Benzovindiflupyr (122305) Human Health Risk Assessment 0408961. 0408960 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, O.C. 20460 

MEMORANDUM 

Date: January 28, 20 15 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Benzovindiflupyr New Active Ingredient Human Health Risk Assessment to 

Support the Proposed Uses on Cereals (wheat, tritical c, barley, rye, and oat), 

Blueberries (non-bearing), Corn (field, pop, and sweet), Peanuts, Turf , and 

Ornamentals; Crop Groups 8-10, 9, and 11-1 O; Crop Subgroups 1 C, 6C, 13-0?F, 

20A, and 20C; and Establishment of Tolerances on Imported Coffee and 

Sugarcane. 

PC Code: 122305 

Decision No.: 473382, 473383 

Petition No.: 2F812 I & 2E8123 

Risk Assessment Type: Single Chemical 

Aggregate 

TXR No.: NA 

MRID No.: A 

DP Barcode: 0408961, 0 408960 

Registration No.: 100-RUTI, JOO-RUTA. 100-

RUTL, 100-RUTR, 100-RUTO, IOO-RUTT, IOORUTU, 100-RUTE, IOO-RUIN 

Regulatory Action : Section 3 Registration 

Case No.: NA 

CAS No.: 1072957-71-1 

40 CFR: NA (New Active Ingredient) 

FROM: 

L:=::> 

Danette Drew, Chemist/Risk sscsso W.--. ll~ ~ J~ 

William Irwin, Ph.D., DAB'fo. /i' ic logist ~d<. Seyed Tadayon, Chemis 

Peter Savoia, Chemist . 0--..: 

Risk Assessment Branc 1 ( B V /VII) 

Health Effects Division (HED) (7509P) 

THROUGH: Michael S. Metzger, Branch Chief, RAB VNll r j fl J }. 

HED (7509P) {J~ tJj_ . 

TO: Shaunta Hill, PM 

Page 1 of 82 

Fungicide Branch 

Registration Division (7505P) 
Benzovindiflupyr (122305) Human Health Risk Assessment 0408961. 0408960 

Syngenta has 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, tuberous and corm vegetables, lowbush blueberries (non-bearing), turf and ornamentals. 

Syngenta has also requested that tolerances for benzovindiflupyr on imported coffee and 

sugarcane be established. The Registration Division of the Office of Pesticide Programs (OPP) 

has requested that HED evaluate hazard and exposure data and conduct dietary, residential, 

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

health that will result from the proposed uses of benzovindiflupyr. 

HED has evaluated the toxicity and exposure databases for benzovindiflupyr, and has conducted 

a human health risk assessment in support of the proposed uses. A summary of the findings and 

an assessment of human health risk resulting from the proposed uses of benzovindi flupyr are 

provided in this document. 

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Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960

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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 Animal............. 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
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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

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1.0 Executive Summary

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 

fuzzy 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-1H-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 Mexico]. The submitted studies 

(toxicology, residue chemistry, exposure) provide a complete database for conducting this 

aggregate 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 studies but only 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 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 indications 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 observed in the acute neurotoxicity (ACN) or subchronic neurotoxicity (SCN) studies. Benzovindiflupyr caused decreased activity and decreased 

grip strength in the neurotoxicity studies; however, there were no supportive neurohistopathology in any toxicological study, even at the highest doses tested. A developmental 

neurotoxicity study was 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 for a subchronic inhalation toxicity study was waived. There was no 

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

studies in the database.

Benzovindiflupyr caused 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

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studies. Benzovindiflupyr is classified as “Suggestive Evidence of Carcinogenic Potential”. The 

Agency has determined 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. 

Therefore, the 10X Food Quality Protection Act (FQPA) Safety Factor (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 residues of concern 

are parent compound plus hydroxylated benzovindiflupyr (metabolite SYN546039). For drinking 

water, the residue of concern is benzovindiflupyr. 

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 commodities. Except where precluded by policy 

differences, international harmonization of recommended tolerance levels was achieved. 

Conservative 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). Acute and chronic

dietary (food and drinking water combined) risk estimates for the proposed uses of 

benzovindiflupyr 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 (postapplication incidental oral) exposure estimates are not of risk concern [i.e., margins of exposure 

(MOEs) are > 100]. While there is the potential for post-application dermal exposures from 

residential uses, no dermal hazard was identified in the toxicity database for benzovindiflupyr. 

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 benzovindiflupyr, 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

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short-term) risk estimates of concern for adults or children exposed to benzovindiflupyr as a 

result of the proposed uses.

Occupational exposures (handler and post-application) are anticipated from the proposed uses of 

benzovindiflupyr. 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 not of concern. While there 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 exposures.

The Worker Protection Statement interim Restricted Entry Interval (REI) of 12 hours is adequate 

to protect agricultural workers from post-application exposures to benzovindiflupyr. 

