Page 2 of 83

TABLE OF CONTENTS

 pg.

1.0 EXECUTIVE SUMMARY .................................................................................................4

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

2.2.3 Recommended Tolerances.......................................................................................7

2.2.4 Revisions to Petitioned for Tolerances..................................................................10

2.3 Label Recommendations ...................................................................................................10

3.0 INGREDIENT PROFILE..................................................................................................11

3.1 Chemical Identity ..............................................................................................................11

3.2 Physical/Chemical Properties ............................................................................................11

3.3 Pesticide Use Pattern..........................................................................................................11

3.4 Anticipated Exposure Pathways ........................................................................................13

3.5 Environmental Justice........................................................................................................14

4.0 HAZARD CHARACTERIZATION/ASSESSMENT.......................................................14

4.1 Toxicology Studies Available for Analysis.......................................................................14

4.2 Absorption, Distribution, Metabolism, & Elimination ......................................................15

4.3 Toxicological Effects.........................................................................................................16

4.4 Safety factor for Infants and Children ...............................................................................18

4.4.1 Completeness of the Toxicology Database............................................................18

4.4.2 Evidence of Neurotoxicity .....................................................................................19

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ........19

4.4.4 Residual Uncertainty in the Exposure Database....................................................19

4.5 Toxicity Endpoint and Point of Departure Selections.......................................................20

4.5.1 Dose-Response Assessment...................................................................................20

4.5.2 Recommendation for Combining Exposure Routes ..............................................20

4.5.3 Cancer Classification .............................................................................................21

4.5.4 Summary of Points of Departure Used in Risk Assessment..................................22

5.0 DIETARY AND DRINKING WATER RISK ASSESSMENT........................................23

5.1 Metabolite/Degradate Residue Profile...............................................................................23

5.1.1 Summary of Plant and Animal Metabolism Studies..............................................23

5.1.2 Summary of Environmental Degradation ..............................................................23

5.1.3 Comparison of Metabolic Pathways......................................................................24

5.1.4 Residues of Concern Summary and Rationale.......................................................24

5.2 Food Residue Profile..........................................................................................................25

5.2.1 Residues in Crops ..................................................................................................25

5.2.2 Residues in Meat, Milk, Poultry and Eggs ............................................................25
Page 3 of 83

5.2.3 Residues in Processed Commodities .....................................................................26

5.2.4 Storage Stability.....................................................................................................26

5.3 Water Residue Profile ........................................................................................................26

5.4 Dietary and Drinking Water Exposure and Risk ...............................................................27

5.4.1 Acute Dietary and Drinking Water Exposure and Risk Estimates........................27

5.4.2 Chronic Dietary and Drinking Water Exposure and Risk Estimates.....................27

6.0 RESIDENTIAL EXPOSURE/RISK CHARACTERIZATION ........................................28

6.1 Residential Bystander Postapplication Inhalation Exposure .............................................28

6.2 Spray Drift .........................................................................................................................28

7.0 AGGREGATE EXPOSURE/RISK CHARACTERIZATION..........................................29

8.0 CUMULATIVE RISK.......................................................................................................29

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION...................................30

9.1 Exposure Scenarios ...........................................................................................................30

9.2 Handler Exposure...............................................................................................................30

9.2.1 Handler Exposure Scenarios..................................................................................30

9.2.2 Handler Exposure Data ..........................................................................................32

9.2.3 Handler Exposure Assumptions.............................................................................32

9.2.4 Handler Exposure and Risk ...................................................................................33

9.3 Post-Application Exposure ................................................................................................36

10.0 REFERENCES ..................................................................................................................37

Appendix A. Toxicity Profile and Executive Summaries..............................................................38

A.1 Toxicity Data Requirements..................................................................................38

A.2 Toxicity Profiles.....................................................................................................39

A.3 Hazard Identification and Endpoint Selection .......................................................50

A.4 Executive Summaries.............................................................................................53

Appendix B. Metabolism ..............................................................................................................69

Appendix C. Physical/Chemical Properties...................................................................................83

Appendix D. Review of Human Research.....................................................................................83
Page 4 of 83

1.0 EXECUTIVE SUMMARY

This assessment provides information to support a Section 3 registration for the use of the 

new active ingredient, fluxapyroxad on cereal grains, legume vegetables, oil seed crops, peanuts, 

pome fruit, stone fruit, root and tuber vegetables, fruiting vegetables, and cotton. This document 

addresses the exposures and estimated risk associated with the proposed new uses of 

fluxapyroxad. It provides an assessment of proposed tolerances (pesticide residue limits in food) 

to ensure that they meet the safety standard established by the Food Quality Protection Act 

(FQPA) of 1996. This assessment was conducted as part of a global review involving the U.S., 

Canada, and Australia. 

Use Profile

Fluxapyroxad (3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1Hpyrazole-4-carboxamide) is a fungicide belonging to the carboxamide class of chemicals. It is a 

new active ingredient proposed for use on a wide range of crops to control a broad spectrum of 

fungal diseases. Fluxapyroxad is a pyrazole carboxamide. The mode of pesticidal action as a 

fungicide is inhibition of succinate dehydrogenase in complex II of the mitochondrial respiratory

chain, resulting in inhibition of spore germination, germ tubes, and mycelial growth. 

Applications may be made using groundboom, airblast, aerial, and standard slurry or mist-type 

seed treatment equipment. There are no fluxapyroxad products proposed for homeowner use and 

there are no products proposed for application to residential areas. Recommended tolerances for 

combined residues of fluxapyroxad and its major metabolites in/on plant and animal

commodities range from 0.003 ppm to 20 ppm. 

BASF Corporation is requesting a Section 3 registration of four fluxapyroxad products. 

The products are proposed for use on various seed and food crops. The technical product to be 

registered is XEMIUM Technical (7969-GRE). The proposed formulations are BAS 700 01 F 

Fungicide (7969-GNA, an emulsifiable concentrate (EC) containing 5.96% fluxapyroxad); BAS 

700 02 F (7969-GNT, for seed treatment, 28.78% ai); BAS 700 03 F (7969-GNI, for seed 

treatment, 28.70%; BAS 700 04 F (7969-GNO, EC formulation with 26.55% ai); and two coactive ingredient products with pyraclostrobin: BAS 703 01 F (7969-GRN, with fluxapyroxad at 

21.26% (2.09 lb ai/gal) and pyraclostrobin at 21.26 %) and BAS 703 02 F (7969-GRR, with 

fluxapyroxad 14.33% and pyraclostrobin at 28.58%). Crop applications may be begin at 

emergence, but typical applications begin as plants touch across rows. Maximum single 

application rates range from 0.09 lbs ai/A for most crops to 0.18 lb ai/A for dry shelled beans. 

Maximum seasonal application rates range from 0.18 to 0.36 lb ai/A. Proposed pre-harvest 

intervals (PHIs) are 0 days for pome and stone fruit crops, 21 days for cereal grains and 7 days 

for other commodities. A 365 day plant back interval (PBI) is required for all crops that are not 

on the label. 
Page 5 of 83

Hazard Identification

An extensive toxicity database for fluxapyroxad was submitted to the Agency for 

registration of fluxapyroxad. This database is sufficient for hazard characterization and endpoint 

selection for the anticipated routes (oral, dermal, and inhalation) and durations of exposure 

(acute, subchronic, and chronic) for the proposed uses. 

The primary target organ for fluxapyroxad exposure via the oral route is the liver with 

secondary toxicity in the thyroid for rats only. Liver toxicity was observed in rats, mice, and 

dogs, with species differences in both the time of onset, sensitivity, and nature of effects. Rats 

were the most sensitive species for all durations of exposure. In rats, adaptive effects of 

hepatocellular hypertrophy and increased liver weights and changes in liver enzyme activities 

were first observed. As the dose or duration of exposure to fluxapyroxad increased, clinical 

chemistry changes related to liver function also occurred, followed by hepatocellular necrosis, 

neoplastic changes in the liver, and tumors. Thyroid effects were observed only in rats. These 

effects were secondary to changes in liver enzyme regulation, which increased metabolism of 

thyroid hormone, resulting changes in thyroid hormones, thyroid follicular hypertrophy and 

hyperplasia, and thyroid tumor formation. Tumors were not observed in species other than rats 

or in organs other than the liver and thyroid. The Agency classified fluxapyroxad as “not likely” 

to cause tumors in humans based on convincing evidence that carcinogenic effects are not likely

below a defined dose range. This classification was based on a full panel of in vitro and in vivio

studies that showed no evidence of genotoxicity, together with mechanistic studies in the liver 

and thyroid of rats that satisfied stringent criteria for establishing tumorgenic modes of action. 

No evidence of neurotoxicity was observed in response to repeated administration of 

fluxapyroxad. An acute neurotoxicity study showed decreased rearing and motor activity. This 

occurred on the day of dosing only in the absence of histopathological effects or alterations in 

brain weights. This indicated that any neurotoxic effects of fluxapyroxad are likely to be 

transient and reversible due to alterations in neuropharmacology and not from neuronal damage. 

No evidence of reproductive toxicity was observed. Developmental effects observed in both 

rats and mice (thyroid follicular hypertrophy and hyperplasia in rats and decreased defecation, 

food consumption, body weight/body weight gain, and increased litter loss in rabbits) occurred at 

the same doses as those that caused adverse effects in maternal animals, indicating no 

quantitative susceptibility. Since the maternal toxicities of thyroid hormone perturbation in rats 

and systemic toxicity in rabbits likely contributed to the observed developmental effects there is 

low concern for qualitative susceptibility. An immunotoxicity study in mice showed no evidence 

of immunotoxic effects from fluxapyroxad. 

The Agency has determined that the 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 fluxapyroxad. 

Fluxapyroxad acute toxicity to mammals is low by all routes of exposure.

No hazards were identified for exposures via the dermal route in dermal toxicity studies. Oral 
Page 6 of 83

studies were extrapolated for assessment of inhalation hazards, since no repeated-dose inhalation 

studies were available. However, an inhalation study is not required at this time.

Dose Response Assessment

Toxicological points of departure (PODs) were selected for dietary/drinking water and 

occupational exposure scenarios for this assessment. Acute and chronic reference doses (RfDs) 

were selected for assessment of food and drinking water exposures. The population adjusted 

dose (PAD) is equivalent to the reference dose (RfD) divided by the additional FQPA Safety

Factor, which was reduced to 1X. An acute RfD/PAD for all populations was selected from an 

acute neurotoxicity study in rats based on decreased motor activity and decreased rearing. A 

chronic RfD/PAD for all populations was selected from a chronic toxicity/carcinogenicity study

in rats based on non-neoplastic changes in the liver (foci, masses). A POD for short-term 

inhalation exposure was selected from 28 day dietary study in rats based on thyroid effects 

(thyroid follicular hypertrophy/hyperplasia). A POD for intermediate-term inhalation exposure 

was selected from a 90 day dietary study in rats based also on thyroid effects. PODs for shortand intermediate-term dermal exposure were not selected because there was no systemic toxicity

up to the limit dose in the 28-day dermal toxicity study in rats. An uncertainty factor of 100x 

was applied to endpoints selected for all exposure routes (10x for interspecies extrapolation, 10x 

for intraspecies variation). 

Exposure/Risk Assessment and Risk Characterization

Dietary (food and water) and occupational exposure and risk assessments were conducted 

for cereal grains, legume vegetables, oil seed crops, peanuts, pome fruit, stone fruit, root and 

tuber vegetables, fruiting vegetables, and cotton. Worker inhalation exposures were assessed for 

handler and post-application activities. Screening level acute and moderately refined chronic 

dietary and drinking water risk assessments for fluxapyroxad show that dietary and drinking 

water exposure estimates for the proposed uses are below HED’s level of concern for the general 

population and all population subgroups. Occupational exposure and risk estimates indicate that 

worker handler and post-application exposures are not of concern at the maximum allowable 

application rates for the proposed new uses.

Use of Human Studies

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 studies, listed in Appendix D, 

have been determined to require a review of their ethical conduct. Some of these studies are also 

subject to review by the Human Studies Review Board. All of the studies used have received the 

appropriate review.
Page 7 of 83

2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies/Conditions of Registration

A revised Section F must be submitted. The Agency is denying the registrant’s requested 

tolerance for subgroup 1A. For future consideration of a tolerance for subgroup 1A, field trials 

on carrot and radish must be submitted. BASF Methods L0137/01 and L0140/02 will be 

submitted to the Analytical Chemistry Laboratory (ACL), and to FDA for updating PAM II, and 

to USDA for enforcement of tolerances in livestock commodities. The label must be revised as 

indicated in Section 2.3 below. 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The residue analytical methods available for enforcement of fluxapyroxad tolerances 

include the LC/MS/MS method used for data gathering and proposed for enforcement. This 

method uses reversed-phase HPLC with gradient elution, and includes 2 ion transitions to be 

monitored for the parent fluxapyroxad. 

2.2.2 International Harmonization

There are no Codex MRLs established for residues of fluxapyroxad in any commodities. 

International harmonization is not an issue at this time.

2.2.3 Recommended Tolerances

Pending submission of a revised Section B (see requirements under Directions for Use), 

and a revised Section F (see requirements under Proposed Tolerances), there are no residue 

chemistry issues that would preclude granting a Section 3 registration for the requested uses of 

fluxapyroxad, or establishment of tolerances for residues of fluxapyroxad as follows:

Tolerances are established for residues of fluxapyroxad, including its metabolites and 

degradates, in or on the commodities in Table 1. Compliance with the tolerance levels 

specified below is to be determined by measuring only fluxapyroxad [3-

(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-

carboxamide] in or on the commodity. 

Table 1. Proposed and Recommended Tolerances for Fluxapyroxad

Crop Group or 

Commodity

Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity Definition

Apple, wet pomace 3.5 2

Barley, bran 6 -- Calculated tolerance level (3.0 ppm) is the 

same as the Grain, Cereal, Group 15 tolerance, 
Page 8 of 83

Table 1. Proposed and Recommended Tolerances for Fluxapyroxad

Crop Group or 

Commodity

Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity Definition

so it is not needed.

Beet, sugar -- 0.1 Although there are not sufficient data to 

establish a tolerance on crop group 1A, there 

are no data deficiencies that would preclude the 

unconditional registration of sugar beets. 

Beet, sugar, dried pulp 0.16 0.1

Beet, sugar, tops 4 7

Cattle, fat 0.1 0.05 Rounded to 0.05 ppm.

Cattle, kidney 0.01 -- Covered by tolerance in/on meat byproducts

Cattle, liver 0.1 -- Covered by tolerance in/on meat byproducts

Cattle, meat 0.01 0.01

Cattle, meat byproducts 0.1 0.03

Corn, field, grain 0.1 0.01

Corn, oil, refined 0.05 0.03 Corn, oil

Corn, pop, grain --

0.01

Separate tolerance is needed because there is 

more than a 10x difference between the needed 

tolerance and the crop group tolerance.

Corn, sweet, kernels plus 

cobs with husks 

removed

-- 0.015 Separate tolerance is needed because there is 

more than a 10x difference between the needed 

tolerance and the crop group tolerance.

Cotton, undelinted seed 0.01 0.01

Cotton, gin byproducts 0.01 0.01

Egg 0.01 0.002

Fruit, pome, group 11 0.7 0.8

Fruit, stone, group 12 1.4 2

Goat, fat 0.1 0.05

Goat, kidney 0.01 -- Covered by tolerance in/on meat byproducts

Goat, liver 0.1 -- Covered by tolerance in/on meat byproducts

Goat, meat 0.01 0.01

Goat, meat byproducts 0.1 0.03

Grain, aspirated 

fractions

16.0 6

Grain, cereal, group 15, 

except field corn grain

2.5 3 Grain, cereal, group 15 (except field corn, 

except wheat) More than 10x difference: wheat 

0.3 ppm, sorghum 0.7 ppm, barley 2 ppm, rice 

3 ppm, sweet corn 0.15 ppm; wheat will be 

excluded from crop group as well.

Grain, cereal, forage, 

fodder and straw, group 

16

25 20 More than 10x difference – corn forage 2 ppm,

corn stover 5 ppm, wheat forage 10 ppm, wheat 

hay 15 ppm, wheat straw, 15 ppm, sorghum 

forage 4 ppm, stover 2 ppm, barley hay 15 

ppm, barley straw 20 ppm, rice straw 2 ppm. 

However, crop group tolerance will be set as is.

Hog, fat 0.01 -- Swine, fat – not needed – Category 3

Hog, liver 0.01 -- Swine, liver– not needed – Category 3

Hog, meat 0.01 -- Swine, meat– not needed – Category 3
Page 9 of 83

Table 1. Proposed and Recommended Tolerances for Fluxapyroxad

Crop Group or 

Commodity

Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity Definition

Hog, meat byproducts 0.01 -- Swine, meat byproducts– not needed –

Category 3

Horse, fat 0.1 0.05

Horse, kidney 0.01 -- Covered by tolerance in/on meat byproducts

Horse, liver 0.1 -- Covered by tolerance in/on meat byproducts

Horse, meat 0.01 0.01

Horse, meat byproducts 0.1 0.03

Milk 0.02 0.005

Milk, fat 0.1 -- A milk tolerance was established to harmonize 

with PMRA. A milk fat tolerance is/is not 

required because milk fat is account for through 

the milk tolerance. 

Oilseeds, group 20 0.6 0.9 Highest residue in canola was 0.84 ppm, 

rounded to 0.9 ppm

Peanut 0.02 0.01

Peanut, refined oil 0.06 0.02

Peanut, meal 0.03 -- Not needed, only 1.5x concentration

Plum, prune 4 3

Potato, wet peel 0.2 0.1

Poultry, byproducts 0.01 -- Not needed – estimated residues more than 10x 

lower than LOQ (Category 3)

Poultry, fat 0.01 -- Not needed – estimated residues more than 10x 

lower than LOQ (Category 3)

Poultry, liver 0.01 -- Not needed – estimated residues more than 10x 

lower than LOQ (Category 3)

Poultry, meat 0.01 -- Not needed – estimated residues more than 10x 

lower than LOQ (Category 3)

Poultry, skin 0.01 -- Not needed – estimated residues more than 10x 

lower than LOQ (Category 3)

Rapeseed, 

(cultivars/varieties 

and/or hybrids including 

canola and crambe

0.60 --

not needed, included in oilseeds, group 20

Rice, bran 4.5 4.5

Rice hulls 10 8 Rice, hulls 

Sheep, fat 0.1 0.03

Sheep, kidney 0.01 0.01 Covered by tolerance in/on meat byproducts

Sheep, liver 0.1 0.02 Covered by tolerance in/on meat byproducts

Sheep, meat 0.01 0.01

Sheep, meat byproducts 0.1 0.03

Soybean, hulls 6.5 0.3

Soybean, seed 0.2 0.15

Sunflower, seed 0.60 -- Not needed, included in oilseed, group 20

Vegetable, Foliage of 

legume, group 7

18 30

Vegetables, Fruiting, 0.6 0.7
Page 10 of 83

Table 1. Proposed and Recommended Tolerances for Fluxapyroxad

Crop Group or 

Commodity

Proposed 

Tolerance 

(ppm)

Recommended 

Tolerance (ppm)

Comments; Correct Commodity Definition

group 8

Vegetable, legume, dried 

shelled (except soybean)

subgroup 6C

0.35 0.4

Pea and bean, dried shelled, except soybean, 

subgroup 6C 

Vegetable, legume, 

edible podded, subgroup 

6A

1.4 2

Vegetable, legume,

succulent shelled,

subgroup 6B

0.45 0.5

Pea and bean, succulent shelled, subgroup 6B

Vegetable, root, 

subgroup 1A

0.1 -- Beet, sugar. Data was only submitted for sugar 

beets. No data were submitted for the other 

two representative commodities of the crop 

subgroup (carrot and radish). A crop subgroup 

tolerance is not possible. Field trial data for 

carrot and radish are also required to establish a 

crop group tolerance.

Vegetable, tuberous and 

corm, subgroup 1C

0.04 0.02

Vegetable, tuberous and 

corm, except potato, 

subgroup 1D

0.04 -- Tolerance on this subgroup is not needed since 

all commodities are included in subgroup 1C

Wheat, bran 6 0.6

Wheat, germ 3 -- Not needed, concentration is only 1.5x

Wheat, grain -- 0.3 Tolerance is set separately from crop group 

tolerance because residues in wheat grain are 

more than 5x lower than the highest residue.

2.2.4 Revisions to Petitioned-For Tolerances

As noted in section 2.2.3 HED has recommended for different tolerances than proposed 

by the registrant. HED has used the OECD calculator to determine the appropriate tolerances.

2.3 Label Recommendations

The label must be revised to delete use on root and tuber vegetables, subgroup 1A. Only

use on sugar beets from subgroup 1A is allowed. The petitioner must clarify the PHI for 

peanuts. The 365 day plant back interval must remain on the label.
3.0 INGREDIENT PROFILE 

3.1 Chemical Identity 

TABLE 2. Fluxapyroxad Test Compound Nomenclature.

