, HED recommends that the same entry be used for both types of commodities. The tolerances should be defined as follows:

Tolerances are established for residues of the fungicide benzovindiflupyr, includi ng 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 benzovindiflupyr ( N

- [9

- (dichloromethylene)

- 1,2,3,4

- tetrahydro

- 1,4

- methanonaphthalen

5

- yl]

- 3

- (difluoromethyl)

- 1

- methyl

- 1 H

- pyrazole

- 4

- carboxamide ) in or on the commodity.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 9 of 82 Table 2.2.3. Tolerance Summary for Benzovindiflupyr. Commodity Proposed

Tolerance (ppm) HED

Recommended Tolerance (ppm) Comments (correct commodity

definition)

Apple, wet pomace 0.6 None Required A f ruit, pome, group 11

- 10

tolerance of 0.2 ppm will cover any potential residues in processed apple, wet pomace. Blueberry NR 1 0.01 For use on only the lowbush variety of blueberry in non

cropping years following a 365

- day PHI. Barley, grain 1.5 1.5 Barley, hay 15 15 Barley, straw 15 15
Cattle, fat 0.01 0.02
Cattle, liver 0.01 0.06
Cattle, meat 0.01 0.01 Cattle, meat byproducts, except
liver 0.01 0.01

Coffee, green bean * 0.06 0.09 Corn, field, forage 3 3 Corn, field, grain 0.02 0.02
Corn, field, stover 15 15 Corn, pop, grain 0.02 0.02 Corn, pop, stover 15 15 Corn, sweet, forage 4 4 Corn, sweet, kernel plus cob with

husks removed 0.01 0.01

Corn, sweet, stover 5 5 Cottonseed, subgroup 20C 0.15 0.15 Cotton, gin byproducts 3 3 Fruit, pome, group 11

- 10 0.2 0.20 Fruit, small vine climbing, except fuzzy kiwifruit, subgroup

13

- 07F 1 1

Goat, fat 0.01 0.02
Goat, liver 0.01 0.06
Goat, meat 0.01 0.01 Goat, meat byproducts, except

liver 0.01 0.01

Grain, aspirated fractions 7 1 5
Horse, fat 0.01 0.02
Horse, liver 0.01 0.06
Horse, meat 0.01 0.01 Horse, meat byproducts, except

liver 0.01 0.01

Milk 0.01 0.01

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 10 of 82 Table 2.2.3. Tolerance Summary for Benzovindiflupyr. Commodity Proposed

Tolerance (ppm) HED

Recommended Tolerance (ppm) Comments (correct commodity

definition)

Milk, fat 0.01 0.02 The calculated tolerance is 0.015 ppm but HED is recommending 0.02 ppm for harmonization. Oat, grain 1.5 1.5 Oat, hay 15 15
Oat, straw 15 15
Pea and bean, dried shelled, except soybean, subgroup 6C 0.2 0.20

Pea, hay 7 7 Pea, field, hay
Pea, vine 1.5 1.5 Pea, field, vines

Peanut, nutmeat 0.01 0.01 Peanut Peanut, hay 15 15 Potato, processed waste 0.1 0.10 Potato, processed potato waste

Raisin 4 3 Grape, raisin Rapeseed, subgroup 20A 0.15 0.15 Rye, grain 0.1 0. 1 Rye, hay 15 15 Rye, straw 10 15 Sheep, fat 0.01 0.02 Sheep, liver 0.01 0.06 Sheep, meat 0.01 0.01 Sheep meat byproducts, except

liver 0.01 0.01

Soybean, forage 15 15 Soybean, hay 50 50 Soybean, hulls NR 1 0.20 Soybean, seed 0.07 0.07 Sugarcane, cane * 0.04 0.04
Tomato, dried NR 4 Tomato processing study data

show residues concentrate in dried tomatoes @ 7.8x. The registrant did not include it in their petition nor does the Agency normally set tolerances on this processed fraction. However, PMRA is proposing to set an MRL @ 4 ppm for this processed commodity.

This tolerance is recommended for

harmonization. Vegetable, cucurbit, group 9 0.2 0.30 Vegetable, fruiting, group 8

- 10 0.8 1.5 Vegetable, tuberous and corm, subgroup 1C 0.02 0.02

Wheat, forage 2 4 4

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 11 of 82 Table 2.2.3. Tolerance Summary for Benzovindiflupyr. Commodity Proposed

Tolerance (ppm) HED

Recommended Tolerance (ppm) Comments (correct commodity

definition)

Wheat, grain 2 0.1 0.10 Wheat, hay 2 15 15
Wheat, straw 2 10 15

1 NR

– None Requested

2 The establishment of tolerances on wheat includes registration on triticale as well.

*Note to RD: The tolerance regulation should include a footnote to the tolerance stating: “There is no U.S. registration for use of benzovindiflupyr on coffee or sugarcane”.



### 2. 2.4 Revisions to Petitioned

- For Tolerances

Many of the proposed tolerances requested by the petitioner are different from those recommended by HED. This can primarily be attributed to the petitioner having input data differently into the calculation procedures for tolerance determination. For example, several trials considered to be independent trials by the petitioner were determined by the Agency to be replicate (not independent) trials and, as such, these data are inputed differently than data from independent trails. In addition, the petitioner did not propose a tolerance for the dried tomato

processe d commodity. It was also unclear how the petitioner calculated tolerances proposed for the aspirated grain fractions and raisin processed commodities but these limits were not comparable to the Agency’s determination. Therefore, the petitioner must submi t a revised Section F in which the proposed tolerances are the same as those recommended by HED.



### 2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

The labels must reflect that following application of benzovindiflupyr to primary crops up to a seasonal rate of 0.268 lb. ai/A (300 g ai/ha) plant

- back intervals of 180 days or longer are to be observed for rotated crops. The labels should also specify that the use on greenhouse grown tomatoes is not permitted ; a dditional residue data woul d be required if the registrant intends to

support a greenhouse tomato use. Labels should clearly specify that use on blueberries is

restricted to “lowbush” blueberries since these are the only variety that have a non

- cropping year of production.



### 2.3.2 Recommendations from Occupational Assessment

None.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 12 of 82 

### 3.0 In troduction

3.1 Chemical Identity

The structure and chemical identi t y for benzovindiflupyr are shown in Table 3.1. The structures

for metabolites discussed in this risk assessment are shown in Appendix B.

Table 3.1. Benzovindiflupyr Nomenclature.

Compound

Common name Benzovindiflupyr Company experimental name SYN545192 (Trade name; SolatenolTM)

IUPAC name N

- [(1 RS ,4 SR )

- 9

- (dichloromethylene)

- 1,2,3,4

- tetrahydro

- 1,4

- methanonaphthalen

- 5

- yl]

- 3

- (difluoromethyl)

- 1

- methylpyrazole

- 4

- carboxamide

CAS name 1H

- pyrazole

- 4

- carboxamide,N

- [9

- (dichloromethylene)

- 1,2,3,4

- tetrahydro

- 1,4

- methanonaphthalen

- 5

- yl]

- 3

- (difluoromethyl)

- 1

- methyl

CAS # 1072957

- 71

- 1

End

- use product/EP A15457B/EC, A18126B/WG, A18993A/EC, A19334A/EC, and A19188A/SL



### 3.2 Physical/Chemical Characteristics

The physical and chemical properties are detailed in Appendix C.

Benzovindiflupyr has a low vapor pressure (2.4 x 10

- 11 

### mm Hg @ 25 oC) and is, therefore, not a volatile pesticide. Based on its octanol water partition coefficient (Log K ow 

### = 4.3 at 25°C)

, benzovindiflupyr may be considered moderately lipophilic. Benzovindiflupyr has low water solubility and does not dissociate ; ho w ever, e nvironmentally, it is a moderately mobile chemical that is expected to persist in the environment in ae robic and anaerobic conditions. Based on the environmental fate parameters, there is the potential for benzovindiflupyr to re ach water

resources.



### 3.3 Pesticide Use Pattern

Products containing the fungicide b enzovindiflupyr are proposed for use on a wide variety of

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 13 of 82 crops as well as turf grass and ornamentals

. Several formulations of benzovindiflupyr are proposed for registration by the petitioner ; t he end

- use products are an emulsifiable concentrate (EC) in solo formulation as well as in premixes with propiconazole and difenoconazole. It is also formulated as a wettable granule (WG) in a premix with azoxystrobin and as a soluble concentrate (SL) in a premix with difenoconazole

. The various end

- use products may be applied through a variety of application methods including aerial, chemigation, ground

- boom sprayer, air blast sprayer , and handheld equipment . The proposed labels allow for the use of adjuvants.

Benzovindiflupyr will generally applied 1

- 4 times with retreatment intervals ranging from 7 to

60 days, depending on crop, pest, and country/region. The recommended application rates for agricultural crops range fr om 0.05 to 0.09 lb. ai per acre (50

- 100 g ai/ha) in the United States, Canada, and Mexico.

A summary of the proposed use directions , i.e. proposed good agricultural practices ( GAP s ), is provided below in Table 3.3. See Section 2.3.1 above for the recom mended label modifications.

Table 3.3. Proposed Use Directions/ GAPs for Use of Benzovindiflupyr (SYN545192).

Country/ Region Product

(type) Application Application rate per

treatment Maximu

m seasonal

rate (g ai/ha) [lb. ai/A] Minimu

m PHI (days) Method Growth stage

& season (BBCH) Maximu

m number Minimum

interval

between application (days) Water

(L/ha) [Gal/A] Maximu

m rate (g ai/ha) [lb. ai/A]

Pome Fruit (Crop Group 11

- 10 )

Canada A15457B

(EC) Foliar First sign of

disease 4 7 375 [40]

- sufficien

t

coverage 50

[0.045] 200

[0.178] 30

A19334A (EC)

USA A193334A

(EC) Foliar Pink 4 7 450

- 2800 [48

- 299] 50

[0.045] 200

[0.178] 30

A15457B (EC) 450

- 2800 [48

- 299] 50

[0.045]

Small Fruit Vine Climbing Subgroup (Crop Subgroup 13

- 07F) (Grapes)

Canada A15457B

(EC) Foliar First sign of

disease 4 7 150 [16]

- sufficien

t

coverage 75

[0.067] 300

[0.268] 21

A19334A (EC) 50 [0.045] 200

[0.178]

USA A15457B

(EC) Foliar First sign of

disease 4 7 450

- 900 [48

- 96] 75

[0.067] 300

[0.268] 21

A19334A (EC) 450

- 900 [48

- 96]

A18126B (WG) 450

- 900 [48

- 96] Blueberries, lowbush (Non

- bearing)

Canada A15457B

(EC) Broadc

ast
Foliar First sign of

disease in vegetative or ‘sprout’ 2 10 200

- 300 [21

- 32] 75

[0.067] 150

[0.134] 365

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 14 of 82 phase

USA A18126B

(EC) Broadc

ast
Foliar First sign of

disease in vegetative or ‘sprout’ phase 2 10 19

- 280 [2

- 30] 75

[0.067] 150

[0.134] 365

Table 3.3. Proposed Use Directions/ GAPs for use of Benzovindiflupyr (SYN545192).

Country/ Region Product

(type) Application Application rate per

treatment Maximu

m seasonal

rate (g ai/ha) [lb. ai/A] Minimu

m PHI (days) Method Growth stage

& season (BBCH) Maximu

m number Minimum

interval

between application (days) Water

(L/ha) [Gal/A] Maximu

m rate (g ai/ha) [lb. ai/A]

Tuberous and Corm Vegetables Subgroup 1C (Potato)

Canada A15457B

(EC) In

furrow At planting 1 NA 50

- 150 [5.3

- 16] 75

[0.067] 45

[0.067] NA

A18126B (WG)

A15457B (EC) Foliar Prior to

disease

establishment 4 7 150 [16] (ground)

45 [4.8] to

sufficien

t

coverage (aerial) 75

[0.067] 300

[0.268] 14

A19334A (EC) 4

A18126B (WG) 3 [0.201]

USA A15457B

(EC) Soil At planting 1 NA 280 [30] 100

[0.089] 100

[0.089] NA

A18126B (WG)

A19334A (EC) Foliar First sign of

disease 4 7 90

- 280 [9.6

- 30] 75

[0.067] 300

[0.268] 14

A15457B (EC) 93

- 280 [9.9

- 30] 14

A18126B (WG) 90

- 280 [9.6

- 30] 14

Fruit ing Vegetables (Crop Group 08

- 10 ) 1

Canada A18126B

(WG) Foliar Prior to

disease

establishment 3 7 150 min [16] 62.5

[0.056] 187.5

[0.167] 1

A15457B (EC) 4 7 150 min [16] 75

[0.067] 300

[0.268] 1

A19334A (EC) 4 7 150 min [16] 75

[0.067] 300

[0.268] 1

USA A19334A

(EC) Foliar First sign of

disease 4 7 90

- 500 [9.6

- 53] 75

[0.067] 300

[0.268] 0

A15457B (EC) 90

- 500 [9.6

- 53]

A18126B (WG) 90

- 500 [9.6

- 53]
Cucurbit Vegetables (Group 9)

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 15 of 82 Canada A18126B

(WG) Foliar Prior to

disease

establishment 3 7 150 min

190 min [16

- 20]

for

gummy

stem blight 75

[0.067] 225

[0.201] 1

A15457B (EC) 4 7 75 [0.067] 300

[0.268] 1

A19334A (EC) 4 7 75 [0.067] 300

[0.268] 1

USA A19334A

(EC \ ) Foliar First sign of

disease 4 7 90

- 500 [9.6

- 53] 75

[0.067] 300

[0.268] 0

A15457B (EC) 90

- 500 [9.6

- 53]

A18126B (WG) 90

- 500 [9.6

- 53]

Table 3.3. Proposed Use Directions/ GAP for use of Benzovindiflupyr (SYN545192).

Country/ Region Product

(type) Application Application rate per

treatment Maximu

m seasonal

rate (g ai/ha) [lb. ai/A] Minimu

m PHI (days) Method Growth stage

& season (BBCH) Maximu

m number Minimum

interval

between application (days) Water

(L/ha) [Gal/A] Maximum

rate (g ai/ha) [lb. ai/A]

Pulses (Crop Subgroup 6C)

Canada A15457B

(EC) Foliar First sign of

disease 2 14 100

- 200 [11

- 21] (ground)

45 min [4.8] (aerial) 75

[0.067] 150

[0.134] 15

A18126B (WG) 62.5 [0.055] 125

[0.112] 15

A18993A 75 [0.067] 150

[0.134] 30

USA A19334A

(EC) Foliar First sign of

disease 2 14 45

- 190 [4.8

- 20] 75

[0.067] 150

[0.134] 14

A15457B (EC) 45

- 190 [4.8

- 20]

A18126B (WG) 45

- 190 [4.8

- 20]
Cottonseed (Crop Subgroup 20C)

USA and

Mexico A18126B

(WG) Foliar Flowering 3 10 90

- 280 [9.6

- 30] (ground)

19 [2] (aerial) 75

[0.067] 225

[0.201] 45

A15457B (EC) 2 Foliar Flowering 3 10 75 [0.067] 225

[0.201] 45

Mexico A18993A

(EC) Foliar Flowering 3 10 75 [0.067] 225

[0.201] 45

A19334A (EC) Foliar Flowering 3 10 75 [0.067] 225

[0.201] 45

Peanut

USA and

Mexico A18993A

(EC) Foliar 30 days after planting 3 14 140

- 300 [15

- 32] 75

[0.067] 225

[0.201] 30

A18126B (WG)

A15457B (EC) Foliar 30 days after planting 3 14 93

- 280 [9.9

- 30] 75

[0.067] 225

[0.201] 30

A18126B (WG) Soil 14

- 21 days after planting 1 NA 93

- 280 [9.9

- 30] 100

[0.089] 100

[0.089] NA

A15457B Soil 14

- 21 days 1 NA 93

- 280 100 100 NA

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 16 of 82

(EC) after planting [9.9

- 30] [0.089] [0.089]

Mexico A19334A

(EC) Foliar 30 days after planting 3 14 93

- 280 [9.9

- 30] 75

[0.067] 225

[0.201] 30

Table 3.3. Proposed Use Directions/ GAP for use of Benzovindiflupyr (SYN545192).

Country/ Region Product

(type) Application Application rate per

treatment Maximu

m seasonal

rate (g ai/ha) [lb. ai/A] Minimu

m PHI (days) Method Growth stage

& season (BBCH) Maximum

number Minimum

interval

between application (days) Water

(L/ha) [Gal/A] Maximu

m rate (g ai/ha) [lb. ai/A]

Rapeseed (Crop Subgroup 20A) (Canola Varieties)

Canada A15457B

(EC) Foliar 2nd true leaf to bolting 1 NA 200 [21]

- sufficien

t

coverag

e (ground)

45 [4.8]min (aerial) 75

[0.067] 75

[0.067] 30

A18993A (EC)

A19334A (EC)

United

States A15457B

(EC) Foliar 2nd true leaf to bolting 1 NA 200

- sufficien

t

coverag

e (ground)

45 min (aerial) 75

[0.067] 75

[0.067] 30

Soybean

Canada A15457B

(EC) Foliar First sign of

disease 2 7 100

- 200 [11

- 21] (ground)

Min 45 [4.8] (aerial) 75

[0.067] 150

[0.134] 14

A18126B (WG) 62.5 [0.055] 125

[0.112] 15

18993A (EC) 75 [0.067] 150

[0.134] 30

USA and

Mexico A19334A

(EC) Foliar R1

- R3 2 7 90

- 280 [9.6

- 30] (ground)

19 (aerial) [2] 75

[0.067] 150

[0.134] 14

A18126B (WG)

A15457B (EC) 2

A18993A (EC)
Barley and Oats

Canada A15457B

(EC) Foliar Prior to

disease development 2 14 200 [21]

- sufficien

t

coverag

e (ground) 45 [4.8]

min 75

[0.067] 150

[0.134] Normal

maturity

18993A (EC) 45

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 17 of 82 (aerial)

USA and

Mexico A18126B

(WG) Foliar Prior to

disease development 2 14 19

- 280 [2

- 30] 75

[0.067] 150

[0.134] Not

Specified

A15457B2 (EC)

A18993A (EC)

Table 3.3. Proposed Use Directions/ GAPs for use of Benzovindiflupyr (SYN545192).

Country/ Region Product

(type) Application Application rate per

treatment Maximu

m seasonal

rate (g ai/ha) [lb. ai/A] Minimu

m PHI (days) Method Growth stage

& season (BBCH) Maximum

number Minimum

interval

between application (days) Water

(L/ha) [Gal/A] Maximu

m rate (g ai/ha) [lb. ai/A]

Corn (field corn, popcorn, and sweet corn)

Canada A18993A

(EC) Foliar First sign of

disease 2 14 45 [4.8]

min (aerial) 200 [21]

min

– sufficien

t

coverage (ground) 75

[0.067] 150

[0.134] 14

A15457B (EC) 7 75 [0.067] 150

[0.134] 7

A18126B (WG) 14 45 [4.8]

min (aerial)

100

– 200 [11

- 21] (ground) 56

[0.05] 112

[0.010] 14

USA and

Mexico A18993A

(EC) Foliar V5

- R1 4 7 19

- 280 [2

- 30] 75

[0.067] 300

[0.268] 7

A18126B (WG)

A15457B (EC) 2 18

- 280 [1.9

- 30]

Mexico A19334A

(EC) Foliar V5

- R1 4 7 19

- 280 [2

- 30] 75

[0.067] 300

[0.268] 7

Wheat

Canada A15457B

(EC) Foliar Prior to

disease development 2 14 200 [21]

- sufficien

t

coverage (ground) 45 [4.8] min(aeri al) 75

[0.067] 150

[0.134] Normal

maturity

18993A (EC) 150 [0.134] 45

USA and

Mexico A18993A

(EC) Foliar Prior to

disease development 2 14 19

- 280 [2

- 30] 75

[0.067] 150

[0.134] Not

Specified

A15457B2 (EC)

A18126B (WG)

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 18 of 82 Coffee

Brazil A18126B

(WG) Foliar 1st spray at

BBCH 72 3 60 400

- 500 [43

- 53] 45

[0.04] 135

[0.120] 21

A17961A (EC)
Sugar Cane

Brazil A18126B

(WG) Foliar 1st spray at

BBCH 19 5 30 100

- 200 [11

- 21] 30

[0.026] 150

[0.134] 30

1 The representative commodities for Crop Group 8

- 10 (Fruiting Vegetables) are tomato (standard size and one cultivar of small tomato); bell pepper and one cultivar of non

- bell pepper; one cultivar of small non

- bell pepper or one cultivar of small eggplant.

2 USA only . The Brazilian field trials reflect the proposed non

- domestic use rates.



### 3.4 Anticipated Exposure Pathways

Benzovindiflupyr is proposed for use on numerous agricultural crops as well as on turf (which include lawns, golf courses, recreational parks, sod farms, etc.) and ornamentals

. Exposure to benzovindiflupyr may occur from ingestion of residues on foods and in drinking water. There is the potential for dermal and inhalation exposures from the residential application of

benzo vindiflupyr products by adults. In addition, there is the potential for residential post

application exposures for both adults (dermal only) and children (dermal and incidental oral) from contact with previously treated turf. Occupational exposures are expected from the application (dermal and inhalation) of benzo vindiflupyr and from reentry into previously treated areas (dermal only). A quantitative dermal assessment is not required for benzovindiflupyr as a

dermal hazard was not identified. This risk assessment considers the relevant exposure pathways

base d on all of the proposed uses of benzovindiflupyr.