There are no human health risk concerns that would preclude granting 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 (Section 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 requested Section 3 registration for

benzovindiflupyr and establishing the recommended 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, 
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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 not recovered by the FDA multiresidue 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 maximum residue levels (MRLs) or U.S. 

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

agree that the residue definition for tolerance enforcement is benzovindiflupyr only.

The majority of the recommended MRLs are 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, including its 

metabolites and degradates, in or on the commodities in the table below. Compliance 

with the tolerance levels specified below is to be determined by measuring only 

benzovindiflupyr (N-[9-(dichloromethylene)-1,2,3,4-tetrahydro-1,4-methanonaphthalen5-yl]-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxamide) in or on the commodity.
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Table 2.2.3. Tolerance Summary for Benzovindiflupyr.

Commodity Proposed 

Tolerance 

(ppm)

HEDRecommended 

Tolerance (ppm)

Comments (correct commodity 

definition)

Apple, wet pomace 0.6 None Required A fruit, pome, group 11-10 

tolerance of 0.2 ppm will cover any 

potential residues in processed 

apple, wet pomace.

Blueberry NR1 0.01 For use on only the lowbush 

variety of blueberry in noncropping 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 15

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
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Table 2.2.3. Tolerance Summary for Benzovindiflupyr.

Commodity Proposed 

Tolerance 

(ppm)

HEDRecommended 

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 NR1 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, forage2 4 4
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Table 2.2.3. Tolerance Summary for Benzovindiflupyr.

Commodity Proposed 

Tolerance 

(ppm)

HEDRecommended 

Tolerance (ppm)

Comments (correct commodity 

definition)

Wheat, grain2 0.1 0.10

Wheat, hay2 15 15

Wheat, straw2 10 15

1NR – None Requested

2The 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 

processed 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 submit 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; additional residue data would 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.
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3.0 Introduction

3.1 Chemical Identity

The structure and chemical identity 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

N

N

F

F

O

N

H

Cl Cl

Common name Benzovindiflupyr

Company experimental name SYN545192 (Trade name; SolatenolTM)

IUPAC name N-[(1RS,4SR)-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-methylCAS # 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 Kow = 4.3 at 25°C),

benzovindiflupyr may be considered moderately lipophilic. Benzovindiflupyr has low water 

solubility and does not dissociate; however, environmentally, it is a moderately mobile chemical 

that is expected to persist in the environment in aerobic and anaerobic conditions. Based on the 

environmental fate parameters, there is the potential for benzovindiflupyr to reach water 

resources. 

3.3 Pesticide Use Pattern

Products containing the fungicide benzovindiflupyr are proposed for use on a wide variety of 
Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960

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crops as well as turf grass and ornamentals. Several formulations of benzovindiflupyr are 

proposed for registration by the petitioner; the 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 from 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 (GAPs), is 

provided below in Table 3.3. See Section 2.3.1 above for the recommended 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 

Method Growth stage (days)

& 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

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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 

Method Growth stage (days)

& 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)

InfurrowAt 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

Fruiting 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

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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 

Method Growth stage (days)

& 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 

Method Growth stage (days)

& 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 

Method Growth stage (days)

& 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 

benzovindiflupyr products by adults. In addition, there is the potential for residential postapplication 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 benzovindiflupyr 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 

based 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. Executive 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 (OPP) considers a large variety of 

consumer subgroups according to well-established procedures. In line with OPP policy, HED 

estimates risks to population subgroups from pesticide exposures that are based on patterns of 

that subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Extensive data on food consumption patterns are compiled 

by the 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 used 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 

exposure 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 consider exposure to bystanders and farm 

workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

Based on the proposed use patterns, all required studies for benzovindiflupyr (SolatenolTM) 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 toxicology 

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

Based on a weight of evidence (WOE) approach, the Hazard and Science Policy Council 

(HASPOC) recommended that a subchronic inhalation toxicity study is not needed for 

benzovindiflupyr (TXR No. 0057049, W. Irwin). This approach considered all of the available 

hazard and exposure information for, including (1) the physical/chemical properties and low 

volatility (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, occupational handler high-end screening MOEs ranged 

from 900 to 9,500,000 (only one scenario resulted in a MOE < 1000 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 

gavage 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 

bioavailability was essentially complete (i.e. at 1 mg/kg [14C] 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 T1/2 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 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 using radiolabels in both rings of benzovindiflupyr, total 

radioactivity was extensively distributed throughout the body by the first sampling time 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 clear differences in tissue distribution profiles between the labels nor were 

any pronounced gender or dose differences apparent. The 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 extensively metabolized in rat resulting in at least 8 types of metabolite 

(e.g. desmethyl, hydroxy, dihydroxy, desmethyl hydroxy, desmethyl dihydroxy, ring-open, 

glucuronide conjugate, 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 major 

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. Some quantitative 

differences were observed between males and females, minor differences were observed by the 

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

only in females. 