Chemical structure

Common name Fluxapyroxad (ISO, proposed)

Company experimental name BAS 700 F

IUPAC name 3-(difluoromethyl)

CAS name 3-(difluoromethyl)

carboxamide

CAS # 907204

Molecular Formula C18H12

End-use product/EP Xemium Technical, BAS 700 01F, BAS 700 02F, BAS 700 03F, BAS 700 04F

3.2 Physical/Chemical Characteristics

A detailed description of the physiciochemical properties of fluxapyroxad is provided in 

Appendix C. Fluxapyroxad exhibits relatively low solubility in water and higher solubility in 

organic solvents. It has a very low vapor pressure

persistent in terrestrial and aquatic environments and is moderately to slightly mobile in soil. 

Fluxapyroxad does not present significant concerns for bioaccumulation based on the 

lipophilicity of the compound and on results of bioconce

3.3 Pesticide Use Pattern

Fluxapyroxad is a fungicide belonging to the carboxamide class of chemicals. It is a new 

active ingredient proposed for use on a wide range of crops to control a broad spectrum of fungal 

diseases. Product registrations and proposed use patterns and form

Table 3.

Page 11 of 83

INGREDIENT PROFILE 

Fluxapyroxad Test Compound Nomenclature.

 

Fluxapyroxad (ISO, proposed)

BAS 700 F

(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluorobiphenyl-2-yl)pyrazole

(difluoromethyl)-1-methyl-N-(3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)-1

carboxamide

907204-31-3

12F5N3O

Xemium Technical, BAS 700 01F, BAS 700 02F, BAS 700 03F, BAS 700 04F

Physical/Chemical Characteristics

A detailed description of the physiciochemical properties of fluxapyroxad is provided in 

Appendix C. Fluxapyroxad exhibits relatively low solubility in water and higher solubility in 

ery low vapor pressure (6.1 x 10-11 Torr at 25 ̊ C). Fluxapyroxad is 

persistent in terrestrial and aquatic environments and is moderately to slightly mobile in soil. 

Fluxapyroxad does not present significant concerns for bioaccumulation based on the 

lipophilicity of the compound and on results of bioconcentration studies in fish. 

Fluxapyroxad is a fungicide belonging to the carboxamide class of chemicals. It is a new 

active ingredient proposed for use on a wide range of crops to control a broad spectrum of fungal 

roduct registrations and proposed use patterns and formulations are provided in 

yl)pyrazole-4-carboxamide 

1H-pyrazole-4-

Xemium Technical, BAS 700 01F, BAS 700 02F, BAS 700 03F, BAS 700 04F

A detailed description of the physiciochemical properties of fluxapyroxad is provided in 

Appendix C. Fluxapyroxad exhibits relatively low solubility in water and higher solubility in 

Fluxapyroxad is 

persistent in terrestrial and aquatic environments and is moderately to slightly mobile in soil. 

Fluxapyroxad does not present significant concerns for bioaccumulation based on the 

 

Fluxapyroxad is a fungicide belonging to the carboxamide class of chemicals. It is a new 

active ingredient proposed for use on a wide range of crops to control a broad spectrum of fungal 

lations are provided in 
Page 12 of 83

Table 3. Summary of Directions for Use of Fluxapyroxad 

Applic. Timing, 

Type, and Equip.

Formulation Applic. Rate

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Cereal Grains

Foliar spray

Ground, Aerial or 

Chemigation

5.96% EC

26.55% EC

21.26% EC

14.33% EC

0.09 2 0.18 21

Use Directions and Limitations: A minimum 7-day RTI is specified. Applications may be begin at emergence, but typical 

applications begin as plants touch across rows. A 7 day PHI is allowed for sweet corn only.

Seed Treatment 28.7% SC 0.01 Not provided Not applicable Not applicable

Use Directions and Limitations: Rate is expressed in lb ai/100 lb seed. Apply in enough water to ensure adequate coverage, but 

without damaging the seed. A higher rate of 0.02 lb ai/100 lb seed is allowed on sweet corn and sorghum seed. A higher rate of 

0.05 lb ai/100 lb seed is allowed on wheat seed.

Cotton, Sunflower

Seed Treatment 28.7% SC 0.0103 Not provided Not applicable Not applicable

Use Directions and Limitations: Rate is expressed in lb ai/100 lb seed. Apply in enough water to ensure adequate coverage, but 

without damaging the seed. A higher rate of 0.02 lb ai/100 lb seed is allowed on sweet corn and sorghum seed. A higher rate of 

0.05 lb ai/100 lb seed is allowed on wheat seed.

Oilseeds, Dried Shelled Peas, Soybeans

Foliar spray

Ground, aerial or 

chemigation

5.96% (0.52 lb/gal) EC

26.55% (2.47 lb/gal) EC

21.26% (2.09 lb/gal) EC

14.33% (1.39 lb/gal) EC

0.09 2 0.18 7 

Use Directions and Limitations: A minimum 7-day RTI is specified. Applications may be begin at emergence, but typical 

applications begin as plants touch across rows. DO NOT harvest for forage, green chop, vines, or hay within 7 days of last 

application (14 days for 1.39 and 2.09 lb/gal EC). Do not feed soybean hay for 14 days after application (21 days for 2.09 

lb/gal EC). No livestock feeding restrictions for oilseeds. 

Dried Shelled Beans

Foliar spray

Ground, aerial or 

chemigation

5.96% (0.52 lb/gal) EC

26.55% (2.47 lb/gal) EC

21.26% (2.09 lb/gal) EC

14.33% (1.39 lb/gal) EC

0.18 2 0.36 7 

Use Directions and Limitations: A minimum 7-day RTI is specified. Applications may be begin at emergence, but typical 

applications begin as plants touch across rows. DO NOT harvest for forage, green chop, vines, or hay within 7 days of last 

application (14 days for 1.39 and 2.09 lb/gal EC).

Edible Podded Legume Vegetables, Succulent Shelled Beans and Peas

Foliar spray

Ground, aerial or 

chemigation

5.96% (0.52 lb/gal) EC

26.55% (2.47 lb/gal) EC

21.26% (2.09 lb/gal) EC

14.33% (1.39 lb/gal) EC

0.09 2 0.18 7

Use Directions and Limitations: A minimum 7-day RTI is specified. Applications may be begin at emergence, but typical 

applications begin as plants touch across rows. DO NOT harvest for forage, green chop, vines, or hay within 7 days of last 

application (14 days for 1.39 and 2.09 lb/gal EC). 

Fruiting Vegetables Group, Sugar Beets, Tuberous & Corm Vegetables Subgroup

Foliar spray 5.96% (0.52 lb/gal) EC 0.09 3 0.27 7
Page 13 of 83

Table 3. Summary of Directions for Use of Fluxapyroxad 

Applic. Timing, 

Type, and Equip.

Formulation Applic. Rate

(lb ai/A)

Max. No. 

Applic. per 

Season

Max. Seasonal 

Applic. Rate

(lb ai/A)

PHI

(days)

Ground, aerial or 

chemigation

26.55% (2.47 lb/gal) EC

21.26% (2.09 lb/gal) EC

14.33% (1.39 lb/gal) EC

Use Directions and Limitations: A minimum 7-day RTI is specified (14 days for sugar beets). Apply a minimum of 20 gallons 

of spray volume per acre, and increase the spray volume as the plants grow during the season. Spray volume should be 

proportional to the amount of plant tissue to be covered such that 100 gallons of spray per acre is used on mature plants. DO

NOT make more than two (2) consecutive applications of fluxapyroxad before alternating to a labeled fungicide with a different 

mode of action. Sugar beet leaves, roots and tops may be fed no sooner than 7 days after last application. Use of the 2.09 lb/gal 

EC on sugar beets is not permitted.

Peanut

Foliar spray

Ground, aerial or 

chemigation

5.96% (0.52 lb/gal) EC

26.55% (2.47 lb/gal) EC

14.33% (1.39 lb/gal) EC

0.09 3 0.27 7

Use Directions and Limitations: A minimum 14-day RTI is specified. DO NOT make more than two (2) consecutive 

applications of fluxapyroxad before alternating to a labeled fungicide with a different mode of action. Do not graze or harvest 

for peanut forage. The 1.39 lb/gal EC label states that a 7 day PHI is required in the crop specific use directions, and 14 days in 

the overview table.

Pome Fruit Group

Foliar spray

Ground, aerial or 

chemigation

5.96% (0.52 lb/gal) EC

26.55% (2.47 lb/gal) EC

21.26% (2.09 lb/gal) EC

14.33% (1.39 lb/gal) EC

0.09 4 0.36 0

Use Directions and Limitations: Do not use less than 10 gallons of spray solution per acre. A minimum 7-day RTI is specified. 

DO NOT make more than two (2) consecutive applications of fluxapyroxad before alternating to a labeled fungicide with a 

different mode of action. No restriction on livestock grazing or feeding.

Stone Fruit Group

Foliar spray

Ground, aerial or 

chemigation

5.96% (0.52 lb/gal) EC

26.55% (2.47 lb/gal) EC

21.26% (2.09 lb/gal) EC

14.33% (1.39 lb/gal) EC

0.11 3 0.33 0

Use Directions and Limitations: Do not use less than 10 gallons of spray solution per acre. A minimum 7-day RTI is specified. 

DO NOT make more than two (2) consecutive applications of fluxapyroxad before alternating to a labeled fungicide with a 

different mode of action.

3.4 Anticipated Exposure Pathways

Dietary (food and water) and occupational exposures via dermal and inhalation pathways 

are expected based on proposed uses of fluxapyroxad on a variety of food commodities. Acute 

and chronic dietary exposure and risk assessments were conducted for the proposed uses. HED 

assessed occupational exposure and risk from proposed uses of fluxapyroxad for seed and foliar 

applications on cereal grains, sorghum, legume vegetables (succulent and dry), oil seed crops 

(canola and sunflower), peanuts, pome fruit, stone fruit, root and tuber vegetables (potatoes and 

sugar beets), fruiting vegetables, and cotton. Worker exposures were assessed for handler and 
Page 14 of 83

post-application activities. There are no residential uses for fluxapyroxad so residential exposure 

to children via incidental oral activities is not anticipated. 

3.5 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.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, 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. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas postapplication 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/ASSESSMENT

4.1 Toxicology Studies Available for Analysis

An extensive toxicity database for fluxapyroxad was submitted to the Agency for 

registration of fluxapyroxad. Submitted studies via the oral route cover durations and endpoints 

relevant for hazard characterization for acute and chronic dietary assessments. These studies 

include metabolism and pharmacokinetic studies, subchronic and chronic dietary studies in rats, 

mice, and dogs; prenatal developmental studies in rats and rabbits, a 2-generation reproduction 

and fertility effects study in rats, acute and subchronic neurotoxicity studies in rats, an 

immunotoxicity study in mice, a complete battery of in vitro and in vivo genotoxicity studies, 

and carcinogenicity studies in rats and mice. Supplemental studies were submitted to further 

investigate the mode of action of fluxapyroxad on the liver and thyroid. These studies, together 

with a dermal toxicity study and dermal penetration study, are also appropriate for hazard 

characterization for short-term to intermediate-term exposures via the dermal route. 

Occupational exposures are also anticipated via the inhalation route, but no subchronic inhalation 

study was submitted. Therefore, extrapolation from oral studies appropriate for short-term to 

intermediate-term exposures will be used for inhalation hazard characterization. A subchronic 

inhalation study is not required at this time. There are no toxicity studies available for 

fluxapyroxad in the general literature, as it is a new active ingredient. 

Acute toxicity studies (acute oral, dermal, and inhalation studies in rats, eye irritation and 

dermal irritation studies in rabbits, and a skin sensitization study in guinea pigs) were also 
Page 15 of 83

submitted for each formulation for labeling purposes that can also inform hazard 

characterization. 

There are three metabolites of fluxapyroxad: two soil metabolites (M700F001 and 

M700F002) and a metabolite found on food crops (M700F048). There are no toxicity studies of 

these metabolites in the general literature. However, subchronic dietary studies in rats, prenatal 

developmental studies in rabbits, and a complete battery of in vitro and in vivo genotoxicity

studies were submitted to the Agency for these metabolites. Metabolism and pharmacokinetic 

studies were also submitted for the M700F048 plant metabolite. These studies are sufficient for 

hazard characterization. 

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

Pharmacokinetic and metabolism studies with radiolabeled fluxapyroxad in rats show that 

plasma levels of radiolabel scaled with dose, indicating that uptake was not saturated up to dose 

levels of 500 mg/kg. There were no sex differences observed in the rate or extent of absorption. 

The time to peak plasma levels (tMAX) was dependent upon on dose, and ranged from 1 hour (at 5 

mg/kg) to 24 hours (at 500 mg/kg) with maximum mean plasma concentrations (CMAX) ranging 

from 1.85/1.57 μg Eq/g to 65.31/66.08 μg Eq/g in males/females. Areas under the curve (AUCs) 

ranged from 45.4/35.7 μg Eq h/g (at 500 mg/kg) to 4215.2/5667.4 μg Eq h/g (at 5 mg/kg) in 

males/females. The initial half-life of elimination ranged from 14.5/12.0 h (at 5 mg/kg) to 

27.3/24.5 h (at 500 mg/kg) in males/females. 

Mass balance, tissue distribution and biliary excretion studies were performed in rats at 

doses of 150 mg/kg and 7.5 mg/kg. These studies indicated that radioactivity was widely 

distributed in both sexes within 16 hours, with bioavailability estimated to be between 65-80%. 

A similar pattern of distribution was observed in males and females: the highest concentrations 

were found in the gut contents and stomach contents. However, lower concentrations were 

found in numerous other organs/tissues, including the liver, thyroid, adrenal glands, kidney, 

pancreas, testes/uterus, and brain. For both male and female rats, radioactivity declined in all 

tissues over time. The time course of the amount of radioactivity found in urine and feces 

indicated the excretion occurred predominantly within three days after dosing, indicating a low 

potential for bioaccumulation. For both dose groups, the majority of the radioactivity (84-94%) 

was excreted via the feces within 168 hours. The amount excreted via the urine during this time 

was 3-17%. Bile duct cannulation experiments showed that the bile was a major route of 

excretion, with 51-64% of radioactivity eliminated via this route. Negligible amounts were 

excreted as expired air in rats. Residue chemistry studies in ruminants indicated that 

fluxpyroxad and metabolites are excreted in milk. 

Metabolism studies revealed that the main biotransformation steps of BAS 700 F in rats 

are hydroxylation at the biphenyl ring system (sometimes repeatedly), N-demethylation at the 

pyrazole ring system, loss of a fluorine atom at the biphenyl ring system, and conjugation with 

glucuronic acid or sulfate, and conjugation with glutathione derivatives. These reactions 

produced approximately 51 different metabolites. Minor biotransformation steps produced 
Page 16 of 83

additional metabolites, including M700F001 (from hydrolysis of the amide bond between the 

pyrazole and biphenyl rings) and M700F002 (from N-demethylation of M700F001). These 

metabolites were also found in soil, as described below. 

No information was provided on the pharmacokinetics and metabolism of the soil 

metabolite M700F001 or impurities. Pharmacokinetic studies in rats showed that the soil 

metabolite M700F002 was systemically bioavailable and distributed to the bone marrow, blood 

and liver after oral administration. Pharmacokinetic and metabolism in rats on the plant 

metabolite M700F048 also showed systemic bioavailability with distribution to the bone 

marrow, blood, and liver after administration via the oral route. Excretion was primarily via the 

feces in both sexes, and was rapid (within 12-24 hours of dosing). 

A dermal penetration study was submitted by the registrant that utilized the BAS 703 02 

F formulation, which contains both fluxapyroxad and pyraclostrobin (BAS 500F). The Agency

calculated a dermal absorption factor of 8.4% at dose of 5.6 μg/cm2for potential use in future 

risk assessments. 

4.3 Toxicological Effects

In mammals, the primary target organ for fluxapyroxad exposure via the oral route is the 

liver. Liver toxicity in response to fluxapyroxad via the oral route was observed in several 

species: rats, mice, and dogs. The sensitivity to liver toxicity and the development and 

manifestations of liver toxicity over time varied with species. In rats, the most sensitive species, 

adaptive effects of hepatocellular hypertrophy and increased liver weights and changes in liver 

enzyme activities were first observed. As the dose or duration of exposure to fluxapyroxad 

increased, clinical chemistry changes related to liver function were observed, followed by

hepatocellular necrosis and neoplastic liver changes (foci, masses), which were considered 

adverse effects. Liver toxicity was also observed in mice and dogs. In subchronic studies in 

mice, increased liver weights were observed along with fatty changes in the liver, with few 

observations of hepatocellular hypertrophy. At higher doses, liver necrosis was also observed. 

Liver effects in subchronic studies in dogs were limited to increased liver weights at high doses. 

However, in chronic studies, increased liver weights were observed in conjunction with fibrosis 

and cirrhosis.

Fluxapyroxad administration via the oral route resulted in toxic effects in the thyroid. 

These thyroid effects occurred secondary to the effects on the liver and were seen only in rats. 

Thyroid effects in rats were observed throughout the toxicity database and included changes in 

serum thyroid hormone levels, enlarged thyroid, increased thyroid weights, and/or microscopic 

effects of thyroid follicular hypertrophy and hyperplasia. These effects showed a clear threshold, 

were evident within weeks and were observed out to two years. Although these effects were 

observed in male and female rats, males were usually more sensitive. Threshold doses at which 

thyroid effects occurred in the rat were accompanied by changes in the liver that were considered 

adaptive or potentially adverse. These changes included increased liver weights, hepatocellular 

hypertrophy, and changes in liver-associated clinical chemistry parameters. These results 
Page 17 of 83

suggested that the effects in the thyroid were secondary to fluxapyroxad-induced changes in 

thyroid hormone metabolism by the liver and not due to direct action of fluxapyroxad on the 

thyroid. Supplementary studies (including a perchlorate discharge assay and measurement of T4-

metaboilizing Phase II enzyme activities) confirmed indirect thyroid effects. The most sensitive 

of these thyroid effects are perturbations in thyroid hormone levels, which occur temporally

before histopathological alternations in the thyroid. 

Chronic oral administration of fluxapyroxad resulted in treatment-related liver tumors in 

male and female rats and thyroid tumors in male rats only. No tumors were observed in male or 

female mice. Also, no evidence of mutations or chromosomal damage were observed in a panel 

of guideline in vitro assays, and no evidence of chromosomal damage was observed in a 

guideline mouse erythrocyte micronucleus study in vivo. Together, these data indicated that the 

thyroid and liver tumors observed in rats were due to non-genotoxic and/or species-related 

factors and not due to genotoxic effects. Supplemental studies supporting non-genotoxic modes 

of action for liver and thyroid tumors also indicated clear thresholds protective for tumorgenic 

effects. 

Although the primary effects of oral fluxapyroxad exposure were on the thyroid and liver, 

effects in other organ systems were also noted. However, the doses at which these other effects 

occurred exceeded those of the liver and thyroid effects. Treatment-related effects of decreased 

rearing (in males only) and decreased motor activity (in both sexes) were observed after dosing 

via oral gavage in the acute neurotoxicity study. These effects were considered equivocal for 

neurotoxcity, since they may indicate transient and reversible neurotoxicity from a bolus 

exposure and/or general malaise. There were no neurotoxic effects observed in the subchronic 

dietary toxicity study. Fluxapyroxad did not cause reproductive toxicity in rats. Developmental 

toxicity in rats was limited to decreased body weight and body weight gain in offspring and was 

observed at the same dose levels that caused thyroid dysregulation in parental animals. 

Developmental toxicity in rabbits was limited to paw hyperflexion, a malformation that usually

reverses as the animal matures, and was observed at the same dose levels that caused reduced 

maternal body weight. There were clear NOAELs for these developmental effects. 

An unusual effect of tooth whitening was observed was observed in rats in several 

studies. This effect was observed with increasing oral doses of fluxapyroxad. This was likely

due to decreased deposition of a yellow iron-containing pigment in the "outer outer enamel” 

layer of the teeth. Bone thickening and white discoloration of the skull bones were also 

observed, as was increased deposition of Perl’s Prussian Blue stain (indicative of iron) in other 

bone tissues. These effects in the teeth and bones suggested treatment-related changes in iron 

storage, but there was no evidence of microscopic damage to these tissues or clinical evidence of 

compromised tissue function. . The Agency considered the potential for flurosis to result from 

any fluoride released during metabolism of fluxpyroxad. The Agency concluded that it is 

unlikely that fluxapyroxad would cause fluorosis because detailed histopathological evaluation 

of the teeth did not show changes consistent withfluorosis at the highest dose in parental and F1 

males of the rat 2-generation reproduction and fertility effects study. 
Page 18 of 83

Immunotoxicity was investigated via the oral route in male mice. No immunotoxic 

effects of fluxapyroxad were observed at doses up to and including the limit dose. 

A dermal toxicity study in rats was the only route-specific study that was submitted for

occupational assessments. No toxic effects of fluxapyroxad were observed at doses up to and 

including the limit dose. 

Acute toxicity studies show that fluxapyroxad exhibits low acute toxicity by all exposure 

routes (EPA Toxicity Category III or IV) and is not a dermal sensitizer.