### 3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Execut ive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low Income Populations," ( http://www.archives.gov/federal

- register/executive

- orders/pdf/12898.pdf ). As a part of every pesticide risk assessment, the Office of Pesticide Programs (O PP ) considers a large variety of consumer subgroups according to well

- established procedures. In lin e with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Ex tensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and/or the CDC under the National Health and Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA), and are us ed in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary

expo sure to 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 toddlers, youths,

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 19 of 82 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 that c onsider 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

4.1 Toxicology Studies Available for Analysis

Based on the proposed use pattern s , all required studies for benzovindiflupyr (S olatenol TM 

### ) have

been submitted. The available toxicology database is comprehensive and is sufficient for assessing the toxicity and characterizing the hazard of the chemical. The available toxicolog y studies for benzovindiflupyr are listed in Table A.1 in Appendix A. The data from the following studies were used to evaluate the hazard potential of benzovindiflupyr :

- Developmental Rat Studies

- Developmental Rabbit Studies

- Reproduction Rat Study

- Chronic/Cancer Mouse Study

- Chronic/Cancer Rat Study

- 28 Day Mouse Study

- 28 Day Rat Study

- 90 Day Mouse Study

- 90 Day Rat Study

- 90 Day Dog Study

- 1 Year Dog Study

- Acute Neurotoxicity (ACN) Rat Study

- Subchronic Neurotoxicity ( SCN ) Rat Study

- 28 Day Dermal Rat Study

- Genotoxicity Studies

- Immunotoxicity Study

- Metabolism and Pharmacokinetics

- Special Thyroid Studies

- Toxicity Studies on Metabolites

B ased on a weight of evidence (WOE) approach, the Hazard and Science Policy Council ( HASPOC) reco mmended that a sub chronic inhalation toxicity study is not needed for benzovindiflupyr (TXR No. 005 7049

, W. Irwin )

. This approach considered all of the available hazard and exposure information for, including (1) the physical/chemical properties and low

v olatility ( 2.4 x 10

- 11 

### mm Hg at 25°C ) ; (2) the low acute inhalation toxicity; and (3) using an oral

POD and equivalent inhalation toxicity, o ccupat ional handler high

- end screening MOEs ranged

from 900 to 9,500,000 (only one scenario resulted in a MOE < 100 0 at an MOE of 900)

.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 20 of 82 

### 4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

The oral absorption of total radioactivity was estimated following a single low or high oral

gavag e dose of benzovindiflupyr (1 or 40 mg/kg) to bile duct cannulated male and female rats (i.e. urine, bile, cage wash, and carcass up to 48 hours post dose ) . Absorption was similar in

male and female rats following low and high doses (79

- 81% and 61

- 62%, respectively) . During the first 48 hours post dose

, the majority of the administered radioactivity had been excreted (97 % and 89% following 1 mg/kg and 90 % and 86% following 40 mg/kg in males and females, respectively). In a study comparing the kinetics of an intravenous or oral dose, the systemic oral

bioavail ability was essentially complete (i.e. at 1 mg/kg [ 14 

### C] SYN545192 was 129% in males

and 99% in females ). At 1 mg/kg oral dosing, the Tmax in blood was at 1

- 2 hours and at 3

- 4

hours with T 1/2 

### values of 25.40 hours and 47.97 hours in females and males, respe ctively. At 40 mg/kg oral dosing, the whole blood Cmax values were 8.0 μM in females and 10.8 μM in males. The whole blood AUC in females was 5.06 and 180.2 μg equiv

- h/mL at 1 mg/kg and 40 mg/kg, respectively (0

- 120 hours). The whole blood AUC in males was 11.6 and 231.4 μg equiv

- h/mL at 1 mg/kg and 40 mg/kg, respectively (0

- 120 hours).

Whole body autoradiography usi ng radiolabels in both rings of benzovindiflupyr , total radioactivity was extensively distributed throughout the body by the first sampling ti me of 5 hours in males and 1 hour in females and had declined markedly in both sexes by 72 hours post

dose. There were no cle ar differences in tissue distribution profiles between the labels nor were any pronounced gender or dose differences apparent. Th e highest tissue concentrations were present in the Harderian gland and liver with lower concentrations in the adrenal gland, heart,

brown fat

, kidney and skeletal muscle (i.e. concentrations of 56.4, 55.2, 42.5, 28.0, 37.2

, 23.1,

and 11.6 μM

, respectively at 5 hours after a single 40 mg/kg dose in females).

Benzovindiflupyr was extensi vely metabolized in rat resulting in at least 8 types of metabolite ( e.g. desmethyl, hydroxy, dihydroxy, desmethyl hydroxy, desmethyl dihydroxy, ring

- open, glucuronide conj ugate, sulphate conjugate). The majority of the administered radioactivity (70%

- 85% dose) was identified following a single oral dose of benzovindiflupyr. Demethylation, bicyclo ring hydroxylation and phenyl ring hydroxylation together accounted for a maj or proportion of the dose (35%

- 60% dose). No significant differences were observed following a single dose at 40 mg/kg or 1 mg/kg or repeat daily dosing at 1 mg/kg/day. S ome quantitative

differences were observed betwe en males and females, m inor differences were observed by the

prese nce of ring

- open metabolites primarily in males and the presence of a sulphate conjugate only in females

.

T he predominant route of elimination was via the f eces. Following a single oral dose of 1 mg/kg, elimination via the f eces accounted for 84 and 90% of the administered dose and urinary

excretion accounted for 12 and 6 % of the administered dose in mal es and females, respectively.

Similar results were observed f ollowing a sing le oral dose of 40 mg/kg. In the 48 hours following dosing

, 76% and 69% of the administered dose was excreted via bile following 1 mg/kg and the bile duct cannulation study indicated that significant enterohepatic recirculation occurred for the parent compound.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 21 of 82 Following d aily oral doses of 1 mg/kg, benzovindiflupyr appeared to be approaching steady state concentrations by the end of the 14 day dosing period. Following the cessation of dosing, all

tissue concentration s steadily declined. L iver and kidney had the greatest conce ntrations of radioactivity, followed by the adrenals and thyroid. The total tissue and carcass residues at the final sampling time accounted for less than 0.2% of the total radio

- labeled dose administered (63 days after the last dose on Day 14) . T he termin al phase half

- life for tissue depletion ranged from 2.5 days in plasma to 69 days in the testes.



### 4.2.1 Dermal Absorption

T he in vivo dermal absorption of benzovindiflupyr in rats was measured at 0.001, 0.01 and 1.5 mg/cm 2 

### , however, the 28

- day dermal tox icity study did not indicate any adverse effects following repeated dermal applications at the limit dose of 1000 mg/kg/day. Thus, a quantitative dermal risk assessment is not necessary for benzovindiflupyr and a dermal absorption factor is not required si nce no developmental, reproductive, neuro, or immunotoxicity concerns were detected. If changes occur in the formulation and/or use pattern of benzovindiflupyr, then HED may need to revisit the need for a dermal assessment.



### 4.3 Toxicological Effects

Benzovindiflupyr is a pyrazole carboxamide fungici de proposed for foliar use on numerous crops and on turf grass and ornamentals

. The pesticidal mode of action of this group of fungicides is inhibition of succinate dehydrogenase (SDH , mitochondrial Comple x II )

. SDH is a functional part of the tricarboxylic acid cycle (TCA), the mitochondrial electron transport chain and

oxidative phosphorylation utilized to synthesize ~90% of the energy in eukaryotes needed for protein synthesis, DNA synthesis, work, and ion pumping

.

The rat is the most sensitive species tested and the target organs are the liver, thyroid and kidneys. Acute studies were done in the rat, while sub

- chronic and chronic oral toxicity studies

have been conducted in t he rat, mouse, rabbit and dog. Hepatotoxicity was manifested as changes in liver weights, liver hypertrophy, decreased triglycerides, and increased urea. The kidney effects were tubular cell pigment deposits and changes in the tubular basophilia. Distended large intestines, soft f eces and hyperplasia of the colon and caecum occurred in the mouse studies. Indications of general malaise including decreased body weight, body weight gain, food consumption, decreased activity, decreased grip strength, piloerection, decreased

response to stimulus, hunched posture, gait changes and ataxia were reported in a number of studies. The pituitary pars distalis had hypertrophy, while the thyroid and mammary glands had hyperplasia. In several studies, females tended to be the more sensitive gender and gavage dosing tended to have lower effect doses than dietary studies.

Benzovindiflupyr produced effects in rat fetuses in developmental toxicity studies at maternally

toxic doses (i.e. decreased fetal weight and ossification)

. In the rabbit developme ntal study, there were no adverse effects in either the does or the fetuses at the highest dose tested. In rat reproduction studies, offspring effects occurred at higher doses higher than those causing

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 22 of 82 parental effects, thus there was no quantitative incre ase in sensitivity in rat pups. There were no single

- dose developmental effects identified in the developme ntal toxicity studies in rats or

rabbits. Although decreases in growing follicle count s were noted in the reproduction toxicity study , th is effect did not result in reduced f unctional fertility in the rat. Furthermore, the antral follicle counts at a later stage in development were not decreased, so the decreased growing

follicle count effect is not considered adverse. Regan et al concluded that “ The utility of follicle counts to detect female reproductive toxicity in rats that cannot be detected by other means has not been demonstrated. There is little published information supporting the ability of follicle counting to detect reproductive t oxicity that could not be detected by qualitative microscopic

assessment or other standard methods ” ( Toxicologic Pathology , 33:409

– 412, 2005). No evidence of specific neurotoxicit y were observ ed in the a cute oral (gavage) and sub

- chronic oral (dietary)

neu rotoxicity (ACN and SCN) studies in rats, conducted on the benzovindiflupyr technical product. Benzovindiflupyr caused decreased activity and decreased grip strength in the neurotoxicity studies; however, there was no supportive neuro

- histopathology in any study, even at the highest doses tested. Immune system toxicity was negative by the T

- cell Dependent Antigen Response ( TD AR) assay in the mouse. Benzovindiflupyr did not display systemic

effects in the 28

- day dermal study, even at the limit dose of 1000 mg/kg/day.

The CARC, in accordance with the Agency’s 2005 Guidelines for Carcinogen Risk Assessment,

classified benzovindiflupyr as showing “ Suggestive Evidence of Carcinogenic Potential ” based on the presence of granular cell tumors of the brain in male rats. The CARC concluded that a

non

- genotoxic mode of action for thyroid tumors observed in male rats has been established as a result of upregulation of UDPGT, increased clearance of T3 and T4 hormones and increased TSH levels, resulting in increased thy roid cell proliferation, which progress to form thyroid tumors. There was no evidence of carcinogenicity in female rats or in male or female mice. In addition, there is no concern for mutagenicity.

Quantification of carcinogenicity is not required. When there is suggestive evidence of carcinogenicity, the Agency does not attempt a dose

- response assessment as the nature of the data generally would not support one. Therefore, the Agency has determined that quantification of risk using a non

- linear appr oach (i.e., RfD) will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to benzovindiflupyr.

Benzovindiflupyr has low acute toxicity by the dermal and inhalation routes, with moderate toxicity via the oral route. It is not a dermal sensitizer, but causes mild skin irritation and moderate eye irritation. The oral LD 50 

### value was 66 mg/kg, which is less than some doses in the

other acute and sub

- chronic guideline studies and much lower than the oral LD 50 

### values for very similar chemicals such as hydroxy

- benzovindiflupyr and isopyrazam which were over 2000 mg/kg. The pyrazole acid and amide metabolites ( SYN545720, S YN508272 and NOA449410 ) had lower LD50 values than benzovindiflupyr in the acute oral studies, as well as being negative for both genotoxicity testing and for inhibition of mammalian succinate dehydrogenase (SDH)

. The pyrazole acid metabolites ( SYN545720 a nd NOA449410 ) had higher LOAELs than benzovindiflupyr in the rat 28

- day, rat 90

- day and rabbit developmental studies. Thus, these

metabolites are not expected to be more toxic than the parent molecule

. Conversely compared to these metabolites, benzovindifl upyr potently inhibited mammalian SDH in an in vitro study, with

an IC 50 

### value of 35.2 nM. This IC 50 

### value is over 1000 times less than the liver target tissue

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 23 of 82 levels (i.e. 55.2 μM) measured in the metabolism studies employing a single oral dose near

sever al study LOAEL values and 330 times less than the skeletal muscle levels (i.e. 11.6 μM). The whole blood Cmax values were 8.0 μM in females and 10.8 μM in males.



### 4.4 Safety factor for Infants and Children (FQPA Safety Factor)

The 10X FQPA safety factor to account for potential increased susceptibilit y of infant s and

children is reduced to 1X for benzovindiflupyr based on the following considerations:

1) The toxicology and exposure data bases for benzovindiflupyr are complete and the toxicology studies are adequate for assessing increased susceptibility under FQPA; 2) There was no evidence of quantitative or qualitative susceptibility in fetuses or offspring in the rat and rabbit developmental studies or in the rat reproduction study. Benzovindiflupyr produced effects in rat fetuses (i.e. decreased fetal weight and

ossification ) in developmental toxicity st udies at maternally toxic doses . In the rabbit developmental study, there were no adverse effects in either the does or the fetuses at the highest dose teste d. In reproduction studies, offspring effects occurred at doses higher than the doses causing parental effects; thus, there was no quantitative increase in sensitivity in rat pups. The LOAELs and NOAELs for the rat developmental and rat reproduction studi es were clearly defined. 3) There is n o evidence of specific neurotoxicity . A developmental neurotoxicity study is not required (see 4.4.2 below) 4) There are no residual uncertainties in the toxicology database

5 ) Exposure assessments are conservative and wil l not under

- estimate exposure (see 4.4.4 below)

.



### 4.4.1 Completeness of the Toxicology Database

T he toxicology database for benzovindiflupyr is considered complete for evaluating and characterizing its toxicity, assessing of children’s susceptibility under FQPA and selecting endpoints for the exposure pathways of concern. The only missing study is a sub

- chronic inhalation study, but HED has de termined that this study can be waived based on weight of

evidence considerations.



### 4.4.2 Evidence of Neurotoxicity

Acute oral (gavage) and sub

- chronic oral (dietary) neurotoxicity studies in rats were conducted

on the benzovindiflupyr technical product. No evidence of specific neurotoxicity was seen in

these studies. Benzovindiflupyr caused changes in apical endpoints such as decreased activity and decreased grip str ength in the ACN study . There was no corroborative neuro

- histopathology

demonstrated in any study, ev en at the highest doses tested

. The liver, thyroid and kidneys are the primary target organs and the metabolism/pharmacokinetic (PK) studies suggest preferential partitioning of benzovindiflupyr to those target organs, but not the brain. Based on its target organs, PK and its lack of evidence of neuro

- histopathology in any acute and repeated

- dose

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 24 of 82 toxicity studies, benzovindiflupyr does not demonstrate potential for neurotoxicity. Since benzovindiflupyr did not demonstrate susceptibility to the young or specific neurotoxicity, a developmental neurotoxicity (DNT) study is not required.



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

Animal

There is no evidence for increased susc eptibility following pre

- natal exposures to benzovindiflupyr based on effects seen in developmental toxicity studies in rabbits or rats. There was no evidence of increased susceptibility in a two

- generation reproduction study in rats following pre

- or post

- natal exposure to benzovindiflupyr.

There is no evidence of neuropathology or abnormalities in the development of the fetal nervous system from the available toxicity studies conducted with benzovindiflupyr . Clear NOAELs/LOAELs were established for the developmental effects seen in rats, as well as for the offspring effects seen in the two

- generation reproduction study. The dose

- response relationship

for the effects of concern is well characterized. The NOAEL used for the acute dietary risk assessment (10 mg/kg/day), based on effects observed i n the ACN study, is protective of the developmental and offspring effects observed in rats and rabbits in the developmental studies

with the NOAELs of 15

- 35 mg/kg/day. Based on these considerations, there are no residual uncertainties for pre

- and/or post

- natal susceptibility.



### 4.4.4 Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database for benzovindiflupyr with respect to dietary (food and water) and non

- occupational residential (turf and ornamental use) e xposure.

A complete database with respect to both the nature and magnitude of residues expected in food has been provided. The dieta ry food exposure assessments are highly conservative (residues on food and feed crops based on tolerance level residues, assuming 100% crop treated) resulting in high

- end estimates of dietary food exposure. Also, highly conservative, modeled drinking water estimates of exposure were included in the assessments. Non

- occupational residential exposure

estimates were based on conservative default (non

- chemical specific) assumptions. Actual exposures and risks from benzovindiflupyr in food and drinking water, and from residential uses,

are likely to be much lower than estimated in this risk assessment.



### 4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose

- Response Assessment

Toxicity endpo ints and points of departure (POD s) for dietary exposure scenarios to benzovindiflupyr are summarized below. Detailed description of the studies used as a basis for the selected endpoints are presented in Appendix A.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 25 of 82 An acute reference dose (a RfD ) of 0.10 mg/kg is based on a NOAEL of 10 mg/kg/day selected from an ACN study in rats (LOAEL =30 mg/kg in females ) based on multiple clinical

observations ( reduced activity, swaying gait, collapse, muscle twitching, and ruffled fur )

, decreases in mean body temperature, decreases in locomotor activity parameters, and/or decreases in mean grip strength. The effects observed in the acute neurotoxicity study were observed after a single oral exposure and

, therefore

, are appropriate for the acute dietary scenario for the general population. However, there also were clinical signs in dams, includin g ataxia, decreased activity, hunched posture, ruffled fur, which were observed at a comparable dose in the rat developmental study (LOAEL of 30 mg/kg/day). These clinical signs were only observed in the adult rat and the developmental effects (i.e, decrea sed fetal weight and delayed ossification) observed were not attributable to a single exposure. Therefore, the NOAEL from the acute neurotoxicity study is protective of the effects observed in the rat developmental study and a female specific (13

- 49 y ears old ) acute dietary assessment is not warranted. The acute dietary POD for general population utilizing the ACN study is protective for this scenario. An uncertainty factor of 100x (10x to account for interspecies extrapolation and 10x for intraspecies

var iation) was applied to the aRfD.

A chronic reference dose (cRfD) of 0.082 mg/kg/day was selected from the parental effects of the reproduction study in rats ( NOAEL=8.2 mg/kg/day, LOAEL= 19.4 mg/kg/day in fe males),

based on decreased body weight and dec reased food consumption

. The endpoint selected is appropriate for both the duration and the population of concern. This POD is also supported by findings from the combined chronic toxicity/carcinogenicity study in rats and the carcinogenicity study in mice. The range of doses tested in these studies (2.0 to 40.5 mg/kg/day ) are comparable

to the 2

- generation reproduction NOAELs/LOAELs. Due to dose

- spread selection across the chronic toxicity studies, the NOAEL of 8.2 mg/kg/day from the 2

- generation reproduction study

is protective of the suite of effects seen in these studies including the decreases in body weight, food consumption, clinical signs, and the histopathological changes seen in the kidneys, thyroid and mammary glands in rats, and the hyperplasia of the colon/caecum seen in mice (LOAELs

27

- 30 mg/kg/day) . The lower NOAEL of 4.88 mg/kg/day established for male rats in the

combined chronic to xicity/carcinogenicity study is an artifact of dose selection since the NOAEL

for adult males in the two

- generation reproductive toxicity in rats was 6.8 mg/kg/day (comparable to the female NOAEL in the combined chronic toxicity/carcinogenicity study ).

Fur thermore, the LOAELs for adult males and females in the in the combined chronic toxicity/carcinogenicity study in rats are comparable ( 30.17 and 27.44 mg/kg/day, respectively).

In the two

- generation reproductive toxicity in rats a higher NOAEL was identif ied in female rats (8.2 mg/kg/day) even though the LOAEL for females is lower than for males (19.4 mg/kg/day and 40.5 mg/kg/day, respectively). Thus, selecting the higher NOAEL (8.2 mg/kg/day) is protective of the effects seen in all the chronic toxicity studies in the benzovindiflupyr database. An uncertainty factor of 100x (10x to account for interspecies extrapolation and 10x for intra

species variation) was applied to the cRfD.

The short

- term and intermediate

- term incidental oral POD is based on the NOAEL of 8.2 mg/kg/day with the lowest LOAEL of 19.4 mg/kg/day established for female rats in the reproduction study . The POD is based on decreased body weight and decreased food consumption in parental animals as well as increases in liver weights, centr ilobular

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 26 of 82 hepatocellular hypertrophy

, increased incidence of cell hypertrophy in the pars distalis of the pituitary , reduced body weight, delayed preputial separation, and decreased spleen weights in the F1 and/or F2 offspring

. Since juvenile animals were n ot more sensitive than the adult animals in

the two

- generation reproduction study, the short

- term incidental oral POD is based on the Parental/Offspring NOAEL of 8.2 mg/kg/day with the lowest LOAEL of 19.4 mg/kg/day established for female rats in the repro duction study. This endpoint is appropriate for the population of concern (infants and children). The POD would also address the decreases in body weight, body weight gain and food consumption observed in the 90

- day rat study at the identical

NOAEL of 8.2 mg/kg/day in adult females, as well as the liver weight changes and histopathological lesions of the liver were seen in the adult rats in the 90

- day rat study and in the F1 offspring at termination in the two

- generation reproduction study, as well as the b ody weight

decreases in the 90

- day mouse study (adults).

A dermal POD and endpoint of concern is not recommended and quantification of dermal risk is not required since no systemic or dermal toxicity was seen following repeated dermal applications of benz ovindiflupyr at the limit dose (1000 mg/kg/day) to rats for 28 days. Additionally, there are no concerns for developmental or reproductive toxicity, neurotoxicity, or immunotoxicity since adult animals in the dermal toxicity study had displayed toxic effec ts, and fetuses and offspring were not more sensitive than adults when orally dosed with benzovindiflupyr

.

The short

- term and i ntermediate

- term inhalation POD is based on the NOAEL of 8.2 mg/kg/day with the lowest LOAEL of 19.4 mg/kg/day established for female rats in the reproduction study based on decreased body weight and decreased food consumption. An inhalation toxicity study with benzovindiflupyr is not a vailable. Therefore, an oral study was selected for the inhalation endpoint. The inhalation toxicity is assumed to be equivalent to the oral toxicity. This study is appropriate for both short and intermediate term since the database does not suggest progre ssion

of NOAEL values over time. The short

- and intermediate

- term inhalation POD is based on the NOAEL of 8.2 mg/kg/day with the lowest LOAEL of 19.4 mg/kg/day established for female rats in the reproduction study. The POD would be protective of the decrea ses in body weight, body weight gain and food consumption observed in the 90

- day rat study at the identical NOAEL of 8.2 mg/kg/day in females, as well as the liver weight changes and histopathological lesions of the

liver were seen in the adult rats in the 90

- day study and in the F1 offspring at termination in the

two

- generation reproduction study, as well as the body weight decreases in the 90

- day mouse study.