The predominant route of elimination was via the feces. Following a single oral dose of 1 

mg/kg, elimination via the feces accounted for 84 and 90% of the administered dose and urinary 

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

Similar results were observed following a single 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 daily 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 concentrations steadily declined. Liver and kidney had the greatest concentrations 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). The terminal phase half-life for tissue depletion ranged 

from 2.5 days in plasma to 69 days in the testes.

4.2.1 Dermal Absorption

The in vivo dermal absorption of benzovindiflupyr in rats was measured at 0.001, 0.01 and 1.5 

mg/cm2, however, the 28-day dermal toxicity 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 since 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 fungicide 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 Complex 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 the 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 feces 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 developmental 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 increase in sensitivity in rat pups. There were no 

single-dose developmental effects identified in the developmental toxicity studies in rats or

rabbits. Although decreases in growing follicle counts were noted in the reproduction toxicity 

study, this effect did not result in reduced functional 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 toxicity that could not be detected by qualitative microscopic 

assessment or other standard methods” (Toxicologic Pathology, 33:409–412, 2005). No evidence 

of specific neurotoxicity were observed in the acute oral (gavage) and sub-chronic oral (dietary) 

neurotoxicity (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 (TDAR) 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 thyroid 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 approach (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 LD50 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 LD50 values for very 

similar chemicals such as hydroxy-benzovindiflupyr and isopyrazam which were over 2000 

mg/kg. The pyrazole acid and amide metabolites (SYN545720, SYN508272 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 and 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, benzovindiflupyr potently inhibited mammalian SDH in an in vitro study, with 

an IC50 value of 35.2 nM. This IC50 value is over 1000 times less than the liver target tissue 
Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960

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levels (i.e. 55.2 μM) measured in the metabolism studies employing a single oral dose near 

several 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 susceptibility of infants 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 studies 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 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. The LOAELs and NOAELs for the rat developmental and 

rat reproduction studies were clearly defined.

3) There is no 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 will not under-estimate exposure (see 

4.4.4 below).

4.4.1 Completeness of the Toxicology Database

The 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 determined 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 strength in the ACN study. There was no corroborative neuro-histopathology 

demonstrated in any study, even 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 
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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 susceptibility 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 in 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) exposure. 

A complete database with respect to both the nature and magnitude of residues expected in food 

has been provided. The dietary 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 endpoints and points of departure (PODs) 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. 
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An acute reference dose (aRfD) 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, including 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, decreased 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 years 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 

variation) 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 females),

based on decreased body weight and decreased 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 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 comparable (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. 

An uncertainty factor of 100x (10x to account for interspecies extrapolation and 10x for intraspecies 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, centrilobular 
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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 not 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 reproduction 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 body 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 benzovindiflupyr 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 effects, and 

fetuses and offspring were not more sensitive than adults when orally dosed with 

benzovindiflupyr.

The short-term 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 

based on decreased body weight and decreased food consumption. An inhalation toxicity study 

with benzovindiflupyr is not available. 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 progression 

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 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.

4.5.2 Recommendation for Combining Routes of Exposures for Risk 

Assessment

As part of conducting 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, the 

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 (dermal and inhalation) due to the 

lack of a dermal toxicity endpoint.
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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 should have a cancer classification of “Suggestive Evidence of 

Carcinogenic Potential”. A quantitative cancer risk assessment is not needed; the 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

Tables 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 Assessments

Exposure/ 

Scenario

Point of Departure Uncertainty/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological 

Effects

Acute Dietary

(All 

Populations, 

including 

Infants and 

Children)

NOAEL=10 

mg/kg/day

UFA= 10x

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

Non-Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of Departure Uncertainty/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological 

Effects

Chronic 

Dietary 

(All 

Populations)

Parental/Offspring

NOAEL = 8.2 

(females) mg/kg/day

UFA= 10x

UFH= 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 Oral 

Short –Term 

(1-30 days)

Parental/Offspring 

NOAEL = 8.2 

(females) mg/kg/day

UFA= 10x

UFH= 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 the pituitary, 

reduced body weight, 

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

Non-Occupational Human Health Risk Assessments

Exposure/ 

Scenario

Point of Departure Uncertainty/FQPA 

Safety Factors

RfD, PAD, 

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological 

Effects

separation, and decreased 

spleen weights in the F1 

and/or F2 offspring.

Dermal ShortTerm (1-30 

days) and 

IntermediateTerm (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. Additionally, 

there are no concerns for developmental, reproductive, neurotoxicity, or immunotoxicity.

Inhalation 

Short-term (1-

30 days) and 

IntermediateTerm (1-6 

months)

Parental/Offspring

NOAEL: 8.2 

mg/kg/day (F)

UFA= 10x

UFH= 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, 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.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Suggestive Evidence of Carcinogenic Potential” Quantification of 

carcinogenicity is not required. The 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 level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = 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.
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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 

IntermediateTerm (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. Additionally, 

there are no concerns for developmental, reproductive, neuro, or immunotoxicity.