Subchronic oral toxicity studies in rats, developmental toxicity studies in rabbits, and in 

vitro and in vivo genotoxicity studies were performed for fluxapyroxad metabolites F700F001, 

M700F002, and M700F048. The Agency considers these studies sufficient for hazard 

identification and characterization. Like fluxapyroxad, no genotoxic effects were observed for 

any of these metabolites. All three metabolites displayed lower subchronic toxicity via the oral 

route than fluxapyroxad, with evidence of non-specific toxicity (decreased body weight) 

observed only for M700F0048 at the limit dose. Only M700F0048 exhibited developmental 

toxicity at doses similar to those that caused developmental effects in rabbits with fluxapyroxad 

treatment. However, these effects (abortions and resorptions) were of a different nature than for 

fluxapyroxad (paw hyperflexion) and are likely secondary to maternal toxicity. These data are 

sufficient for the Agency to conclude that these metabolites do not have hazards that exceed 

those of fluxapyroxad in nature, severity, or potency. 

The complete toxicity profile for fluxapyroxad is provided in Appendix A.

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

The FQPA Safety Factor is reduced to 1X. This reduction is based on the availability of 

a complete toxicity database with clear NOAELs for characterizing neurotoxicity and sensitivity

during development, supplemental studies that characterize the effects fluxapyroxad on thyroid 

hormones, and no residual uncertainties in the exposure data base. The information used to 

reduce uncertainties in hazard and exposure of infants and children is described in detail below.

4.4.1 Completeness of the Toxicology Database

The Agency considers the toxicity database used to characterize the hazards of 

fluxapyroxad to infants and children as complete. A 2-generation reproductive and 

developmental toxicity study in rats and developmental toxicity studies in rats and rabbits are 

available to assess the quantitative and qualitative susceptibility of the fetus, infants, and children 

to fluxapyroxad. In addition to these lifestage-specific studies, a full toxicity database of 

guideline and supplemental studies available in adult animals to evaluate neurotoxicity, 

immunotoxicity, genotoxicity, and thyroid effects. 
Page 19 of 83

4.4.2 Evidence of Neurotoxicity

Acute and subchronic neurotoxicity studies are available for fluxapyroxad. Treatmentrelated effects of decreased rearing and motor activity were observed only in the acute 

neurotoxicity study and only on the day of dosing. These effects are equivocal, as they may

indicate transient and reversible neurotoxicity and/or general malaise. No developmental 

neurotoxicity study is available for fluxapyroxad. However, the Agency has considered the 

potential for fluxapyroxad to cause developmental neurotoxicity as a result of thyroid hormone 

disruption, which is more sensitive than the endpoints used in a developmental neurotoxicity

study. The Agency has evaluated supplemental thyroid hormone data submitted by the registrant 

and considered the ontogeny of thyroid hormone metabolism to determine that adverse thyroid 

hormone disruptions in the young are unlikely to occur at dose levels similar to the points of 

departure chosen for risk assessment. The Agency has low concern for neurotoxic effects of 

fluxapyroxad at any life stage. 

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

No evidence of quantitative susceptibility was observed in a reproductive and 

developmental toxicity study in rats or in developmental toxicity studies in rats and rabbits. 

Developmental toxicity in rats in a 2 generation study was limited to decreased body weight and 

body weight gain in offspring and was observed at the same dose levels that caused thyroid 

follicular hypertrophy/hyperplasia in parental animals. However, low birth weights, which can 

result from thyroid dysregulation in maternal animals, was observed in the first generation only, 

with no decreased body weights observed in the second generation until lactation day 7. 

Developmental toxicity in rabbits was limited to paw hyperflexion, a malformation that is not 

considered to result from a single exposure and that usually reverses as the animal matures. This 

effect was observed in untreated controls and all treatment groups but was significantly increased 

only at the high dose at which reduced maternal body weight was also observed. Although these 

developmental effects differed from the maternal effects and so indicate qualitative 

susceptibility, these developmental effects are of low concern to the Agency. The Agency’s 

rationale for low concern for developmental toxicity is that these effects were of low severity, 

were likely secondary to maternal toxicity, and demonstrated clear NOAELs. Nonetheless, the 

risk assessment is protective of paw hyperflexion because this effect occurs at dose levels higher 

than the points of departure selected for risk assessment for repeat-exposure scenarios.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The residue data base is 

adequate. The dietary risk assessment is conservative and will not underestimate dietary

exposure to fluxapyroxad. There are no residential uses proposed for fluxapyroxad. 
Page 20 of 83

4.5 Toxicity Endpoint and Point of Departure Selection

4.5.1 Dose-Response Assessment

Acute and chronic dietary endpoints were selected from acute, subchronic, and chronic 

oral toxicity studies in the database for fluxapyroxad. The endpoint of decreased motor activity

and decreased rearing identified in the acute neurotoxicity study in rats was chosen for the acute 

dietary endpoint because it is clearly adverse and clearly results from a single exposure. Paw 

hyperflexion was not considered to be a single-dose effect and thus was not selected for an acute 

endpoint. No other endpoints in the toxicity database for fluxapyroxad were identified that were 

likely to result from a single exposure. The endpoint of liver foci and masses identified in the 

chronic toxicity/carcinogenicity study in rats was chosen for the chronic dietary endpoint. The 

duration of exposure in this study is appropriate for a chronic dietary endpoint and the point of 

departure at this endpoint is protective for all adverse effects in rats and other species that occur 

at higher doses and/or for shorter durations of exposure. 

There are no residential uses for fluxapyroxad and so residential risks will not be 

assessed. However, endpoints were chosen for occupational exposure scenarios. A dermal 

toxicity study was selected for short-term and intermediate-term dermal scenarios because it is a 

route-specific study that also assessed all of the endpoints used in the other exposure scenarios 

and durations of exposure (e.g. neurological endpoints, thyroid and liver histopathology). 

Although developmental toxicity was not assessed in the dermal toxicity study, the Agency has 

low concern for developmental toxicity because the only observed effect, paw hyperflexion, was 

likely secondary to maternal toxicity and is not considered severe, since this effect is usually

reversible as the animal matures. No hazard was identified at the limit dose in the dermal 

toxicity study. No inhalation studies were available for short-term and intermediate-term 

inhalation scenarios. Therefore, endpoints from oral studies were evaluated. The endpoint of 

changes in thyroid hormones and thyroid follicular hypertrophy/hyperplasia from the 28-day oral 

study in rats was identified for short-term inhalation. This is the most sensitive endpoint in the 

most sensitive species for an adverse effect for a duration of exposure ranging from 1-30 days. 

The endpoint of thyroid follicular hypertrophy/hyperplasia was identified from the 90 day oral 

toxicity study in rats for intermediate-term inhalation. This endpoint was chosen because the 

duration of exposure is relevant to a 1-6 month intermediate-term exposure and this was the most 

sensitive endpoint in the most sensitive species. Although thyroid hormones were not measured 

in the dermal study, calculation of dermal equivalency dose from the developmental study and 

dermal absorption data indicates that a dermal endpoint is not required for this effect. 

4.5.2 Recommendation for Combining Exposure Routes

Under FQPA, when there are potential residential exposures to a pesticide, HED must 

aggregate exposures from three major sources: oral, dermal and inhalation exposures. These 

combined residential exposures must then be aggregated with exposure from food and water to 

determine aggregate risk. Since there are no residential incidental oral exposures to 

fluxapyroxad, aggregate exposure from food and non-food oral exposures is not required. 
Page 21 of 83

4.5.3 Cancer Classification

Tumors related to fluxapyroxad treatment were observed in the liver of male and female 

rats and in the thyroid in male rats only. Males were more sensitive than females to the 

tumorgenic effects of fluxapyroxad in the liver. The combined incidence of liver adenomas and 

carcinomas in males ranged from 10% at 11 mg/kg bw/day to 43% at 145 mg/kg bw/day

compared to 2% in controls. For females, the combined incidence of adenomas and carcinomas 

ranged from 8% at 82 mg/kg bw/day to 14% at 182 mg/kg bw/day compared to 2% in controls. 

Dose and temporal concordance data supported a non-genotoxic mitogenic MOA for liver 

adenomas and carcinomas in rats. This MOA is based on early changes in liver enzyme 

regulation and increased cell proliferation that lead to microscopic and macroscopic foci and 

then to adenoma and carcinoma formation. The endpoint of changes in liver enzyme regulation 

at 2.1/2.7 mg/kg bw/day in males/females provides a clear threshold for liver tumors. 

The incidence of treatment-related combined thyroid follicular adenomas and carcinomas 

in male rats ranged from 15% at 68 mg/kg bw/day to 18% at 145 mg/kg bw/day compared to 5% 

in controls. Dose and temporal concordance data supported a MOA for thyroid tumorgenesis in 

rats in which early changes in liver enzyme regulation lead to dysregulation of thyroid hormone 

homeostasis, thyroid follicular hypertrophy/hyperplasia, and thyroid tumors. The endpoint of 

changes in liver enzyme regulation at 2.1/2.7 mg/kg bw/day in males/females provides a clear 

threshold for thyroid tumors. 

In accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment (March, 

2005), the CARC classified fluxapyroxad as “Not likely to be Carcinogenic to Humans” based 

on convincing evidence that carcinogenic effects are not likely below a defined dose range (J. 

Kidwell, June 9, 2011, TXR 0055930). This decision was based on the following considerations:

(i) No treatment-related tumors were seen in male or female mice when tested at doses 

that were adequate to assess carcinogenicity (including the Limit Dose);

(ii) Treatment-related liver tumors were seen in male rats at doses > 250 ppm (11 

mg/kg/day) and in female rats at doses > 1500 ppm (82 mg/kg/day);

(iii) Treatment-related thyroid follicular cell tumors were seen in male rats only at doses >

1500 ppm (68 mg/kg/day);

(iv) There is no mutagenicity concern from in vivo or in vitro assays;

(v) The hypothesized mode of action (i.e, a non-genotoxic) for each tumor type (i.e., the 

liver and thyroid) was supported by adequate studies that clearly identified the 

sequence of key events, dose-response concordance and temporal relationship to the 

tumor types. The mode of action met the criteria established by the Agency. The 

Agency does not have cancer concerns for workers because the proposed use patterns 

indicate that workers will not be exposed to fluxapyroxad for long enough periods at 

levels sufficient to induced liver and/or thyroid tumors. 
Page 22 of 83

4.5.4 Summary of Points of Departure Used in Risk Assessment

Toxicological doses/endpoints selected for the fluxapyroxad risk assessment are provided 

in Tables 4 and 5.

Table 4. Summary of Toxicological Doses and Endpoints for Fluxapyroxad for Use in Dietary and NonOccupational 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 

(General Population, 

including Infants and 

Children and Females 

13-49 years of age)

NOAEL= 

125 

mg/kg/day

UFA= 10 x

UFH=10 x

FQPA SF= 

1x

Acute RfD = 1.25 

mg/kg/day

aPAD=

1.25 mg/kg/day

Acute neurotoxicity study in rats

LOAEL = 500 mg/kg/day based on 

decreased motor activity (both sexes) 

and decreased rearing (males only)

Chronic Dietary (All 

Populations)

NOAEL= 

2.1

mg/kg/day

UFA= 10 x

UFH=10 x

FQPA SF= 

1x

Chronic RfD=

0.021

mg/kg/day

cPAD = 

0.021

mg/kg/day

Chronic toxicity/carcinogenicity study 

in rats 

LOAEL = 11 mg/kg/day based on 

non-neoplastic changes in the liver 

(foci, masses)

Cancer (oral, dermal, 

inhalation)

Classification: Not likely to be carcinogenic to humans at doses sufficient to induce liver 

and/or thyroid tumors. 

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). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = 

reference dose. MOA=mode of action. 

Table 5. Summary of Toxicological Doses and Endpoints for Fluxapyroxad 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 ShortTerm (1-30 

days)

NOAEL=

1000

mg/kg/day

UFA=10x

UFH=10x

NA: No hazard 

identified 

28-day dermal toxicity study in rats

LOAEL = Not observed 

Dermal 

IntermediateTerm (1-6 

months)

NOAEL=

1000 

mg/kg/day

UFA=10x

UFH=10x

NA: No hazard 

identified

28-day dermal toxicity study in rats

LOAEL = Not observed

Inhalation 

Short-Term (1-

30 days)

NOAEL=

9

mg/kg/day

UFA=10x

UFH=10x

Occupational 

LOC for MOE = 

100

28-day oral toxicity study in rats 

LOAEL = 176 mg/kg/day based on 

changes in thyroid hormones and thyroid 

follicular hypertrophy/hyperplasia 

Inhalation 

Intermediateterm (1-6 

months)

NOAEL=

7.3

mg/kg/day

UFA=10x

UFH=10x

Occupational 

LOC for MOE = 

100

LOAEL = 35.1 mg/kg/day based on 

thyroid follicular hypertrophy/hyperplasia 
Page 23 of 83

Table 5. Summary of Toxicological Doses and Endpoints for Fluxapyroxad 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

Cancer (oral, 

dermal, 

inhalation)

Classification: Not likely to be carcinogenic to humans at doses sufficient to induce liver and/or 

thyroid tumors. 

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). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

5.0 DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The nature of the residue in plants and animals is adequately understood. Fluxapyroxad 

metabolism studies were conducted using an aniline label and a pyrazole label in soybeans, 

tomato, and wheat; in the rotational crops spinach, radish, and wheat; and in animal studies in 

goats, hens. The primary residue found in plant and livestock commodities is fluxapyroxad 

parent. Metabolite residues to be included in the risk assessment are M700F008 and M700F010 

for milk residues only.

5.1.2 Summary of Environmental Degradation

Fluxapyroxad does not readily undergo aerobic or anaerobic degradation in soil, with 

half-lives ranging from 213 to 1,827 days. In terrestrial field dissipation studies, dissipation halflives ranged from 17 to 436 days and fluxapyroxad was detected infrequently below the top 6 

inches of the soil. Fluxapyroxad is moderately to slightly mobile based on adsorption KOC values 

(496 to 1,424 mL/goc) in studies conducted on U.S. and foreign soils. Fluxapyroxad is stable to 

hydrolysis (pH values of 5, 7 and 9) and to soil and aqueous photolysis. Fluxapyroxad has the 

potential to leach to ground water, particularly where high water tables are present, high 

rainfall/irrigation occurs, and where sandy soils with low organic matter exist. As previously

noted, fluxapyroxad was detected infrequently at depths greater than 6 inches in terrestrial field 

dissipation studies. However, given its persistence and mobility, the terrestrial field dissipation 

studies, which only lasted a maximum of 472 days, may not have been long enough to capture 

leaching over time. Fluxapyroxad does not readily undergo aerobic or anaerobic degradation in 

aquatic systems, with half-lives of 420 to 731 days. Fluxapyroxad is not expected to volatilize 

(vapor pressure 6.1 x 10-11 Torr at 25 ̊ C). It will not likely bioaccumulate based on results of 

bioconcentration studies in fish. 
Page 24 of 83

5.1.3 Comparison of Metabolic Pathways

Submitted data shows that fluxapyroxad is metabolized mainly by hydroxylation at the 

biphenyl moiety (sometimes repeatedly), loss of a fluorine atom at the biphenylring (presumably 

by substitution with a hydroxyl-group), N-demethylation at the pyrazole moiety, hydrolysis of 

the amide bond, and oxidation of the difluoromethyl group. Conjugation of the hydroxyl-groups 

in addition to these reactions led to the observed large number of metabolites. The metabolic 

pathway of fluxapyroxad is similar in primary and rotational crops but with some variation in 

metabolite levels. In general, the parent compound is the main residue followed by the 

metabolites M700F008, M700F002 and M700F048. For livestock, the parent, M700F008, 

M700F005, M700F004, M700F010 and dimer of the parent were observed as major residues in 

fat, muscle, milk, liver, kidney and/or egg commodities. In the rat, the parent was the main 

residue followed by M700F008, and their corresponding metabolites hydroxylated in the 

biphenyl moiety (M700F009, M700F005, and M700F006). Other reactions led to the formation 

of a large number of minor metabolites. Metabolite structures are provided in Appendix B.

5.1.4 Residues of Concern Summary and Rationale

HED has concluded that the residue of concern for tolerance expression for all 

commodities is parent only based on the recommendation of the Residues of Concern 

Knowledgebase Subcommittee (ROCKS). Although there was concern expressed about 

metabolites in livestock commodities (particularly M700F008 being present at greater levels than 

parent in most matrices), for tolerance setting the parent compound alone is adequate as an 

indicator for misuse. 

The ROCKS recommended inclusion of parent fluxapyroxad and M700F008 for risk 

assessment for primary and rotational crops. While the parent is generally the most significant 

residue in plants, results from crop field trials with cherries and peppers show a higher relative 

level of M700F008 with respect to the parent at longer PHIs. The M700F008 metabolite is 

demethylated parent and is expected to have comparable toxicity to the parent. The major 

residues observed in the confined rotational studies are parent fluxapyroxad and M700F008, 

M700F002 and M700F048. The metabolite M700F002 was observed as a major residue in 

rotational spinach only and was not detected at all in the field studies of accumulation in 

rotational crops. The metabolite M700F048 was observed as a major residue in radish tops in 

the confined study, but was seen at much lower levels than the parent and M700F008 in the field 

studies. Toxicity studies with M700F002 and M700F048 show that these two metabolites are 

not likely to be more toxic than the parent. For livestock commodities, except milk, the ROCKS 

recommended that fluxapyroxad and M700F008 be included for risk assessment purposes based 

on results from metabolism and feeding studies which show that parent fluxapyroxad and 

M700F008 are the major residues in ruminant and poultry commodities. For milk only, the 

ROCKS recommended that fluxapyroxad, M700F008 and M700F010 be included for risk 

assessment purposes based on the metabolism study in goat showed the presence of M700F010 

at 12-15% TRR in milk which is highly consumed commodity by children. M700F010 is 
Page 25 of 83

hydroxylated parent and likely to have comparable toxicity to the parent. For water, the ROCKS 

committee recommended including parent fluxapyroxad only in the risk assessment. Parent 

fluxapyroxad and M700F001 were the only two major residues identified in the environmental 

fate studies. Although M700F001 was identified as a major degradate, available evidence 

suggests that this degradate has lower toxicity than the parent and will be present in low 

concentrations relative to the parent in drinking water. 

Table 6: Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance 

Expression

Matrix Residues of Concern1

For Risk Assessment For Tolerance Expression

Plants Primary Crop Fluxapyroxad and M700F008 Fluxapyroxad

Rotational Crop Fluxapyroxad and M700F008 Fluxapyroxad

Livestock Ruminant Fluxapyroxad, M700F008 and 

M700F0102

Fluxapyroxad

Poultry Fluxapyroxad and M700F008 Fluxapyroxad

Drinking Water Fluxapyroxad NA

1

Fluxapyroxad is 3-(difluoromethyl)-1-methyl-N-(3′,4′,5′-trifluoro[1,1′-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide. M700F008 

is 3-(difluoromethyl)-N-(3′,4′,5′-trifluorobiphenyl-2-yl)pyrazole-4-carboxamide. M700F010 is 3-(difluoromethyl)-N-(hydroxy3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

2 The metabolite M700F010 will be considered a residue of concern for milk only.

5.2 Food Residue Profile 

5.2.1 Residues in Crops

An adequate number and crop field trials conducted in appropriately representative 

locations are available for fluxapyroxad for the majority of crop applications and use patterns 

(application rate and PHI) submitted on the label. However, field trials on carrot and radish must 

be submitted in order to allow use on root and tuber vegetables, subgroup 1A. Submitted field 

trial data for fluxapyroxad on cereal grains, legume vegetables (succulent and dry), oil seed crops 

(canola and sunflower), peanuts, pome fruit, stone fruit, root and tuber vegetables (potatoes and 

sugar beets), and fruiting vegetables reflect the use of 2-4 foliar applications of an emulsifiable 

concentrate formulation. Decline studies were submitted for each commodity, as required. Seed 

treatment studies for fluxapyroxad on cotton reflect the use of an SC formulation. Adequate 

confined and field rotational crop data were provided for fluxapyroxad. The field rotational crop 

studies show finite residues at 30, 60, 90, and 120 day plant back intervals (PBIs) except for 

wheat, which is also a primary crop. The confined rotational crop studies show no quantifiable 

residues at a 365 day plant back interval. Detailed information on residue data from crop field 

trials on fluxapyroxad and its metabolites is provided in the Residue Chemistry Chapter.

(D390223)

5.2.2 Residues in Meat, Milk, Poultry, and Eggs

The magnitude of the residue of fluxapyroxad and metabolites M700F002 and 

M700F008 in dairy cattle tissues, milk, laying hen tissues and eggs was determined in acceptable 

feeding studies in dairy cattle and laying hens. Based on these studies, tolerances are needed for 
Page 26 of 83

cattle meat, fat, milk products and eggs. Tolerances are not needed for cattle liver and kidney or 

for any poultry tissues because estimated residues are more than 10x lower than the level of 

quantitation (LOQ).

5.2.3 Residues in Processed Commodities

Processing studies were provided for processed commodities associated with cereal 

grains, oil seed crops (canola and sunflower), peanuts, pome fruit, stone fruit, root and tuber 

vegetables (potatoes and sugar beets), and fruiting vegetables. Concentration was observed in 

some processed commodities and tolerances are being set in those commodities (see Table 1).