### 4.5.2 Recommendation for Combining Routes of Exposures for Risk

Assessment

As part of conductin g a human health risk assessment, HED considers risks from individual routes of exposure (oral, dermal, and inhalation). For benzovindiflupyr, the risks are combined based on the common toxicity endpoint of body weight decreases. For residential handler, t he only route of exposure assessed quantitatively is via inhalation. For children exposed in residential settings, only incidental oral was assessed quantitatively. For the occupational risk assessment, it is not possible to combine routes of exposure (der mal and inhalation) due to the lack of a dermal toxicity endpoint.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 27 of 82 

### 4.5.3 Cancer Classification and Risk Assessment Recommendation

The CARC committee determined based on a weight

- of

- evidence approach of the overall tumor profile that benzovindiflupyr sho uld have a cancer classification of “ Suggestive Evidence of Carcinogenic Potential ”

. A quantitative cancer risk assessment is not needed; t he Agency has determined that quantification of risk using a non

- linear approach (i.e., RfD) will adequately

account for any chronic toxicity, including carcinogenicity, which could result from exposure to benzovindiflupyr.



### 4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human

Risk Assessment

Table s 4.5.4 .1 and 4.5.4.2 summarize the toxicological doses and endpoints selected for use in

the human health risk assessment for benzovindiflupyr

.

Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Benzovindiflupyr for Use in Dietary and

Non

- Occupational Human Health Risk A ssessments 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, including

Infants and Children) NOAEL=10

mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Acute RfD =

0.10 mg/kg/day

aPAD =0.10 mg/kg/day Acute neurotoxicity

screening battery (rat) (MRID 48604455)

NOAEL=10 mg/kg/day LOAEL = 30 mg/kg/day based on multiple clinical observations, decreases in mean body temperature, decreases in locomotor activity parameters, reduced food consumption and/or decreases in mean grip strength

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 28 of 82 Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Benzovindiflupyr for Use in Dietary and

Non

- Occupational Human Health Risk A ssessments Exposure/

Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological

Effects

Chronic Dietary

(All Populations) Parental /Offspring

NOAEL = 8.2 (females) mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Chronic RfD

= 0.082 mg/kg/day

cPAD = 0.082 mg/kg/day 2

- Generation

Reproduction Study (rat) (MRID 48604449)

Parental/Offspring NOAEL = 8.2 mg/kg/day (F)

LOAEL = 19.4 mg/kg/day (F) based on decreased body weight

and decreased food consumption in parental

animals as well as

increases in liver weights, centrilobular hepatocellular hypertrophy, increased

incidence of cell hypertrophy in the pars distalis of the pituitary, reduced body weight, delayed preputial separation, and decreased spleen weights in the F1 and/or F2 offspring.

Incidental O ral

Short

– Term (1

- 30 days) Parental/Offspring

NOAEL = 8.2 (females) mg/kg/day UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for

MOE = 100 Two

- Generation

Reproduction Toxicity Study (rat) (MRID 48604449)

Parental/Offspring NOAEL = 8.2 mg/kg/day (F)

LOAEL = 19.4 mg/kg/day (F) based on decreased body weight

and decreased food consumption in parental

animals as well as

increases in liver weights, centrilobular hepatocellular hypertrophy, increased

incidence of cell hypertrophy in the pars

distalis of th e pituitary, reduced body weight, delayed preputial

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 29 of 82 Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Benzovindiflupyr for Use in Dietary and

Non

- Occupational Human Health Risk A ssessments Exposure/

Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD,

Level of

Concern for

Risk

Assessment Study and Toxicological

Effects

separation, and decreased spleen weights in the F1 and/or F2 offspring.

Dermal Short

Term (1

- 30 days) and

Intermediate

Term (1

- 6 months) A POD and endpoint of concern is not recommended and quantifica tion of dermal risk is not

required since no systemic or dermal toxicity was seen following repeated dermal applications of benzovindiflupyr at the Limit Dose (1000 mg/kg/day) to rats for 28 days. Additionally, there are no concerns for developmental, repr oductive, neurotoxicity, or immunotoxicity.

Inhalation

Short

- term (1

- 30 days) and

Intermediate

Term (1

- 6 months) Parental /Offspring

NOAEL: 8.2 mg/kg/day (F) UF A = 10x

UF H = 10x FQPA SF= 1x Residential

LOC for

MOE = 100 2

- Generation

Reproduction Study (rat) (MRID 48604449)

Parental/Offspring NOAEL = 8.2 mg/kg/day (F)

LOAEL = 19.4 mg/kg/day (F) based on decreased body weight

and decreased food consumption in parental

animals as well as

increases in liver weights, centril obular hepatocellular hypertrophy, increased

incidence of cell hypertrophy in the pars distalis of the pituitary, reduced body weight, delayed preputial separation, and decreased spleen weights in the F1 and/or F2 offspring.

Cancer (oral, dermal, inhalation) Classification: “ Suggestive Evidence of Carcinogenic Potential ” Quantification of

carcinogenicity is not required. T he RfD would be protective of non

- carcinogenic and carcinogenic effects observed in the rat carcinogenicity study or mode of ac tion studies conducted at higher doses. 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 environmental ly relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among membe rs of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of key data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 30 of 82 Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Benzovindiflupyr for Use in Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty

Factors Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Dermal

Short

- Term (1

- 30 days) and

Intermediate

Term (1

- 6 months) A POD and endpoint of concern is not recommended and quantification of dermal risk is not

required since no systemic or dermal toxicity was seen following repeated dermal applications of benzovindiflupyr at the Limit Dose (1000 mg/kg/day) to rats for 28 days. Additi onally, there are no concerns for developmental, reproductive, neuro, or immunotoxicity.

Inhalation Short (1

- 30 days) and

Intermediate

term (1

- 6 months) NOAEL: 8.2

mg/kg/day (F) UF A = 10x

UF H = 10x Occupational

LOC for MOE

= 100 2

- Generation Reproduction Study (rat)

(MRID 48604449)

Parental/Offspring NOAEL = 8.2 mg/kg/day (F) LOAEL = 19.4 mg/kg/day (F) based on decreased body weight and decreased food consumption in parental animals as well as increases in liver weights,

centri lobular hepatocellular hypertrophy, increased incidence of cell hypertrophy in the pars distalis of the pituitary, reduced body weight, delayed preputial separation, and decreased spleen weights in the F1 and/or F2 offspring.

Cancer (oral, dermal, inhalation) Classification: “ Suggestive Evidence of Carcinogenic Potential ” Quantification of

carcinogenicity is not required. T he RfD would be protective of non

- carcinogenic and carcinogenic effects observed in the rat carcinogenicity study or mode of action studies conducted at higher doses.

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 l evel. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL t o extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of key data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.



### 5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 31 of 82 

### 5 .1.1 Summary of Plant and Livestock Metabolism Studies

5.1.1.1 Plant Metabolism Studies

Residue Chemistry Memo, D 422374

, P. Savoia, 1/15/15



### Plant metabolism data were submitted for the three diverse primary crops of tomato, soybean,

and wheat and for the rotational crops of lettuce, turnip and spring wheat

. Studies for all commodities reflected labeling in both the phenyl and pyrazole rings. The metabolic profile was

shown to be substantially similar in plants with some variation on the extent and nature of conjugates found. In general, metabolism in plants proceeds through; 1) N

- demethylation of the pyrazole ring (SYN546206); 2) hydroxylatio n of the alicyclic ring (SYN546039 and

SYN546040 ); and 3) cleavage between the pyrazole and phenyl rings ( NOA449410 and SYN545720). The submitted plant metabolism studies adequately address the requirement to

elucidate the nature of the residue in plants for benzovindiflupyr.



### 5.1.1.2 Livestock Metabolism Studies

Residue Chemistry Memo, D422374, P. Savoia, 1/15/15



### Livestock metabolism studies were submitted for poultry (laying hen) and ruminants (lactating goat) . Studies in both animals reflected labeling in bot h the phenyl and pyrazole rings

. The metabolic pathways observed in hens and goats were found to be similar a nd include demethylation of the pyrazole ring

, hydroxylation of the alicyclic ring, and cleavage between the pyrazole and phenyl ri ngs. The submitted livestock metabolism studies adequately address the requirement to elucidate the nature of the residue in livestock for benzovindiflupyr

.



### 5.1.2 Summary of Environmental Degradation

Drinking Water Memo, D409374, G. Rothman, 10/29/ 14



### Benzovindiflupyr is very persistent in terrestrial and aquatic environments. It has low mobility

and low solubility

. Benzovindiflupyr is persistent to hydrolysis, soil photolysis, anaerobic and aerobic soil metabolism, and anaerobic and aerobic aquatic metabolism. It does degrade in natural aquatic environments exposed to light with a half

- life of approximately 11.2 days. The major tr ansformation products observed were NOA449410 and SYN508272. However, this transformation pathway is not expected to be prevalent in the environment given that the occurrence of light penetration in water bodies nearby agricultural fields is low given the ir turbid properties. B enzovindiflupyr is not expected to escape from dry or moist soil sur faces or water bodies to the atmosphere via volatilization given its low vapor pressure and low Henry’s Law

Constant

.



### 5.1.3 Comparison of Metabolic Pathways

The metabolism of benzovindiflupyr in the rat is detailed in Section 4.2 and the metabolism in plants and livestock is discussed in Section 5.1.1. Based on the submitted data, the metabolic

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 32 of 82 profile in plants is similar in diverse crops of tomato, soybean, an d wheat. Metabolism primarily involves demethylation, hydroxylation, conjugation, and cleavage of the phenyl and pyrazole rings. Metabolism in the rat and livestock (ruminants and poultry) is similar and primarily involves demethylation, hydroxylation, and conjugation, typically leaving the parent molecule largely intact.



### 5.1.4 Residues of Concern Summary and Rationale

ROCKS Memo, D416202

, I. Negrón

- Encarnación, 2/3/ 14



### The HED Residues of Concern Knowledge base Sub

- committee (ROCKS) considered the available data on the nature and magnitude of residues for benzovindiflupyr and concluded that

for the currently proposed uses, only parent compound benzovindiflupyr should be included for

tolerance enforcement of residues in plant and livestock commodities. For risk assessment

purposes , the residues of concern (ROC) include both parent benzovindiflupyr and the metabolite SYN546039 for both plant and livestock commodities. For drinking water, the residue

of concern is just parent benzovindiflupyr.

Parent benzovindiflupyr was identified as the major residue in crop metabolism studies and/or crop field trials. It is considered an appropriate marker of misuse; therefore, is recommended as

the residue of concern for tolerance enforcement for plant commodities . Hydroxylated benzovindiflupyr ( SYN546039 ) was also observed in the metabolism studies and crop field

trials. Based on i t s structural similarity to parent benzovindiflupyr a similar toxicity is assumed.

For risk assessment purposes, the ROCKS recommend ed inclusion of both parent benzovindiflupyr and SYN546039 for plant commodities.

Parent benzovindiflupyr and SYN546039 are the main residues identified in the ruminant and poultry metabolism and in the ruminan t feeding study. The ROCKS recommend ed their inclusion as ROC for risk assessment on livestock commodities. Since parent benzovindiflupyr was observed in the feeding study, it is considered an appropriate marker of misuse for livestock

commodities and is recommended as the ROC for tolerance enforcement.

For drinking water, the ROC for risk assessment is benzovindiflup yr. The parent compound i s very stable in aqueous environments. It has been observed to degrade in natural aquatic environments exposed to light with the major transformation products of NOA449410 and

SYN508272. However, there is little potential for this transformation pathway to occur in the

environment based on the proposed uses since the light penetration is low in water bodies near

a gricultural fields due to turbidity.

The residues of concern for benzovindiflupyr are summ arized in T able 5.1.4 below.

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

Matrix Residues Included in Risk

Assessment Residues Included in Tolerance Expression

Plants Primary

Crop Benzovindiflupyr and SYN546039 Benzovindiflupyr

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 33 of 82 Table 5.1.4. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues Included in Risk

Assessment Residues Included in Tolerance Expression

Rotational Crop Benzovindiflupyr and SYN546039 Benzovindiflupyr

Livestock Ruminant Benzovindiflupyr and SYN546039 Benzovindiflupyr

Poultry Benzovindiflupyr and SYN546039 Benzovindiflupyr
Drinking Water Benzovindiflupyr Not Applicable



### 5 .2 Food Residue Profile

Residue Chemistry Memo, D422374, P. Savoia, 1/15/15



### Adequate residue chemistry data have been provided for benzovindiflupyr. Sufficient field trials with appropriate geographic representation were submitted. Residue studies used validated analytical methods and are supported by adequate storage stability data.

The metabolism of benzovindiflupyr was investigated in three different plants, i.e., tomato, soybean, and wheat. Parent benzovindiflupyr was identified as the major residue in both metabolism studies and crop field trials. In crop field trials, benzovindiflupyr was found in most of the food and feed crops at quantifiable levels but occurred more often in the foliage and forage and was generally below the LOQ (0.01 ppm) in grain and seed. The primary biotransformation product observed in both the metabolism studies and crop field trials is h ydroxylated benzovindiflupyr ( SYN546039 ). In crop field trials t h is metabolite was generally found at levels near the LOQ (0.01 ppm) except in the foliage and forage portions of plants wher e the residues were typically greater. Detectable r esidues of benzovindiflupyr are not expected in rotational

crops following a 180

- day plant back interval

.

Processing stu dies were performed for the appropriate proposed use crops. B enzovindiflupyr plus metabolite residues were found to concentrate in the processed commodities of apple wet pomace, aspirated grain fractions (AGF), peanut oil, potato processed waste, raisin, soybean hulls, and dried tomatoes.



### 5.3 Water Residue Profile

Drinking Water Memo, D 409374, G. Rothman, 10/29/14



### Water monitoring data are not available for benzovindiflupyr , therefore estimated drinking water concentrations (EDWCs) for use in the dietary assessment are based on modeled surface and ground water valu es. This screening drinking water assessment utilizes the PRZM/EXAMS Surface Water Concentration Calculator (SWCC Version 1.106, released May 22, 2014) to assess surface water. Multiple application scenarios for the surface wate r analysis are presented

i n the screening drinking water assessment to identify the upper

- bound EDWC associated with

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 34 of 82 all of the proposed uses for benzovindiflupyr. Ground water concen trations are estimated using

the Tier 1 mode of the PRZM

- GW Model (Version 1.07, released January 23, 2014).

The maximum surface and ground water EDWCs for use in the human health risk assessment for benzovindiflupyr are shown in Table 5.3. The surface water values were selected for use in the dietary exposure assessment since they were higher tha n the ground water values.

Table 5.3. Maximum Estimated Surface Water and Ground Water Concentrations for Benzovindiflupyr

Scenario Surface Water Conc., ppb Ground Water Conc., ppb 3

Acute 8.4 1 0.14 3

Chronic 5.4 2 <0.14 3

1 Based on SWCC PA Corn crop scenario.

2 Based on SWCC NY Grape crop scenario.

3 Based on PRZM

- GW FL Citrus scenario.



### 5.4 Dietary Risk Assessment

Dietary Exposure Memo, D421979, and D421980 S. Tadayon, 10/14/14 Anticipated Residue Memo, D422881, P. Savoia, 1/15/15



### 5. 4.1 Description of Residue Data Used in Dietary Assessment

The acute and chronic dietary exposure assessments for benzovindiflupyr on food crops are unrefined analyses that used tolerance level residues

, 100% crop treated , and used default processing factors

. T he use of tolerance levels residues for the proposed crops in the dietary assessments adequately account for the combined residues of concern for risk assessment.

Residues of the SYN546039 metabolite , a residue of concern for risk assessment, do not appear at concentrations > 10% of parent compound in food crop field tr ials . In addition, the maximum combined residues of the benzovindiflupyr parent and SYN546039 metabolite do not exceed the recommended tolerance levels (which were based on parent compound only ).

Anticipate d residues (ARs) were used for the acute and chronic dietary exposure assessments for benzovindiflupyr on livestock commodities. A calculation of the maximum reasonably balanced diets for livestock was perfor med to determine the dietary burdens , and resulting expected tissue residues, for cattle and poultry. The calculations included both parent benzovindiflupyr and the

SYN546039 metabolite

. These ARs are considered very conservative and are based on a

maximu m theoretical diet, maximum residues in feed based on maximum application rates and minimum PHIs from field trials, as well as maximum residues found in feeding or metabolism studies (at exaggerated rates). Since there are no swine feeding or metabolism s tudies, the residues from cattle studies were used to calculate hog commodity ARs. F or poultry and swine

tissues , secondary transfer of benzovindiflupyr and the SYN546039 metabolite is expected to be negligible . Based on this negligible transfer of the re sidues of concern, and that poultry and swine commodities do not need tolerances for benzovindiflupyr ( category 3 of 40 CFR 180.6(a) ), these commodities were not included in the dietary assessments.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 35 of 82 

### 5.4.2 Percent Crop Treated Used in Dietary Assessment

T he acute and chronic dietary risk assessment s assumed 100% crop treated for all commodities

.



### 5.4.3 Acute Dietary Risk Assessment

A highly conservative acute dietary risk assessment was conducted which used tolerance level

residues for food

, anticipated residues ( based on maximum theoretical diets ) for livestock commodities, 100 % crop treated for all commodities

, and screening level estimated drinking

water concentrations

. A cute dietary (food and water) risk estimates for the proposed uses of

b enzovindif

lupy r did not exceed HED’s level of concern (>100% of the acute population adjusted dose; aPAD) for the general U.S. population or any population subgroup. At the 95 th


### percentile, the risk estimate was 10% of the aPAD for the general U.S. population. The risk estimate for the most highly exposed subgroup, children 1

- 2 year s old, was 30% of th e aPAD ( see Table 5.4.6. )

.



### 5.4.4 Chronic Dietary Risk Assessment

A highly conservative chronic dietary risk assessment was co nducted which used tolerance level residues for food, anticipated residues (based on maximum theoretical diets) for livestock

commodities

, 100% crop treated for all commodities

, and screening level estimated drinking water concentrations. Chronic dietary (food and water) risk estimates for the proposed uses of

b enzovindiflupyr did not exceed HED’s level of concern (>100% of the chronic population adjusted dose; cPAD) for the general U.S. population or any population subgroup. At the 95 th


### percentile, the r isk estimate was 4% of the cPAD for the general U.S. population. The risk estimate for the most highly exposed subgroup, children 1

- 2 year s old, was 14% of the cPAD ( see Table 5.4.6.).



### 5.4.5 Cancer Dietary Risk Assessment

Benzovindiflupyr was considered to have "Suggestive evidence of carcinogenic potential".

However , quantification of risk using a non

- linear approach ( i.e., RfD) adequately accounts for all chronic toxicity, including carcinogenicity, that could result from exposure to

be nzovindiflupyr ; therefore a separate cancer assessment was not performed.



### 5.4.6 Summary Table

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 36 of 82 Table 5.4.6 Summary of Dietary (Food and Drinking Water) Exposure and Risk

Estimate s for Benzovindiflupyr

. 1

Population Subgroup Acute Dietary (95th Percentile) Chronic Dietary

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

General U.S. Population 0.010055 10 0.003199 4.0

All Infants (< 1 year old) 0.019173 19 0.005108 6.4

Children 1

- 2 years old 0.030274 30 0.010990 14

Children 3

- 5 years old 0.022549 23 0.007871 9.8

Children 6

- 12 years old 0.012495 13 0.004151 5.2

Youth 13

- 19 years old 0.006797 6.8 0.002284 2.9

Adults 20

- 49 years old 0.008050 8.1 0.002677 3.3

Adults 50

- 99 years old 0.007443 7.4 0.002477 3.1

Females 13

- 49 years old 0.007471 7.5 0.002413 3.0

1 Highest exposure identified in bold ; aPAD = acute population adjusted dose = 0.10 mg/kg/da y ; cPAD = chronic population adjusted dose = 0. 082 mg/kg/day

.



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

Occupational/Residential Exposure Memo, D421981, S. Tadayon, 9/3/14



### Benzovindiflupyr is proposed for use on turf (e.g. golf courses, recreational parks, home lawns, and sod farms) and ornamentals (residential landscape areas)

. These uses may potentially result in residential (non

- occupational) handler and post

- application exposures . I nhalation and dermal

exposures may occur for adults applying benzovindiflupyr . P ost

- application exposures may include dermal exposures for adults and children , as well as incidental oral exposures to children. Therefore, residential handler and residential post

- application exposure assessments have been conducted according to HED’s 2012 Residential Standard Operating Procedures (SOPs) 1



### . Note

that while dermal exposures are expected from benzovindiflupyr, there are not quantitatively assessed as a dermal toxicity endpoint i s not identified for benzovindiflupyr. Only the inhalation and incidental oral exposures are assessed for the proposed residential uses.

1 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 37 of 82 

### 6. 1 Residential Handler Exposure

The proposed uses of benzovindiflupyr on turf and ornamentals in a residential setting by

homeowners may result in residential handler ( adults who are involved in the pesticide application process ) exposure . Residential handler exposure is expected to be short

- term (ST) in

duration . I ntermediate

- term (IT ) exposures are not likely because of the intermittent nature of applications by homeowners. In addition, since the toxicity endpoints and PODs are the same for all durations, the ST assessment will be protective of any longer term exposures that may result

from residential uses. Residential handlers are assumed to be wearing short

- sleeved shirts, short pants, shoes and socks during application of benzovindi flupyr ( i.e., no protective equipment). The assessments were conducted assuming the maximum application rate s and used unit exposure values and estimates for area treated or amount handled along with algorithms taken
from HED’s 2012 Residential SOPs.

T he quantitative exposure/risk assessment developed for residential handlers is based on the following scenarios:

 Mixing/Loading/Applying Liquid to ornamentals and turf with Hose

- End Sprayer

 Mixing/Loading/Applying Liquid to ornamentals and turf with Manu ally

- pressurized

handwand

 Mixing/Loading/Applying Liquid to ornamentals and turf with Backpack

 Mixing/Loading/Applying Liquid to ornamentals an turf with a Sprinkler Can

Since no dermal hazard was identified for benzovindiflupyr in the toxicological datab ase, only inhalation exposure assessments were conducted for residential handlers. Inhalation margins of exposure (MOEs) are well above the level of concern ( LOC ) of 100 for all scenarios assessed and are not of concern ( estimated ST inhalation MOEs are a ll ≥ 180,000 ). Short

- term inhalation residential handler estimated exposure and risk estimates are shown in Table 6.1 below.