Inhalation 

Short (1-30 

days) and 

Intermediateterm (1-6 

months)

NOAEL: 8.2 

mg/kg/day (F)

UFA= 10x

UFH= 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, 

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.

Cancer (oral, 

dermal, 

inhalation)

Classification: “Suggestive Evidence of Carcinogenic Potential” Quantification of 

carcinogenicity is not required. The 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 level. LOAEL = lowest observed adverse effect level. UF = 

uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = 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
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5.1.1 Summary of Plant and Livestock Metabolism Studies

5.1.1.1 Plant Metabolism Studies

Residue Chemistry Memo, D422374, 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) hydroxylation 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 both the phenyl and pyrazole rings. The 

metabolic pathways observed in hens and goats were found to be similar and include

demethylation of the pyrazole ring, hydroxylation of the alicyclic ring, and cleavage between the 

pyrazole and phenyl rings. 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 transformation 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 their turbid 

properties. Benzovindiflupyr is not expected to escape from dry or moist soil surfaces 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

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profile in plants is similar in diverse crops of tomato, soybean, and 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 Knowledgebase 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 its structural similarity to parent benzovindiflupyr a similar toxicity is assumed. 

For risk assessment purposes, the ROCKS recommended 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 ruminant feeding study. The ROCKS recommended 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 benzovindiflupyr. The parent compound is 

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 

agricultural fields due to turbidity.

The residues of concern for benzovindiflupyr are summarized in Table 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
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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 hydroxylated 

benzovindiflupyr (SYN546039). In crop field trials this metabolite was generally found at levels 

near the LOQ (0.01 ppm) except in the foliage and forage portions of plants where the residues 

were typically greater. Detectable residues of benzovindiflupyr are not expected in rotational 

crops following a 180-day plant back interval.

Processing studies were performed for the appropriate proposed use crops. Benzovindiflupyr 

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, D409374, 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 values. 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 water analysis are presented 

in the screening drinking water assessment to identify the upper-bound EDWC associated with 
Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960

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all of the proposed uses for benzovindiflupyr. Ground water concentrations 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 than 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 8.41 0.143

Chronic 5.42 <0.143

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. The 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 trials. 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).

Anticipated 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 performed 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 

maximum 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 studies, the 

residues from cattle studies were used to calculate hog commodity ARs. For poultry and swine 

tissues, secondary transfer of benzovindiflupyr and the SYN546039 metabolite is expected to be 

negligible. Based on this negligible transfer of the residues 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.
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5.4.2 Percent Crop Treated Used in Dietary Assessment

The acute and chronic dietary risk assessments 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. Acute dietary (food and water) risk estimates for the proposed uses of 

benzovindiflupyr 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 95th

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 years old, was 30% of the aPAD

(see Table 5.4.6.). 

5.4.4 Chronic Dietary Risk Assessment

A highly conservative chronic 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. Chronic dietary (food and water) risk estimates for the proposed uses of 

benzovindiflupyr 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 95th

percentile, the risk estimate was 4% of the cPAD for the general U.S. population. The risk 

estimate for the most highly exposed subgroup, children 1-2 years 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 

benzovindiflupyr; therefore a separate cancer assessment was not performed.

5.4.6 Summary Table
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Table 5.4.6 Summary of Dietary (Food and Drinking Water) Exposure and Risk

Estimates 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

1Highest exposure identified in bold; aPAD = acute population adjusted dose = 0.10 mg/kg/day; 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. Inhalation and dermal 

exposures may occur for adults applying benzovindiflupyr. Post-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 is 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
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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. Intermediate-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 benzovindiflupyr (i.e., no protective equipment). 

The assessments were conducted assuming the maximum application rates and used unit 

exposure values and estimates for area treated or amount handled along with algorithms taken 

from HED’s 2012 Residential SOPs. 

The 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 Manually-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 database, 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 all ≥ 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 Exposure and Risk Estimates for Benzovindiflupyr

Exposure Scenario Level of 

Concern

Inhalation 

Unit 

Exposure

(mg/lb ai)

Maximum 

Application 

Rate1

Area

Treated or 

Amount 

Handled 

Daily2

Inhalation

Dose

(mg/kg/day)3 MOE4

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/ ft2 1000 ft2 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 ft2 1000 ft2 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
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1 Based on proposed benzovindiflupyr 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 (μg/lb ai) x Conversion Factor (0.001 mg/μg) 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. Postapplication inhalation exposures while performing activities in previously 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 have 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 

protective 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 parks, golf courses, treated sod). The assessment of children’s 

exposures to treated 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 estimates 

resulting from residential post-application exposures. Incidental oral MOEs for children 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 Benzovindiflupyr

Lifestage Post-application Exposure Scenario Dose1 MOEs2

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/cm2

) x (fraction hand surface area mouthed/event (0.127/event) x typical surface area of one 

hand (150 cm2)) 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 cm2). 