5.2.4 Storage Stability

Adequate storage stability data for fluxapyroxad, per se, are available to support the 

storage conditions and durations of field trial samples for raw agricultural commodities. The 

available data indicate that residues of fluxapyroxad are relatively stable for up to 24 months 

in/on apple (fruit), tomato (fruit), triticale (whole plant), soybean (seed), avocado (fruit), dried 

pea (seed), cereal (grain), potato (tuber), grape (fruit), lemon (fruit), and wheat (straw) stored at -

20 C. Storage stability of metabolite M700F008 was investigated for 24 months. Some 

instability was seen for the metabolite M700F008 in oily and starchy commodities. Residues of 

M700F008 have been corrected to account for the 57% recovery in the storage stability studies in 

oily commodities.

5.3 Water Residue Profile

Drinking water residues were incorporated directly into the acute and chronic dietary

analyses as “water, direct, all sources” and “water, indirect, all sources.” Estimated Drinking 

Water Concentrations (EDWCs) for fluxapyroxad were provided by the Environmental Fate and 

Effects Division (EFED) (D138009, C. Peck, 9/21/11). EFED generated the surface water 

estimates using the Tier I aquatic model FIRST (FQPA Index Reservoir Screening Tool). 

Ground water estimates were calculated using the Tier 1 Screening Concentration in Ground 

Water model (SCIGROW). EDWCs for fluxapyroxad (parent only) were derived based on 

fluxapyroxad use on dry shelled beans (except soybeans) at 0.18 lbs ai/acre/application, applied 

2 times per year with a 7-day reapplication interval for a maximum total annual application rate 

of 0.36 lb ai/A/yr. Surface and groundwater EDWCs for fluxapyroxad are provided in Table 3. 

Estimated drinking water residues for peak concentration of 0.014 mg/L (ppm) were used in the 

acute assessment. Estimated 30 year annual average drinking water concentrations of 0.0067

mg/L (ppm) were used the chronic assessment. 

Table 7. EDWCs for the Fluxapyroxad Human Health Risk Assessment 

Drinking Water Source Peak (μg/L) Annual Mean (μg/L)

Surface Water 14.1 6.7

Ground Water 0.087 0.087
Page 27 of 83

5.4 Dietary and Drinking Water Exposure and Risk

HED conducted screening-level acute and chronic dietary and drinking water exposure 

and risk assessments using the Dietary Exposure Evaluation Model with the Food Commodity

Intake Database (DEEM-FCIDTM). Dietary risk assessment incorporates both exposure and 

toxicity of a given pesticide. For acute and chronic dietary assessments, the risk is expressed as 

a percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result 

in no unreasonable adverse health effects). This dose is referred to as the population adjusted 

dose (PAD). The PAD is equivalent to the reference dose (RfD) divided by the additional FQPA 

Safety Factor, if applied. For acute and non-cancer chronic exposures, HED is concerned when 

estimated dietary risk exceeds 100% of the PAD. 

5.4.1 Acute Dietary and Drinking Water Exposure and Risk Estimates

A conservative acute dietary exposure analysis was performed for the general population 

and all population subgroups. Tolerance level residues adjusted to account for the metabolites of 

concern (M700F008, M700F010) and 100 % crop treated assumptions were used. DEEM 

default and empirical processing factors were used to modify the tolerance values. The acute 

analysis incorporated the 1 in 10 year peak surface drinking water estimate from application of 

fluxapyroxad to dry shelled beans. The resulting 95th percentile acute exposure estimates are 

not of concern for the general population or for any subgroup population. The 95th percentile 

acute population adjusted dose (aPAD) for children 1-2 years old, the subgroup with the highest 

risk estimate, is 6%. The 95th percentile aPAD for the general population is 2%.

Table 8. Summary of Acute Dietary Exposure and Risk for Fluxapyroxad

Population Subgroup aPAD (mg/kg/day) Acute (95th Percentile)

Exposure (mg/kg/day) % aPAD

General U.S. Population

1.25

0.023310 2

All Infants (< 1 year old) 0.074082 6

Children 1-2 years old 0.068058 5

Children 3-5 years old 0.047241 4

Children 6-12 years old 0.026755 2

Youth 13-19 years old 0.015850 2

Adults 20-49 years old 0.016730 1

Adults 50+ years old 0.013855 1

Females 13-49 years old 0.014264 1

5.4.2 Chronic Dietary and Drinking Water Exposure and Risk Estimates

A moderately refined chronic dietary exposure analysis was performed for the general 

U.S. population and various population subgroups. Highest average field trial (HAFT) residues 

for parent plus metabolite were used for all plant commodities. For livestock commodities 

tolerance level residues adjusted to account for the metabolites of concern (M700F008, 

M700F010) were used. An assumption of 100 % crop treated was also used for the chronic 

dietary analysis. DEEM default and empirical processing factors were used to modify the 

tolerance values. The chronic analysis incorporated the 10 year average surface drinking water 
Page 28 of 83

estimate from application of fluxapyroxad to dry shelled beans. Chronic dietary risk estimates 

are not of concern for general population or other population subgroups. The population 

subgroup with the highest risk estimate is children 1-2 years old with a % chronic PAD (cPAD) 

of 48%. The % cPAD for the general U.S. population is 14%.

Table 9. Summary of Chronic Dietary Exposure and Risk for Fluxapyroxad

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) % cPAD

General U.S. Population

0.022

0.002923 14

All Infants (< 1 year old) 0.008474 40

Children 1-2 years old 0.010055 48

Children 3-5 years old 0.007369 35

Children 6-12 years old 0.004011 19

Youth 13-19 years old 0.002217 11

Adults 20-49 years old 0.002204 11

Adults 50+ years old 0.002007 10

Females 13-49 years old 0.001986 10

6.0 RESIDENTIAL EXPOSURE/RISK CHARACTERIZATION

A residential assessment is not required because there are no fluxapyroxad products 

proposed for registration for homeowner use and there are no products proposed for application 

to residential areas. 

6.1 Residential Bystander Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative residential bystander 

postapplication inhalation exposure assessment was not performed for fluxapyroxad at this time. 

However, volatilization of pesticides may be a potential source of postapplication inhalation 

exposure to individuals nearby to 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. The Agency received the 

SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report and may, as appropriate, develop policies and procedures, 

to identify the need for and, subsequently, the way to incorporate postapplication inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are put into place, the 

Agency may revisit the need for a quantitative postapplication inhalation exposure assessment 

for fluxapyroxad.

6.2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying 

operations. This is particularly the case with aerial application, but, to a lesser extent, could also 

be a potential source of exposure from the ground application method employed for 

fluxapyroxad. The Agency has been working with the Spray Drift Task Force, EPA Regional 
Page 29 of 83

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 at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

7.0 AGGREGATE EXPOSURE/RISK CHARACTERIZATION

In accordance with the FQPA, when there are potential residential exposures to a 

pesticide, aggregate risk assessment must consider exposures from three major routes: oral, 

dermal, and inhalation. There are three sources for these types of exposures: food, drinking 

water, and residential uses. 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. The proposed/registered 

fluxapyroxad uses are not expected to result in residential exposure. Therefore, the acute and 

chronic exposure estimates provided in the Dietary Exposure Section represent aggregate 

exposure. 

8.0 CUMULATIVE RISK

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, 

modify, or revoke a tolerance, the Agency consider “available information” concerning the 

cumulative effects of a particular pesticide's residues and “other substances that have a common 

mechanism of toxicity.”

EPA does not have, at this time, available data to determine whether fluxapyroxad has a 

common mechanism of toxicity with other substances. Unlike other pesticides for which EPA 

has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has 

not made a common mechanism of toxicity finding as to fluxapyroxad and any other substances 

and, fluxapyroxad does not appear to produce a toxic metabolite produced by other substances 

which have tolerances in the U. S. For the purposes of this tolerance reassessment action, 

therefore, EPA has not assumed that fluxapyroxad has a common mechanism of toxicity with 

other substances. For information regarding EPA’s efforts to determine which chemicals have a 

common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the 

policy statements released by EPA’s OPP 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/fedrgstr/EPA_PEST/2002/January/Day_16/.
Page 30 of 83

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

9.1 Exposure Scenarios

Occupational handler and post-application exposure scenarios are assessed for the risk 

assessment of the proposed crop and seed commodities. Based on the product labels and 

information provided by the registrant, short- and intermediate-term exposure is assessed for 

occupational handlers and post-application activities. Chronic exposure is not expected for the 

proposed use patterns. Only inhalation exposures are assessed for proposed new uses of 

fluxapyroxad. Dermal exposures are not assessed because PODs for short- and intermediateterm dermal exposure were not selected as there was no systemic toxicity up to the limit dose in 

the subchronic dermal toxicity study in rats. Labels for fluxapyroxad formulations require that 

mixers, loaders, applicators and other handlers (seed treatment activities) wear long-sleeved shirt 

and long pants, chemical resistant gloves, protective eyewear, and shoes plus socks.

9.2 Handler Exposure 

The term “handler” applies to individuals who mix, load, and apply the pesticide product. 

There is a potential for exposure to fluxapyroxad during mixing, loading, and application 

activities through inhalation routes only. Occupational handler exposure is expected for 

individuals involved in commercial seed treatment (primary handlers), and planting treated seeds 

(secondary handlers) as well as aerial, flagging, airblast, and groundboom applicators.

According to proposed labels, applications may be begin at plant emergence, but typical 

applications begin as plants touch across rows. The following handler exposure scenarios 

evaluated for this assessment are based on information provided in the proposed labels. 

9.2.1 Handler Exposure Scenarios

9.2.1.1 Mixing and Loading Scenarios

• Open mixing/loading for aerial application;

• Open mixing/loading for groundboom application;

• Open mixing/loading for airblast application.

9.2.1.2 Application Scenarios

• Applying sprays with aerial equipment;

• Applying sprays with groundboom equipment;

• Applying sprays with airblast equipment

.

9.2.1.3 Flagging

The Agency has evaluated scenarios that may be limited in nature such as flagging during 

aerial applications because engineering controls (i.e. Global Positioning Satellite technology) are 
Page 31 of 83

now predominantly used as indicated by the 1998 National Agricultural Aviation Association 

(NAAA) survey of their membership. It appears, however flaggers are still used in 

approximately 10 to 15 percent of aerial application operations. In cases like these, the Agency

strongly encourages the use of the engineering control system, but will continue to evaluate risks 

for flaggers and any other population where a clear exposure pathway exists until the potential 

for exposure is eliminated. The Agency is aware that NAAA is conducting another survey of its 

membership on exposure issues and will consider those results as is timely and appropriate.

For pesticide handlers, HED presents estimates of dermal exposure for “baseline” (i.e. workers 

wearing a single layer of work clothing consisting of a long sleeved shirt, long pants, shoes, plus 

socks and no protective gloves, as well as for “baseline” and the use of protective gloves or other 

personal protective equipment (PPE), as might be necessary. However, dermal exposures were 

not assessed for this analysis because there was no systemic toxicity up to the limit dose in the 

subchronic dermal toxicity study in rats. The fluxapyroxad product labels for foliar treatments 

recommend applicators and other handlers to wear long-sleeved shirt and long pants, and shoes 

plus socks. 

9.2.1.4 Seed Treatment

Occupational seed treatment handlers may experience short- and intermediate-term 

exposure to fluxapyroxad while performing seed treatment activities in commercial settings. In 

addition, occupational secondary handlers may experience short- and intermediate-term exposure 

while planting fluxapyroxad-treated seeds. No chemical-specific handler exposure data were 

submitted in support of this use pattern. For assessing commercial seed treatment and seed 

planting activities, unit exposure data were taken from HED ExpoSAC Policy 14: SOPs for Seed 

Treatment and MRID 47054702. The amount of active ingredient handled depends on the 

application rate (lb ai/lb seed) and the pounds of seed treated in a day (or the pounds of seed that 

can be planted in a day), all of which vary depending upon the seed type. Values for the amount 

of seed treated and planted per day were obtained from HED ExpoSAC Policy 15. The results 

are presented in Table 5.

Treating Seed (Primary Handler)

Potential occupational exposure scenarios from the use of fluxapyroxad as a commercial 

seed treatment include:

 Mixing, loading, applying liquid formulations;

 Bagging treated seed;

 Sewing bags; and

 Multiple activities.

Typically, for large-scale commercial seed treatments, workers perform only those 

specific individual tasks listed above; however, it is assumed that workers also may perform 

multiple activities throughout the day. As a result a “multiple activities” scenario (i.e. where one 

worker performs all seed treatment tasks such as loading/applying, sewing, bagging, cleaning, 
Page 32 of 83

calibration, repair, forklift driver, etc.) was addressed.

Planting Treated Seed (Secondary Handler)

Potential occupational exposure scenarios from the use of fluxapyroxad as a commercial 

seed treatment include planting treated seed (secondary handler). Planting treated seed consists 

of the farmer purchasing bags of treated seed, placing the seed in the hopper and applying seed to 

fields (considered a secondary handler exposure scenario). The fluxapyroxad product labels

discuss inhalation exposures exclusively for mixers, loaders, applicators and other handlers (seed 

treatment activities) to wear long-sleeved shirt and long pants, chemical resistant gloves, 

protective eyewear, and shoes plus socks.

9.2.2 Handler Exposure Data

No chemical-specific handler exposure data were submitted in support of this 

registration. It is HED’s policy to use data from the USEPA OPP Occupational Pesticide Handler 

Unit Exposure Surrogate Reference Table (5/4/11).

http://www.epa.gov/pesticides/science/handler-exposure-data.html).

9.2.3 Handler Exposure Assumptions 

• Average body weight of an adult handler is 80 kg.

• Exposure duration short-term (1- 30 days), intermediate-term (1-6 months)

• Maximum label application rates for aerial, groundboom and airblast:

- 0.09 – 0.18 lb ai/A

• Maximum label application rates for seed treatment:

- 0.01- 0.05 lb ai/100 lb seed 

• Area treated for aerial, groundboom and airblast application: 

- 1200 acres per day for aerial application

- 200 acres per day for groundboom application to corn, soybean and wheat

- 80 acres per day for groundboom application to all other crops

- 20 acres per day for airblast application to stone fruit

• Amount (pounds) of Seed Treated per Day (Primary Handler)

- Beans and Peas (CG6 and CG7) – 194,000

- Soybean, Sorghum - 718,000

- Sunflower and safflower - 718,000

- Cereal Grains (CG 15 and 16) – 718,000

- Corn (field, sweet, pop) – 550,000

- Cotton – 160,000

- Peanut – (Loader/Applicator) = 120,000), (Sewer, Bagger, and Multiple activities = 

718,000)

• Amount (pounds) of Seed Treated per Day (Secondary Handler)

- Beans and Peas (CG6 and CG7) – 194,000

- Soybean – 20,000
Page 33 of 83

- Sunflower and safflower – 7,700

- Barley – 19,000

- Oat - 26,000

- Triticale – 20,000

- Rye - 24,000

- Wheat – 30,000

- Corn (field, sweet, pop) – 3,000

- Sorghum – 800

- Cotton – 3,600

- Peanut – 11,000

-

9.2.4 Handler Exposure and Risk Estimates

A target LOC or MOE of 100 is considered adequate for inhalation. All worker 

exposures are assessed as short- and intermediate-term based on label prescribed uses and 

expected exposure durations. Exposure and risk estimates indicate non-cancer risks are not of 

concern for occupational handler activities for the proposed new uses (MOEs > 100). 

Summaries of occupational handler exposure and risk calculations, assumptions, and results are

provided in Tables 10, 11 and 12.

Table 10: Short and Intermediate-Term Risk Assessment For Agricultural Uses of Fluxapyroxad

Exposure 

Scenario

Inhalation

Unit

Exposure

(μg/lb ai)1

Crops

Application

Rate

(lb ai/A)2

Area 

Treated

(A/day) 3

MOE 5

Short-Term Intermed-Term

Inhalation

Mixer/Loader 

Aerial

Fixed Wing

(enclosed cockpit)

0.219

Fruiting vegetables, oilseed crops 

(flax, rape, and sunflower seed), 

pome fruits, stone fruits, sugar 

beet, tuberous and corn 

vegetables (incl. Potatoes),oat, 

peanut, rye, triticale

0.09 350 100,000 85,000

Dried shelled beans 0.18 52,000 42,000

corn, soybean, wheat 0.09 1200 30,000 25,000

Groundboom 

(open Cab) 0.219

Dried shelled beans 0.18

80

230,000 190,000

Fruiting vegetables, oilseed crops 

(flax, rape, and sunflower seed), 

pome fruits, stone fruits, sugar 

beet, tuberous and corn 

vegetables (incl. Potatoes),oat, 

peanut, rye, triticale

0.09 460,000 370,000

corn, soybean, wheat 200 180,000 150,000

Airblast

(open cab) stone fruits 0.11 40 750,000 610,000

Applying 
Page 34 of 83

Table 10: Short and Intermediate-Term Risk Assessment For Agricultural Uses of Fluxapyroxad

Exposure 

Scenario

Inhalation

Unit

Exposure

(μg/lb ai)1

Crops

Application

Rate

(lb ai/A)2

Area 

Treated

(A/day) 3

MOE 5

Short-Term Intermed-Term

Inhalation

Aerial

Fixed Wing

(enclosed cockpit)

0.068

Fruiting vegetables, oilseed crops 

(flax, rape, and sunflower seed), 

pome fruits, stone fruits, sugar 

beet, tuberous and corn 

vegetables (incl. Potatoes),oat, 

peanut, rye, triticale

0.09 350 340,000 270,000

Dried shelled beans 0.18 170,000 140,000

corn, soybean, wheat 0.09 1200 98,000 80,000

Groundboom 

(open Cab)

(Chemigation)6 0.068

Dried shelled beans 0.18

80

150,000 120,000

Fruiting vegetables, oilseed crops 

(flax, rape, and sunflower seed), 

pome fruits, sugar beet, tuberous 

and corn vegetables (incl. 

Potatoes),oat, peanut, rye, triticale

0.09 290,000 240,000

corn, soybean, wheat 200 120,000 95,000

Airblast

(open cab) Stone fruits 0.11 20 36,000 29,000

Flagging 

Aerial

Fixed Wing

(enclosed cockpit)

0.35 corn, soybean, wheat40.09 1200 33,000 26,000

1 Inhalation unit exposure values represent no respirator. 

2 Application rates are based on maximum values found in proposed labels 

3 Daily area treated is based on the area that can be reasonably applied in a single day for each exposure scenario of concern based on the application 

method and formulation/packaging type. (standard EPA/OPP/HED values).

4Corn, Soybeans, and Wheat have the most conservative MOEs, therefore representative for Flagging activities.

5

Short-/Intermediate-Term MOE = Inhalation NOAEL (9.0 mg/kg/day or 7.3 mg/kg/day ) / Daily Inhalation Dose). The LOC is 100. 

6 Chemigation: Aerial applicator MOEs are protective.

* Daily Dose (mg/kg/day) was calculated by Unit Exposure * 100 % Inhalation absorption factor * Application rate * Area treated} / 70 kg. {Where: 

inhalation absorption is assumed to be 100%}

Table 11. Short- and Intermediate-Term Primary Handler Exposures and Risks for Fluxapyroxad Seed Treatment

Seed Type

Inhal 

UEa

mg/lb

Max App Rateb

lb ai/lb seed

Amt Treatedc

lb seed/day

Inhal Dosed

mg/kg/day

Short-Term 

Inhal MOEe

Intermediate-Term 

Inhal MOEf

Loader/Applicator (No Respirator)

Peanuts 0.00034 0.0001 5,500 0.000058 180,000 140,000

Dried Shelled Beans 0.00034 0.0001 194,000 0.000094 110,000 89,000

Soybean 0.00034 0.0001 718,000 0.00035 29,000 24,000

Cereal Grains 0.00034 0.0005 718,000 0.00017 5,900 4,800
Page 35 of 83

Table 11. Short- and Intermediate-Term Primary Handler Exposures and Risks for Fluxapyroxad Seed Treatment

Seed Type

Inhal 

UEa

mg/lb

Max App Rateb

lb ai/lb seed

Amt Treatedc

lb seed/day

Inhal Dosed

mg/kg/day

Short-Term 

Inhal MOEe

Intermediate-Term 

Inhal MOEf

Corn 0.00034 0.0005 550,000 0.0013 7,700 6,200

Cotton 0.00034 0.0002 160,000 0.00016 66,000 54,000

Sunflower and 

safflower 0.00034 0.0002 718,000 0.0017 15,000 12,000

Sorghum 0.00034 0.0002 718,000 0.0007 15,000 12,000

Sewer (No Respirator)

Peanuts 0.00023 0.0001 718,000 0.00024 44,000 35,000

Dried Shelled Beans 0.00023 0.0001 194,000 0.000064 160,000 130,000

Soybean 0.00023 0.0001 718,000 0.00024 44,000 35,000

Cereal Grains 0.00023 0.0005 718,000 0.0012 8,700 7,100

Corn 0.00023 0.0005 550,000 0.0009 11,000 9,200

Cotton 0.00023 0.0002 160,000 0.00011 98,000 79,000

Sunflower and 

safflower 0.00023 0.0002 718,000 0.00047 22,000 18,000

Sorghum 0.00023 0.0002 718,000 0.00047 22,000 18,000

Bagger (No Respirator)

Peanuts 0.00016 0.0001 718,000 0.00016 63,000 51,000

Dried shelled Beans 0.00016 0.0001 194,000 0.000044 230,000 190,000

Soybean 0.00016 0.0001 718,000 0.00016 63,000 51,000

Cereal Grains 0.00016 0.0005 718,000 0.00082 13,000 10,000

Corn 0.00016 0.0005 550,000 0.00063 16,000 13,000

Cotton 0.00016 0.0002 160,000 0.000073 140,000 110,000

Sunflower and 

safflower 0.00016 0.0002 718,000 0.00033 31,000 25,000

Sorghum 0.00016 0.0002 718,000 0.00033 31,000 25,000

Multiple Activities (No Respirator)

Peanuts 0.0016 0.0001 718,000 0.0016 6,300 5,100

Dried Shelled Beans 0.0016 0.0001 194,000 0.00044 23,000 19,000

Soybean 0.0016 0.0001 718,000 0.0016 6,300 5,100

Cereal Grains 0.0016 0.0005 718,000 0.0082 1,300 1,200

Corn 0.0016 0.0005 550,000 0.0063 1,600 1,300

Cotton 0.0016 0.0002 160,000 0.00073 14,000 11,000

Sunflower and 

safflower 0.0016 0.0002 718,000 0.0033 3,100 2,500

Sorghum 0.0016 0.0002 718,000 0.0033 3,100 2,500

Planters

Peanuts 0.0034 0.0001 11,000 0.000047 190,000 210,000

Dried Shelled Beans 0.0034 0.0001 8,000 0.000034 260,000 190,000

Soybean 0.0034 0.0001 20,000 0.000085 110,000 86,000

Cereal Grains 0.0034 0.0005 26,000 0.00011 81,000 66,000

Corn 0.0034 0.0005 3,000 0.000064 140,000 110,000

Cotton 0.0034 0.0002 3,600 0.000031 290,000 240,000

Sunflower and 

safflower 0.0034 0.0002 800 0.000068 1,300,000 1,100,000

Sorghum 0.0034 0.0002 800 0.000068 1,300,000 1,100,000

a Unit Exposures from HED Exposure Science Advisory Council Policy 14: Standard Operating Procedures for Seed Treatment. 

b Application Rates based on proposed label uses for fluxapyroxad.
Page 36 of 83

c HED default for lb seed planted per day from HED Exposure Science Advisory Council Policy 15, 

d Daily Inhalation Dose (mg/kg/day) = daily inhalation unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount planted (lb 

seed/day) x absorption factor (100%) / body weight (70 kg adult).

e Short-term Inhalation MOE = NOAEL (9.0 mg/kg/day for short-term exposure) / Inhalation Dose (mg/kg/day). Level of concern = 

100.

f Intermediate-term Inhalation MOE = NOAEL (7.3 mg/kg/day for intermediate-term exposure) / Inhalation Dose (mg/kg/day). Level 

of concern = 100.