Table 6.1. Short

- Term Residential Handler E xposure and Risk Estimates for B enzovindiflupyr

Exposure Scenario Level of

Concern Inhalation

Unit Exposure (mg/lb ai) Maximum

Application

Rate 1 Area

Treated or

Amount

Handled Daily 2 Inhalation

Dose (mg/kg/day) 3 MOE 4

Emulsifiable Concentrate(EC)

M/L/A with a Hose

- end Sprayer to Turf and

Ornamentals 100 0.022 0.067 lb ai/A 0.5 acres 0.0000092 890,000

M/L/A with a Manually Pressurized Handwand to Turf

and ornamentals 100 0.018 0.0023 lb ai/gal 5 gal 0.0000026 3,200,000

M/L/A with a Sprinkler Can 100 0.022 0.0015/1000 lb

ai/ ft 2 1000 ft 2 0.00000041 20,000,000

M/L/A with a backpack sprayer to Turf and ornamentals 100 0.14 0.0023 lb ai/gal 5gals 0.00002 410,000

Water Dispersible Granular (WDG)

M/L/A with a Hose

- end Sprayer to Ornamental 100 0.022 0.067 lb ai/A 0.5 acres 0.0000092 890,000

M/L/A with a Manually Pressurized Handwand to

Ornamentals 100 1.1 0.00067 lb ai/gal 5 gal 0.000046 180,000

M/L/A with a Sprinkler Can to Ornamentals 100 0.022 0.0015/1000 ft 2 1000 ft 2 0.00000041 20,000,000

M/L/A with a backpack sprayer to Ornamentals 100 1.1 0.00067/gal 5gals 0.000046 180,000

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 38 of 82 1 Based on pr o posed b enzovindiflupyr labels

. 2 Exposure Science Advisory Council Policy #9.1. Based on HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ).

3 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) x Conversion Factor (0.001 mg/ μ g) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A or gallons/day) / BW ( 80 kg).

4 Short

- Term Inhalation MOE = Short

- Term Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day) where NOAEL = 8.2 mg/kg/day

.



### 6.2 Residential Post

- Application Exposure

There is the potential for post

- application exposure to individuals (adults and children) as a result of being in an environment that has been previously treated with benzovindiflupyr

. Post

application inhalation exposure s while performing activities in pr eviously treated turf or

ornamentals are not expected and were not assessed primarily due to the very low vapor pressure (2.4 x 10

- 11 

### mm Hg @ 25 oC) and the expected dilution in outdoor air after an application has

occurred. In addition, no dermal hazard was identified in the toxicity database for benzovindiflupyr and, therefore, a quantitative residential post

- application dermal risk assessment is not required and was not completed. However, incidental oral exposures to children contacting treated turf ha ve been assessed. Residential post

- application exposures are generally considered to be intermittent and short

- term in duration . Since the benzovindiflupyr toxicity endpoints and PODs are the same regardless of duration, the short

- term assessment is

protec tive of any longer term exposures that may occur from the residential uses of benzovindiflupyr.

For the residential turf use scenario, post

- application incidental oral exposure is assessed for children (1 to 2 years old as the sentinel population ). The turf use site assessed was residential lawn turf as exposures from that use are expected to be higher than any potential exposures from other turf uses (i.e., recreational park s, golf courses, treated sod)

. The assessment of children’s

exposures to tre ated turf was conducted assuming the maximum label application rate (0. 067 lbs

ai/acre ). Table 6.2 summarizes the short

- term incidental oral exposure and risk estimate s resulting from residential post

- application exposures. I ncidental oral MOEs for childr en ranged from 8,000 to 3,600,000 on the day of application

, using default input values, and are not of

concern

.

Table 6.2 Residential Post

- Application Short

- Term Oral Exposure and Risk Estimates for B enzovindiflupyr

Lifestage Post

- application Exposure Scenario Dose 1 MOEs 2

Child Turf

- sprays Hand to Mouth 0.0010 8,000
Object to Mouth 0.000031 260,000
Incidental Soil Ingestion 0.0000023 3,600,000

1 Hand

- to

- Mouth = [Hand residue loading (mg/cm 2 ) x (fraction hand surface area mouthed/event (0.127/event) x typical surface area of one hand (150 cm 2 )) x (exposure time (1.5 hrs/day)*number of replenishment intervals/hr (4 intervals/hr) x (1

- (1

- saliva extraction factor (0.5)^(number of hand

- to

- mouth contact events per hour (13.9 events/hr); Hand Residue Loading = (fraction of ai on hands compared to total surface residue from dermal TC study (0.06) x dermal exposure (mg))/typical surface area of one hand (150 cm 2 ). Object

- to

- Mouth = ((Object Residue (μg/cm 2 ) x CF1 (1.0E

- 3 mg/μg) x Object Sur face Area Mouthed/Event (10 cm 2 /event)) x (Exposure Time (1.5 hrs/day) x #Replenishment I ntervals/hr (4)) x (1

- ((1

- Extraction by Saliva (0.48))^(#Object

- to

- Mouth Events/hr (8.8 events/hr)/#Replenishment intervals/hr))))/Body Weight (11kg)

. Soil Ingestion = (Soil Residue (7.0746975 μg/g) x Ingestion Rate (50 mg/kg/day) x CF(0.000001))/Body Weight (11 kg).

2 MOE = NOAEL/Daily Dose (mg ai/kg/day); Oral NOA EL =8.2 /kg/day.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 39 of 82 

### 6.3 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.3 reflects the residential risk estimates for use in the b enzovindiflupyr aggregate

assessment. T he scenarios and lifestages resulting in the highest residential exposures are selected for use in the aggregate assessment and are considered protecti ve of other exposure

scenarios . An aggregate assessment that includes residential scenarios is only needed for short

term exposures as there are no intermediate

- or long term

- exposures expected from the proposed

non

- occupational residential uses. The appr opriate residential scenarios for the benzovindiflupyr

aggregate assessments are:

 The short

- term residential exposure for use in the adult aggregate assessment reflects the inhalation exposure estimate from treating ornamentals with a m anually pressuriz ed

handwand or backpack sprayer.

 The short

- term residential exposure for use in the child aggregate assessment reflects turf
post

- application h and

- to

- mouth exp osure for children 1 to <2 years old

.

Table 6.3 . Residential Exposures for the Be n zovindiflupyr Aggregate Assessment.

Lifestage Exposure

Scenario Dose (mg/kg/day) 1 MOE 2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adult

Male Handler:

Treating

Ornamentals NA 0.000046 N/A 0.000046 NA 0.000046 N/A 180,000

Adult Female

Child Post

Application:

Treated Turf NA NA Hand to

mouth

0.0010 0.0010 NA NA 8,000 8,000

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed.

2 MOE = the MOEs associated with the highest residential doses (From Tables 6.1 and 6.2)

. Total = dermal + inhalation + incidental

oral.



### 6. 4 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 method s (e.g., groundboom and airblast) employed for b enzovindiflupyr

. The agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a

Data Call

- In issued by EPA), EPA Regional Offic es 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 ( htt p://www.epa.gov/opp00001/factsheets/spraydrift.htm ). The agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides. The potential for spray drift will be quantitat ively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Ass essment (SOPs)

- Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This

document outlines the quantification of indirect non

- occupational exposure to drift.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 40 of 82 Furthermore, residential turf uses were qu antitatively assessed as part of this risk assessment; risk estimates addressed in the residential turf assessment provide a worst case estimate of potential exposure from spray drift . T he turf scenario for same day contact with directly sprayed

lawn turf is protective of any exposure of children via spray drift from agricultural benzovindiflupyr applications. For direct applications to turf, the post

- application incidental oral MOE is 8,000 ( 80x above the level of concern, an MOE= 100) for children and is not of risk

concern.



### 6.5 Residential Bystander Post

- application Inhalation Exposure

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

- application inhalation exposure assessment was not performed for benzovindiflupyr at this time primarily beca use of the very low vapor pressure ( 2.4 x 10

- 11 

### mm Hg at 25°C) and low to moderate acute inhalation toxicity (Toxicity Category III). However, v olat ilization of pesticides may be a source of post

application inhalation exposure to individuals nearby pesti cide applications. 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 the SAP’s final repo rt on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html )

. During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for

b enzovindiflupyr

.



### 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 quantitative 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.

Based on the proposed uses of benzovindiflupyr, exposures can occur both from dietary sources (food and water) and in residential settings. Uses of benzovin diflupyr that may result in residential exposures include turf (such as lawn s and golf courses) and residential landscape

ornamentals.

The aggregate risk assessments are intended to be representative of exposures that may co

- occur. The scenarios expected to result in the highest exposures are used as representative scenarios for the aggregate assessment and are considered protective of other scenarios. The lifestages selected for the aggregate assessments represent the population subgroups expected to be the most highly

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 41 of 82 exposed for each scenario. For more information on the residential exposure scenarios selected for aggregate assessment, see Section 6.3 above.



### 7.1 Acute Aggregate Risk

Typically, HED does not consider residential exposures when assessin g acute aggregate risk unless such exposures can be characterized as a series of single

- day exposures, which is not the

case for benzovindiflupyr . Therefore, acute aggregate risk estimates for benzovindiflupyr are equivalent to the acute dietary (food and drinking water) risk estimates (Section 5.4) and are

below HED’s level of concern.



### 7.2 Short

- Term Aggregate Risk

The short

- term aggregate risk for benzovindiflupyr includes background contribution from dietary (food and drinking water) exposure plus the highest short

- term residential exposures for adults and children (Table 7.2.1 below). There is no dermal toxicity endpoint therefore only oral and inhalation exposu res are considered in the aggregate assessment. The short

- term aggregate assessment for adults includes residential exposure from mixing, loading and applying benzovindiflupyr to ornamentals . The short

- term aggregate risk estimate for adults is below

HED’ s level of concern. The short

- term aggregate assessment for children includes post

application exposure from treated turf . The short

- term aggregate risk estimate for children is
below HED’s level of concern.

Table 7.2 .1 Short

- Term Aggregate Risk Calculations

Population Short

- or Intermediate

- Term Scenario

NOAEL mg/kg/day LOC 1 Max

Allowable Exposure 2 mg/kg/day Average

Food and

Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 Tota l

Exposure mg/kg/day 4 Aggregate

MOE (food, water, and residential) 5

Adult (Handler treating ornamentals) 8.2 100 0.082 0.003199 0.000046 0.003245 2500

Child ( Post

application treated turf) 8.2 100 0.082 0.01099 0.0010 0.01199 680

1 LOC=100 (10x inter

- and 10x intra

- species uncertainty factors)

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC

3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. (Residential exposures for

adults and for children 1

- 2 yrs old, see Table 6.3).

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure). (Ave food and water exposures for the general U.S. population and for children 1

- 2 yrs old, see Table 5.4.6)

5 Aggregate MOE = [NOAEL / (Avg Food & Water Exposu re + Residential Exposure)]

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 42 of 82 

### 7.3 Intermediate

- /Long

- Term Aggregate Risk

There are no intermediate

- or long term

- exposures expected from the proposed non

- occupational residential uses of benzovindiflupyr.



### 7.4 Cancer Aggregate Risk

Benzovindiflupyr was considered with "Suggestive evidence of carcinogenic potential".

However , quantification of risk using a non

- linear approach ( i.e., RfD) adequately accounts for all chronic toxicity, including carcinogenicity, that could result from exposure to

benzo vindiflupyr

. A separate cancer assessment was not performed.



### 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 yet made a comm on mechanism of toxicity finding

as to benzovindiflupyr and other carboxamide class pesticides

. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the

cumulative effects of such chemica ls, 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/.



### 9.0 Occupational Exposure/Risk Characterization

Occupational/ Residential Exposure Mem o, D421981 , S. Tadayon, 9/3/14



### 9.1 Short

- /Intermediate

- Term Handler Risk

Occupational exposure is expected from the proposed uses of benzovindiflupyr on agricultural crops, turf, and ornamentals. T he occupational exposure and risk assessment generally addresses risks to workers exposed in an occupational setting via the dermal and inhalation routes of

exposure. However, since no dermal hazard was identifi ed in the toxicity database for

benzovindif

l upyr , a quantitative dermal assessment is not required and risks were quantitatively assessed for inhalation exposure only. Based on the proposed use pattern of benzovindif l upyr
, short

- and intermediate

- term exp osures are anticipated for handlers for the following reasons: (1) the product can be applied at least twice per season (2) the product can be applied to multiple application sites, and (3) there may be a large agribusiness and/or commercial applicators w ho may apply a product over a period of weeks

. Long

- term exposure is not expected for the proposed use patterns. S ince the same endpoint and point of departure were selected for short

and intermediate

- term durations, short

- term exposure and risk estimate s are considered to be protective of intermediate

- term exposure and risk

.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 43 of 82 G eneric default data were used in this assessment as surrogate data in the absence of chemical

specific data, including the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1)

. Estimates of inhalation exposure were calculated for various levels of personal protective equipment (PPE). Results are presented for “baseline” level of attire defined as a single layer of clothing consisting of a long sleeved shirt, long pants, sh oes plus socks, no protective gloves, and no respirator

. The benzovindif l upyr product labels direct mixers, loaders, applicators and other

handlers to wear coveralls, long

- sleeved shirts, long pants, protective eyewear, chemical

- resistant gloves, and shoes plus socks.

All occupational handler scenarios assessed for the proposed uses of benzovindif l upyr resulted in

estimated short

- and intermediate

- term inhalation margins of exposure (MOEs) above the LOC of 100 for all scenarios assessed and, therefore, are not of concern (MOEs ≥100). MOEs ranged from 900 to 9,500,000. Occupational handler risk estimates are shown in Table 9.1.

Table 9.1 Short

- and Intermediate

- Term Occupational Risk assessment f or B enzovindifl u pyr

Exposure Scenario Crop or Target a Baseline

Inhalation

Unit Exposure b Maximum

Application

Rate c Area

Treated or

Amount

Handled Daily d Baseline Inhalation

Dose e MOE f

μg/lb ai lb ai/A or

lb ai/gal Acres or

gals mg/kg/day LOC = 100

Mixer/Loader Emulsifiable Concentrate

Mixing/Loading Liquids for Aerial Application Orchard Crops 4

0.219 0.046

350 0.000044 190,000

Sod Farms 6 0.067 0.000064 130,000 Typical Field Crops 2 0.089 0.0000853 96,000 Typical Field Crops 1

0.068 350 0.000065 130,000 High

- Acreage Field Crops 3 1200 0.000224 37,000 Mixing/Loading Liquids for Airblast Application Nursery Plants 20 0.0000037 2,200,000

Orchard Crops 4 0.046 40 0.0000050 2,000,000

Mixing/Loading Liquids for Chemigation Orchard Crops 4 0.046

350 0.0000441 190,000 Typical Field Crops 2 0.089 0.0000853 100,000

Sod Farms 6

0.068 0.000065 130,000 Typical Field Crops 1
High

- Acreage Field Crops 3

Greenhouse Plants 5 60 0.0000112 730,000 Nursery Plants 5

Mixing/Loading Liquids for

Groundboom Application Golf Courses 6 (tees and greens only) 0.067 5 0.00000033 3,000,000

Golf Courses 6 (fairways, tees, and greens) 0.067 40 0.0000073 1,000,000

Field

- Grown Ornamentals 5

0.068 40 0.0000075 1,100,000 Nursery Plants 6 60 0.0000112 730,000 Greenhouse Plants 5

Sod Farms 6 0.067

80 0.0000146 560,000 Typical Field Crops 2 0.089 0.0000195 420,000 Typical Field Crops 1 0.068 0.0000149 550,0000 High

- Acreage Field Crops 3 200 0.0000373 220,000

Mixer/Loader Water Dispersible Granular

Mixing/Loading

WDG for Aerial Application Typical Field Crops 2

8.36 0.089 350 0.0035 2,300
Typical Field Crops 1 0.068 350 0.00266 3,100

High

- Acreage Field Crops 3 1200 0.00914 900

Typical Field Crops 2 0.089 350 0.0035 2,300 Typical Field Crops 1 0.068 0.00266 3,100

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 44 of 82 Table 9.1 Short

- and Intermediate

- Term Occupational Risk assessment f or B enzovindifl u pyr

Exposure Scenario Crop or Target a Baseline

Inhalation

Unit Exposure b Maximum

Application

Rate c Area

Treated or

Amount

Handled Daily d Baseline Inhalation

Dose e MOE f

μg/lb ai lb ai/A or

lb ai/gal Acres or

gals mg/kg/day LOC = 100

Mixing/Loading

WDG for Chemigation High

- Acreage Field Crops 3

Greenhouse Plants 5 0.067 60 0.00045 18,000 Nursery Plants 5
Mixing/Loading

WDG for Airblast Application Nursery Plants 0.067 20 0.00015 55,000

Mixing/Loading

WDG for

Groundboom Application Typical Field Crops 2 0.089 80 0.0008 1,000 Typical Field Crops 1 0.068 80 0.00061 13,000 High

- Acreage Field Crops 3 200 0.0015 5,400

Greenhouse Plants 5

0.067 60 0.00045 18,000 Nursery Plants 5

Field

- Grown Ornamentals 5
Nursery Plants 6

Greenhouse Plants 5
Applicator

Applying Sprays for Aerial Application Orchard Crops 4

0.0049 0.046

350 0.00000099 8,300,000

Sod Farms 6 0.067 0.00000144 5,700,000 Typical Field Crops 2 0.089 0.00000191 4,300,000 Typical Field Crops 1 0.068 350 0.00000146 5,600,000 High

- Acreage Field Crops 3 1200 0.000005 1,600,000

Applying Sprays for

Groundboom Application Golf Courses 6 (tees and greens only)

0.34 0.067 5 0.00000143 5,700,000

Golf Courses 6 (fairways, tees, and greens) 40 0.0000114 720,000

Field

- Grown Ornamentals 0.068 40 0.0000116 710,000 Nursery Plants 5 0.068 60 0.0000174 470,000 Greenhouse Plants 5

Sod Farms 6 0.067 80 0.0000228 360,000 Typical Field Crops 2 0.089 80 0.0000303 270,000 Typical Field Crops 1 0.068 80 0.000231 350,000 High

- Acreage Field Crops 3 200 0.0000578 140,000

Applying Sprays for

Airblast Application Orchard Crops 4 4.71 0.046 40 0.000108 710,000

Nursery Plants 0.067 20 0.000080 100,000
Flagger

Flagging for Aerial Applications Orchard Crops 4

0.35 0.046

350 0.0000705 120,000

Sod Farms 6 0.067 0.000103 80,000 Typical Field Crops 1 0.068 0.000104 79,000 High

- Acreage Field Crops 3

Typical Field Crops 2 0.089 0.000136 60,000

Mixer/Loader/Applicator Emulsifiable Concentrate

M/L/A Liquids for Backpack Sprayers Orchard (Ground/Soil) 4 2.58 0.0046 lb ai/gal)

40

gallons 0.0000059 1,000,000

Greenhouse Plants (Foliar) 5 140

0.00068 lb ai/gal 0.000048 170,000 Nursery Plants (Foliar) 5

Nursery Plants (Ground/Soil) 5 2.58 8.78e

- 7 3,000,000

Landscaping 5 (trees/shrubs/bushes) 140 0.000048 170,000 Landscaping (plants/flowers) 5
Landscaping 6 2.58 0.0023 0.00000296 3,000,000

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 45 of 82 Table 9.1 Short

- and Intermediate

- Term Occupational Risk assessment f or B enzovindifl u pyr

Exposure Scenario Crop or Target a Baseline

Inhalation

Unit Exposure b Maximum

Application

Rate c Area

Treated or

Amount

Handled Daily d Baseline Inhalation

Dose e MOE f

μg/lb ai lb ai/A or

lb ai/gal Acres or

gals mg/kg/day LOC = 100

(turf, lawns, athletic fields, parks, etc) lb ai/gal

M/L/A Liquids for Manually

Pressurized Handwand Sprayers Greenhouse Plants (Foliar) 5

30 0.00068 lb ai/gal 40

gallons 0.00001 800,000 Nursery Plants (Foliar) 5
Landscaping 5 (trees/shrubs/bushes) Landscaping (plants/flowers) 5

Landscaping 6 (turf, lawns, athletic fields, parks, etc) 30 0.0023 lb ai/gal 0.000035 240,000

M/L/A Liquids for Mechanically

Pressurized Handgun Sprayers Orchard Crops (Foliar) 4 3.9 0.0046 lb ai/gal

1000

gallons 0.000224 37,000 Orchard Crops (Ground/Soil) 4
Greenhouse Plants (Foliar) 5 120

0.00068 lb ai/gal 0.000102 80,000 Greenhouse Plants (Ground/Soil) 5
Nursery Plants (Foliar) 5

3.9 0.0000331 300,000 Nursery Plants (Ground/Soil) 5
Landscaping (trees/shrubs/bushes) 5
Typical Field Crops (Foliar) 1 3.9 0.0068 lb ai/gal 0.000331 25,000 Typical Field Crops 1 (Ground/Soil) Typical Field Crops (Foliar) 2 3.9 0.0089 lb ai/gal 0.000434 19,000 Typical Field Crops 2 1 (Ground/Soil)

Golf Courses (tees and greens only) 6

1.9 0.067 5

acres 0.00000796 1,000,000 Golf Courses (fairways, tees, and

greens) 6 Landscaping (turf, lawns, athletic fields, parks, etc) 6

Mixer/Loader/Applicator Water Dispersible Granular

M/L/A WDG

formulation for Backpack Sprayers Greenhouse Plants (Foliar) 5 140

0.00067 lb ai/gal 40 0.000047 170,000 Nursery Plants (Foliar) 5
Nursery Plants (Ground/Soil) 5 2.58 0.00000086 9,500,000 Landscaping 5 (trees/shrubs/bushes) 140 0.000047 170,000 Landscaping (plants/flowers) 5

M/L/A WDG

formulation for Manually

Pressurized Handwand Sprayers Greenhouse Plants (Foliar) 5

30 0.00067 lb ai/gal 40

gallons 0.0000101 810,000 Nursery Plants (Foliar) 5
Landscaping 5 (trees/shrubs/bushes)

Landscaping (plants/flowers) 5

M/L/A WDG for Mechanically

Pressurized Handgun Sprayers Greenhouse Plants (Foliar) 5

120 0.00067 lb ai/gal 1000

gallons 0.000101 8,100 Greenhouse Plants (Ground/Soil) 5
Nursery Plants (Foliar) 5
Nursery Plants (Ground/Soil) 5

3.9 1000 gallons 0.000033 250,000 Landscaping (trees/shrubs/bushes) 5
Typical Field Crops (Foliar) 1 0.0068 lb ai/gal 0.00033 25,000 Typical Field Crops 1 (Ground/Soil) Typical Field Crops (Foliar) 2 0.0089

lb ai/gal 0.000434 19,000 Typical Field Crops 2 (Ground/Soil)

a Crop or Target

1 Typical Field Crops at 0.068 lb ai/A or 0.0068 lb ai/gal. Blueberries, canola, cucurbits, fruiting vegetables, grapes, legumes, peanuts, tuberous and corm vegetables.