 Object-to-Mouth = ((Object Residue (μg/cm2) x CF1 (1.0E-3 mg/μg) x Object Surface Area Mouthed/Event (10 cm2/event)) x (Exposure 

Time (1.5 hrs/day) x #Replenishment Intervals/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 NOAEL =8.2/kg/day. 
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6.3 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.3 reflects the residential risk estimates for use in the benzovindiflupyr aggregate 

assessment. The scenarios and lifestages resulting in the highest residential exposures are 

selected for use in the aggregate assessment and are considered protective of other exposure

scenarios. An aggregate assessment that includes residential scenarios is only needed for shortterm exposures as there are no intermediate- or long term- exposures expected from the proposed 

non-occupational residential uses. The appropriate 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 manually pressurized 

handwand or backpack sprayer.

 The short -term residential exposure for use in the child aggregate assessment reflects turf 

post-application hand-to-mouth exposure for children 1 to <2 years old.

Table 6.3. Residential Exposures for the Benzovindiflupyr Aggregate Assessment.

Lifestage Exposure 

Scenario

Dose (mg/kg/day)1 MOE2

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

PostApplication: 

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 methods (e.g., groundboom and 

airblast) employed for benzovindiflupyr. 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 Offices and State Lead Agencies for pesticide 

regulation and other parties to develop the best spray drift management practices (see the 

agency’s Spray Drift website for more information 

(http://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 quantitatively 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 Assessment (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. 
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Furthermore, residential turf uses were quantitatively 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. The 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 because 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, volatilization of pesticides may be a source of postapplication inhalation exposure to individuals nearby pesticide 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 report 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

benzovindiflupyr.

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 benzovindiflupyr that may result in 

residential exposures include turf (such as lawns 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

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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 assessing 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 exposures 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 postapplication 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 LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

Aggregate 

MOE (food, 

water, and 

residential)5

Adult

(Handler 

treating 

ornamentals)

8.2 100 0.082 0.003199 0.000046 0.003245 2500

Child (Postapplication 

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 Exposure + Residential Exposure)]
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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 

benzovindiflupyr. 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 common 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 chemicals, see the policy statements released by EPA’s Office of 

Pesticide Programs concerning common mechanism determinations and procedures for 

cumulating effects from substances found to have a common mechanism on EPA’s website at 

http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

Occupational/Residential Exposure Memo, 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. The 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 identified in the toxicity database for 

benzovindiflupyr, a quantitative dermal assessment is not required and risks were quantitatively 

assessed for inhalation exposure only. Based on the proposed use pattern of benzovindiflupyr, 

short- and intermediate-term exposures 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 who 

may apply a product over a period of weeks. Long-term exposure is not expected for the 

proposed use patterns. Since the same endpoint and point of departure were selected for shortand intermediate-term durations, short-term exposure and risk estimates are considered to be 

protective of intermediate-term exposure and risk.
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Generic default data were used in this assessment as surrogate data in the absence of chemicalspecific 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, shoes plus socks, no protective gloves, and 

no respirator. The benzovindiflupyr 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 benzovindiflupyr 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 for Benzovindiflupyr

Exposure Scenario Crop or Targeta

Baseline 

Inhalation 

Unit 

Exposureb

Maximum

Application 

Ratec

Area 

Treated or 

Amount 

Handled 

Dailyd

Baseline Inhalation

Dosee MOEf

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 Crops4

0.219

0.046

350

0.000044 190,000

Sod Farms6 0.067 0.000064 130,000

Typical Field Crops2 0.089 0.0000853 96,000

Typical Field Crops1

0.068

350 0.000065 130,000

High-Acreage Field Crops3 1200 0.000224 37,000

Mixing/Loading 

Liquids for Airblast 

Application

Nursery Plants 20 0.0000037 2,200,000

Orchard Crops4 0.046 40 0.0000050 2,000,000

Mixing/Loading 

Liquids for 

Chemigation

Orchard Crops4 0.046

350

0.0000441 190,000

Typical Field Crops2 0.089 0.0000853 100,000

Sod Farms6

0.068

Typical Field Crops 0.000065 130,000 1

High-Acreage Field Crops3

Greenhouse Plants5

60 0.0000112 730,000 Nursery Plants5

Mixing/Loading 

Liquids for 

Groundboom 

Application

Golf Courses6

(tees and greens only) 0.067 5 0.00000033 3,000,000

Golf Courses6

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

Field-Grown Ornamentals5

0.068

40 0.0000075 1,100,000

Nursery Plants6

60 0.0000112 730,000 Greenhouse Plants5

Sod Farms6 0.067

80

0.0000146 560,000

Typical Field Crops2 0.089 0.0000195 420,000

Typical Field Crops1

0.068 0.0000149 550,0000

High-Acreage Field Crops3 200 0.0000373 220,000

Mixer/Loader Water Dispersible Granular

Mixing/Loading 

WDG for Aerial 

Application

Typical Field Crops2

8.36

0.089 350 0.0035 2,300

Typical Field Crops1

0.068

350 0.00266 3,100

High-Acreage Field Crops3 1200 0.00914 900

Typical Field Crops2 0.089 350 0.0035 2,300

Typical Field Crops1 0.068 0.00266 3,100
Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960