* in the case where there are several crops under the crop group assessed, the crop with the highest amount of seeds planted per day was 

assessed to cover that crop group (i.e., beans and peas, cereal grains)

9.3 Post-Application Exposure 

HED uses the term “post-application” to describe those individuals who can be exposed 

to pesticides after entering areas previously treated with pesticides and performing certain tasks 

or activities (also often referred to as reentry exposure). Post-application exposures are expected 

to occur primarily via the dermal route. Based on the Agency's current practices, a quantitative 

occupational post-application inhalation exposure assessment was not performed for 

fluxapyroxad at this time; an inhalation exposure assessment was performed for occupational 

handlers. This assessment resulted in risk estimates that did not exceed HED’s level of concern 

at baseline inhalation PPE. Handler exposure resulting from application of pesticides outdoors is 

likely to result in higher exposure than post-application exposure. Therefore, it is expected that 

these handler inhalation exposure estimates would be protective of most occupational postapplication inhalation exposure scenarios. However, there are multiple potential sources of postapplication inhalation exposure to individuals performing post-application activities in 

previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice 

and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, 

and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received 

the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for fluxapyroxad.

The potential for post-application exposures following the planting of fluxapyroxadtreated seeds is unlikely because sustained levels of contact with treated seed after it has been 

placed in the soil or other planting media would not be expected because no routine cultural 

practice required for the production of agricultural commodities involves such an activity as 

defined in the no/low contact criteria in the Worker Protection Standard (WPS). Therefore, no 

quantitative post-application assessment is required for exposure to treated seeds that have 

already been planted.
Page 37 of 83

10.0 REFERENCES

Fluxapyroxad; Occupational Exposure Assessment to Support the Request for Registration of 

Fluxapyroxad on seed and various food crops, J. Miller D390242, 2/8/12

Fluxapyroxad (BAS 700F) on Small Grains, Oilseeds, Corn, Cotton, Sugar Beet, Tubers & Corm 

Vegetables, Legumes, Fruiting Vegetables except Cucurbits, Pome Fruits and Stone Fruits 

Evaluation of Analytical Methods and Residue Data. S. Hummel, D390223, 2/8/12

Fluxapyroxad – Acute and Chronic Dietary Exposure and Risk Assessments for Proposed Use of 

New Active Ingredient on Small Grains, Oilseeds, Corn, Cotton, Sugar Beets, Tuber & Corm 

Vegetables, Legumes, Fruiting Vegetables except Cucurbits, Pome Fruit and Stone Fruit. B. 

Daiss, D390245, 2/8/12 

Fluxapyroxad (BAS 700F). Report of the Residues of Concern Knowledgebase Subcommittee

(ROCKS). I. Negrón-Encarnación, D390225, 7/14/11 

Fluxapyroxad (BAS 700F) New Chemical Screen for Toxicology. J. Ryman, D377679, 7/30/10

CARC Report (J. Kidwell, June 9, 2011, TXR 0055930).
Page 38 of 83

APPENDIX A. TOXICOLOGY PROFILE AND EXECUTIVE SUMMARIES

A.1 TOXICOLOGY DATA REQUIREMENTS

The requirements (40 CFR 158.340) for food use for fluxapyroxad are in Table 1. Use of the new 

guideline numbers does not imply that the new (1998) guideline protocols were used. 

Guideline 

No. Study Type Technical MRID No. Required Submitted

870.3100

870.3150

870.3200

870.3250

870.3465

Subchronic (Oral) Toxicity - Rodent ................................

Subchronic (Oral) Toxicity - Non-Rodent................................

21/28-Day Dermal Toxicity................................................................

90-Day Dermal Toxicity

90-Day Inhalation Toxicity................................................................

Y

Y

N

N

Y

Y

Y

Y

N

N

47923567 

47923568

47923569

47923571

---

---

870.3700a

870.3700b

870.3800

Prenatal Developmental Toxicity - Rodent................................

Prenatal Developmental Toxicity - Non-Rodent................................

Reproduction and Fertility Effects................................................................

Y

Y

Y

Y

Y

Y

47923603

47923604

47923602

870.4100a

870.4100b

870.4200a

870.4200b

870.4300

Chronic (Oral) Toxicity - Rodent ................................................................

Chronic (Oral) Toxicity - Non-Rodent (Dog)................................

Carcinogenicity - Rat

Carcinogenicity - Mouse

Combined Chronic Toxicity /Carcinogenicity................................

Y

Y

Y

Y

Y

Y

Y

Y

Y

Y

47923591

47923592

47923570

47923591

47923592

47923591

47923592

870.6100a

870.6100b

870.6200a

870.6200b

870.6300

870.7800

Neurotoxicity - Acute Delayed Neurotox.- Hen ................................

Neurotoxicity - Subchronic - Hen................................................................

Neurotoxicity Screening Battery - Acute - Rat................................

Neurotoxicity Screening Battery -Subchronic - Rat ................................

Developmental Neurotoxicity..................

Immunotoxicity.............................................................

N

N

Y

Y

N

Y

N

N

Y

Y

N

Y

---

---

47923605 

47923606

---

47923633
Page 39 of 83

A.2 TOXICITY PROFILES 

A.2.1 Acute Toxicity

Table A.2.1.1 Acute Toxicity Profile – Fluxapyroxad

Guideline 

No.

Study Type MRID(s) Results Toxicity 

Category

870.1100 Acute oral – rat (females) 47923607 LD50 = >2000 mg/kg III

870.1200 Acute dermal – rat 47923559 LD50 >2000 mg/kgM & F III

870.1300 Acute inhalation – rat 47923560 LC50 >5.1 mg/L M & F IV

870.2400 Acute eye irritation – rabbit 47923562 Slightly irritating IV

870.2500 Acute dermal irritation – rabbit 47923561 Slightly irritating IV

870.2600 Dermal sensitization – guinea pig 47923813 No sensitization -

TableA.2.1.2 Acute Toxicity Profile – Fluxapyroxad Metabolites

Guideline 

No.

Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral – rat (females) M-1 47701678 LD50 = >2000 mg/kg III

870.1100 Acute oral – rat (females) M-3 47701679 LD50 = >2000 mg/kg III

870.1100 Acute oral – rat (females) M-25 47701680 LD50 = >2000 mg/kg III

870.1100 Acute oral – rat (females) M-28 47701755 LD50 = >2000 mg/kg III

870.1100 Acute oral – rat (females) I-3 47701681 LD50 = >2000 mg/kg III

870.1100 Acute oral – rat (females) I-4 47701682 LD50 = >2000 mg/kg III

870.1100 Acute oral – rat (females) I-5 47701683 LD50 = >2000 mg/kg III

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)

Guideline No

Study Type

MRID/Classification

Doses Results

870.3050

28 day dietary in rats

47923564 (2009)

Acceptable, guideline

0, 100, 500, 2000, 6000 

ppm

0/0, 9/9.4, 43.7/47.8, 

176/183, 530/531, mkd 

M/F

Males

NOAEL=100 ppm ( 9.0 mkd)

LOAEL 500 ppm (176 mkd) based on thyroid follicular 

hypertrophy/hyperplasia and clinical chemistry changes 

Females 

NOAEL=500 ppm (47.8 mkd)

LOAEL=2000 ppm (531 mkd) based on decreased 

prothrombin time and clinical chemistry changes

Non-Guideline

Thyroid hormone 

levels-28 days-rat 

47923594 (2009)

Acceptable, nonguideline

0, 50, 250, 1500, 3000 

ppm

(0/0, 3.5/4.4, 19/20, 

105/117, 214/237 mkd) 

Increased TSH, decreased T4 in males only at 3000 ppm only 

days 14 through 28. Accompanied by increased absolute and 

relative liver and thyroid weights. Supports hypothesis that 

an increased conjugation and elimination of circulating 

thyroxine (T4) leads to compensatory release of thyroid 

stimulating hormone (TSH) from the pituitary, secondary to 

BAS 700 F liver enzyme induction. 

Non-Guideline

Perchlorate discharge 

study-28 days rat 

47923595 (2009)

Acceptable, nonguideline

0, 3000 ppm 

The similarities in the behavior of BAS 700 F to 

phenobarbitol in this perchlorate discharge assay support the 

hypothesis that BAS 700 F causes increases in thyroid 

hormones by an indirect mechanism. 
Page 40 of 83

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)

Guideline No

Study Type

MRID/Classification

Doses Results

0/0, 283/247 mkd

Non-Guideline 

Enzyme induction

47923599 (20210)

Acceptable, nonguideline

50 ppm

Mechanistic investigations of enzyme induction (thyroid and 

liver).

Non-Guideline 

Enzyme induction 

47923593 (2010)

Acceptable, nonguideline

0, 250, 1500, 3000 ppm

0/0, 16/19, 96/126, 

192/234 mkd 

Mechanistic investigations of enzyme induction (thyroid and 

liver). 

Non-Guideline 

S-phase induction

1-3-7-14 days 

47923598 (2010)

Acceptable, nonguideline

0, 50, 250, 1500, 3000 

ppm

Mechanistic tnvestigations of hepatocellular proliferation. 

Non-Guideline 

S-phase induction

7-28-91 days 

47923597 (2010) 

Acceptable, nonguideline

50 ppm only 

Mechanistic tnvestigations of hepatocellular proliferation. 

870.3050

28 day dietary in mice 

47923565 (2009)

Acceptable, guideline

0, 500, 2500, 7000 ppm

0/0, 112/150, 552/746, 

1452/2100 mkd M/F

Males 

NOAEL=2500 ppm (552 mkd)

LOAEL =7000 ppm (1452 mkd) based on hematological 

changes.

Females 

NOAEL=7000 ppm (2100 mkd)

LOAEL=Not observed

No EPA guideline, 

OECD 407 –28 day 

dietary in dogs 

47923566 (2009)

Acceptable/non-EPA 

guideline 

0, 2500, 7500, 20000 

ppm

0/0, 74/85, 211/230, 

521/503 mkd M/F

NOAEL=2500 ppm (74/85 mkd M/F)

LOAEL-=7500 ppm (211/230 mkd M/F) based on vomiting 

(M/F) and clinical chemistry changes

870.3100

90-day dietary in mice

47923568 (2009)

Acceptable/guideline

0, 100, 400, 2000, 6000 

ppm

0/0, 21/32, 77/128, 

390/610, and 

Males

NOAEL=2000 ppm (390 mkd)

LOAEL 6000 ppm (1136 mkd) based on decreased body 

weight and body weight gain and multifocal necrosis in the 

liver

Females 

NOAEL=6000 ppm (1657 mkd)
Page 41 of 83

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)

Guideline No

Study Type

MRID/Classification

Doses Results

1136/1657 mkd (M/F) LOAEL=Not observed. 

870.3100

90-Day dietary in rats

47923567 (2009)

Acceptable, guideline

0, 100, 500, 2000, 6000 

ppm

0/0, 6.1/7.3, 31.2/35.1, 

126/144, and 407/424 

mkd (M/F)

NOAEL = 500 ppm (31.2 mkd) males; 100 ppm (7.3 mkd) 

females 

LOAEL = 2000 ppm (126 mkd) males; 500 ppm (35.1 mkd 

females) based on changes in thyroid hormone levels and 

thyroid follicular hypertrophy/hyperplasia 

870.3150

90-Day Oral Toxicity 

Feeding-dog

47923569 (2009)

Acceptable/guideline

0, 300, 1500, 

10000/7500 (M/F)

0/0, 9/10, 45/51, 

295/238 mkd M/F

NOAEL=1500 ppm (45/51 mkd M/F) 

LOAEL=10000 ppm (295 mkd) males, 7500 ppm (238 mkd) 

females based on vomiting and clinical chemistry changes

870.3200

28-Day Dermal 

Toxicity-rat 

47923571 (2009)

Acceptable, guideline

0, 100, 300, 1000 mkd 

NOAEL=1000 mkd

LOAEL=not observed 

870.3465

90-Day Inhalation

Still required, data gap

870.3700a

Prenatal 

Developmental- rat

47923603 (2009)

Acceptable, guideline

0, 25, 200 and 1000 

mkd (gavage in CMC)

Maternal

NOAEL=200 mkd

LOAEL =1000 mkd based on increased absolute and relative 

thyroid weights and thyroid hypertrophy/hyperplasia 

Offspring 

NOAEL=1000 mkd 

LOAEL =Not observed 

870.3700b

Prenatal 

Developmentalrabbit

47923604 (2009)

Acceptable, guideline

0, 10, 25 and 60 mkd

Maternal

NOAEL=25 mkd

LOAEL =60 mkd based on decreased body weight 

Offspring 

NOAEL=25 mkd 

LOAEL =60 mkd based on decreased fetal body weights and 

increased incidence of paw hyperflexion 

870.3800

Reproduction and 

Fertility Effects-rat

47923602 (2009)

Acceptable, guideline

0, 10, 50 and 300 mkd

Parental

NOAEL=10 mkd

LOAEL =50 mkd based on thyroid follicular 

hypertrophy/hyperplasia 

Fertility/Reproductive Performance

NOAEL=300 mkd

LOAEL =Not observed. 

Offspring 
Page 42 of 83

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)

Guideline No

Study Type

MRID/Classification

Doses Results

NOAEL=10 mkd 

LOAEL =50 mkd decreased pup body weight/body weight 

development 

870.4100

Chronic Toxicity-dog

47923570 (2009)

Acceptable/guideline

0, 300, 1500, 

12000/9000 ppm (M/F)

0/0, 8/9, 39/43, 335/257 

mkd M/F

Females

NOAEL=300 ppm ( 9 mkd)

LOAEL =1500 ppm (43 mkd) based on hepatic fibrosis and 

clinical chemistry changes

Males 

NOAEL=1500 ppm ( 39mkd)

LOAEL=12000 ppm (335 mkd) based on vomiting, heptaic 

fibrosis and cirrhosis, and clinical chemistry changes (liver 

enzyme elevation)

870.4300 

Chronic 

toxicity/carcinogenicity 

in rats 

47923591 (2009)

Acceptable, guideline

0, 50, 250, 1500, 3000 

ppm

0/0, 2.1/2.7, 11/14, 

68/82, 145/182 mkd 

(M/F)

Chronic toxicity 

NOAEL=50 ppm (2.1/2.7 mkd in males/females)

LOAEL =250 ppm (11/1 mkd) based on neoplastic changes in 

the liver (foci, masses). 

Carcinogenicity-see CARC report 

Classified as“ not likely to be carcinogenic to humans” at 

doses below those that cause liver enzyme induction in rats. 

870.4300 

Chronic 

toxicity/carcinogenicity 

in mice

47923592 (2009)

Acceptable, guideline

0, 150, 750, 3000, 6000 

ppm

0/0, 21/33, 107/158, 

468/652, 996/1307 mkd 

(M/F)

Chronic toxicity 

NOAEL=750ppm (158/107 mkd M/F) 

LOAEL =3000 ppm (468/652) mkd M/F based on decrease 

body weight. 

Carcinogenicity

NOAEL=6000 ppm (996/1307 mkd M/F) 

LOAEL =Not observed

Gene Mutation

870.5100 

In vitro Bacterial Gene 

Mutation

47923572 (2008)

Acceptable, guideline

0, 20, 100, 500, 2500, 

5000 μg/plate S9 

Not mutagenic in the reverse mutation assay in Salmonella 

typhimurium or Escherichia coli with or without metabolic 

activation. 

Gene Mutation

870.5300 

In vitro Mammalian 

Cells Gene Mutation 

(Chinese Hamster 

Ovary Cells) 

47923579 (2007)

Acceptable, guideline

0-100 μg/ml S9 

Does not induce forward mutations in CHO cells with or 

without metabolic activation. 

Cytogenetics 

870.5375 

In vitro Mammalian 

Cytogenetics

Chromosomal 

Aberration Assayhuman peripheral blood 

lymphocytes

47923577 (2008)

Acceptable, guideline

0-400 μg/ml S9 

Does not cause clastogenic effects in V79 cells with or 

without metabolic activation. 

Cytogenetics-other 47923584 (2006) Did not lead to any increase in polychromatic erythrocytes. 
Page 43 of 83

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)

Guideline No

Study Type

MRID/Classification

Doses Results

870.5395 In Vivo

Mammalian 

Cytogenetics -

Erythrocyte 

Micronucleus-mouse

Acceptable, guideline

0, 500, 1000, 2000 mkd 

870.6200a

Acute Neurotoxicity-rat

47923605 (2009)

Acceptable, guideline

0, 125, 500, 2000 mkd 

NOAEL (neurotoxicity) =125 mk

LOAEL (neurotoxicity)=500 mk based on decreased motor 

activity (both sexes) and decreased rearing (males only). 

870.6200b

Subchronic 

Neurotoxicity-rat

47923606 (2009)

Acceptable, guideline

0, 200, 100, and 5000 

ppm

0, 11.5/13.4, 57.7/67.2, 

302.2/337.7 mkd M/F 

NOAEL (neurotoxicity)=5000 ppm (302/338 mkd M/F)

LOAEL (neurotoxicity) =Not observed 

870.7485

Metabolism and 

Pharmacokinetics-rat

47923555 (2009)

47923556 (2009)

The times to maximum plasma levels (TMAX) were 24 hours 

(500 mg/kg bw), 8 hours (50 mg/kg bw), and 1 hour (5 mg/kg 

bw) in both sexes. No sex differences in the rate or extent of 

absorption was observed. AUCs scaled with dose, indicating 

that absorption was not saturated. 

Radioactivity was widely distributed in both sexes with a 

similar pattern: the highest concentrations were found in the 

gut contents and stomach contents. However, lower 

concentrations were found in numerous other organs/tissues, 

including the liver, thyroid, adrenal glands, kidney, pancreas, 

testes/uterus, and brain. For males and females, radioactivity 

declined in all tissues over time. The time course of the 

amount of radioactivity found in urine and feces indicated the 

excretion occurred predominantly within three days after 

dosing. Bile duct cannulation experiments showed that the 

bile was a major route of excretion. 

The main biotransformation steps of BAS 700 F in rats are 

hydroxylation at the biphenyl ring system, N-demethylation at 

the pyrazole ring system, loss of a fluorine atom at the 

biphenyl ring system, and conjugation with glucuronic acid or 

with glutathione derivatives. A further, but negligible 

transformation route is cleavage at the amide bond between 

the pyrazole ring system and the biphenyl ring system. 

870.7600

Dermal penetration

47923632 (2010)

Acceptable, guideline

5.6, 33,4, 1670 μg/cm2

for 8 h exposure and 24 

and 120 h termination

The dermal absorption factor is 8.38%.
Page 44 of 83

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)

Guideline No

Study Type

MRID/Classification

Doses Results

*In a formulation with 

pyraclostrobin (BAS 

500 F) 

870.7800 

Immunotoxicity-mice 

(male)

47923633 (2009)

Acceptable, guideline

0, 500, 2000 and 6000 

ppm

0, 106, 450 and 1323 

mg/kg/d

Not immunotoxic. 