2 Typical Field Crops at 0.089 lb ai/A or 0.0089 lb ai/gal (10 gals/A dilution) Peanuts, s and tuberous and corm vegetables (soil directed)

. 3 High

- Acreage Field Crops at 0.068 lb ai/A or 0.0068 lb ai/gal. Corn, cotton, cereals and, soybeans.

4 Orchard crop s Pome fruits at 0.046 lb ai/A or 0.0046 lb ai/gal.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 46 of 82 5 Nursery Plants” include ornamentals, vegetables, trees, container stock, greenhouse plants including ornamentals, roses, cut flowers, container stock and vegetables at 0.068 lb ai/A or 0.00068 lb ai/gal (100 gals /A dilution)

. 6 Turf and sod farms 0.067 lb ai/A or 0.0023 lb ai/gal

b Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2012); Level of mitigation = Bas eline.

c Based on the maximum application rates on the proposed labels (Reg. Nos 100

- 1 to 100

- 9, See table 4.1 and 4.2)

. d Exposure Science Advisory Council Policy #9.1.

e Inhalation Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Tre ated or Amount Handled Daily (A or gal/day) ÷ BW (80kg).

f Short

- term and intermediate

- term Inhalation MOE = Inhalation NOAEL (8.2 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).



### 9.2 Short

- /Intermediate

- Term Post

- Application Risk

9.2.1 Dermal Post

- A pplication Risk

There is the potential for post

- application exposure to workers as a result of proposed uses of

benzovindif

l upyr . However, since no dermal hazard was identified in the toxicity database for

benzovindif

l upyr , a quantitative occupational post

- applica tion dermal risk assessment is not required and was not completed. As a result, no dislodgeable foliar residue (DFR) studies are required to support the proposed uses of benzovindiflupyr.



### 9.2.2 Inhalation Post

- A pplication Risk

Based on the Agency's curr ent practices, a quantitative post

- application inhalation exposure assessment was not performed for benzovindif l upyr at this time primarily because of very low vapor pressure ( 2.4 x 10

- 11 

### mm Hg @ 25 oC), the low to moderate acute inhalation toxicity (Toxic ity Category I II ), and the low proposed use rate ( ≤ 0. 089 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 Ro denticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 2



### . The Agency is in the process of evaluating the SA P report. In addition, the Agency is continuing to evaluate the available post

applicati on inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the a gency's risk assessments.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

- application inhalation exposure into the agency's risk assessments.

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

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

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 47 of 82 higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of occupational post

- application inhalation exposure scenarios.

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

- application inhalation

exposure. However, the 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 inhalati on risk estimate for commercial airblast application are well

above the level of concern (i.e., MOE > 100) with MOEs ≥ 100,000.

The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting workers from inhalation exposu res during and after greenhouse applications through the use of ventilation requirements.[40 CFR 170.110, (3) (Restrictions associated with pesticide applications)].



### 9.2.3 Restricted Entry Interval

The REI specified on the proposed labels is based on the acute toxicity of b enzovindifl u pyr
, which is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin irritation potential. It is not a dermal sensitizer. Occupational s hort

- and intermediate

- term
post

- application risk estimates were not evaluated for b enzovindifl u pyr

. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute III for acute dermal, eye irritation and primary skin irrigation are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from post

- application exposures to

b enzovindifl u pyr

.



### 10.0 References

Toxicology Reference s

Author: Jess Rowland

Date: 9/30/14

TXR No.: 0057062

Title: Benzovindiflupyr: Report of the Cancer Assessment Review Committee

.

Date: 1/14/15

TXR No.: 0057409

Title: Benzovindifl u pyr

- Solatenol: Summary of the Hazard and Science Policy Council

(HASPOC): Recommendations on the Need for an Inhalation Toxicity Study.

Regan, KS, “ STP Position Paper: Ovarian Follicular Counting in the Assessment of Rodent Reproductive Toxicity”, Toxicologic Pathology , 33:409

– 412, 2005

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 48 of 82 Residue Chemistry References

Author: Ideliz Encarnacion

Date: 2/3/14

DP Number: D416202

Title: Benzovindiflupyr (SolatenolTM). Report of the Residues of Concern

Knowledgebase Subcommittee (ROCKS).

Author: Peter Savoia

Date: 1/15/15

DP Number: D417210, D420023, D422027, D422028 & D422374

Title: Benzovindiflupyr. Petition for the Section 3 Regi stration and Establishment of

Permanent Tolerances of the New Fungicide Active Ingredient Benzovindiflupyr

for Use on: B arley, Blueberry, Corn, Cotton, Cucurbit Vegetables, Fruiting Vegetables, Oat, Pea, Peanut, Pome Fruit , Rapeseed, Rye, Small Fruit Vine Climbing (Except Fuzzy Kiwifruit), Soybean, Tuberous and Corm Vegetables, and Wheat, as well as on Coffee and Sugarcane Imported into the U.S. Summary of Analytical Chemistry and Residue Data.

Drinking Water Assessment

Author: Gabe Rothman

Date: 10/29/14

DP Number: D 409374

Title: Tier I Dri nking Water Assessment for the new chemical Solatenol (P.C. Code:

122305 ) proposed Section 3 uses on blueberries, canola, cereal crops (oats, wheat, rye, and barley), corn, cotton, cu curbits, tomatoes, grapes, legumes, ornamentals, peanuts, pomegranate, soybeans, potatoes, turf grass, and ornamentals (DP

Barcode 409374 )

.

Dietary Exposure Assessment

Author: Peter Savoia

Date: 1/15/15

DP Number: D422881

Title: Benzovindiflupyr. Anticipated Residue Calculations for Incorporation into the

Dietary Assessment of Benzovindiflupyr.

Author: Seyed Tadayon

Date: 10/14/14

DP Number: D421979, D421980

Title: Benzovindiflupyr: Acute and Chronic Aggregate Dietary ( Food and Drinking

Water) Exposure and Risk Assessments for Proposed Uses on Barley, Grain; Coffee; Corn, Field, Grain; Corn, Pop, Grain; Corn, Sweet, Kernel Plus Cob with Husks Removed; Cottonseed (Subgroup 20C); Fruit, Pome, Group 11

- 10; Fruit,

Small Vine Climbing, Except Fuzzy Kiwi, Subgroup 13

- 07F; Oat, Grain; Pea and

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 49 of 82 Bean, Dried Shelled, Except Soybean, Subgroup 6C; Peanut; Rapeseed, Subgroup

20A; Rye, Grain; Soybean, Seed; Sugarcane, cane; Vegetable, Cucurbit, Group 9; Vegetable, Fruiting, Group 8

- 10; Vegetable, Tuberous and Corm, Subgroup 1C; and Wheat, Grain.

Occupational and Residential Assessment

Author: Seyed Tadayon

Date: 9/3/14

DP Number: D421981

Title: Benzovindiflupyr: Occupational and Residential Exposure and Risk Assessment

for the Proposed Uses of the New Fungicide, on Cereals, Blueberries, Corn, Cotton, Cucurbits, Fruiting vegetables, Small Fruit Vines climbing subgroup (except fuzzy kiwifruit), Legume Vegetables, Peanuts, Pome fruit, Rapeseed, Tuberous and Corm, Ornamentals Crops and Turf grass.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 50 of 82 

### A ppendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements The toxicological data requirements (40 CFR 158.340) for food uses for benzovindiflupyr are in

Table A1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1 .1 Benzovindiflupyr Toxicology Data Requirements

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 Sub

- chronic (rodent)

................................ .................. 870.3150 Oral Sub

- chronic (non

- rodent)

................................ ........... 870.3200 21/28

- Day Dermal

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

- Day Dermal

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

- Day Inhalation

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

yes

yes

no

no yes

yes

yes

---

*

870.3700a Developmental Toxicity (rodent)

................................ ....... 870.3700b Developmental Toxicity (non

- rodent)

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

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

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .................... 870.4100b Chronic Toxicity (non

- rodent)

................................ ............ 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

-- In vitro, Mammalian cells

870.5375 Mutagenicity

-- Structural Chromosomal Aberration

870.5395 Mutagenicity

-- In Vivo Mammalian Cytogenetics yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen)

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

- Day Neurotoxicity (hen)

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

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

- Day Neurotoxicity Screening Battery (rat)

.................... 870.6300 Developmental Neurotoxicity

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

no

yes

yes

no ---

--- yes

yes

---

870.7485 General Metabolism

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

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

................................ ................................ .... yes CR

yes yes

yes

yes

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 51 of 82 C R: Conditionally Required, * Waived by the HASPOC (TXR# 0057409)

--- : Not Provided.



### A.1.2 Acute Toxicity Profile

Guideline [OCSPP] Study Title Results Toxicity Category

870.1100 Acute Rat Oral Toxicity Study

(2010, MRID 48604427)

Up

- Down Method

17.5 (N=1), 55 (N=4), 175 (N=3) mg/kg LD 50 =66.3 mg/kg (HED calculation)

Note: The LD 50 value for hydroxy

- benzovindiflupyr ( SYN546039) is > 2000 mg/kg (MRID 48604458), putting doubt on this LD 50 value for benzovindiflupyr

. Animals were fasted prior to dosing, which can sensitize

them to toxins. At the dose of 55 mg/kg, there were only 1 of 4 animals that

died. II

870.1200 Acute Rat Dermal Toxicity

(2010, MRID 48604428) LD 50 >2000 mg/kg III

870.1300 Acute Rat Inhalation Toxicity

Study (Nose

- Only) (2010, MRID

48604429 ) LC 50 > 0.56 mg/L III

870.2400 Primary Rabbit Eye Irritation

Study (2011, MRID 48604431 ) Moderately Irritating III

870.2500 Primary Rabbit Skin Irritation

Study (2010, MRID 48604430 ) Mild Irritant IV

870.2600 Local Lymph Node Assay, Mouse

(2010, MRID 48604432 ) Non

- Sensitizer NA



### A.1.3 Repeat Dose Toxicity Profile

Guideline [OCSPP] Study Title Results

870.3050

28

- Day Oral Toxicity in

Rodents 28

- Day Repeated Oral Dietary Toxicity Study in the Rat (2010, MRID 48604433 )

0, 100, 400 and 1200 ppm: 0, 9, 36 and 99 mg/kg/day

Acceptable

- Guideline NOAEL: 36 mg/kg/day (M/F)

LOAEL: 99 mg/kg/day (M/F), based on decreased body weight, BWG, hypoglycemia, and decreased serum potassium levels

870.3050

28

- Day Oral Toxicity in

Rodents 28

- Day Dietary Toxicity Study in CD

- 1

Mice (2010, MRID 48604435 )

0, 100, 300 or 500 ppm: NOAEL: 15.6 mg/kg/day (M) 19.0 mg/kg/day (F)

LOAEL: 47.4 mg/kg/day (M), 57.9 mg/kg/day (F), based on decreased body weight and lower body weight gain.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 52 of 82 Guideline [OCSPP] Study Title Results

0, 15.6, 47.4 and 81.8 mg

for males 0, 19.0, 57.9 and 91.5 mg/kg/day for females

Acceptable

- Non

- Guideline (N=5) (Tubulointerst itial nephritis was observed in the kidneys in both sexes at 81.8 mg/kg/day in males and 91.5 mg/kg/day in females).

870.3100

90

- Day Oral Toxicity in

Rodents 90

- Day Dietary Study in Rats (2010, MRID 48604436 )

0, 100, 750 or 1500 ppm: 0, 7.6, 53.8 and 108.7 mg/kg/day for males 0, 8.2, 58.8 and 108.8 mg/kg/day for females

Acceptable

- Guideline NOAEL: 7.6 mg/kg/day (M), 8.2 mg/kg/day (F)

LOAEL: 53.8 mg/kg/day (M), 58.8 mg/kg/day (F), based on reduction in body weight, body weight gain, food consumptio n and food utilization. Decrease in core body temperature and glucose in females. Increased liver weight in females and hepatic centrilobular hypertrophy of the liver and increased urea in males

870.3100

90

- Day Oral Toxicity in

Rodents 13

- Week Dietar y Toxicity Study in CD

- 1

Mice (2011, MRID 48604437 )

0, 100, 300 or 500 ppm: 0, 17.0, 55.6 and 97.9 mg/kg/day for males 0, 20.9, 59.6 and 102.8 mg/kg/day for

females

Acceptable

- Guideline NOAEL: 17.6 mg/kg/day (M), 20.9 mg/kg/day (F)

LOAEL: 55.6 mg/kg/day (M) and 59.6 mg/kg/day (F) based on initial body weight loss for up to 7 days which led to 2 males from the high dose satellite group being terminated in extremis. Group mean body weights lower during the initial phases of the study returning to control values thereafter, clinical chemistry changes, higher incidence of soft feces in males from day 31 onward. In males decreased triglycerides and distended large intestine in one animal of each sex.

870.3150

90

- Day Oral Toxicity in

Non

- Rodents 13

- Week Oral (Capsule) Toxicity Study in the Beagle Dog (2010, MRID 48604439 )

0, 30, 375 or 750 mg/kg/day

Acceptable

- Guideline NOAEL: 30 mg/kg/day

LOAEL: 375 mg/kg/day (M & F) based on feces containing mucus or yellow stained feces, initial slight body weight loss during the first week of treatment, reduced body weight gain in males, reduced food intake during the first two weeks of the study and decreased plasma calcium val ues were observed in males

870.3200

28

- Day Dermal Toxicity 28

- Day Dermal Toxicity (Semi

- Occlusive) Study in the Wistar Rat (2012, MRID

48604441 )

0, 100, 300 or 1000 mg/kg/day

Acceptable

- Guideline NOAEL: 1000 mg/kg/day

LOAEL: Not achieved at the limit dose

870.3700a

Prenatal Developmental Toxicity in Rats Prenatal Developmental Toxicity Study in the Han Wistar Rat (gavage) (2011, MRID 48604451 )

0, 7.5, 15, 30 mg/kg/day

Acceptable

- Guideline Maternal

NOAEL: 15 mg/kg/day

LO AEL: 30 mg/kg/day based on clinical signs (ataxia, decreased activity, hunched posture, and ruffled fur)

Developmental

NOAEL: 15 mg/kg/day

LOAEL: 30 mg/kg/day based on decreased fetal weight

and ossification

870.3700b

Prenatal Developmental Toxicity in Rabbits Prenatal Developmental Toxicity Study in New Zealand White Rabbits (gavage) (2011, MRID 48604453 ) Parental and Developmental

NOAEL: 35 mg/kg/day

LOAEL: Not established

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 53 of 82 Guideline [OCSPP] Study Title Results

0, 10, 20, and 35 mg/kg/day

Acceptable/Non

- Guideline (Range finding study had decreased body weight gain, 2

of 10 animals euthanized and one abortion at 50 mg/kg/day)

870.3800

Reproduction and Fertility Effects Two

- Generation Reproduction Toxicity Study in the Han Wistar Rat (2012, MRID 48604449 )

0, 25, 100, 600 ppm in males

Parental: 0, 1.7, 6.8, 40.5 mg/kg/day; F1: 0, 1.9, 7.8, 48.0 mg/kg/day

0, 25, 100, 250 ppm in females

Parental: 0, 2.0, 8.2, 19.4 mg/kg/day; F1: 0, 2.1, 8.7, 22.0 mg/kg/day

Acceptable/Guideline Parental
NOAEL: 6.8 mg/kg/day (M), 8.2 mg/kg/day (F)

LOAEL: 40.5 mg/kg/day (M), 19.4 mg/kg/day (F) due to decreased body weight, decreased body weight gain, the liver weight adjusted for body weight was increased and decreased food consumption.

Offspring

NOAEL: 7.8 mg/ kg/day (M, F1), 8.7 mg/kg/day (F, F1)

LOAEL: 48.0 mg/kg/day (M), 22.0 mg/kg/day (F), in

males decreased body weight, centrilobular hepatocellular hyper trophy in both generations and increased incidence of cell hypertrophy in the pars distalis of the pituit ary in the F1 generation. In females, reduced body weight in both generations. In F1 male pups, the weight of the spleen adjusted for the body weight was statistically significantly reduced. The time until preputial separation in F1 male pups was increased

.

Reproduction

NOAEL: 40.5 mg/kg/day (M, HDT), 19.4 mg/kg/day (F, HDT)

LOAEL: Not achieved in either gender

870.4100

Chronic Toxicity, Non

Rodent 52

- Week Oral (Capsule) Toxicity Study in the Beagle Dog (2011, MRID 48604440 )

0, 25, 250 and 500 mg/kg/day

Acceptable

- Guideline NOAEL: 25 mg/kg/day

LOAEL: 250 mg/kg/day based on reduced body weight, body weight gain in males and females; salivation, vomiting of feed, fluid, capsule or mucus as well as feces containing mucus in both sexes

870.4200

Carcinogenicity in

Mouse 80

- Week Mouse Dietary Carcinogenicity Study (2012, MRID 48604448 )

0, 20, 60 or 200 ppm: 0, 2.62, 7.55 and 26.18 mg/kg/day for males 0, 2.89, 8.67 and 29.26 mg/kg/day for

females

Acceptable

- Guideline NOAEL: 7.55 mg/kg/day (M), 8.67 mg/kg/day (F)

LOAEL: 26.18 mg/kg/day (M), 29.26 mg/kg/day (F) based on hyperplasia of the colon/caecum in males and females, piloerection and rolling gait in females.

870.4200

Carcinogenicity & Chronic Toxicity in the

Rat 104

- Week Rat Dietary Carcinogenicity Study with Combined 52 Week Toxicity Study (2012, MRID 48604446 )

0, 25, 100 or 600 ppm for males: 1.21, 4.88 and 30.17 mg/kg/day

0, 25, 100 or 400 ppm for females: 0, 1.65, 6.66 and 27.44 mg/kg/day NOAEL: 4.88 mg/kg/day (M), 6.66 mg/kg/day (F)

LOAEL: 30.17 (M)/27.44 (F) mg/kg/day, based on decreased body weights, body weight gains, food consumption, food utilization, lack of response to tactile stimulus and liver changes in both genders; hunched or held low body position, piloerection, staining on fur and thin appearance, slow reaction to tail flick and rolling gait, increased tubular cell pigment deposits in the kidneys, focal c

- cell hyperplasia of the thyroid, lobular hyperplasia of the mammary glands and pigmented

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### Page 54 of 82 Guideline [OCSPP] Study Title Results

Acceptable

- Guideline macrophages in the spleen in female s. At the highest dose in males, thyroid follicular cell adenomas.

870.5100

Bacterial Reverse

Mutation Test Salmonella Typhimurium and E. Coli Reverse Mutation Assay (2011, MRID 48604442 )

0, 3, 10, 33, 100, 333, 1000, 2500 and 5000 μg/plate

Acceptable

- Guideline Negative No substantial increase in revertant colony numbers of any of the six tester strains was observed at any dose level, neither in the presence nor absence of metabolic

activation

870.5300

In Vitro Mammalian

Cell Gene Mutation T est Cell Mutation Assay at the Thymidine

Kinase Locus (TK +/

- ) in Mouse Lymphoma

L5178Y Cells (2010, MRID 48604444 )

Experiment I

- without S9 mix: 2.5; 5.0; 10.0; 15.0; and 20.0 μg/mL & with S9 mix: 5.0; 10.0; 20.0; 30.0; and 40.0 μg/mL Experiment II

- with out S9 mix: 5.0; 10.0; 20.0; and 30.0 μg/mL & with S9 mix: 10.0; 20.0; 30.0; 40.0; and 50.0 μg/mL Experiment III

- without S9 mix: 2.5; 5.0; 10.0; 20.0; and 30.0 μg/mL

Acceptable

- Guideline Negative

Did not induce mutations with and without metabolic

activation under the conditions used.

870.5375

In Vitro Chromosome

Aberration Test Chromosome Aberration Test in Human Lymphocytes In Vitro (2010, MRID

48604443 )

Experiment I

- with & without S9 mix: 3.1, 5.5, 9.6, 16.9, 29.5, 51.7, 90.5, 158.3, 277.1, 484.9, 848.6, 1485.0 μg/mL Experiment II

- without S9 mix 0.06, 0.11, 0.19, 0.34, 0.60, 1.04, 1.83, 3.2, 5.6, 9.8, 17.14, 30.0 μg/mL & with S9 mix: 1.3, 2.5, 5.0, 7.5, 10.0, 15.0, 20.0, 30.0 μg/mL

Acceptable

- Guideline Negative

Considered to be non

- clastoge nic in this chromosome aberration test in the absence and presence of metabolic activation when tested up to cytotoxic concentrations.

870.5395

In Vivo Micronucleus

Test Micronucleus Test in Bone Marrow Cells of Wistar (Han) Rats (2011, MRID 48604445 )

0, 43.8, 87.5, 175.0 mg/kg/day in males 0, 75 mg/kg/day in females

Acceptable

- Guideline Negative Benzovindiflupyr did not induce micronuclei in bone

marrow cells when tested to the maximum tolerated dose of 175 mg/kg/day in male and 75 mg/kg/day in

fema le Wistar (Han) rats. The positive control cyclophosphamide induced the appropriate response.

870.6200a

Acute Neurotoxicity Acute Oral (Gavage) Neurotoxicity Study

in the Rat (2011, MRID 48604455 )

0, 10, 30 and 80 mg/kg

Acceptable/Guideline NOAEL: 30 mg/kg (M) and 10 mg/kg (F)

LOAEL: 80 mg/kg (M) and 30 mg/kg (F), based on multiple clinical observations, decreases in mean body temperature, decreases in locomotor activity parameters, and/or decreases in mean grip strength. Other findings noted for 80 mg /kg males and the 30 and 80 mg/kg females included lower mean food consumption.