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Table 9.1 Short- and Intermediate-Term Occupational Risk assessment for Benzovindiflupyr

Exposure Scenario Crop or Targeta

Baseline 

Inhalation 

Unit 

Exposureb

Maximum

Application 

Ratec

Area 

Treated or 

Amount 

Handled 

Dailyd

Baseline Inhalation

Dosee MOEf

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 Crops3

Greenhouse Plants5

0.067 60 0.00045 18,000 Nursery Plants5

Mixing/Loading 

WDG for Airblast 

Application

Nursery Plants 0.067 20 0.00015 55,000

Mixing/Loading 

WDG for 

Groundboom 

Application

Typical Field Crops2 0.089 80 0.0008 1,000

Typical Field Crops1

0.068 80 0.00061 13,000

High-Acreage Field Crops3 200 0.0015 5,400

Greenhouse Plants5

0.067 60 0.00045 18,000

Nursery Plants5

Field-Grown Ornamentals5

Nursery Plants6

Greenhouse Plants5

Applicator

Applying Sprays for 

Aerial Application

Orchard Crops4

0.0049

0.046

350

0.00000099 8,300,000

Sod Farms6 0.067 0.00000144 5,700,000

Typical Field Crops2 0.089 0.00000191 4,300,000

Typical Field Crops1

0.068 350 0.00000146 5,600,000

High-Acreage Field Crops3 1200 0.000005 1,600,000

Applying Sprays for 

Groundboom 

Application

Golf Courses6

(tees and greens only)

0.34

0.067

5 0.00000143 5,700,000

Golf Courses6

(fairways, tees, and greens) 40 0.0000114 720,000

Field-Grown Ornamentals 0.068 40 0.0000116 710,000

Nursery Plants5

0.068 60 0.0000174 470,000 Greenhouse Plants5

Sod Farms6 0.067 80 0.0000228 360,000

Typical Field Crops2 0.089 80 0.0000303 270,000

Typical Field Crops1

0.068 80 0.000231 350,000

High-Acreage Field Crops3 200 0.0000578 140,000

Applying Sprays for 

Airblast Application

Orchard Crops4

4.71 0.046 40 0.000108 710,000

Nursery Plants 0.067 20 0.000080 100,000

Flagger

Flagging for Aerial 

Applications

Orchard Crops4

0.35

0.046

350

0.0000705 120,000

Sod Farms6 0.067 0.000103 80,000

Typical Field Crops1

0.068 0.000104 79,000 High-Acreage Field Crops3

Typical Field Crops2 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

Landscaping6 2.58 0.0023 0.00000296 3,000,000
Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960

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Table 9.1 Short- and Intermediate-Term Occupational Risk assessment for Benzovindiflupyr

Exposure Scenario Crop or Targeta

Baseline 

Inhalation 

Unit 

Exposureb

Maximum

Application 

Ratec

Area 

Treated or 

Amount 

Handled 

Dailyd

Baseline Inhalation

Dosee MOEf

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 

ManuallyPressurized 

Handwand Sprayers

Greenhouse Plants (Foliar)5

30 0.00068

lb ai/gal 40

gallons

0.00001 800,000 Nursery Plants (Foliar)5

Landscaping5(trees/shrubs/bushes)

Landscaping (plants/flowers)5

Landscaping6

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

M/L/A Liquids for 

MechanicallyPressurized 

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

Nursery Plants (Ground/Soil) 3.9 0.0000331 300,000 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 Crops2 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 

ManuallyPressurized 

Handwand Sprayers

Greenhouse Plants (Foliar)5

30 0.00067

lb ai/gal

40

gallons 0.0000101 810,000

Nursery Plants (Foliar)5

Landscaping5(trees/shrubs/bushes)

Landscaping (plants/flowers)5

M/L/A WDG for 

MechanicallyPressurized 

Handgun Sprayers

Greenhouse Plants (Foliar)5

120 0.00067

lb ai/gal

1000

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

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 Crops2

(Ground/Soil)

a Crop or Target

1Typical 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.

2Typical 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).

3High-Acreage Field Crops at 0.068 lb ai/A or 0.0068 lb ai/gal. 

Corn, cotton, cereals and, soybeans.