Non-guideline 

S-phase Response Liver

1, 3, 7, 14 days-rat

47923598 (2009)

0, 50, 250, 1500 and 

3000 ppm

Cell proliferation in both sexes was dose-dependent at 

maximal at Day 7 (males) and Days 7& 14 (females).

Non-guideline 

S-phase Response Liver

7, 28, 91 days-rat

47923596 (2009)

0, 50 ppm (nominal)-

Acceptable, nonguideline

47923596 (2009)

Acceptable, nonguideline

0. 250, 1500, 3000 ppm 

(nominal)

Cell proliferation in males was maximal at Day 7 and was 

nearly absent by Day 28. Cell proliferation in females was 

maximal at Day 7 declined Days 28 and 91, but was still 

above controls in higher dose groups. All effects were dosedependent. 

Reversibility investigated at 28 days treat/28 days recovery. 

Non-guideline

Enzyme induction 

(Phase I and Phase II) 

with Thyroid Hormone 

Levels-14 days 

47923593 (2009)

Acceptable, nonguideline

0, 250, 1500, 3000 ppm 

1/1, 16/19, 96/126, 

192/234 mkd 

Dose-dependent increase in Phase I and Phase II enzymes in 

both sexes and increased liver and thyroid weights with 

correlating histopathology. Effects partially (thyroid 

histopathology) to totally (all other effects) reversible in 4 

week recovery group. 

Non-OPPTS guideline, 

OECD 486 

47923589 (2009)

Acceptable, nonguideline

0, 1000, 2000 mkd 

Does not induce unscheduled DNA synthesis. 

Table A.2.5 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for 

Metabolite M700F001 

Guideline No

Study Type 

MRID 

Classification

Doses 

Results 

870.3100

90-Day dietary in rats

47923608 (2009)

Acceptable, -guideline

0/0, 94.6/98.8, 

NOAEL=953.6/983.1 mkd in M/F

LOAEL=Not observed 
Page 45 of 83

Table A.2.5 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for 

Metabolite M700F001 

Guideline No

Study Type 

MRID 

Classification

Doses 

Results 

285.7/295.1, 

953.6/983.1 mkd M/F 

870.3700b

Prenatal 

Developmentalrabbit

47923613 (2009)

Acceptable, guideline

0, 40, 100, and 250 

mkd

Maternal

NOAEL=250 mkd

LOAEL =Not observed. 

Offspring 

NOAEL=250 mkd 

LOAEL =Not observed 

Gene Mutation

870.5100 

In vitro Bacterial Gene 

Mutation

47923609 (2009)

Acceptable, guideline

Not mutagenic.

Gene Mutation

870.5300 

In vitro Mammalian 

Cells Gene Mutation 

(Chinese Hamster 

Ovary Cells) 

47923611 (2009)

Acceptable, guideline

Not mutagenic.

Cytogenetics 

870.5375 

In vitro Mammalian 

Cytogenetics

Chromosomal 

Aberration Assayhuman peripheral blood 

lymphocytes

47923610 (2009)

Acceptable, guideline

Not clastogenic. 

Cytogenetics-other

870.5395 In Vivo

Mammalian 

Cytogenetics -

Erythrocyte 

Micronucleus-mouse

47923612 (2009)

Acceptable, guideline

O, 500, 1000, 2000 

mkd

Did not lead to any increase in polychromatic erythrocytes. 

Table A.2.5 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for 

Metabolite M700F002 

Guideline No

Study Type 

MRID 

Classification

Doses 

Results 

870.3050

28 day dietary in rats

47923615 (2009)

Acceptable, guideline

0/0, 113/113.4, 

275.9/394.8, 

1164.8/1253.3 mkd

NOAEL= 1164.8/1253.3mkd in M/F

LOAEL=Not observed 

870.3100 47923616 (2009)
Page 46 of 83

Table A.2.5 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for 

Metabolite M700F002 

Guideline No

Study Type 

MRID 

Classification

Doses 

Results 

90-Day dietary in rats Acceptable, -guideline

0/0, 113/113.4, 

275.9/394.8, 

1164.8/1253.3 mkd

0/0, 95.1/98.0, 

285.3/299.5, 

958.4/928.7 mkd M/F

NOAEL=958.4/928.7 mkg M/F

LOAEL=not observed 

870.3700b

Prenatal 

Developmentalrabbit

47923622 (2000)

Acceptable, -guideline

0, 100, 300, 1000 mkd

Maternal

NOAEL=300 mkd

LOAEL =1000 mkd based on increased mortality and 

abortions.

Offspring 

NOAEL=1000 mkd 

LOAEL =Not observed

Gene Mutation

870.5100 

In vitro Bacterial Gene 

Mutation

47923617 (2007)

Acceptable, guideline

Not mutagenic.

Gene Mutation

870.5300 

In vitro Mammalian 

Cells Gene Mutation 

(Chinese Hamster 

Ovary Cells) 

47923619 (2008)

Acceptable, -guideline

Not mutagenic. 

Cytogenetics 

870.5375 

In vitro Mammalian 

Cytogenetics

Chromosomal 

Aberration Assayhuman peripheral blood 

lymphocytes

47923618 (2008)

Acceptable, -guideline

Not clastogenic. 

Cytogenetics-other

870.5395 In Vivo

Mammalian 

Cytogenetics -

Erythrocyte 

Micronucleus-mouse

47923620 (2009)

Acceptable, guideline

O, 375, 750, 1500 mkd

Did not lead to any increase in polychromatic erythrocytes. 

Non-OPPTS guideline, 

OECD 417

47923621 (2009)

Acceptable, nonguideline

1000 mkd, oral 

(gavage) 

M700F002 is systemically bioavailable and its presence in 

the bone marrow and blood after an oral application is 

confirmed.
Page 47 of 83

Table A.2.4 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for 

Metabolite M700F048 

Guideline No

Study Type 

MRID 

Classification

Doses 

Results 

870.3050

28 day dietary in rats

47923624 (2009)

Acceptable, guideline\

0, 50, 200, 1000 mkd 

(nominal)

0/0, 47.l/51.4, 

189.3/208.2, not 

calculable/1477.8 M/F

NOAEL=47.1/51.4 mkd in males, 1477.8 mkd females. 

LOAEL= 189.3 in mkd males based on decreased absolute 

and realtive monocyte counts. The LOAEL was not 

observed in females. 

870.3700b

Prenatal 

Developmentalrabbit

47923631 (2009)

Acceptable, guideline

0, 10, 30 and 100 

mg/kg bw/d

Maternal

NOAEL=30 mkd

LOAEL = 100 mkd based on mortality, abortions, and 

resorptions 

Offspring 

NOAEL=30 mkd 

LOAEL =100 mkd based on incresed aborptions and late 

resorptions. 

Gene Mutation

870.5100 

In vitro Bacterial Gene 

Mutation

47923625 (2009)

Acceptable, guideline

Not mutagenic. 

Gene Mutation

870.5300 

In vitro Mammalian 

Cells Gene Mutation 

(Chinese Hamster 

Ovary Cells) 

47923627 (2009)

Acceptable, guideline

Not mutagenic. 

Cytogenetics 

870.5375 

In vitro Mammalian 

Cytogenetics

Chromosomal 

Aberration Assayhuman peripheral blood 

lymphocytes

47923626 (2009)

Acceptable, guideline

Clastogenic with metabolic activation. 

Cytogenetics-other

870.5395 In Vivo

Mammalian 

Cytogenetics -

Erythrocyte 

Micronucleus-mouse

47923628 (2009)

Acceptable, guideline

0, 500, 1000, 2000 

mkd

Did not lead to any increase in polychromatic erythrocytes. 

870.7485

Metabolism and 

Pharmacokinetics-rat

47923557 (2009)

Acceptable, guideline

In both sexes, the major route of excretion was the feces 

(85.47% in males and 86.4% in females) with maximum 

excretion within 12-24 hours after dosing. The minor route 

of excretion was in the urine (2.4% in males and 6.8% in 

females). 

Non-OPPTS guideline, 47923630 (2009) M700F048 is 5077265 is systemically bioavailable and its 
Page 48 of 83

Table A.2.4 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for 

Metabolite M700F048 

Guideline No

Study Type 

MRID 

Classification

Doses 

Results 

OECD 417 Acceptable, nonguideline

1000 mkd, oral 

(gavage) 

presence in the bone marrow, blood and liver after an oral 

application is confirmed.

Non-OPPTS guideline, 

OECD 486 

47923629 (2009)

Acceptable, nonguideline

0, 1000, 2000 mkd 

Does not induce unscheduled DNA synthesis. 

Table A.2.5 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for

Artificial Batch

Guideline No

Study Type 

MRID 

Classification

Doses 

Results 

Gene Mutation

870.5100 

In vitro Bacterial Gene 

Mutation

47923573 (2009)

Acceptable, guideline 

No evidence of mutagenicity.

Gene Mutation

870.5300 

In vitro Mammalian 

Cells Gene Mutation 

(Chinese Hamster 

Ovary Cells) 

47923580 (2009)

Acceptable, guideline 

No evidence of forward mutations. 

Cytogenetics 

870.5375 

In vitro Mammalian 

Cytogenetics

Chromosomal 

Aberration Assayhuman peripheral blood 

lymphocytes

47923578 (2009)

Acceptable, guideline

Clastogenic in V79 cells in the presence or absence of 

metabolic activation. 

Cytogenetics-other

870.5395 In Vivo

Mammalian 

Cytogenetics -

Erythrocyte 

Micronucleus-mouse

47023585 (2009)

Acceptable, guideline

0, 500, 1000, 2000 

mkd 

Did not lead to any increase in polychromatic erythrocytes

Non-OPPTS guideline, 

OECD 486 

47923590 (2009)

Acceptable, nonguideline

0, 2.5, 5 mkd 

Does not induce unscheduled DNA synthesis. 
Page 49 of 83

Table A.2.5 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for 

Impurity B

Guideline No

Study Type 

MRID 

Classification

Doses 

Results 

Gene Mutation

870.5100 

In vitro Bacterial Gene 

Mutation

47923574 (2009)

Acceptable, guideline

Not mutagenic.

Gene Mutation

870.5300 

In vitro Mammalian 

Cells Gene Mutation 

(Chinese Hamster 

Ovary Cells) 

47923581 (2009)

Acceptable, guideline

Not mutagenic.

Cytogenetics-other

870.5395 In Vivo

Mammalian 

Cytogenetics -

Erythrocyte 

Micronucleus-mouse

47923586 (2009)

Acceptable, guideline

0, 15, 30, 60 mkd 

Did not lead to any increase in polychromatic erythrocytes. 

Table A.2.3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for

Impurity C

Guideline No

Study Type 

MRID 

Classification

Doses 

Results 

Gene Mutation

870.5100 

In vitro Bacterial Gene 

Mutation

47923576 (2008)

Acceptable, guideline

Not mutagenic.

Gene Mutation

870.5300 

In vitro Mammalian 

Cells Gene Mutation 

(Chinese Hamster 

Ovary Cells) 

47923583 (2008)

Acceptable, guideline

Not mutagenic.

Cytogenetics-other

870.5395 In Vivo

Mammalian 

Cytogenetics -

Erythrocyte 

Micronucleus-mouse

47923588 (2008)

Acceptable, guideline 

0, 500, 1000, 2000 

mkd 

Did not lead to any increase in polychromatic erythrocytes. 
Page 50 of 83

A.3 HAZARD IDENTIFICATION AND ENDPOINT SELECTION

A.3.1 Acute Reference Dose (aRfD) – All populations (General Population, including 

infants and children and females ages 13-49)

Study Selected: Acute Neurotoxicity Study in Rats

MRID No.: 47923606

Dose and Endpoint for Risk Assessment: NOAEL= 125 mg/kg/day. The LOAEL of 500 

mg/kg/day was based on decreased motor activity (both sexes) and decreased rearing (males 

only) seen on the day of dosing. 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability); FQPA 

SF = 1X 

Acute RfD= acute PAD = 125 mg/kg/day = 1.25 mg/kg/day

 100

Comments about Study/Endpoint/Uncertainty Factors: The study is appropriate for acute 

dietary exposure due to the route (oral) and duration (acute) of dosing. The effects are clearly 

adverse and result from a single exposure. 

Endpoints from the developmental rat and rabbit studies as well as the 2-generation reproduction 

study were not selected since there were no effects seen that were attributable to a single 

exposure. Therefore, the dose and endpoint from the ACN study was selected and is considered 

protective of potential acute toxicity for all populations (i.e. the general population, including 

infants and children and females ages 13 to 49 years old). 

A.3.2 Chronic Reference Dose (cRfD)-All Populations

Study Selected: Chronic Toxicity/Carcinogenicity Study in Rats 

MRID No: 47923591

Dose and Endpoint for Risk Assessment: NOAEL= 2.1 mg/kg/day (50 ppm). The LOAEL of 

11 mg/kg/day (250 ppm) was based on non-neoplastic changes (increased liver weight, liver foci, 

changes in clinical chemistry, including prothrombin time and cholesterol levels) in the liver of 

male rats. 

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability); FQPA 

SF = 1X 
Page 51 of 83

Chronic RfD = chronic PAD= 2.1 mg/kg/day = 0.021 mg/kg/day

 100 

Comments about Study/Endpoint/Uncertainty Factors: The study is appropriate for chronic 

dietary exposure due to the route (oral) and duration (chronic) of dosing. These effects are 

consistent with the liver being the target organ and are supported by the effects seen in the 28-

and 90-day studies. This point of departure is also protective of the liver adenomas occurring at 

250 ppm in male rats.

A.3.3 Incidental Oral Exposure (Short-Term (1-30 days))

Study Selected: 28-Day Dietary Toxicity Study in the Rat

MRID No: 47923564

Dose and Endpoint for Risk Assessment: NOAEL = 9 mg/kg/day (100 ppm) in males. The 

LOAEL in males of 176 mg/kg/day (500 ppm) was based on changes in thyroid follicular 

hypertrophy/hyperplasia. 

Uncertainty Factor: The residential level of concern for MOE is 100 (10X inter-species, 10X 

intra-species factor) (proposed)

Comments about Study/Endpoint/UF: The selected endpoint is the most sensitive endpoint 

and most sensitive species for this route and duration of expsoure. 

A.3.4 Incidental Oral Exposure (Intermediate-Term (1-6 months))

Study Selected: 90-Day Dietary Toxicity Study in the Rat

MRID No: 47923567

Dose and Endpoint for Risk Assessment: NOAEL = 7.3 mg/kg/day (100 ppm). The LOAEL = 

500 ppm (35.1 mg/kg/day) based on thyroid hormones and thyroid follicular 

hypertrophy/hyperplasia. 

Uncertainty Factor: The residential level of concern for MOE is 100. 

Comments about Study/Endpoint/UF: The selected endpoint is the most sensitive endpoint 

and most sensitive species for this route and duration of expsoure. 

A.3.5 Occupational and Residential Dermal Exposure (Short- and Intermediate-Term)

In a 28-day dermal toxicity study in rats, no dermal irritation or systemic effects were observed 

up to the limit dose of 1000 mg/kg/day. This is a route-specific study that also assessed all of the 

endpoints used in the other exposure scenarios and durations of exposure (e.g. neurological 

endpoints, thyroid and liver histopathology). In addition, no increased susceptibility was seen 
Page 52 of 83

between offspring and adult animals in the developmental toxicity studies in rats and rabbits and 

in the 2-generation reproduction study in rats. Therefore, the quantification of dermal risk is 

not required since no hazard was identified.

A.3.6 Occupational and Residential Inhalation Exposure (Short-Term)

Study Selected: 28-Day Dietary Toxicity Study in the Rat

MRID No: 47923564

Dose and Endpoint for Risk Assessment: NOAEL = 9 mg/kg/day (100 ppm) in males. The 

LOAEL in males of 176 mg/kg/day (500 ppm) was based on changes in thyroid hormones and 

thyroid follicular hypertrophy/hyperplasia. 

Uncertainty Factor: The occupational and residential level of concern for MOE is 100. 

Comments about Study/Endpoint/UF: No inhalation studies are available for fluxapyroxad; 

therefore, a 28-day oral toxicity study in rats was used for inhalation risk assessment. The 

selected endpoint is the most sensitive endpoint and most sensitive species for this duration of 

exposure. 

A.3.7 Occupational and Residential Inhalation Exposure (Intermediate-Term)

Study Selected: 90-Day Dietary Toxicity Study in the Rat

MRID No: 47923567

Dose and Endpoint for Risk Assessment: NOAEL = 7.3 mg/kg/day (100 ppm). The LOAEL = 

500 ppm (35.1 mg/kg/day) based on thyroid follicular hypertrophy/hyperplasia. 

Uncertainty Factor: The occupational and residential level of concern for MOE is 100.

Comments about Study/Endpoint/UF: No inhalation studies are available for fluxapyroxad; 

therefore, a 90-day oral toxicity study in rats was used for inhalation risk assessment. The 

selected endpoint is the most sensitive endpoint and most sensitive species for this route and 

duration of expsoure. 

Based on the proposed use pattern for fluxapyroxad, occupational long-term inhalation exposure 

is not anticipated.
Page 53 of 83

A. 4 EXECUTIVE SUMMARIES

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity – Rat MRID 47923567

BAS 700 F (Batch: COD–000826; Purity: 99.6%) was administered to male and female Wistar 

rats at dietary dose levels of 0, 100, 500, 2000, or 6000 ppm (0/0, 6.1/7.3, 31.2/35.1, 126/144, 

and 407/424 mg/kg bw/day in males/females) for at least 90 days. Significant decreases in body

weight and body weight gain were observed in 6000 ppm males and females and were 

considered adverse. 

A functional observational battery and motor activity measurements were performed at the end 

of the dietary exposure period. However, no evidence of neurotoxicity was observed in these 

investigations. Also, no signs of neurotoxicity were noted in daily cageside or weekly clinical 

examinations and no opthamoscopic changes were noted. 

In the liver, a number of changes were observed. These included changes of a number of clinical 

chemistry parameters, increased absolute and relative liver weights at ≥ 500 ppm as well as 

histopathological changes (increased incidence and severity of centrilobular hepatocyte 

hypertrophy in both sexes at ≥ 500 ppm (which is considered adaptive and not adverse), and 

hepatocellular single cell necrosis in top dose males (which is considered clearly adverse). The 

clinical chemistry changes considered potentially indicative of adverse effects were increased 

serum cholesterol and triglycerides in females at ≥ 2000 ppm and in males at 6000 ppm and 

decreased prothrombin time in females at ≥ 500 ppm, which indicated potential for increased

blood clotting. The increase of γ-glutamyltransferase activities in males at ≥2000 ppm and the 

top dose group of both sexes was regarded equivocal, since elevated GGT can be associated with 

both adaptive and adverse effects 

Changes in thyroid hormone levels were observed in males at ≥100 ppm with thyroid follicular 

cell hypertrophy/hyperplasia present at ≥2000 ppm. In females, both changes in thyroid

hormone levels and thyroid follicular hypertrophy/hyperplasia were observed at ≥500 ppm. 

Additionally, an increased tubular deposition of pigment indicative of a mild tubulonephrosis 

was observed in kidneys of top dose females and was not considered adverse. 

The LOAEL is 2000 ppm (126 mg/kg bw/day) in males and 500 ppm (35.1 mg/kg bw/day) 

in females, based on thyroid follicular hypertrophy and hyperplasia. The NOAEL is 500 

ppm (31.2 mg/kg bw/day) in males and 100 ppm (7.3 mg/kg bw/day) in females. 

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline 

requirement for a 90-day oral toxicity study (OPPTS 870.3100; OECD 408) in rats. 
Page 54 of 83

870.3100 90-Day Oral Toxicity – Mice MRID 47923568

BAS 700 F (Batch: COD–000826; Purity 99.6%) was administered to C57BL/6 J Rj mice 

(10/sex/dose) at dietary dose levels of 0, 100, 400, 2000 and 6000 ppm (corresponding to 0/0, 

21/32, 77/128, 390/610, and 1136/1657 mg/kg bw/day) for at least 91 days. Significant 

decreases in body weight (-12.6%) and body weight gain (-32.5%) were observed in top dose 

males were considered adverse. 

The liver was identified as a target organ as indicated by changes of a number of clinical 

chemistry parameters down to a dietary dose level of 400 ppm in males as well as statistically

significant increases of absolute and relative liver weights at 2000 ppm or higher in both sexes. 

The clinical chemistry changes consisted of increased alkaline phosphatase, alanineaminotransferase (ALAT) and urea levels in top dose males as well as decreased triglyceride 

(males only) and albumin, total protein and cholesterol levels in both sexes. An increased 

incidence of multifocal necrosis was observed in the liver of 5/10 6000 pm males and, in 

conjunction with increased liver enzymes, was considered potentially adverse. 

The LOAEL is 6000 ppm (1136 mg/kg bw/day) in males, based on decreased body weight 

and body weight gain and multifocal necrosis in the liver. The LOAEL in females was not 

observed. The NOAEL is 2000 ppm (390 mg/kg bw/day) in males and 6000 ppm (1657 

mg/kg bw/day) in females. 