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### Page 55 of 82 Guideline [OCSPP] Study Title Results

870.6200b

Sub

- Chronic Neurotoxicity 13

- Week Dietary Neurotoxicity Study in

Wistar Rats (2011, MRID 48604457 )

0, 100, 400, and 800 ppm in males: 0, 6.31, 25.95, or 50.67 mg/ kg/day 0, 100, 250, and 500 ppm in females: 0, 7.48, 19.17, or 37.99 mg/kg/day

Acceptable/Non

- Guideline NOAEL: 50.67 mg/kg/day (M), 37.99 mg/kg/day (F)

LOAEL: Not achieved

870.7485

Metabolism and

Pharmacokinetics The Pharmacokinetics of [Pyrazole

- 14C]

- SYN545192 in the Rat Following Single

Oral Administration (2011, MRID 48604426 )

The Excretion and Tissue Distribution of [14C]

- SYN545192 in the Rat Following Single Oral Administration (2011, MRID 48604425 )

Analysis of SYN545192 and Its Rat Metabolites From Dietary Studies (2011, MRID 48604434 )

Acceptable

- Guideline Absorption was similar in male and female rats following low and high doses (79

- 81% and 61

- 62%, respectively). During the first 48 hours post dose the majority of the ad ministered radioactivity had been excreted (97% and 89% following 1 mg/kg and 90% and 86% following 40 mg/kg in males and females, respectively). At 1 mg/kg oral dosing, the Tmax in blood

was at 1

- 2 hours and at 3

- 4 hours with T 1/2 values of

25.40 hours an d 47.97 hours in females and males, respectively. At 40 mg/kg oral dosing, the whole blood Cmax values were 8.0 μM in females and 10.8 μM in

males. The whole blood AUC values in females were 5.06 and 180.2 μg equiv

- h/mL at 1 mg/kg and 40 mg/kg, respectivel y (0

- 120 hours). The whole blood AUC values in males were 11.6 and 231.4 μg equiv

- h/mL at 1 mg/kg and 40 mg/kg, respectively (0

- 120 hours).

The highest tissue concentrations were present in the Harderian gland and liver with lower concentrations in

the a drenal gland, heart, brown fat and kidney (i.e. concentrations of 56.4, 55.2, 42.5, 28.0, 37.2 and 23.1 μM, respectively at 5 hours after a single 40 mg/kg dose in females). In skeletal muscle the concentrations were 11.6 μM. B enzovindiflupyr was extensive ly metabolized in rat giving rise to at least 8 types of metabolite ( e.g. desmethyl, hydroxy, dihydroxy, desmethyl hydroxy, desmethyl dihydroxy, ring

- open, glucuronide conjugate, sulphate conjugate).

The predominant route of elimination was via the fece s. In the 48 hours following dosing, 76% and 69% of the administered dose was excreted via bile following 1 mg/kg and the bile duct cannulation study indicated that significant enterohepatic recirculation occurred for the parent compound.

870.7600

Dermal Penetration SYN545192 EC Formulation (A17056F)

– In Vivo Dermal Absorption in the Rat (2011, MRID 48604460)

F ormulation at 0.001, 0.01 and 1.5 mg/cm 2

Acceptable

- Guideline At doses of 0.001, 0.01 and 1.5 mg/cm 2 , the d ermal absorpt ion results at 24 hours of 19.59%, 6.8% and

8.92 %, respectively. At 72 hours were 13.11%, 12.54%

and 17.43 % at the three dose levels, respectively. At 120 hours were 16.77%, 6.95% and 12.49 % at the three dose levels, respectively.

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### Page 56 of 82 Guideline [OCSPP] Study Title Results

Special Study

In Vitro Dermal

Penetratio n SYN545192 EC (A15457B)

– In Vitro Absorption through Human Epidermis using [14C

- Radiolabelled]

- SYN545192 (2013, MRID 48932601)

SYN545192 EC (A15457B)

– In Vitro Absorption through Rat Epidermis using [14C

- Radiolabelled]

- SYN545192 (2013, MRID 48932602)

0.1, 1.0, 100 g/L formulation concentrations equivalent to 0.001, 0.01 and 1.5 mg/cm 2 The mean in vitro dermal absorption in the young male rat skin was 12.0% for the high dose, 28.6% for the

medium dose and 56.5% for the low dose. The mean in

vitro total absorbed dose for el derly female human skin was 0.47% for the high dose, 0.56% for the medium

dose and 2.7 7% for the low dose. Tape stripping was not performed for the rat epidermis samples.

870.7800

Immunotoxicity 28

- Day Dietary Immunotoxicity Stu dy in

CD

- 1 Female Mice (2012, MRID 48604461 )

0, 100, 200, and 400 ppm: 26.4, 47.1, and 97.1 mg/kg/day

Acceptable/Guideline Systemic Toxicity and Immunotoxicity

NOAEL: 97.1 mg/kg/day

LOAEL: Not achieved based on the AFC assay or other parameters monitored for systemic toxicity

Special Study 14

- Day dietary thyroid mode of action study in rats with a 63

- day recovery period (2012, MRID 48604553)

0, 100, 600, 1200 ppm Treatment with 600 ppm S YN545192 resulted in decreased body weight gains, decreased food consumption, increased liver weight (day 15), increased incidence of centrilobular hepatocyte hypertrophy,

decreased serum T 3 , increased TSH, increased hepatic UDPGT activity and increased hepatic microsomal protein content. Treatment with 1200 ppm SYN545192 resulted in increased liver weight, increased incidence of centrilobular hepatocyte hypertrophy, increased hepatic UDPGT activity, increased hepatic microsomal protein content, decreased serum T 3 , decreased serum T 4 , increased serum TSH, increased thyroid weight and increased thyroid follicular cell proliferation by BrdU incorporation. All of these effects were fully reversed

after a 63

- day recovery period following 14 days of

treatment. The 1200 ppm phenobarbital sodium salt positive control had the expected responses. Special Study Effect on Hepatic UDP Glucuronosyltransferase activity towards thyroxine as substrate after dietary administration for up to 28 days to male

rats. (2012, M RID 48604554)

0, 100, 750, 1500 ppm At doses of 750 ppm and greater, benzovindiflupyr is an inducer of hepatic microsomal UDP glucuronosyltransferase activity towards thyroxine as

substrate in male rats.

Special Study Effect on rat thyroid peroxidase activity in

vitro.

MRID 48604555

0.01, 0.1, 1 and 10 μM SYN545192 is not an inhibitor of rat thyroid peroxidase activity in vitro

.

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### Page 57 of 82 Guideline [OCSPP] Study Title Results

Special Study A histological extension study of male thyroid tissue from rat toxicity study (2012, MRID 48604556)

0, 100, 750, 1500 ppm SYN545192 resulted in minimal follicular cell hypertrophy at 1500 ppm over 8, 15 and 29 days and at 750 ppm over 29 days of administ ration.

Special Study Complex II (Succinate Dehydrogenase) Assay in Mammalian Mitochondria of Benzovindiflupyr and its Metabolite

SYN508272 (2014, MRID 49282502) Benzovindiflupyr potently inhibited mammalian mitochondrial succinate dehydrogenase with an IC 50 value of 35.3 +/

- 2.0 nM

The benzovindiflupyr metabolite SYN508272 was effectively inactive with an IC 50 value >286 μM Special Study Complex II (Succinate Dehydrogenase) Assay in Mammalian Mitochondria of Benzovindiflupyr and its Metabolite

NOA4494 10 (2014, MRID 49282503) Benzovindiflupyr potently inhibited mammalian mitochondrial succinate dehydrogenase with an IC 50 value of 35.3 +/

- 2.0 nM

The benzovindiflupyr metabolite NOA449410 was effectively inactive with an IC 50 value >284 μM



### A.2 Benzovindiflupyr Toxicity Comparison with Metabolites

Parameter Benzovindiflupyr SYN545720

CSCD465008

M700F002

Sedaxane, Benzovindiflupyr, Isopyrazam, Fluxapyroxad SYN508272

CSCC210616

BASF M700F007 BASF Reg 5621781

Benzovindiflupyr, Sedaxane,

Flux apyroxad NOA449410

CSAA798670 CA4312 (intermediate)

BASF M700F001 BASF Reg 5069089

Sedaxane, Benzovindiflupyr, Fluxapyroxad

Structure

Mitochondrial

Succinate Dehydrogenase

Inhibition IC 50 2.2 nM in Fungi

MRID 49282501

35.2 nM in Beef Heart

MRID 49282502

MRID 49282503 >567 μM in Fungi

MRID 48836603

NA in Beef Heart NA in Fungi

>286 μM in Beef Heart

MRID 49282502 >568 μM in Fungi

MRID 48836603

>284 μM in Beef Heart

MRID 49282503

Acute Oral

LD 50 66 mg/kg

MRID 48604427 (ACN LOAEL: 80/30 mg/kg (M/F), no deaths) >2000 mg/kg

MRID 47473366 >500 and <2000 mg/kg >2000 mg/kg

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### Page 58 of 82 Bacterial

Reverse

Mutation Assay Negative

MRID 48604442 Negative

MRID 47746852 NA Negative

MRID 47473401

In vitro Cytogenetics,

Chromosome

Aberration

Test Negative

MRID 48604443 Negative

MRID 47746860 NA Negative

MRID 47923610

Mammalian

Cell Gene

Mutation Negative

MRID 48604444 Negative

MRID 47746856 NA Negative

MRID 47923611

Rat 28

- Day Dietary Study NOAEL: 36 mg/kg/day

(M/F)

LOAEL: 99 mg/kg/day (M/F), based on decreased body weight, BWG, hypoglycemia, and decreased serum potassium

levels

MRID 48604433 NOAEL =497/1107 mg/kg/day (M/F)

LOAEL =1018/ND mg/kg/day (M/F) decreased kidney weights

MRID 47746827 NA NOAEL >1007/1043 mg/kg/day (M/F)

MRID 48836614

Rat 90

- Day Dietary Study NOAEL: 7.6 mg/kg/day

(M), 8.2 mg/kg/day (F)

LOAEL: 53.8 mg/kg/day (M), 58.8 mg/kg/day (F), based on reduction in body weight, body weight gain, food consumption and food

utilization . Decrease in core body temperature and glucose in females. Increased liver weight in females and hepatic centrilobular hypertrophy of

the liver and increased urea

in males

MRID 48604436 NOAEL >958.4/928.7 mg/kg/day (M/F)

MRID 47923616 NA NOAEL > 953.6/983.1 mg/kg/day (M/F)

MRID 47923608

Rabbit Developmental Study Maternal

NOAEL = 35 mg/kg/day

LOAEL = None 1

Fetal

NOAEL =35 mg/kg/day

LOAEL = None

MRID 48604453 Maternal

NOAEL =300 mg/kg/day

LOAEL =1000 mg/kg/day

increased abortions and mortality

Fetal

NOAEL >1000 mg/kg/day

MRID 47923622 NA Maternal

NOAEL =250 mg/kg/day

LOAEL =NA

Fetal

NOAEL =250 mg/kg/day

LOAEL =NA

Doses at 500

- 1000 mg/kg/day not well tolerated (deaths, abortions, BW)

MRID 47923613

1 In a range finding developmental toxicity study in rabbits (Sawhney Coder, 2011a), severe body weight loss and reduced food consumption at 100 mg/kg/day resulted in early termination of all animals. Excessive body weight loss and reduced food consumption also led to abortion and moribundity in som e animals at 50 mg/kg/day.

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### Page 59 of 82 A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD)

– All Populations

Study Selected: Acute Neurotoxicity Study in Rats

MRID No: 48604455

Dose and Endpoint for Risk Assessment: NOAEL of 10 mg /kg/day established in the female rats. LOAEL: 30 mg/kg (F), based on multiple clinical observations ( reduced activity, swaying gait, collapse, muscle twitching, and ruffled fur ) , decreases in mean body temperature, decreases in locomotor activity parameters, and/or decreases in mean grip strength.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability

, 1x FQPA Safety Factor )

.

Comments: The effects observed in the acute neurotoxicity study were observed after a single oral exposure and

, therefore

, are appropriate for the acute dietary scenario for the general population. However, there also were clinical signs in dams, including ataxia, decr eased activity, hunched posture, ruffled fur, which were observed at a comparable dose in the rat developmental study (LOAEL of 30 mg/kg/day). These clinical signs were only observed in the adult rat and the developmental effects (i.e, decreased fetal weig ht and delayed ossification) observed were not attributable to a single exposure. Therefore, the NOAEL from the acute neurotoxicity study is protective of the effects observed in the rat developmental study and a female specific (13

- 49

y ears old ) acute die tary assessment is not warranted.

a RfD = a PAD = 10 mg/kg/day = 0. 1 mg/kg/day

100

A.3.2 Chronic Reference Dose (cRfD)

– All Populations

Study Selected: Two

- Generation Reproduction Toxicity Study in Rats

MRID No: 48604449

Dose and Endpoint for Risk Assessment: Parental NOAEL = 8.2 mg/kg/day (F) LOAEL = 19.4 mg/kg/day (F) based on decreased body weight and decreased food consumption.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability

, 1x FQPA Safety Factor )

.

Co mments: The endpoint selected is appropriate for both the duration and the population of

concern. This POD is also supported by findings from the combined chronic toxicity/carcinogenicity study in rats and the carcinogenicity study in mice. The range of do ses tested in these studies (2.0 to 40.5 mg/kg/day ) are comparable to the 2

- generation reproduction

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### Page 60 of 82 NOAELs/LOAELs. Due to dose

- spread selection across the chronic toxicity studies, the NOAEL of 8.2 mg/kg/day from the 2

- generation reproduction study is prot ective of the suite of effects seen in these studies including the decreases in body weight, food consumption, clinical signs, and the histopathological changes seen in the kidneys, thyroid and mammary glands in rats, and the hyperplasia of the colon/caecu m seen in mice (LOAELs 27

- 30 mg/kg/day) . The lower NOAEL of 4.88 mg/kg/day established for male rats in the combined chronic toxicity/carcinogenicity study is an artifact of dose selection since the NOAEL for adult males in

the two

- generation reproductive toxicity in rats was 6.8 mg/kg/day (comparable to the female

NOAEL in the combined chronic toxicity/carcinogenicity study ). Furthermore, the LOAELs for

adult males and females in the in the combined chronic toxicity/carcinogenicity study in rats are

compar able ( 30.17 and 27.44 mg/kg/day, respectively). In the two

- generation reproductive toxicity in rats a higher NOAEL was identified in female rats (8.2 mg/kg/day) even though the LOAEL for females is lower than for males (19.4 mg/kg/day and 40.5 mg/kg/day, respectively). Thus, selecting the higher NOAEL (8.2 mg/kg/day) is protective of the effects seen in all the chronic toxicity studies in the benzovindiflupyr database.

cRfD = cPAD = 8.2 mg/kg/day = 0.0 8 mg/kg/day

100

A.3.3 Incidental Oral

– All Durations

Study Selected: Two

- Generation Reproduction Toxicity Study in Rats

MRID No: 48604449

Dose and Endpoint for Risk Assessment: Offspring/Parental NOAEL = 8.2 mg/kg/day (F) LOAEL = 19.4 mg/kg/day (F) based on decreased body weight and decreased food consumption in parental animals as well as increases in liver weights, centrilobular hepatocellular hypertrophy

, increased incidence of cell hypertrophy in the pars distalis of the pituitary , reduced body weight, delayed preputial separation, and decr eased spleen weights in the F1 and/or F2 offspring

.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor).

Comments : Since juvenile animals were not more sensitive than the adult animals in the tw o

generation reproduction study, the short

- term incidental oral POD is based on the Parental/Offspring NOAEL of 8.2 mg/kg/day with the lowest LOAEL of 19.4 mg/kg/day established for female rats in the reproduction study. This endpoint is appropriate for th e population of concern (infants and children). The POD would also address the decreases in body weight, body weight gain and food consumption observed in the 90

- day rat study at the identical NOAEL of 8.2 mg/kg/day in adult females, as well as the liver weight changes and histopathological lesions of the liver were seen in the adult rats in the 90

- day rat study and in the F1 offspring at termination in the two

- generation reproduction study, as well as the body weight

decreases in the 90

- day mouse study (a dults).

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### Page 61 of 82 A.3.4 Dermal

--- All Durations

A dermal POD and endpoint of concern is not recommended and quantification of dermal risk is not required since no systemic or dermal toxicity was seen following repeated dermal applications of benzovindiflupyr at t he Limit Dose (1000 mg/kg/day) to rats for 28 days (MRID 48604441) . Additionally, there is no evidence for a quantitative susceptibility in the young and

no concerns for reproductive, neuro toxicity , or immunotoxicity . T herefore

, the parameters

evaluated in the repeat dermal toxicity study are reflective of potential dermal toxicity.

A.3.5 Inhalation

– Short and Intermediate Terms

Study Selected: Two

- Generation Reproduction Toxicity Study in Rats

MRID No: 48604449

Dose and Endpoint for Risk Assessment: P arental NOAEL = 8.2 mg/kg/day (F) LOAEL = 19.4 mg/kg/day (F) based on decreased body weight and decreased food consumption.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA Safety Factor).

Comments: An inhalation toxicity study with benzovindiflupyr is not available. Therefore, an oral study was selected for the inhalation endpoint. This study is appropriate for both short and intermediate term since the toxicity database does not suggest progression of toxicity over time.

The short

- and intermediate

- term inhalation POD is based on the NOAEL of 8.2 mg/kg/day with the lowest LOAEL of 19.4 mg/kg/day established for female rats in the reproduction study. The

POD would be protective of the decreases in body weight, body weight gain and food consumption observed in the 90

- day rat study at the identical NOAEL of 8.2 mg/kg/day in females, as well as the liver weight changes and histopathological lesions of the liver were seen

in the adult rats in the 90

- day study and in the F1 offspring at termination in the two

- generation reproduction study, as well as the body weight decreases in the 90

- day mouse study.

A.4 Executive Summaries

A.4.1 Sub

- chronic Toxicity

870.3050 28

- Day Oral Toxici ty

– Rat

In a sub

- chronic toxicity study ( MRID 48604433), each of five male and five female Wistar HanTM:HsdRccHanTM: WIST strain rats, for twenty

- eight consecutive days, at dietary concentrations of 100, 400 and 1200 ppm (equivalent to a mean achieved dosage of 9, 36 and 99 mg/kg/day).

The study NOAEL is 36 mg/kg/day in both genders, based on a LOAEL of 99 mg/kg/day in both genders, based on decreased body weight, BWG, hypoglycemia, and decreased serum potassium

levels

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### Page 62 of 82 This sub

- chronic toxicity study in the rat is acceptable and satisfies the guideline requirement for

a sub

- chronic oral study (OPPTS 870.3050) in rats.

870.3050 28

- Day Oral Toxicity

– Mouse

In a sub

- chronic toxicity study ( MRID 48604435 ), groups of 5 male and 5 female CD

- 1 mice

w ere fed diets containing 0, 100, 300 or 500 ppm SYN545192 for a period of at least 28 days ( 0, 15.6, 47.4 and 81.8 mg for males and 0, 19.0, 57.9 and 91.5 mg/kg/day for females) . Additional satellite groups of 7 control male and 7 female animals, and 15 ma le and 15 female animals at all other dose levels, were incorporated onto the study for toxicokinetic sampling and analysis.

The study NOAEL is 15.6 mg/kg/day in males and 19.0 mg/kg/day in females with a LOAEL of 47.4 mg/kg/day in males and 57.9 mg/kg/d ay in females, based on decreased body weight and lower body weight gain. Tubulointerstitial nephritis was observed in the kidneys in both sexes at 81.8 mg/kg/day in males and 91.5 mg/kg/day in females.

This sub

- chronic toxicity study in the rat is acce ptable/non

- guideline and satisfies the requirement for a sub

- chronic oral study (OPPTS 870.3050) in rats.

870.3100 90

- Day Oral Toxicity

– Rat

In a sub

- chronic toxicity study (MRID # 48604436 )

, SYN545192 was administered to Han

Wistar 10 rats/sex/dose in the diet at dose levels of 0, 100, 750 or 1500 ppm for 90 days ( 0, 7.6, 53.8 and 108.7 mg/kg/day for males and 0, 8.2, 58.8 and 108.8 mg/kg/day for females)

.

The NOAEL was 7.6 mg/kg/day in males and 8.2 mg/kg/day in females. The LOAEL was 53.8 mg/kg/day i n males and 58.8 mg/kg/day in females, based on reduction in body weight, body weight gain, food consumption and food utilization; decrease in core body temperature and glucose in females, with increased liver weight in females and hepatic centrilobular hy pertrophy

of the liver and increased urea in males

This sub

- chronic toxicity study in the rat is acceptable and satisfies the guideline requirement for

a sub

- chronic oral study (OPPTS 870.3100; OECD 408) in rats.

870.3100 90

- Day Oral Toxicity

– Mouse

In a sub

- chronic toxicity study (MRID# 48604437 ) , benzovindiflupyr was administered to 10

CD

- 1 mice/sex/dose in diet at dose levels of 0, 100, 300 or 500 ppm for 90 days ( 0, 17.0, 55.6 and 97.9 mg/kg/day for males and 0, 20.9, 59.6 and 102.8 mg/kg/day fo r females) . Additional satellite groups of 4 male and 4 female animals were incorporated onto the study for toxicokinetic sampling and analysis.

The study NOAEL was 17.6 mg/kg/day in males and 20.9 mg/kg/day with a LOAEL of 55.6 mg/kg/day in males and 59. 6 mg/kg/day in females based on initial body weight loss for up to 7

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### Page 63 of 82 days which led to 2 males from the high dose satellite group being terminated in extremis. Group mean body weights lower during the initial phases of the study returning to control value s thereafter, clinical chemistry changes, higher incidence of soft feces in males from day 31 onward. In males decreased triglycerides and distended large intestine in one animal of each sex.

This sub

- chronic toxicity study in the mouse is acceptable and satisfies the guideline requirement

for a sub

- chronic oral study (OPPTS 870.3100; OECD 408) in mice.

870.3150 90

- Day Oral Toxicity

– Dog

In a 13

- week dog study ( MRID # 48604439 )

, SYN545192 was administered to 32 Beagle dogs, assigned to 4 groups each containing 4 males and 4 females. They were treated daily orally by capsule at dose levels of 0 (control group 1) or 30, 375 or 750 mg/kg (groups 2, 3 and 4, respectively).

The study NOAEL was 30 mg/kg/day in both genders with a LOAEL of 375 mg/kg/day in both genders based on feces containing mucus or yellow stained feces, initial slight body weight loss during the first week of treatment, reduced body weight gain in males, reduced food intake during the first two weeks of the study and decreased plasma c alcium values were observed in

males.

This study in dogs is acceptable and satisfies the guideline requirement for a 90

- day oral toxicity study in dogs (OPPTS 870.3150; OECD 409).

870.3200 21/28

- Day Dermal Toxicity

– Rat

In a repeat

- dose dermal toxic ity study (MRID# 48604441 

### ), SYN545192 was administered by bandage to the skin once daily at doses of 100, 300 and 1000 mg/kg/day to 10 per gender per

group for a period of 28 days . The control group received the bandage with vehicle (aqueous 0.5% CMC) only

.