4Orchard crops Pome fruits at 0.046 lb ai/A or 0.0046 lb ai/gal.
Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960

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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 = Baseline.

c Based on the maximum application rates on the proposed labels (Reg. Nos100-1 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 Treated 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-Application Risk

There is the potential for post-application exposure to workers as a result of proposed uses of 

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

benzovindiflupyr, a quantitative occupational post-application 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-Application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for benzovindiflupyr 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 

(Toxicity Category III), 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 postapplication activities in previously treated fields. These potential sources include volatilization 

of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency 

sought expert advice and input on issues related to volatilization of pesticides from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, 

and received the SAP’s final report on March 2, 20102. The Agency is in the process of 

evaluating the SAP report. In addition, the Agency is continuing to evaluate the available postapplication 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.

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

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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 inhalation 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 exposures 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 benzovindiflupyr, 

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 short- and intermediate-term 

post-application risk estimates were not evaluated for benzovindiflupyr. 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 

benzovindiflupyr. 

10.0 References

Toxicology References

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: Benzovindiflupyr-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

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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 Registration and Establishment of 

Permanent Tolerances of the New Fungicide Active Ingredient Benzovindiflupyr 

for Use on: Barley, 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: D409374

Title: Tier I Drinking 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, cucurbits, 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

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Appendix 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

CR: 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

LD50=66.3 mg/kg

(HED calculation)

Note: The LD50 value for 

hydroxy-benzovindiflupyr

(SYN546039) is >2000 

mg/kg (MRID 48604458), 

putting doubt on this LD50

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)

LD50>2000 mg/kg III

870.1300 Acute Rat Inhalation Toxicity 

Study (Nose-Only) (2010, MRID 

48604429)

LC50> 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

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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)

(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). 

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 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

870.3100

90-Day Oral Toxicity in 

Rodents

13-Week Dietary 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 values 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

LOAEL: 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

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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 malesParental: 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 femalesParental: 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 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.

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, NonRodent

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 
Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960

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Guideline

[OCSPP]

Study Title Results

Acceptable-Guideline macrophages in the spleen in females. 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 Test

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- 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

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-clastogenic 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 

female 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.
Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960

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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 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 T1/2 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 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). In skeletal muscle the concentrations were 

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, 

sulphate conjugate). 

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.

870.7600

Dermal Penetration

SYN545192 EC Formulation (A17056F) –

In Vivo Dermal Absorption in the Rat

(2011, MRID 48604460)

Formulation at 0.001, 0.01 and 1.5 mg/cm2

Acceptable-Guideline

At doses of 0.001, 0.01 and 1.5 mg/cm2, 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.
Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960

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Guideline

[OCSPP]

Study Title Results

Special Study

In Vitro Dermal 

Penetration

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/cm2

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 human 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.

870.7800

Immunotoxicity

28-Day Dietary Immunotoxicity Study 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 SYN545192 resulted in 

decreased body weight gains, decreased food 

consumption, increased liver weight (day 15), increased 

incidence of centrilobular hepatocyte hypertrophy, 

decreased serum T3, 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 T3, decreased serum T4, 

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, MRID 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.
Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960

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 administration. 

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 IC50

value of 35.3 +/- 2.0 nM

The benzovindiflupyr metabolite SYN508272 was 

effectively inactive with an IC50 value >286 μM

Special Study Complex II (Succinate Dehydrogenase) 

Assay in Mammalian Mitochondria of 

Benzovindiflupyr and its Metabolite 

NOA449410

(2014, MRID 49282503)

Benzovindiflupyr potently inhibited mammalian 

mitochondrial succinate dehydrogenase with an IC50

value of 35.3 +/- 2.0 nM

The benzovindiflupyr metabolite NOA449410 was 

effectively inactive with an IC50 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, 

Fluxapyroxad

NOA449410

CSAA798670 

CA4312 (intermediate)

BASF M700F001

BASF Reg 5069089

Sedaxane, 

Benzovindiflupyr, 

Fluxapyroxad

Structure

N

N

F

F

O

N

H

Cl Cl

Mitochondrial 

Succinate 

Dehydrogenase 

Inhibition IC50

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 

LD50

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
Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960

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 = None1

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 some animals at 50 mg/kg/day.
Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960

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, 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, decreased 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 

years old) acute dietary assessment is not warranted. 

aRfD = aPAD = 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).

Comments: 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
Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960

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 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 

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 

comparable (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 = 0.08 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 decreased 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 twogeneration 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 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 body weight 

decreases in the 90-day mouse study (adults).
Benzovindiflupyr (122305) Human Health Risk Assessment D408961, D408960

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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 the 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, neurotoxicity, or immunotoxicity. Therefore, 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: 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).

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 Toxicity – 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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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 

were 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 male 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/day 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 acceptable/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 in 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 hypertrophy 

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 for 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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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.