This 90-day oral toxicity study in the mouse is classified as totally reliable 

(acceptable/guideline) and satisfies guideline requirements for a 90-day oral toxicity study

(OPPTS 870.3100; OECD 408) in mice. 

870.3150 90-Day Oral Toxicity – Dog MRID 47923569

Administration of BAS 700 F (Batch: COD – 000899; Purity: 99.7%) to groups of 5 Beagle 

dogs/sex/dose at dietary dose levels of 0, 300, 1500 and 10000 ppm in males (0, 9, 45, and 295 

mg/kg bw/day) and 0, 300, 1500 and 7500 ppm in females (0, 10, 51, and 238 mg/kg bw/day) for 

at least 90 days resulted in impaired food consumption in each two high dose males and females. 

This was accompanied by decreased body weight development in one high dose female only. 

Furthermore, vomiting was recorded in all male and female dogs of the high dose group during 

the first two days of treatment.

The liver was identified as the major target organ as indicated by changes in a number of clinical 

chemistry parameters at 1500 and/or 10000/7500 ppm as well as statistically significant changes 

of absolute and/or relative liver weights at 10000 ppm in males and 7500 ppm in females. The 

clinical chemistry changes considered potentially adverse were increase ALP and GGT in both 

sexes at the high dose. Increased absolute and/or relative weights in both sexes were considered 

adaptive and not adverse, since there were not histopathological correlates. 

The LOAEL is 10000 ppm (295 mg/kg bw/day) in males and 7500 ppm (238 mg/kg bw/day) 
Page 55 of 83

in females, based on vomiting and clinical chemistry changes. The NOAEL is 1500 ppm in 

both sexes (45 mg/kg bw/day in males and 51 mg/kg bw/day in females). 

This study is classified as totally reliable (acceptable/guideline) and satisfies guideline 

requirements for a 90-day oral toxicity study (OPPTS 870.3150; OECD 409) in non-rodents. 

870.3200 21/28-Day Dermal Toxicity – Rat MRID 47923571

Dermal Administration of BAS 700 F (Batch: COD-001049; Purity: 99.2%) in a 

carboxymethylcellulose vehicle to 10/sex/dose Wistar rats (6 hours/day; 5 days/week, semiocclusive dressing) for 4 weeks at dose levels of 0, 100, 300 and 1000 mg/kg bw/d caused no

substance-related adverse findings. 

An increase in absolute and relative liver weights in both sexes was possibly treatment related, 

Since there was neither a histopathological correlate nor any accompanying treatment-related 

changes of clinical chemistry parameters, this effect was not considered adverse. 

The LOAEL in males and females was not identified. The NOAEL in males and females 

was 1000 mg/kg bw/day. 

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline 

requirement for a dermal toxicity study (OPPTS 870.3200; OECD 410) in rats. 

870.3465 90-Day Inhalation – Rat 

- NA -

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study – Rat 47923603

BAS 700 F (Batch COD-000899, Purity 99.7%) was administered daily to presumably pregnant 

Crl:WI (Han) Wistar rats by oral gavage in a 0.5% carboxymethylcellulose vehicle during 

gestation days 6-19 at dose levels of 0, 25, 200 and 1000 mg/kg bw. The high dose of 1000 

mg/kg bw/day resulted in increased (12-16%) absolute and relative thyroid weights (with 

correlating microscopic effects of thyroid hypertrophy and hyperplasia (considered adverse). 

Absolute and relative liver weights were increased significantly, but slightly (9-13%) at this dose 

and occurred in the absence of corroborating effects on serum liver enzymes (liver 

histopathology was not examined). This effect was considered as most likely due to 

hepatocellular hypertrophy (due to extensive evidence of hepatocellular hypertrophy in 

conjunction with increased liver weights throughout the database for this chemical) and so was 

not considered adverse. 

The LOAEL for maternal toxicity in females is 1000 mg/kg bw/day, based on increased 
Page 56 of 83

absolute and relative thyroid weights and thyroid hypertrophy/hyperplasia. The NOAEL 

is 200 mg/kg bw/day. 

No treatment-related effects on cesarean section parameters were observed at any dose. No 

treatment-related external, visceral or skeletal malformations were noted. BAS 700 F was not 

teratogenic up to the highest dose tested.

The LOAEL for developmental toxicity was not observed. The NOAEL is 1000 mg/kg 

bw/day. 

This study is classified as totally reliable (acceptable/guideline) and satisfies guideline 

requirements for a prenatal developmental toxicity study (OPPTS 870.3700; OECD 414) in rats. 

870.3700b Prenatal Developmental Toxicity Study – Rabbit MRID 47923604

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat MRID 47923602

BAS 700 F (Batch COD-000899, Purity 99.7%) was administered daily to presumably pregnant 

Himalayan rabbits by stomach tube during gestation days 6-28 post insemination (p.i.) at dose 

levels of 0, 10, 25 and 60 mg/kg bw. The high of 60 mg/kg dose elicited signs of maternal 

toxicity as indicated by one abortion, decreased food consumption (-21.9% during the treatment 

period) corroborated by an increased number of animals with reduced or no defecation, body 

weight loss during gestation days 9 to 11 and a decrease of cumulative body weight gain by

49.3% during the treatment period. Body weighs were decreased 12% by Day 29, which was 

considered adverse. No maternal toxicity was observed at dose levels ≤ 25 mg/kg. 

The LOAEL for maternal toxicity in males is 60 mg/kg bw/day, based on decreased body 

weight. The NOAEL is 25 mg/kg bw/day. 

No treatment-related effects on cesarean section parameters were observed at any dose. No 

treatment-related external, visceral or skeletal malformations were noted. The only treatmentrelated variation was a statistically significant increase in incidence of mean % affected fetuses 

with paw hyperflexion at the high dose level (10.3%). This variation is frequently observed in 

control fetuses (up to 6.7% affected fetuses per study) and may reverse since tendons stretch 

postnatally as limbs grow and are being used. Although this variation occurred in presence of 

substantial maternal toxicity and so may be secondary to maternal toxicity, it was an effect of 

treatment and so is considered potentially adverse. 

The LOAEL for developmental toxicity was 60 mg/kg bw/day, based on decreased fetal 

body weights and an increased incidence of paw hyperflexion, which was considered 

potentially adverse. The NOAEL is 25 mg/kg bw/day. 
Page 57 of 83

This study is classified as totally reliable (acceptable/guideline) and satisfies guideline 

requirements for a prenatal developmental toxicity study (OPPTS 870.3700; OECD 414) in 

rabbits. 

A.4.4 Chronic Toxicity

870.4100b Chronic Toxicity – Dog MRID 47923570

BAS 700 F (Batch: COD – 001026, purity 99.4%) was administered to Beagle Dogs for 12 

months at dietary dose levels of 0, 300, 1500 and 12000 ppm in males (0, 8, 39, and 335 mg/kg 

bw/day) and 0, 300, 1500 and 9000 ppm in females (0, 9, 43, and 257 mg/kg bw/day). Vomiting 

was observed in the all high dose animals at the beginning and midway through the study, and 

was considered adverse. 

In the liver, changes in a number of clinical chemistry parameters at 1500 and/or 12000/9000 

ppm as well as statistically significant changes of absolute and/or relative liver weights at 12000 

ppm in males and 9000 ppm in females were observed. The clinical chemistry changes consisted 

of increased alkaline phosphatase, serum γglutamyl transferase, triglyceride and alanineaminotransferase levels as well as decreased total protein, albumin, cholesterol, total bilirubin, 

creatinine, urea and calcium levels in either or both sexes. Histopathlogical analysis of the organ 

showed an intracytoplasmic iron deposition in hepatocytes as well as multifocal fibrosis 

(considered adverse) at dose levels of 1500 ppm and higher. One high dose male displayed a 

slight cirrhosis.

In the spleen, fine granular iron storage (distinct from hemosiderin) was observed at 1500 and 

9000/12000 ppm. This was accompanied by a diffuse atrophy of the red pulp At 9000/12000 

ppm. No histopathological changes were observed in the white pulp. The findings of iron 

storage and atropy at the high dose were considered potentially adverse. 

Changes were also observed in the gall bladder (epithelial storage of granular brown pigment of 

males and females at 1500 ppm, not considered adverse ) and the prostate (reduced weight and 

atrophy without change of the glandular structure at 12000 ppm, considered potentially adverse). 

The LOAEL is 1500 ppm in females (43 mg/kg bw/day) based on hepatic fibrosis and clinical 

chemistry changes. The NOAEL in females in 9 mg/kd bw/day. The LOAEL in males is 12000 

ppm (335 mg/kg bw/day) based on vomiting, clinical chemistry changes, and hepatic fibrosis and 

cirrhosis. The NOAEL in males is 1500 ppm (39 mg/kg bw/day). 

This study is classified as totally reliable (acceptable/guideline) and satisfies guideline 

requirements for a chronic toxicity study (OPPTS 870.4100; OECD 452) in non-rodents. 
Page 58 of 83

A.4.5 Carcinogenicity

870.4300 Carcinogenicity/Chronic Study – Rat 47923591

BAS 700 F (Batches COD – 000899 up to study day 454 and COD-001049 from study day 455 

to termination; Purity: 99.7% and 99.2%, respectively) was administered to Wistar rats at dietary

dose levels of 0, 50, 250, 1500 and 3000 ppm (0/0, 2.1/2.7, 11/14, 68/82, or 145/182 mg/kg 

bw/day in males/females) for 2 years to assess carcinogenicity. A satellite group of animals was 

sacrificed at one year to assess chronic toxicity. 

In the carcinogenicity group (50/sex/dose), body weight decreases after two years of 8% were 

noted in males at 3000 ppm. In females, body weights were decreased 11.9% or more at ≥ 250 

ppm. This indicated that dosing was adequate. Treatment with BAS 700 F did not affect the 

survival of rats in the carcinogenicity group. Tumors considered a result of treatment were 

observed in the liver and thyroid only. Hepatocellular tumors were in the form of adenomas and 

carcinomas in both sexes, with a significant increase in the combined incidence of these tumor 

types in males at ≥ 1500 ppm and in females at 3000 ppm. Significant increases in hepatocellar 

carcinomas were observed only in males and only at 3000 ppm. Adenomas were observed in 

both sexes at a higher incidence than carcinomas and at lower doses. Significant increases in 

adenomas were observed in males at ≥ 1500 ppm and in females at 3000, ppm. However, 

adenoma incidence was greater than the upper limit of historical controls in males at ≥ 250 ppm 

and in females at ≥1500 ppm, and so was determined to be an effect of treatment. Nonneoplastic changes in the livers of these animals included increases in the absolute and relative 

liver weights of both sexes at 250 ppm in conjunction with centrilobular hepatocellular 

hypertrophy, spongiosis hepatitis in males at 1500 ppm, increased pigment storage (likely 

lipofucsin) in males and females at 1500 ppm, and dark brown liver discoloration at 1500 

ppm.

Thyroid tumors resulting from treatment were in the form of follicular cell adenomas and 

carcinomas. The combined incidence of adenomas and carcinomas was significantly increased 

for males only at 3000 ppm compared to concurrent controls. The incidence was within the 

historical control range, but was still considered an effect of treatment. The individual incidence 

of thyroid follicular adenomas or carcinomas did not reach statistical significance for males or 

females. For males only, the incidence of carcinomas at 3000 ppm was not significantly 

different from concurrent controls, but was greater than the upper limit of the historical control 

values and so was considered treatment related. In males and females, the incidence of 

adenomas did not reach statistical significance at any dose compared to concurrent controls and 

was within the historical control range. These results were consistent with thyroid 

histopathology, which showed significant thyroid follicular hyperplasia in males at 1500 ppm. 

Colloid was also altered in both sexes at 1500 ppm and above. 

In addition, the bones of animals in the carcinogenicity group were examined by gross and 

histopathology. In the femora and other bones of affected animals (nasal turbinates, sternae, 

vertebrae) deposition of Perl's Prussian Blue stain positive material, most probably iron, was 
Page 59 of 83

observed at  250 ppm in both sexes. No changes of the bone structure were identified by light 

microscopy. Gross pathological evaluation identified white discoloration of skull bones (frontal 

bone, dorsal skull, tympanic cavity) that diagnosed as periosteal hyperostosis (i.e. bone 

thickening). These effects were considered potentially adverse. 

Chronic toxicity (one year duration) was also investigated in this study in satellite animals 

(10/sex/dose). Adverse effects on body weight were indicated by terminal body weights in both 

sexes at 3000 ppm that were decreased more than 10% relative to untreated controls. Increased 

absolute and relative liver weights were observed at  250 ppm in males and  500 ppm in 

females in conjunction with centrilobular hepatocellular hypertrophy at  1500 ppm in males 

and females, pigment storage (likely lipofucsin) in males and females at  1500 ppm, and liver 

discoloration at 3000 ppm in both sexes. None of these changes were considered clearly 

adverse. Changes in several clinical chemistry parameters were also observed. These consisted 

of increased serum -glutamyl transferase (considered equivocal) in males and/or females at 

1500 ppm, increased albumin and globulin in males and/or females at  1500 ppm, (not 

considered adverse), increased cholesterol and triglycerides in females at 3000 ppm (considered 

potentially adverse) decreased glucose in males at  250 ppm (not to a magnitude considered 

adverse), and decreased total biliribun in males and females at  250 ppm (not considered 

adverse). In addition, changes of electrolyte levels (Ca2+, Cland inorganic PO4

3-

) were 

observed in females and/or males, at 3000 ppm (PO4

3-

in males ) and  1500 ppm (Ca2+, Clin 

males and females) but were not of a magnitude considered adverse. Also, in female livers a 

decrease of Perl's Prussian Blue stainable iron (as Fe3+) was observed at ≥ 1500 ppm, which was 

not considered adverse. 

The thyroid as well as the femur and other bones were also affected. In the thyroid an increased 

incidence of follicular cell hypertrophy/hyperplasia was observed in males at ≥ 1500 ppm. This 

was observed in conjunction with enlarged thyroid in all males at 3000 ppm. These thyroid 

effects were considered adverse. In the femora, deposition of Perl's Prussian Blue stain positive 

material, most probably iron, was observed. Although there were no light microscopically visible 

changes of the bone structure, this finding was considered to be potentially adverse. 

Discoloration of the teeth (incisors) was also observed in 3000 ppm males and females. This 

was not considered adverse. 

Hematological changes were mainly restricted to female rats and consisted of slightly decreased 

hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin concentrations at 1500 

ppm and/or 3000 ppm. None of these effects were considered adverse. However, shorter 

prothrombin times were recorded for females at dose levels ≥ 250 ppm and in males at ≥ 1500 

ppm, which were considered potentially adverse due to possible hypercoagulability. 

The LOAEL for chronic toxicity in males is 250 ppm (11 mg/kg bw/day in males and 14 

mg/kg bw/day in females) based on non-neoplastic changes in the liver (foci, masses) The 

NOAEL is 50 ppm (2.1 mg/kg bw/day in males and 2.7 mg/kg bw/day in females). 

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline 
Page 60 of 83

requirement for a combined chronic toxicity/carcinogenicity study (OPPTS 870.4300; OECD 

453) in rats. 

870.4300 Carcinogenicity/Chronic Study – Mouse MRID 47923592

BAS 700 F (Batch COD–000899, Purity 99.7% up to study day 349; Batch COD-001049, Purity

99.2% from day 350 to end of study) was administered to C57BL/6 J Rj mice in the diet for 18 

months at doses of 0, 150, 750, 3000 and 6000 ppm (21, 107, 468 and 996 mg/kg bw in males 

and 33, 158, 652 and 1307 mg/kg bw in females). There were no treatment-related neoplasms.

Systemic toxicity was observed as indicated by effects on body weight development in males at 

≥ 3000 ppm and females at 6000 ppm. The liver was identified as the only target organ as 

indicated by increases of relative and/or absolute liver weights in males at ≥ 750 ppm and in 

females at ≥ 3000 ppm. Histopathological examination of the liver revealed mainly periportal 

(males; Zone 3) or peripheral (females; Zone 1) hepatocellular hypertrophy at 6000 ppm and 

≥ 3000 ppm, respectively. This effect is not considered adverse. In addition, an increased 

severity and/or incidence of fatty changes in hepatocytes was observed at dose levels ≥ 750 ppm. 

The LOAEL for chronic toxicity is 3000 ppm (468 mg/kg/day in males and 652 mg/kg/day 

in females) based on decreased body weight. The NOAEL is 750 ppm (158 mg/kg bw/day 

in males and 107 mg/kg bw/day in females). 

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline 

requirement for a chronic toxicity/carcinogenicity study (OPPTS 870.4300; OECD 451) in mice. 

A.4.6 Neurotoxicity

870.6100 Delayed Neurotoxicity Study-Hen-NA

870.6200a Acute Neurotoxicity MRID 47923605

The acute neurotoxicity of BAS 700 F (Batch COD-001026; Purity: 99.4%) was investigated in 

groups of 10 male and female Wistar rats (Crl:WI(Han) after a single administration by gavage 

at dose levels of 0, 125, 500, and 2000 mg/kg bw/d. 

No signs of general systemic toxicity were observed. Treatment-related neurobehavioral effects 

were noted in mid and high dose animals only on the day of treatment. These consisted of slight, 

but statistically significant increase of the landing foot-splay in high dose males, reduction in the 

number of rearings in males at ≥ 500 mg/kg bw/d as well as impaired motor activity in high and

mid dose males and females. No effects on these parameters were observed on study days 7 and 

14. Additionally, no treatment-related neuropathological findings were noted, i.e. no brain 

weight changes or neurohistopathological findings were observed. Therefore, the affected 

clinical parameters were considered an indication of a neuropharmacological effect rather than 

an indication of neuronal damage.
Page 61 of 83

The LOAEL is 500 mg/kg bw in males and females, based on decreased motor activity (in 

both sexes) and decreased rearing (in males only). The NOAEL is 125 mg/kg bw. 

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline 

requirement for a an acute neurotoxicity study (OPPTS 870.6200; OECD 424) in rats. 

870.6200b Subchronic Neurotoxicity MRID 47923606

Dietary administration of BAS 700F (Batch: COD-001026, Purity: 99.4%) to groups of 10 male 

and female Wistar Crl:WI(Han) rats at dietary dose levels of 0, 200, 1000, and 5000 ppm (11.5, 

57.7, and 302.2 mg/kg body weight /day in males and 13.4, 67.2 and 337.7 mg/kg body

weight/day in females) for 3 months did not result in any clinical (general clinical observation, 

FOB and motor activity) or neurohistopathological indication of neurotoxicity. 

Signs of systemic toxicity observed in this study were consistent with those observed in other 

repeated dose rat studies with BAS 700 F. These consisted of slightly impaired body weight 

development in high dose females, changes of clinical chemistry parameters (increased serum -

GT, total protein, albumin, globulin, cholesterol, triglycerides, urea, Ca2+, inorganic PO4

-

and 

Mg2+ levels as well as decreased AS(A)T, glucose and bilirubin levels), increased liver and 

thyroid weights as well as centrilobular hypertrophy of hepatocytes.

Under the conditions of the present study the no observed adverse effect level (NOAEL) for 

neurotoxicity was 5000 ppm, the highest dose tested, which is equivalent to about 302 mg/kg 

bw/d in males and 338 mg/kg bw/d in females.

The NOAEL for neurotoxicity is 5000 ppm (302 mg/kg bw/day in males and 338 mg/kg 

bw/day in females). The LOAEL was not observed. 

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline 

requirement for a chronic neurotoxicity study (OPPTS 870.6200; OECD 424) in rats. 

SA.4.6 Mutagenicity MRIDs 47923572, 47923579, 47923577, 47923584

MRID 47923572S. typhimurium and E. coli were exposed to BAS 700 F (Batch COD-001026; 

purity 99.4%) using dimethylsulfoxide (DMSO) as a solvent in the presence and absence of 

metabolic activation in two independent sets of experiments. Triplicate plates were used per dose 

and per test condition. Vehicle and positive controls were included in each experiment.

In the plate incorporation assay as well as in the preincubation test, BAS 700 F was tested up to 

the limit concentration of 5000 μg/plate. Concentrations of 20, 100, 500, 2500 and 5000 μg/plate 

were used with and without metabolic activation. In both the plate incorporation assay and the 

preincubation assay a weak bacteriotoxic effect was occasionally observed depending on the 

strain and test conditions at concentrations of 500 μg/plate (strain TA1537 in the plate 

incorporation assay) or above. Precipitation of the test substance was noted at concentrations of 

 500 μg/plate with and without metabolic activation in both experiments.

Neither in the first experiment (plate incorporation test) nor in the second experiment 
Page 62 of 83

(preincubation test) a biologically relevant increase in the number of revertant colonies was 

noticed in any of the strains tested in presence or absence of metabolic activation. The positive 

controls induced the appropriate response in the corresponding strains, thus demonstrating the 

sensitivity of the test system.

According to the results of the study, the test substance BAS 700 F is not mutagenic in the 

Salmonella typhimurium/ Escherichia coli reverse mutation assay under the experimental 

conditions of the study.

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline 

requirement for a bacterial reverse mutation test (OPPTS 870.5100, OECD 471). 