There were no treatment

- related effects on mortality, body weight, food consumption, clinical signs of toxicity, FOB parameters, ophthalmology, hematology, clinical chemistry, organ weights or gross and histologic pathology.

The LOAEL was not established in either males or females. The NOAEL is 1000 mg/kg bw/day for both genders.

This dermal toxicity study in the rat is acceptable and satisfies the guideline requirement for a

repeat

- dose dermal toxicity study (OPPTS 870.3250 rat); OECD 410 in the rat.

870.3465 90

- Day Inhalation

– Rat

Due to the inhalation MOEs of 900 to 10,000,000, a 90

- day inhalation study is not required.

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### Page 64 of 82 A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity

- Rat

In this prenatal developmental toxicity study (MRID 48604451), the benzovindiflupyr doses of 7.5, 15, and 30 mg/kg body weight/day were administered orally, by gavage, to pregnant Han Wistar rats from day 6 to 20 post coitum (24/group).

The dose level of 30 mg/kg body weight/day produced obvious maternal toxicity. Clinical signs of decreased activity, hunched posture, ataxia and ruffled fur were noted during the treatment period. Food consumption, body weight and corrected body weight gains were statistica lly significantly reduced. Fetal weights were also statistically significantly reduced in this dose group and at skeletal examination a slight delay in ossification was observed. No test item

related findings were found during the study in the 7.5 and 15 m g/kg body weight/ day dose

groups.

The NOAEL (No

- Observed

- Adverse Effect

- Level) for maternal effects was 15 mg/kg body weight/day, based on clinical signs (ataxia, decreased activity, hunched posture, ruffled fur) at the maternal LOAEL (Lowest Observed Ad verse Effect Level) of 30 mg/kg/day. The NOAEL for developmental toxicity was 15 mg/kg body weight/day based on decreased fetal weight and ossification at the developmental LOAEL of 30 mg/kg body weight/day. No biologically significant morphological altera tions, including teratogenicity, were observed in this study.

The developmental toxicity study in the rat is classified acceptable/guideline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700; OECD 414) in rats.

870.3700b Prenatal Developmental Toxicity

- Rabbit

The test substance, SYN545192, in the vehicle, 0.5% (w/v) aqueous medium viscosity carboxymethylcellulose (CMC), was administered orally by gavage to three groups of 25 time

mated female New Zealand White [Hra:(NZW)SPF] rabbits once daily from gestation days 7 through 28 (MRID 48604453) . Dose levels were 10, 20, and 35 mg/kg/day administered at a dose volume of 10 mL/kg. A concurrent control group composed of 25 time

- mated females received the vehicle (0.5 % medium viscosity CMC) on a comparable regimen. The females were approximately 6 months of age at the initiation of dose administration. All animals were observed twice daily for mortality and moribundity. Clinical observations, body weights, and

food con sumption were recorded at appropriate intervals. On gestation day 29, a laparohysterectomy was performed on each female. The uteri, placentae, and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations, and corpo ra lutea were recorded. Gravid uterine weights were recorded, and net body weights and net body weight changes were calculated. In addition, the livers from all females examined at the scheduled necropsy were weighed. The fetuses were weighed, sexed, and e xamined for external, visceral, and skeletal malformations and developmental variations.

All females survived to the scheduled necropsy on gestation day 29. There were no test

substance

- related clinical or macroscopic findings for females at any dose leve l with statistical

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### Page 65 of 82 significance and/or dose response. There were no test substance

- related effects on mean maternal body weights, net body weights, net body weight losses, gravid uterine weights, or food consumption at any dose level with statistical signi ficance and/or dose response. Marginal effects on maternal body weight gain at 20 and 35 mg/kg/day during gestation days 13

- 20 were

considered to be non

- adverse. Mean maternal absolute liver weights and liver weights adjusted for net body weight were unaff ected by test substance administration at all dose levels. Intrauterine growth and survival and fetal morphology were unaffected by test substance

administration at all dose levels.

Based on the lack of maternal and embryo/fetal developmental toxicity wit h statistical significance and/or dose responsiveness, the NOAEL (no

- observed adverse

- effect level) for both maternal toxicity and embryo/fetal developmental toxicity was 35 mg/kg/day (the highest dose level evaluated) when SYN545192 was administered oral ly by gavage to pregnant New Zealand White rabbits. A study LOAEL (lowest

- observed adverse

- effect level) was not established. However, the rabbit developmental range

- finding study did demonstrate adverse effects at 50 mg/kg/day (decreased maternal body w eight gain was observed throughout the majority of gestation, 2 of 10 animals were euthanized due to excessive weight loss, and a third animal aborted late in gestation).

This study is acceptable/non

- guideline and satisfies the requirement for a developme ntal study in

non

- rodents (OPPTS 870.3700; OECD 414) in rats.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

– Rat Study

Four groups of HanRcc:WIST(SPF) rats (P generation) received the test article, SYN545192, in

the diet for 10 weeks and were then paired (one male with one female) for mating ( MRID 48604449) . The F1 generation animals were selected from the weaned F1 litters. The F1 parents were maintained on test diets for at least 90 days and then were paired for mating. The F2 offspring were sacrificed at weaning. Each group consisted of 25 male and 25 female rats. SYN545192 was administered orally, by ingestion, continuously throughout the study at dietary

levels:

0, 25, 100, 600 ppm in Males

Parental: 0, 1.7, 6.8, 40.5 mg/kg/day;

F1: 0, 1.9, 7.8, 48.0 mg/kg/day

0, 25, 100, 250 ppm in Females

Parental: 0, 2.0, 8.2, 19.4 mg/kg/day;

F1: 0, 2.1, 8.7, 22.0 mg/kg/day

All dams and remaining pups were sacrificed on day 21 p.p. (post

- partum) and males wer e sacrificed when they were no longer needed for reproduction.

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### Page 66 of 82 The parental NOAEL (No Observed Adverse Effect Level) was 100 ppm (equivalent to 6.8 mg/kg/day for P generation males and 8.2 mg/kg/day during pre

- pairing). The parental LOAEL is 600 ppm in m ales (40.5 mg/kg/day) and 250 ppm in females (19.4 mg/kg/day) due to decreased body weight, decreased body weight gain , the liver weight adjusted for body weight

was increased and decreased food consumption.

The offspring NOAEL for general toxic effects was 100 ppm (equivalent to 7.8 mg/kg/day for F1 generation males and 8.7 mg/kg/day during pre

- pairing). The offspring LOAEL is 600 ppm or 48.0 mg/kg/day for males and 250 ppm or 22.0 mg/kg/day for females. In males

, decreased body weight, centrilobular hep atocellular hypertrophy in both generations and increased incidence of cell hypertrophy in the pars distalis of the pituitary in the F1 generation. In females, reduced body weight in both generations. In F1 male pups, the weight of the spleen adjusted for the body weight was statistically significantly reduced. The time until preputial separation in F1 male pups

was increased.

The NOAEL for reproduction was 600 ppm in males or 40.5 mg/kg/day for P generation males during pre

- pairing and 250 ppm or 19.4 mg/ kg/day in females. The LOAEL for reproduction in both genders was not determined, since the NOAEL was the HDT.

This study is acceptable/guideline and satisfies the guideline requirement for a 2

- generation reproductive study (OPPTS 870.3800; OECD 416) in r ats.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity

– Rat

– See A.4.5

870.4100b Chronic Toxicity

– Dog

In a 52

- week dog study ( MRID # 48604440 )

, SYN545192 was administered to 32 Beagle dogs, assigned to 4 groups each containing 4 males and 4 females. They were treated daily orally by capsule at dose levels of 0 (control group 1) or 25, 250 or 500 mg/kg (groups 2, 3 and 4, respectively).

The study NOAEL was 25 mg/kg/day in both genders and the LOAEL was 250 mg/kg/day based

on reduced bod y weight, body weight gain in males and females; salivation, vomiting of feed, fluid, capsule or mucus as well as feces containing mucus in both sexes

This study is classified as acceptable/guideline and satisfies the guideline requirements for a

chronic toxicity study (non

- rodent).

A.4.5 Carcinogenicity

870.4200a Carcinogenicity/Chronic Study

– Rat

In a combined chronic toxicity and carcinogenicity study with SYN545192 (purity 97.0%, MRID

48604446 ), four groups of Han Wistar rats/sex were assigned to the carcinogenicity study and

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### Page 67 of 82 fed diets containing 0, 25, 100 or 600 ppm (males), 400 ppm (females) SYN545192 for at least 104 consecutive weeks. In addition, a chronic toxicity study (comprising a further 4 groups of 12 rats/sex) was included and dosed in an identical fashion for a period of 52 consecutive weeks.

Clinical observations, body weight, food consumption, hematology, coagulation, clinical chemistry, organ weights, gross necropsy and histopathology were assessed in all groups. Urinalysis and oph thalmoscopy were assessed in the carcinogenicity groups only. A detailed functional observation battery assessment was made in the toxicity groups only. All surviving carcinogenicity and toxicity study animals were terminated after the completion of 104 or 52 weeks of treatment respectively and underwent a detailed necropsy examination with a comprehensive histopathological evaluation.

Body weight and body weight gains were decreased throughout treatment at 600/400 ppm in males and females, respectively. Food consumption was decreased throughout treatment at

400 ppm in females and sporadically in males at 600 ppm. Food utilization was decreased in both sexes at 600/400 ppm. In the clinical and detailed function observations, there was a slight

increase in animals exhibiting no reaction to the tactile stimulus at 600/400 ppm and females at 400 ppm exhibited a slower tail flick response and were found to exhibit hunched/held low body posture, piloerection, staining on fur, thin appearance and rolling gait.

Changes to the liver occurred at 600 ppm in males and 400 ppm in females. Relative liver weights were increased in males following 104 weeks of treatment. In the toxicity phase, males and females exhibited centrilobular hypertrophy and females exhibited centrilobular hepatocyte pigmentation. In the carcinogenicity phase, males and females exhibited centrilobular hypertrophy, males exhibited pale foci grossly and eosinophilic cell foci and hepatocyte vacuolation histopathologically, and females exhibited an increase in hepatocyte centrilobular pigment.

Other microscopic changes were seen in 400 ppm females following 104 weeks of treatment and

consisted of increased tubular cell pigment deposits in the kidneys, focal c

- cell hyperplasia of the thyroid, lob ular hyperplasia of the mammary glands and pigmented macrophages in the spleen. Neoplastic changes consisted of an increase in thyroid follicular cell adenomas in 600 ppm

males.

The LOAEL is 600/400 ppm (30.17/27.44 mg/kg bw per day) in males and females respectively, based on decreased body weights, body weight gains, food consumption, food utilization, lack of response to tactile stimulus and liver changes in males and females, thyroid follicular cell adenomas in males and hunched or held low body posit ion, piloerection, staining on fur and thin appearance, slow reaction to tail flick and rolling gait, increased tubular cell pigment deposits in the kidneys, focal c

- cell hyperplasia of the thyroid, lobular hyperplasia of the mammary glands and pigmented m acrophages in the spleen in females. The NOAEL is 100 ppm (4.88/6.66 mg/kg bw per day) in males and females respectively.

This carcinogenicity study in the mouse is acceptable and satisfies the guideline requirement for a carcinogenicity study (OPPTS 87 0.4200) in rats.

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### Page 68 of 82 870.4200b Carcinogenicity (Feeding)

– Mouse

In a carcinogenicity study with SYN545192 (purity 97%, MRID 48604448 ), four groups of 50

CD

- 1 mice/sex/group were fed diets containing 0, 20, 60 or 200 ppm SYN545192 for at least 80

consecuti ve weeks.

The animals were monitored regularly for viability and for signs of ill health or reaction to treatment. Body weights and food consumption were measured and recorded at pre

- determined intervals from pre

- trial up until the completion of treatment . Blood samples for haematology were also collected from all surviving animals prior to terminal kill at week 80. Blood films were made from all surviving animals during week 52/53.

All surviving animals were terminated after the completion of 80 weeks of treatment and underwent a detailed necropsy examination with a comprehensive histological evaluation. There were no adverse effects on survival, body weight, body weight gain, food or water consumption, haematology, organ weights or gross pathology.

Fem ales dosed at 200 ppm exhibited increased incidences of piloerection and rolling gait. Males and females at 200 ppm exhibited increased mucosal hyperplasia of the colon and caecum. This study did not reach the maximum tolerated dose (MTD.)

The LOAEL was 200 ppm (26.18 mg/kg bw per day in males and 29.26 mg/kg bw per day in females) based on hyperplasia of the colon and caecum in males and females and piloerection and rolling gait in females. The NOAEL was 60 ppm (7.55 mg/kg bw per day in males and 8.67

m g/kg bw per day in females).

This carcinogenicity study in the mouse is acceptable and satisfies the guideline requirement for a carcinogenicity study (OPPTS 870.4200; OECD 451) in mice.

A.4.6 Mutagenicity

Benzovindiflupyr was negative in the mutagenicity studies.

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### Page 69 of 82 Study Dose Levels Result

In vitro studies

870.5100
Salmonella Typhimurium and E. Coli Reverse Mutation Assay

(2011, MRID 48604442 ) 0, 3, 10, 33, 100, 333, 1000, 2500 and 5000 μg/plate

Acceptable

- Guideline Negative

No substantial increase in revertant colony numbers of any of the

six tester strains was observed at any dose level, neither in the presence nor absence

of metabolic activation

870.5300
Cell Mutation Assay at the Thymidine Kinase Locus (TK +/

- ) in Mouse Lymp homa L5178Y

Cells

(2010, MRID 48604444 ) Experiment I

- without S9 mix: 2.5; 5.0; 10.0; 15.0; and 20.0 μg/mL & with S9 mix: 5.0; 10.0; 20.0; 30.0; and 40.0 μg/mL Experiment II

- without S9 mix: 5.0; 10.0; 20.0; and 30.0 μg/mL & with S9 mix: 10.0; 20.0; 30.0; 40.0; and 50.0 μg/mL
Experiment III

- without S9 mix: 2.5; 5.0; 10.0; 20.0; and 30.0 μg/mL

Acceptable

- Guideline Negative

Did not induce

mutations with and

without metabolic

activation under the

conditions used.

870.5375

Chromosome Aberration Test in Human Lymphocytes In Vitro

(2010, MRID 48604443 ) Experiment I

- with & without S9 mix: 3.1, 5.5, 9.6, 16.9, 29.5, 51.7, 90.5, 158.3, 277.1, 484.9, 848.6, 1485.0 μg/mL
Experiment II

- without S9 mix 0.06, 0.11, 0.19, 0.34, 0.60 , 1.04, 1.83, 3.2, 5.6, 9.8, 17.14, 30.0 μg/mL & with S9 mix: 1.3, 2.5, 5.0, 7.5, 10.0, 15.0, 20.0, 30.0 μg/mL

Acceptable

- Guideline Negative

Considered to be non

clastogenic in this

chromosome

aberration test in the absence and presence

of metabolic activation when tested up to cytotoxic

concentrations.

In vivo studies

870.5395

Micronucleus Test in Bone Marrow Cells of Wistar (Han)

Rats

(2011, MRID 48604445) 0, 43.8, 87.5, 175.0 mg/kg/day in

males
0, 75 mg/kg/day in females

Acceptable

- Guideline Negative
Benzovindiflupyr did

not induce micronuclei

in bone marrow cells

when tested to the

maximum tolerated dose of 175 mg/kg/day

in male and 75 mg/kg/day in female Wistar (Han) rats. The positive control cyclophosphamide

induced the appropriate respon se.

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### Page 70 of 82 A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study

– Hen

- NA

870.6200a Acute Neurotoxicity Screening Battery

- Rat

In an acute neurotoxicity study ( MRID# 48604455 ) , HanRcc:Wistar (SPF) rats (10 rats/sex/group) were administered single oral gavage doses of SYN545192 (97.0% purity, prepared in 0.5% aqueous carboxymethylcellulose vehicle) at dose levels of 0 (control), 10, 30 and 80 mg/kg, respectively, and observed fo r 15 days. Daily cage side observations were performed on all rats prior to study start, on day 1 (at approximately 1 hour after dose administration), and once daily thereafter. Detailed clinical observations, comprising open field

evaluation of clinical s igns, were performed in a randomized order once prior to study start, on day 1 (at approximately 5

- hours post

- dose) and on days 7 and 14. Functional observation battery (FOB) evaluations were performed once prior to study start, on day 1 (approximately 2 t o 4 hours after dose administration), and on days 7 and 14. Functional observation battery (FOB) evaluations including quantitative assessment of landing foot splay, body temperature, sensory perception and muscle weakness, locomotor activity (LMA) was ass essed over a time period of 30 minutes after each FOB evaluation. Food consumption was recorded during acclimatization and over days 1

- 2, 8

- 9, and 14

- 15. Body weights were measured during acclimatization and on days 1, 8 and 15. At the end of the sch eduled post

- dose observation period (day 15), 5 rats/sex/group were perfusion

- fixed in situ, the brain weights were measured, and selected nervous system tissues were collected, processed and examined microscopically.

Following the administration of a sin gle oral (gavage) dose of SYN545192 to Wistar rats at 10, 30 and 80 mg/kg, evidence of toxicity was limited to the 80 mg/kg males and the 30 and 80 mg/kg females. The majority of treatment

- related findings occurred post

- dose on day 1, and included multiple clinical observations, decreases in mean body temperature, decreases in locomotor activity parameters, and/or decreases in mean grip strength. Other findings noted for 80 mg/kg males and the 30 and 80 mg/kg females included lower mean food consumption ove r the first day of treatment (day 1

- 2) with corresponding reductions (slight but not statistically significant) in body weight gains over the first week of treatment (days 1

- 8). All of these

treatment

- related changes were transient. No clinical and/or behavioral signs of toxicity were evident in any of the rats after day 2, and mean overall (day 1

- 14) food consumption and body weight gain values were not affected by the treatment. At study termination no treatment

- related neurohistopathological lesion s were present. Thus, the transient treatment

- related findings noted in the 80 mg/kg males and the 30 and 80 mg/kg females were attributed to the systemic toxicity rather than to specific neurotoxic effects.

Based on these findings, the LOAEL (lowest

- obs erved adverse effect level) is 30 mg/kg for females and 80 mg/kg for males. The NOAEL (no

- observed

- adverse

- effect level) for generalized systemic toxicity was 10 mg/kg for females and 30 mg/kg for males. The NOAEL for neurotoxicity was 80 mg/kg for both ge nders.

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### Page 71 of 82 The study is classified as an acceptable/guideline study for an acute neurotoxicity study in rats (870.6200).

870.6200b Sub

- chronic Neurotoxicity Screening Battery

- Rat

In this sub

- chronic dietary neurotoxicity study (MRID # 48604457), groups of twelve male and twelve female RccHan:Wistar (SPF) rats were fed SYN545192 admixed to their diet for 13 weeks at concentrations of 0, 100, 400, and 800 ppm (males: 0, 6.31, 25.95, or 50.67 mg/kg/day) or 0, 100, 250, and 500 ppm (females: 0, 7.48, 19.17, or 37.99 mg/kg/day). General cage side observations were made for all animals prior to study start and daily throughout the study. Detailed clinical observations comprising open fiel d evaluation of clinical signs were performed in a randomized order once prior to initiation of treatment and once weekly thereafter. Functional observation batteries (FOBs) including quantitative assessments of landing foot splay, sensory perception and m uscle weakness were performed for all animals in a randomized order once prior to initiation of treatment, and in weeks 2, 5, 9 and 13. Locomotor activities were assessed after each FOB evaluation. Food consumption values were recorded weekly throughout th e study. Body weights were recorded once prior to initiation of treatment on day 1, and weekly thereafter. Ophthalmoscopic examinations were performed for all animals prior to initiation of treatment on day 2, and for the control and high

- dose animals duri ng week 13. At the end of the treatment period, 5 rats/sex/group were perfusion

- fixed in situ. The brain weights were measured and selected nervous tissues were dissected, processed and examined microscopically.

Dietary administration of SYN545192 to Wist ar rats for 13 weeks at concentrations of 0, 100, 400 and 800 ppm (males) or 0, 100, 250 and 500 ppm (females) resulted in treatment related decreases in body weight gain and/or food consumption for the 400 and 800 ppm males and the 500 ppm females. These decreases in body weight gain and food consumption are attributed to generalized system effects rather than specific neurotoxic effects. The ultimate decrease in body weights were less than 10% in both genders, thus not considered to be adverse. The decrea sed food consumption and decreased body weight gains did not have a functional adverse impact on the ultimate body weights, thus were not considered adverse.

The NOAEL values of the study are the highest doses tested, or 50.67 mg/kg/day in males and

37.99 mg/kg/day in females and the LOAEL values were not determined. There was no evidence of neurotoxicity based on the absence of treatment

- related clinical observations, ophthalmoscopic findings, FOB findings, locomotor activity changes, and/or neuropatholog ic findings (i.e., brain weights, macroscopic findings, and microscopic findings). Thus, the NOAEL for neurotoxicity is 800 ppm for males and 500 ppm for females, corresponding to 50.67 mg/kg body weight/day in males and 37.99 mg/kg body weight/day in fema les.

The study is classified as acceptable as a sub

- chronic neurotoxicity study in rats (870.6200).

870.6300 Developmental Neurotoxicity Study

- NA

-

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### Page 72 of 82 A.4.8 Metabolism

The Pharmacokinetics of [Pyrazole

- 14C]

- SYN545192 in the Rat Following Single Oral

Administration (2011, MRID 48604426 ):

Absorption was similar in male and female rats following at low and high doses (79

- 81% and 61

- 62%, respectively). During the first 4 8 hours post dose the majority of the administered radioactivity had been excreted (97% and 89% following 1 mg/kg and 90% and 86% following 40 mg/kg in males and females, respectively). At 1 mg/kg oral dosing, the Tmax in blood was at

1

- 2 hours and at 3

- 4 hours with T 1/2 

### values of 25.40 hours and 47.97 hours in females and males, respectively. At 40 mg/kg oral dosing, the whole blood Cmax values were 8.0 μM in females and 10.8 μM in males. The whole blood AUC values in females were 5.06 and 180.2 μg equiv

- h /mL at 1 mg/kg and 40 mg/kg, respectively (0

- 120 hours). The whole blood AUC values in males were 11.6 and 231.4 μg equiv

- h/mL at 1 mg/kg and 40 mg/kg, respectively (0

- 120 hours).