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 calcium 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 toxicity 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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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 statistically 

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 itemrelated findings were found during the study in the 7.5 and 15 mg/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 Adverse 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 alterations, 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 timemated 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 consumption 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 corpora 

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 examined 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 level with statistical 
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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 significance 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 unaffected 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 with 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 orally 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 weight 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 developmental 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 MalesParental: 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 FemalesParental: 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 were 

sacrificed when they were no longer needed for reproduction.
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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 males (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 hepatocellular 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 rats.

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 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

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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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 ophthalmoscopy 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, lobular 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 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 macrophages 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 870.4200) in rats.
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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 

consecutive 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. 

Females 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 

mg/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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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 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- 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 nonclastogenic 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 response.
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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 for 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 signs, 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 to 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 assessed 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 scheduled 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 single 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 over 

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 lesions 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-observed 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 genders.
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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 field 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 muscle 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 the 

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 during 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 Wistar 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 decreased 

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 neuropathologic 

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 females.

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

1-2 hours and at 3-4 hours with T1/2 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 Following 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/cm2of benzovindiflupyr in 

an emulsifiable concentrate formulation (A17056F) and monitored 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/cm2, 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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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 mice/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 thymus 

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 animal 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 immune 

response when evaluated as either specific activity (AFC/106spleen 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 ppm 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 of 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 numbers, and spleen activity (i.e., 

number of specific IgM antibody-forming cells directed towards the sRBC antigen) were 
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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 NOAEL 

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

SYN545192: 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 period 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 intervals 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 testing.

All main study animals were terminated after completion of 1, 3, 7, or 14 days of treatment (i.e. 

days 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 before 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 (T4) 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 T3 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.
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Treatment with 600 ppm SYN545192 resulted in decreased body weight gains, decreased food 

consumption, increased liver weight (day 15), increased incidence of centrilobular hepatocyte 

hypertrophy, decreased serum T3, 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 T3, decreased serum T4, 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.

Treatment 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 T3, 

decreased serum T4, 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 treatment of male rats with SYN545192 results in 

increased hepatic UDPGT activity, hepatocellular centrilobular hypertrophy, increased liver 

weight, decreased serum T3 and T4, 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 carcinogenicity 

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), male 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 glucuronosyltransferase 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 and 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 increased as expressed 

as specific activity, per gram of liver, per total liver and per relative liver weight after 7 and 28 
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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 weight 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-treated 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 study, 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 assayed 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 significant 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 Wistar 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 

ppm over 8, 15 and 29 days and at 750 ppm over 29 days of administration. 
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In Vitro Absorption through Rat Epidermis Using [14C]-Radiolabelled SYN545192

In Vitro Absorption through Human Epidermis Using [14C]-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 human donors were treated with 10 μL/cm2skin of 14C-SYN545192 at one of three 

doses (0.001, 0.01 and 1.5 mg ai/cm2). Static glass diffusion cell systems with an exposed 

membrane area of 2.54 cm2and 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 human 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) Metabolite 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 49282502). 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. IC50 > 286 μM), while benzovindiflupyr 

(SYN545192) potently inhibited mammalian complex II activity with an IC50 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 concentration) 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 solvent 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 control value.
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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) Parent

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 capability of the 

NOA449410metabolite 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. IC50 > 284 μM), while benzovindiflupyr 

(SYN545192) potently inhibited mammalian complex II activity with an IC50 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 control 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 

requirement. 
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Appendix B. Metabolites 

Table B.1: Benzovindiflupyr and Metabolite Structures.

Common Names 

/ Code Chemical Name (IUPAC/CAS) Chemical Structure

Benzovindiflupyr

(SYN545192, 

CSCD064398)

IUPAC: N-[(1RS,4SR)-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-1H-pyrazole-4-

carboxamide

SYN546039

SYN546422

NOA449410 

(Pyrazole Acid; 

CSAA798670; 

CA4312, 

M700F001)

IUPAC: 3-(difluoromethyl)-1-methyl-1Hpyrazole-4-carboxylic acid

SYN508272 

(Pyrazole Amide; 

CSCC210616)
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Table B.1: Benzovindiflupyr and Metabolite Structures.

Common Names 

/ Code Chemical Name (IUPAC/CAS) Chemical Structure

SYN545720 IUPAC: 3-(difluoromethyl)-1H-pyrazole-4-

carboxylic acid
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Appendix C. Physical/Chemical Properties

Table C.1. Physicochemical Properties of Benzovindiflupyr. 

Parameter Value Reference1

Melting point 148.4  ̊C PAI (MRID No. 48604402)

pH 6.9 TGAI (MRID No. 48604402)

Density 1.466 g/cm3at 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 10-6Pa m3/mol 

at 25°C

PAI (MRID No. 48604402)

Dissociation constant (pKa) 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(KOW) Log Kow = 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 nm

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)
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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 studies 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.