The Excretion and Tissue Distribution of [14C]

- SYN545192 in the Rat Followi ng Single Oral Administration (2011, MRID 48604425 ):

The highest tissue concentrations were present in the Harderian gland and liver with lower concentrations in the adrenal gland, heart, brown fat and kidney (i.e. concentrations of 56.4, 55.2, 42.5, 28.0 , 37.2 and 23.1 μM, respectively at 5 hours after a single 40 mg/kg dose in females). Skeletal muscle had a concentration of 11.6 μM. Benzovindiflupyr was extensively metabolized in rat giving rise to at least 8 types of metabolite ( e.g. desmethyl, hydroxy , dihydroxy, desmethyl hydroxy, desmethyl dihydroxy, ring

- open, glucuronide conjugate, sulfate conjugate).

Analysis of SYN545192 and Its Rat Metabolites From Dietary Studies (2011, MRID 48604434 ):

The predominant route of elimination was via the feces. In the 48 hours following dosing, 76% and 69% of the administered dose was excreted via bile following 1 mg/kg and the bile duct cannulation study indicated that significant enterohepatic recirculation occurred for the parent compound.

The study is classified as acceptable as a metabolism study in rats (870.7485).

870.7600 Dermal Absorption

– Rat

Wistar rats were administered nominal doses of 0.001, 0.01 or 1.5 mg/cm 2 

### of benzovindiflupyr in

an emulsifiable concentrate formulation (A17056F) and mo nitored up to 120 hr post

- dosing (4 males per time point per dose, MRID 48604460 ). At doses of 0.001, 0.01 and 1.5 mg/cm 2 

### , the dermal absorption results at 24 hours of 19.59%, 6.8% and 8.92%, respectively. At 72 hours were 13.11%, 12.54% and 17.43% at the three dose levels, respectively. At 120 hours were 16.77%, 6.95% and 12.49% at the three dose levels, respectively.

The study is classified as acceptable as a dermal absorption study in rats (870.7600).

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### Page 73 of 82 A.4.9 Immunotoxicity

870.7800 Immunotoxicity

The test substance, SYN545192, was offered ad libitum in the diet for 28 consecutive days to female Crl:CD1(ICR) mice at dietary concentrations of 100, 200, and 400 ppm (26.4, 47.1, and 97.1 mg/kg/day), respectively (MRID 48604461) . The concurrent control group (Group 1) and the positive control group (Group 5) were offered the basal diet on a comparable regimen to the

SYN545192

- treated groups. All mice (Groups 1

- 5) were immunized with an intravenous injection of sheep red blood cells (sRBC) on study day 24 . Mice in the positive control group (Group 5) were administered the positive control substance, cyclophosphamide (CPS), via intraperitoneal injection (50 mg/kg/day) once daily for 4 consecutive days (study days 24 through 27). Each group consisted of 10 m ice/group. All animals were euthanized on study day 28. All animals were observed twice daily for mortality and moribundity. Clinical examinations were performed once daily for all animals. Detailed physical examinations were performed approximately weekly , and on the day of the scheduled necropsy. Individual body weights and food consumption values were recorded approximately twice weekly. Complete necropsies were conducted on all animals. The liver, mesenteric lymph node, Peyer’s patches, spleen, and thym us were collected at the scheduled necropsy and the liver, spleen, and thymus were weighed. Spleens were placed in Earle’s Balanced Salt Solution (EBSS)/HEPES buffer and shipped to ImmunoTox®, Inc. After arrival at ImmunoTox®, Inc., spleen cell suspensions were prepared, spleen cell counts were performed, and the number of specific IgM antibody

- forming cells directed towards the sRBC antigen were determined to measure the humoral immune response using the splenic Antibody

- Forming Cell (AFC) assay.

All anim al survived to the scheduled necropsy. There were no SYN545192

- related macroscopic findings or effects on organ weights or food consumption. There were no significant effects on spleen cell number, and SYN545192 did not significantly suppress the humoral i mmune response when evaluated as either specific activity (AFC/10 6 

### spleen cells) or as total activity (AFC/spleen) of splenic IgM to the T

- cell dependent antigen sRBC. Test substance

- related clinical observations of soft feces were often noted in the 400 p pm group throughout the study.

Test substance

- related body weight loss was noted in the 400 ppm group on study day 3 compared to the vehicle control group; however, body weight gains were generally similar to the vehicle control group for the remainder o f the study. Due to the initial body weight loss from study day 0 to 3, body weights were 8.5% lower on study day 3 compared to the vehicle control group. This initial body weight loss resulted in lower cumulative body weight gains and/or losses

in the 400 ppm group throughout the study. Absolute body weights for this group remained slightly lower throughout the study compared to the vehicle control group, with body weights on study day 28 being 6.6% lower. For the positive control group, CPS, statistically significantly lower spleen weight, spleen cell numbers (

- 61%), specific activity (

- 100%), and total spleen activity (

- 100%) of IgM antibody

- forming cells were noted when compared to the vehicle control group. These effects on spleen weights, spleen cell n umbers, and spleen activity ( i.e.

, number of specific IgM antibody

- forming cells directed towards the sRBC antigen) were

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 74 of 82 consistent with the known immunosuppressant effects of CPS and validated the functionality of the assay.

The NOAEL (no

- observed

- adverse effect level for the AFC (humoral immune response) assay of 400 ppm (equivalent to 97.1 mg/kg of body weight/day), the highest dose level evaluated. An immunotoxicity LOAEL (lowest observed adverse effect level) was not achieved. The N OAEL for systemic toxicity was 97.1 mg/kg/day and the LOAEL was not achieved.

The immunotoxicity study in the rat is classified acceptable/guideline and satisfies the guideline requirement for a immunotoxicity study (870.7800).

A.5.0 Special Studies

SY N545192: 14 day dietary thyroid mode of action study in rats with a 63 day recovery period.

Groups of 60 male Han Wistar Crl: WI(Han) rats were assigned to the main study (MRID 48604553) and fed diets containing 100, 600 or 1200 ppm of SYN545192 for a pe riod of up to 14 consecutive days. The control group received blank diet for the same duration as the treated animals. An additional group of 60 male rats were fed diets containing phenobarbital sodium salt

at 1200 ppm to act as a positive control for the liver and thyroid parameters investigated.

A further 2 groups of 15 males were assigned to a recovery study and dosed at 0 or 1200 ppm SYN545192 for 14 consecutive days followed by a 63 day recovery period. The following were assessed at predetermined int ervals from pre

- trial until study completion for all animals: viability, clinical observations, body weights, food and water consumption. Blood samples were also collected from all animals at each scheduled euthanasia time

- point for thyroid

function testi ng. All main study animals were terminated after completion of 1, 3, 7, or 14 days of treatment ( i.e.

d ays 2, 4, 8 or 15) and all recovery study animals were terminated after a subsequent 63 day recovery period (day 78). Each animal underwent a detailed necropsy examination, and the liver and thyroid glands were weighed. The liver, thyroid glands and gross abnormalities from all animals were subjected to histological evaluation. 5

- Bromo

- 2’

- deoxyuridine (BrdU) was

administered to each animal two hours bef ore termination, and cell proliferation in the thyroid by BrdU labelling index was measured. Frozen samples of the liver from each animal were analysed for hepatic microsomal protein content and UDPglucuronosyltransferase (UDPGT) activity with thyroxine (T 4 

### ) as substrate.

Treatment with SYN545192 resulted in dose

- and/or time

- related effects on a number of parameters associated with the liver and/or thyroid. Treatment with 100 ppm SYN545192 resulted in increased hepatic UDPGT activity (using thyroxine as a substrate) on day 4 and

decreased serum T 3 

### and increased hepatic microsomal protein content on day 15 compared to control. As these changes occurred at isolated time points only, the relevance to the mode of

action is unknown.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 75 of 82 Treatment with 600 ppm SYN5 45192 resulted in decreased body weight gains, decreased food consumption, increased liver weight (day 15), increased incidence of centrilobular hepatocyte hypertrophy, decreased serum T 3 

### , increased TSH, increased hepatic UDPGT activity and increased hepat ic microsomal protein content.

Treatment with 1200 ppm SYN545192 resulted in increased liver weight, increased incidence of centrilobular hepatocyte hypertrophy, increased hepatic UDPGT activity, increased hepatic microsomal protein content, decreased ser um T 3 

### , decreased serum T 4 

### , increased serum TSH, increased thyroid weight and increased thyroid follicular cell proliferation by BrdU incorporation. All of these effects were fully reversed after a 63 day recovery period following 14 days of treatment.

Tre atment with 1200 ppm phenobarbital sodium salt resulted in increased liver weight, increased incidence of centrilobular hepatocyte hypertrophy, increased hepatic UDPGT activity towards thyroxine as a substrate, increased hepatic microsomal protein content ,decreased serum T 3 

### , decreased serum T 4 

### , increased serum TSH, increased thyroid weight, increased thyroid follicular cell hypertrophy and increased thyroid follicular cell proliferation by BrdU incorporation.

This study has demonstrated that dietary treat ment of male rats with SYN545192 results in increased hepatic UDPGT activity, hepatocellular centrilobular hypertrophy, increased liver weight, decreased serum T 3 

### and T 4 

### , and increased serum TSH associated with increased thyroid follicular cell replicative DNA synthesis and thyroid weight. These effects can be used as part of a weight

- of

- the

- evidence approach to explain the mode of action for the increased incidence of thyroid follicular cell adenomas observed in male Han Wistar rats in a 2 year carcinogeni city study ( Charles River Study No. 459580 ).

SYN545192: Effect on Hepatic UDPglucuronosyltransferase activity towards thyroxine as substrate after dietary administration for up to 28 days to male rats.

In a special study (MRID 48604554), m ale rats were given diets containing 0 (control), 100, 750 and 1500 ppm SYN545192 for periods of 3, 7, 14 and 28 days. In addition, the effect of treatment of male rats with 0 (control) and 1200 ppm phenobarbital for 7 days on hepatic

microsomal UDP glucuronosyltransfer ase activity towards thyroxine as substrate was also determined. Phenobarbital is a known inducer of hepatic cytochrome P450 (CYP) forms in the

rat and is also known to induce microsomal UDP glucuronosyltransferase activity towards thyroxine as substrate a nd was therefore used as a positive control in this study. Liver microsomes from control, SYN545192

- and phenobarbital

- treated rats were assayed for protein content and UDPglucuronosyltransferase activity towards thyroxine as substrate. Enzyme activity was expressed as specific activity (i.e. per unit of microsomal protein), per gram of liver, per total liver and per relative liver weight.

There were no effects on hepatic microsomal protein content or UDP glucuronosyltransferase activity towards thyroxine as substrate at 100 ppm. Effects on hepatic microsomal protein content only occurred after 7 days of treatment at doses ≥ 750 ppm. UDPglucuronosyltransferase activity towards thyroxine as substrate was i ncreased as expressed as specific activity, per gram of liver, per total liver and per relative liver weight after 7 and 28

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 76 of 82 days of treatment at doses ≥ 750 ppm. After 3 days of treatment, UDPglucuronosyltransferase activity towards thyroxine as substrate was increased as expressed as specific activity, per total liver and per relative liver weight at doses ≥750 ppm. After 14 days of treatment, UDPglucuronosyltransferase activity towards thyroxine as substrate was increased as expressed per relative liver w eight only at 1500 ppm.

The treatment of male rats with 1200 ppm phenobarbital for 7 days significantly increased hepatic microsomal protein content confirming the responsiveness of the test system towards this positive control. In the phenobarbital

- trea ted animals, hepatic microsomal UDPglucuronosyltransferase activity towards thyroxine as substrate expressed as specific activity, per gram of liver, per total liver and per relative liver weight was significantly increased.

Based on the results of this s tudy, SYN545192 at doses of 750 ppm and greater is an inducer of hepatic microsomal UDPglucuronosyltransferase activity towards thyroxine as substrate in male

rats.

SYN545192

- Effect on rat thyroid peroxidase activity in vitro.

The aim of this study (MRID 48604555) was to evaluate the effect of SYN545192 (purity 97%) on rat thyroid peroxidase activity in vitro at dose levels of 0 (control), 0.01, 0.1, 1 and 10 μM. A pooled thyroid gland microsomal preparation from five rats was a ssayed for thyroid peroxidase activity by determining the monoiodination of L

- tyrosine. As a positive control, the effect of 6

- propyl

- 2

- thiouracil (PTU; 10 μM) on rat thyroid peroxidase activity was also determined. Treatment with SYN545192 had no signific ant effect on rat thyroid peroxidase activity at any concentration tested. Treatment with PTU resulted in a 100% inhibition of thyroid peroxidase activity and validated the test system.



### Based on the results of this study, SYN545192 is not an inhibitor of rat thyroid peroxidase activity in vitro

.

SYN545192: A histological extension study of male thyroid tissue from rat toxicity study

In a subchronic toxicity study, SYN545192 (purity 98.3%) was administered orally in the diet to groups of 25 male Han Wis tar Crl: WI(Han) rats at dose levels of 100, 750 or 1500 ppm daily over a period up to 28 consecutive days. A concurrent control group received the vehicle alone (Rat and Mouse (modified) No.1 Diet SQC Expanded (Fine Ground)). Animals were terminated

after 3, 4, 8, 15 or 29 days of treatment, respectively (i.e. after 2, 3, 7, 14 or 28 full days of dietary exposure).

There was an increase in diffuse follicular cell hypertrophy following 7, 14 and 28 days of treatment at 1500 ppm and following 28 days of treatment at 750 ppm.

Dietary administration of SYN545192 resulted in minimal follicular cell hypertrophy at 1500

p pm over 8, 15 and 29 days and at 750 ppm over 29 days of administration.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 77 of 82 In Vitro Absorption through Rat Epidermis Using [ 14 

### C]

- Radiolabelled SYN545192

In Vitro Absorption through Human Epidermis Using [ 14 

### C]

- Radiolabelled

SYN545192

The objective of this study was to determine the in vitro absorption of SYN454192 (Benzovindiflupyr) through human and rat skin over a period of 24 hours ( MRID 48932601, MRID 48932602) . Dorsal skin samples from male Wistar rats and thigh or abdominal skin samples from hu man donors were treated with 10 μL/cm 2 

### skin of 14 

### C

- SYN545192 at one of three doses (0.001, 0.01 and 1.5 mg ai/cm 2 

### ). Static glass diffusion cell systems with an exposed
membrane area of 2.54 cm 2 

### and a volume of approximately 4.5 mL were used in this study.

Mean recoveries for each group (dose level and species) ranged from 90.8 to 103%. All means fell within the acceptable range of 100 +/

- 10% as determined by the OECD Guideline 428. Therefore, study results were not adjusted for incomplete recovery.

Results of this study suggest that SYN545192 is readily absorbed through rat skin, and that dermal absorption is higher in rats than in humans. The pattern of absorption also appears to be similar between rats and humans, with saturation at higher doses (i .e. greater dermal absorption at lower doses).

The mean in vitro dermal absorption in the young male rat skin was 12.0% for the high dose,

28.6% for the medium dose and 56.5% for the low dose. The mean in vitro total absorbed dose for elderly female hum an skin was 0.47% for the high dose, 0.56% for the medium dose and 2.77% for the low dose. Tape stripping was not performed for the rat epidermis samples.

In Vitro Inhibition of Beef Heart Mitochondria Complex II Activity by SYN508272 (MES 114/1) Metabol ite and SYN545192 (SMU9BP005) Parent.

The benzovindiflupyr metabolite SYN508272 (a pyrazole amide) was tested for inhibitory activity against mitochondrial succinate dehydrogenase:ubiquinone reductase (Complex II, SDH) from beef heart mitochondria ( MRID 4 9282502) . The SDH inhibitory capability of the SYN508272 metabolite was compared to the known SDH inhibitory effect of the parent compound benzovindiflupyr. SDH activity was determined by measuring reduction of the colored electron acceptor DCPIP by isolated mitochondria upon addition of the endogenous complex II substrate sodium succinate. The SYN508272 metabolite showed weak SDH inhibitory effects at the top dose of 286 μM (i.e. IC 50 

### > 286 μM), while benzovindiflupyr (SYN545192) potently inhibited m ammalian complex II activity with an IC 50 

### value of 35.3 +/

- 2.0 nM (n = 3) using beef heart mitochondria.

For the benzovindiflupyr metabolite SYN508272, SDH activity averaged 97.0% of solvent control value at 130 nM SYN508272 (the lowest tested concentrat ion) to 81.1% of the solvent control value at 286,000 nM SYN508272 (the highest tested concentration). SYN508272 should

be considered a non

- inhibitor of SDH at environmentally

- relevant concentrations. For benzovindiflupyr, SDH activity averaged 102.7% of s olvent control value at 0.11 nM benzovindiflupyr (the lowest tested concentration) to 8.9% of the solvent control value at 251 nM benzovindiflupyr (the highest tested concentration). The standard error for the SDH assay averaged 2.32% of the solvent contro l value.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 78 of 82 This study is acceptable/non

- guideline, however this special study does not satisfy any guideline requirement.

In Vitro Inhibition of Beef Heart Mitochondria Complex II Activity by NOA449410 (AMS 1234/2) Metabolite and SYN545192 (SMU9BP005) Par ent

The benzovindiflupyr metabolite NOA449410 (a pyrazole acid) was tested for inhibitory activity against mitochondrial succinate dehydrogenase:ubiquinone reductase (Complex II, SDH) from beef heart mitochondria ( MRID 49282503) . The SDH inhibitory capabi lity of the

NOA449410 metabolite was compared to the known SDH inhibitory effect of the parent compound benzovindiflupyr. SDH activity was determined by measuring reduction of the colored electron acceptor DCPIP by isolated mitochondria upon addition of the endogenous complex II substrate sodium succinate. The NOA449410 metabolite showed weak SDH inhibitory effects at the top dose of 284 μM (i.e. IC 50 

### > 284 μM), while benzovindiflupyr (SYN545192) potently inhibited mammalian complex II activity with an IC 50 

### value of 35.3 +/

- 2.0 nM (n = 3) using beef heart mitochondria.

For the benzovindiflupyr metabolite NOA449410 , SDH activity averaged 92.5% of solvent

control value at 130 nM NOA449410 (the lowest tested concentration) to 89.4% of the solvent

control value at 284,000 nM NOA449410 (the highest tested concentration). NOA449410 should

be considered a non

- inhibitor of SDH at environmentally

- relevant concentrations. For benzovindiflupyr, SDH activity averaged 102.7% of solvent control value at 0.11 nM benzovindiflupyr (the lowest tested concentration) to 8.9% of the solvent contro l value at 251 nM benzovindiflupyr (the highest tested concentration). The standard error for the SDH assay averaged 2.07% of the solvent control value.

This study is acceptable/non

- guideline, however this special study does not satisfy any guideline

requ irement.

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 79 of 82 

### Appendix B. Metabolites

Ta ble B .1 : Benzovindiflupyr and Metabolite Structures.

Common Names

/ Code Chemical Name (IUPAC/CAS) Chemical Structure

Benzovindiflupyr

(SYN545192, CSCD064398) IUPAC: N

- [(1 RS ,4 SR )

- 9

- (Dichloromethylidene)

- 1,2,3,4

- tetrahydro

- 1,4

- methanonaphthalen

- 5

- yl]

- 3

- (difluoromethyl)

- 1

- methylpyrazole

- 4

- carboxamide

CAS: N

- [9

- (dichloromethylene)

- 1,2,3,4

- tetrahydro

- 1,4

- methanonaphthalen

- 5

- yl]

- 3

- (difluoromethyl)

- 1

- methyl

- 1 H

- pyrazole

- 4

- carboxamide

SYN546039

SYN546422

NOA449410 (Pyrazole Acid; CSAA798670; CA4312, M700F001) IUPAC: 3

- (difluoromethyl)

- 1

- methyl

- 1 H

pyrazole

- 4

- carboxylic acid

SYN508272 (Pyrazole Amide; CSCC210616)

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 80 of 82 Ta ble B .1 : Benzovindiflupyr and Metabolite Structures.

Common Names

/ Code Chemical Name (IUPAC/CAS) Chemical Structure

SYN545720 IUPAC: 3

- (difluoromethyl)

- 1 H

- pyrazole

- 4

- carboxylic acid

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 81 of 82 

### A ppendix C

. Physical/Chemical Properties

Table C.1. Physicochemical Properties of Benzovindiflupyr.

Parameter Value Reference 1

Melting point 148.4  ̊C PAI (MRID No. 48604402)

pH 6.9 TGAI (MRID No. 48604402)

Density 1.466 g/cm 3 at 20.4°C PAI (MRID No. 48604402)

Water solubility 0.98 mg/L in water at 25°C PAI (MRID No. 48604402)

Solvent solubility (at 25°C) Acetone

– 350 g/L

Dichloromethane

– 450 g/L Ethyl acetate

– 190 g/L

n

- Hexane

– 270 g/L

Methanol

– 76 mg/L

n

- Octanol

– 19 g/L

Toluene

– 48 g/L TGAI (MRID No. 48604402)

Vapor pressure 2.4 x 10

- 11 mm Hg at 25°C

Henry’s Law Constant; 1.3 x 10

- 6 Pa m 3 /mol

at 25°C PAI (MRID No. 48604402)

Dissociation constant (pK a ) No pKa was observed in the pH range of 2.0 to 12.0 by spectrophotometric titration of a

solution of SYN545192 in water. PAI (MRID No. 48604402)

Octanol/water partition coefficient Log(K OW ) Log K ow = 4.3 at 25°C PAI (MRID No. 48604402)

UV/visible absorption spectrum The molar absorption coefficients for the absorbance maximum were found to be ;

Neutral Solution

30.539 l/mol com at 220 nm 11,864 l/mol cm at 249 nm

962 l/mol cm at 295 nm

Acidic Solution 29,989 l/mol cm at 220 nm 11,712 l/mol cm at 249 nm 1,008 l/mol cm at 295 n m

Basic Solution 28,442 l/mol cm at 220 nm 11,527 l/mol cm at 249 nm 1,111 l/mol cm at 295 nm

No other absorbance maximums were

observed between 350 and 750 nm. PAI (MRID No. 48604402)

### Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960



### Page 82 of 82 

### 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 studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database and, the Residential SOPs (lawns and turf) , and are subject to ethics review pursuant to 40 CFR 26, have received that review, and are compliant with applicable ethics requirements. For certain st udies that 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 http://www.epa.gov /pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html

.