MRID 47923579

BAS 700 F (Batch COD-000899; purity 99.7%) was tested in vitro for its ability to induce 

forward mutations in mammalian cells by assessing the mutation of the HPRT locus in Chinese 

Hamster CHO cells. Two independent sets of experiments were conducted in the presence and 

absence of metabolic activation. Based on the results of a preliminary cytotoxicity assay

concentrations of 5 to 100 μg/mL were employed in the original experiment using a 4-hour 

exposure period with and without metabolic activation. In the second experiment concentrations 

of 6.3 to 100 μg/mL were used without metabolic activation for a 24 hour exposure and with 

metabolic activation for a 4 hour exposure. Ethylmethanesulfonate (EMS) and 

methylcholanthrene (MCA) served as positive controls in the experiments without and with 

metabolic activation, respectively. After the incubation period treatment media were replaced by 

culture medium and the cells were incubated for about one week for expression of mutant cells. 

This was followed by a 6 to 8 day incubation of cells in selection medium containing 6-

thioguanine.

Cytotoxic effects indicated by reduced cloning efficiencies of below 20 % of the respective 

vehicle control were observed in both experiments with or without metabolic activation.

An increase in the mutant frequency was not observed neither in the original nor in the 

confirmatory study. The positive control substances, however, resulted in a marked increase in 

mutant frequency.

BAS 700 F does not induce forward mutations in mammalian cells in vitro, under the conditions 

of this study.

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline 

requirement for an in vitro gene mutation test (OPPTS 870.5300, OECD 476). 

MRID 47923577

BAS 700 F (Batch COD-000899; purity 99.7%) was tested in vitro for the ability to induce 

chromosome and numerical aberrations in Chinese Hamster V79 cells in two independent 

experiments in the presence and absence of metabolic activation. Based on the cytotoxicity
Page 63 of 83

results of a previously performed HPRT study, concentrations of 6.3 to 400 μg/mL were tested 

for clastogenic effects with and without metabolic activation in experiments with a pulse 

treatment of 4 hours or continuous treatment of 18 hours. The preparation intervals used were 18 

h or 28 h after the beginning of treatment. Vehicle (DMSO) and positive controls 

(cyclophosphamide (CPP) and ethylmethanesulfonate (EMS) for the experiment with and 

without metabolic activation, respectively) were included to demonstrate the sensitivity of the 

test system.

Prior to cell harvest, addition of Colcemid arrested cells in the metaphase. After slide preparation 

and staining of the cells, at least 200 well spread metaphases per dose and treatment condition 

were analyzed for chromosomal aberrations.

At concentrations of 100 μg/mL and above a sufficient number of metaphases was not available 

for evaluation. Therefore, the highest concentration to be scored was 50 μg/mL. A relevant 

increase in the number of aberrant cells was not observed at any of the tested concentrations with 

or without metabolic activation. A confirmatory experiment was performed using a prolonged 

treatment and preparation interval (4 hours treatment and 24 hours recovery with S9-mix, 18 

hours treatment and 0 hours or 10 hours recovery without S9-mix). In this experiment a slight 

increase above the historical control range was observed for the lowest evaluated concentration 

with metabolic activation only. This increase was not confirmed at higher concentrations and is, 

therefore, considered not relevant.

Based on the results of this study BAS 700 F is considered not to have a clastogenic potential in 

vitro in Chinese hamster V79 cells in the presence or absence of metabolic activation.

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline 

requirement for an in vitro chromosome aberration test (OPPTS 870.5375, OECD 473). 

MRID 47923584

BAS 700 F (batch: COD-000826, purity: 99.6%) was tested for chromosomal damage 

(clastogenicity) and for the ability to induce spindle poison effects (aneugenic activity) in NMRI 

mice using the micronucleus test method. For this purpose, the test substance suspended in corn 

oil was administered twice orally within a 24-hour period to groups of 5 male mice at dose levels 

of 500, 1000, and 2000 mg/kg body weight in a volume of 10 mL/kg body weight. The vehicle 

served as negative and cyclophosphamide and vincristine sulfate as positive controls. The 

vehicle was administered twice at a 24 h interval and the positive controls once. The animals 

were sacrificed 24 hours after the last administration and the bone marrow of the two femora was 

prepared. After staining of the preparations, 2000 polychromatic erythrocytes were evaluated per 

animal and investigated for micronuclei. The normocytes with and without micronuclei 

occurring per 2000 polychromatic erythrocytes were also recorded.

Two oral administrations of BAS 700 F did not lead to any biologically relevant increase in the 

number of polychromatic erythrocytes containing either small or large micronuclei. The rate of 

micronuclei was mostly close to the concurrent negative control and was within the range of the 
Page 64 of 83

historical control data. Inhibition of erythropoiesis, determined from the ratio of polychromatic 

to normochromatic erythrocytes, did not occur. Signs of systemic toxicity were not observed up 

to the highest tested dose of 2000 mg/kg bw.

Both of the positive control chemicals, i.e. cyclophosphamide for clastogenic effects and 

vincristine for induction of spindle poison effects, led to the expected increase in the rate of 

polychromatic erythrocytes containing small (cyclophosphamide) or small and large (vincristine 

sulphate) micronuclei, thus demonstrating the sensitivity of the test system.

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline 

requirement for an erythrocyte micronucleus test (OPPTS 870.5395, OECD 474). 

A.4.7

A.4.8 Metabolism

870.7485 Metabolism – Rat MRIDs 47923555 and 47923556

Biokinetic studies with 14C–BAS 700 F (BASF Reg. Doc. # 2009/1074879) were performed to 

investigate plasma kinetics, mass balance, tissue distribution, urinary and fecal excretion, and 

biliary excretion. 14C–BAS 700 F was administered to male and female Wistar rats (4/sex/dose) 

via oral gavage in a water/0.5% carboxymethylcellulose/1% cremophor vehicle. Plasma kinetics 

were first characterized by administering a single dose of 5, 50, or 500 mg/kg bw and plasma 

concentrations measured at 1, 2, 4, 8, 24, 48, 72, 96, 120, 144, and 168 hours. The times to 

maximum plasma levels (TMAX) were 24 hours (500 mg/kg bw), 8 hours (50 mg/kg bw), and 1 

hour (5 mg/kg bw) in both sexes with maximum mean plasma concentrations (CMAX) of 

65.31/66.08, 13.35/11.83, and 1.85/1.57 μg Eq/g in males/females, respectively. Areas Under 

Curve (AUCs) were 4215.2/5667.4, 434.6/532.4, 45.4/35.7 μg Eq h/g in males, females 

respectively. Importantly, no sex differences in the rate or extent of absorption was observed. 

Also, AUCs scaled with dose, indicating that absorption was not saturated and was most 

probably the result of passive diffusion. Although, the rates of elimination were the same in 

males and females in the time intervals following the Tmax, they were slightly reduced in 

females in the time interval immediately following the tmax. This could be due to the slight 

difference in tissue distribution between males and females and would explain the slightly higher 

AUCs in females at doses of 150 and 500 mg/kg bw and the difference in bile excretion pattern. 

Doses of 150 and 7.5 mg/kg bw 14C–BAS 700 F were chosen for mass balance, tissue 

distribution, and biliary excretion studies, based on the results of the plasma kinetic studies and 

repeated-dose toxicological studies. The duration of these studies (time to sacrifice) was based 

on the times of maximum plasma concentration (MPC), 1⁄2 MPC, 1⁄4 MPC, and 1/8 MPC in each 

sex. In a tissue distribution study with single high and low doses, 150 mg/kg bw 14C–BAS 700 F 

was administered orally (by gavage) to 4/sex/dose with males sacrificed at 16, 48, 72, and 96 

hours and females sacrificed at 16, 56, 80, and 104 hours. The highest tissue concentrations of 

radioactivity in males and females were found at 16 hours. Radioactivity was widely distributed 

in both sexes with a similar pattern: the highest concentrations were found in the gut contents 
Page 65 of 83

and stomach contents. However, lower concentrations were found in numerous other 

organs/tissues, including the liver, thyroid, adrenal glands, kidney, pancreas, testes/uterus, and 

brain. For males and females, radioactivity declined in all tissues over time. In the single, low 

dose study, 7.5 mg/kg bw 14C–BAS 700 F was administered orally (by gavage) to 4/sex/dose 

with males sacrificed at 1, 8, 28, and 48 hours and females sacrificed at 1, 20, 28, and 48 h after 

the administration of the test substance. A similar pattern of distribution of the radiolabel was 

observed as in the high dose group. Radioactivity declined in all tissues over time for the males 

and females except for the gut contents, which increased in 3-fold males from 1 hour to 8 hours 

prior to decreasing. A similar effect occurred in gut content in females, which increased from 1 

to 20 hours about 1.5 fold up to 1.7-fold at 28 hours prior to decreasing at 48 h. 

Mass balance and excretion were investigated in males and females in single dose studies with 

150 or 7.5 mg/kg 14C–BAS 700 F in animals with or without bile catheterization in 4 

animals/sex/dose. Excreta and bile were collected in cannulated animals out to 72 hours, while 

excreta were collected in uncannulated animals out to 168 h. A subset of uncannulated animals 

(2 /sex/dose) were monitored in metabolic cages equipped to measure 14C in expired air. A 

repeated-dose study was also performed in which males and females (4/sex) were administered 

14 doses of unlabeled BAS 700 F one per day on Days 1-14 and 14C–BAS 700 F on Day 15 with 

monitoring out to 168 hours after dose administration. Mean total recoveries of radioactivity

were > 89% in males and females for all dose groups. For all dose groups, the majority of the 

administered radioactivity was excreted via feces (84.43–94.30% after 168 hours). The total 

amount of radioactivity excreted in urine after 168 hours was in the range of 3.47–16.7%. Nonrelevant portions of the administered radioactivity were excreted as CO2 in exhaled air. The time 

course of the amount of radioactivity found in urine and feces indicated the excretion occurred 

predominantly within three days after dosing, indicating low potential for bioaccumulation. Bile 

duct cannulation experiments showed that the bile was a major route of excretion. Within 72 

hours after administration of 14C–BAS 700 F at a dose level of 150 mg/kg bw, excretion via bile 

was found to be 58.86% and 63.19% of the administered radioactivity in males and females, 

respectively. Within 72 hours after administration of 14C–BAS 700 F at a dose level of 7.5 

mg/kg bw, excretion via bile was found to be 50.92% and 55.80% of the administered 

radioactivity in males and females, respectively. These data also demonstrated a gender–

independent excretion pattern for 14C–BAS 700 F. 

Based on the amounts of radioactivity excreted via bile and urine, as well as the radioactive 

residue found in cage wash and carcass, the bioavailability of 14C–BAS 700 F in rats was 

calculated to be about 65% and 67% of the applied dose for males and females at a dose of 

150 mg/kg bw and about 68% and 80% of the applied dose for males and female rats at a dose 

level of 7.5 mg/kg bw.

This study is classified as totally reliable (acceptable/guideline) and, together with the 

metabolism study, satisfies the guideline requirement for a metabolism and pharmacokinetics 

study (OPPTS 870.7485; OECD 417) in rats. 

The metabolic fate of 14C–BAS 700 F was investigated in a follow-up study (BASF Reg. Doc. # 
Page 66 of 83

2009/1019789). Material from the biokinetics study was used for investigation of metabolite 

patterns in urine and feces (dose groups B, C, D) and in bile (dose groups R, S). Three additional 

groups of animals (designated DX, V, and W) were dosed with 14C–BAS 700 F specifically for 

the metabolism study (see Error! Reference source not found.Error! Reference source not 

found.). Urine, plasma, and bile, as well as extracts of feces, liver, fat, and kidney tissue were 

analyzed by HPLC. Individual metabolites were detected down to a level of about 0.1% of the 

dose administered or less. Metabolites were identified by LC–MS and LC–MS/MS. The 

structures and codes of identified BAS 700 F metabolites are shown in Error! Reference source 

not found.Error! Reference source not found..

In urine, 23 metabolites were identified. The main metabolites were in the range of 0.2% to 8.6% 

of the applied dose and identified to be M700F004, M700F005/M700F024 (detected only in 

male rats), M700F009/M700F028, M700F014, M700F015, and M700F061 (detected only in 

female rats). For all dose groups and both genders, no amounts of the unchanged parent 

compound were detectable at any of the time intervals investigated. 

In feces, the unchanged parent compound was found to be the main constituent of the extracts at 

high dose levels, i.e., dose group D, C, and DX (for both labels (19–44% of the dose applied), 

and represented only a minor part of the extractable radioactivity (3% of the dose applied) at the 

low dose level (dose group B). The main metabolites were identified as M700F009 (8–53% of 

the dose applied), M700F005 (ranging from 3–9% of the dose applied), and its isomer 

M700F006 (3–13% of the dose applied), and M700F016 (2–12% of the dose applied). 

In bile, the main metabolites were in the range of 3.4 to 22.0% of the applied dose and identified 

to be M700F004 and its isomer M700F125, M700F009, M700F014 and its isomer M700F123, 

M700F005, M700F024, and M700F122. 

In liver, the main metabolites were in the range of 0.1 to 0.9% of the applied dose and identified 

as M700F005, M700F006, M700F008, and M700F009. The parent compound was identified at 

levels up to 3.7 and 0.4% of the dose applied for the low and the high dose group, respectively. 

In kidney, the main metabolite was identified to be M700F008 (0.02 to 0.11% of the applied 

dose). The active substance was present at levels up to 0.50 and 0.05% of the dose applied for 

the low and the high dose group, respectively. 

In fat, two components were detected: the metabolite M700F008 (0.05 to 0.29% of the applied 

dose) and unchanged BAS 700 F (0.35 to 2.72% of the applied dose). 

In plasma, the main metabolite was identified to be M700F006 (0.03 to 0.11% of the applied 

dose). The parent compound was present at levels up to 0.13 and 0.01% of the dose applied for 

the low and the high dose group, respectively.

The main biotransformation steps of BAS 700 F in rats are hydroxylation at the biphenyl ring 

system, N-demethylation at the pyrazole ring system, loss of a fluorine atom at the biphenyl ring 
Page 67 of 83

system, and conjugation with glucuronic acid or with glutathione derivatives. A further, but 

negligible transformation route is cleavage at the amide bond between the pyrazole ring system 

and the biphenyl ring system.

This study is classified as totally reliable (acceptable/guideline) and, together with the 

biokinetic study, satisfies the guideline requirement for a metabolism and pharmacokinetics 

study (OPPTS 870.7485; OECD 417) in rats. 

870.7600 Dermal Absorption – Rat – MRID 47923632

14C-BAS 700 F formulated as BAS 703 02 F, which contains both fluxapyroxad and 

pyraclostrobin (BAS 500F) was applied to the backs of male Crl:WI (Han) rats (4/dose/group) at 

nominal doses of 1670, 33.4, and 5.6 μg/cm2for 8 hours and protected with semi-occlusive 

dressing. Excreta were collected in metabolic cages over the exposure period. After the 8 hour 

exposure period, the dressing was removed and the skin of all animals was washed. In one 

group, animals were sacrificed and surface radioactivity removed with 2 tape strips prior to 

isolation of application site and surrounding skin and quantification of radioactivity in the 

carcass. For two post-observation groups, clean dressing was applied and the experiment 

continued out to 24 hours or 120 hours with continued collection of excreta. At the end of the 

post-observational period, dressings were removed and skin was washed and surface 

radioactivity removed with 2 tape strips prior to isolation of application site and surrounding skin 

and quantification of radioactivity in the carcass. 

Average recoveries in all groups were acceptable and ranged from 88-105%. The majority of the 

radioactivity in all treatment groups was removed in the first skin wash, and ranged from 89-

94%. Systemic absorption of radioactivity (the amount in the urine, feces cagewash, blood 

cells, plasma, and carcass) increased during over the post-observation period of 24-120 hours for 

all dose groups. Similarly, the amount of radioactivity in the skin at the application site and in 

the surrounding skin decreased over the post-observation period of 24-120 hours for all dose 

groups. Together, this indicates that skin-bound residue (pesticide that was not removed after the 

first wash, or that laterally diffused into the surrounding skin layers) was bioavailable and that 

the 120 hour post-observation period should be used for quantitative estimations of dermal 

absorption. 

The amount of 14C-BAS 700 F that was systemically absorbed at the end of the 120 hours postobservation period increased with decreasing dose, ranging from an average of 0.35% at 1670 

μg/cm2 to 7.81% at 5.6 μg/cm2. Values at 5.6 μg/cm2 were used to calculate a dermal absorption 

factor, which included the amount systemically absorbed (7.81%), the amount in the application 

site skin (0.50%), and the amount in the surrounding skin (0.07%) for a total dermal absorption 

factor that rounds to 8.4%. Inclusion or exclusion of the amount of 14C-BAS 700 F on the skin 

(tape) strips does not changes this value. 

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline 

requirement for a dermal penetration study (OPPTS 870.7600, OECD 427) in rats. 
Page 68 of 83

A.4.9 Immunotoxicity

870.7800 Immunotoxicity – Mouse MRID 47923633

The immunotoxic potential of BAS 700 F (Batch: COD-001049; Purity: 99.2%) in male 

C57BL/6J Rj mice (8/dose) was analyzed using dietary dose levels of 0, 500, 2000 and 6000 

ppm (corresponding to approximate mean intake levels of 106, 450 and 1323 mg/kg/d, 

respectively) for 28 days.

Treatment with BAS 700 F did not result in systemic toxicity as assessed by clinical signs, food 

consumption and body weight development. The parameters used for detection of potential test 

substance related alterations in the morphology of the immune system included a) the 

determination of lymphoid organ weights (spleen and thymus) and b) the total lymphocyte count 

as well as lymphocyte subpopulation distribution including natural killer cells. Furthermore, 

functional parameters comprising of the analysis of the primary humoral (IgM response) immune 

response to sheep red blood cells (SRBC) and natural killer cell activity were integrated in this 

study. None of the parameters mentioned above was affected by treatment with BAS 700 F up to 

the highest dose level.

Concurrent treatment with positive control substance, cyclophosphamide (12 mg/kg bw/d by oral 

gavage) induced clear signs of immunotoxicity, demonstrating the reliability of the test system 

under the study conditions employed. 

Based on the obtained results it can be concluded that BAS 700 F did not have an 

immunomodulatory/immunotoxic potential under the conditions of this study.

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline 

requirement (OPPTS 870.7800) for an immunotoxicity study.
Page 69 of 83
Page 70 of 83

APPENDIX B. METABOLISM

B. 1 Chemical Names and Structures

Metabolite Designation (Code)

Chemical Name Molecular Mass Structure

BAS 700 F

=M700F000

3-(difluoromethyl)-1-methyl-N-(3',4',5'-trifluoro[1,1'-

biphenyl]-2-yl)-1Hpyrazole-4-carboxamide

M = 381

M700F001

3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid M = 176

M700F002

3-(difluoromethyl)-1H-pyrazole-4-carboxylic acid M = 162

M700F004

3-(difluoromethyl)-1-methyl-N-((1-glucuronyl)oxy-3',4',5'-

trifluoro-[1,1'-biphenyl]-2-yl -1H-pyrazole-4-carboxamide

M = 573

M700F005

3-(difluoromethyl)-1-methyl-N-(4-hydroxy-3',4',5'-

trifluoro[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 397

M700F006

3-(difluoromethyl)-1-methyl-N-(hydroxy-3',4',5'-trifluoro[1,1'-

biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 397

M700F008

3-(difluoromethyl)-N-(3',4',5'-trifluoro[1,1'-biphenyl]-2-yl)-1Hpyrazole-4-carboxamide

M = 367

M700F009

3-(difluoromethyl)-N-(hydroxy-3',4',5'-trifluoro[1,1'-biphenyl]-

2-yl)-1Hpyrazole-4-carboxamide

M = 383

F F

F

N

O

N

N

F

F

H

O

N

N

F

F

OH

O

N

N

H

F

F

OH

F

N

O

N

N

F

F

H

F

F

O-GlcA

F F

F

N

O

N

N

F

F

H

OH

F F

F

N

O

N

N

F

F

H

OH

F F

F

N

O

N

N

H

F

F

H

F F

F

N

O

N

N

H

F

F

H

OH
Page 71 of 83

M700F010

3-(difluoromethyl)-N-(hydroxy-3',4',5'-trifluoro[1,1'-biphenyl]-

2-yl)-1Hpyrazole-4-carboxamide

M = 383

M700F011

3-(difluoromethyl)-1-methyl-N-(hydroxy-(1-glucuronyl)oxy3',[4' or 5']-difluoro-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-

carboxamide

M = 571

M700F012

3-(difluoromethyl)-N-((1-glucuronyl)oxy-3',4',5'-trifluoro-[1,1'-

biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 559

M700F013

3-(difluoromethyl)-1-methyl-N-((1-glucuronyl)oxy-3',4',5'-

trifluoro-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 573

M700F014

3-(difluoromethyl)-N-((1-glucuronyl)oxy-3',4',5'-trifluoro-[1,1'-

biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 559

M700F015

3-(difluoromethyl)-1-methyl-N-((1-glucuronyl)oxy-3',[4' or 5']-

difluoro-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 555

M700F016

3-(difluoromethyl)-1-methyl-N-(methylthio-hydroxy-3',4',5'-

trifluoro-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 443

F F

F

N

O

N

N

H

F

F

H

OH

F

N

O

N

N

F

F

H

F

O-GlcA

OH

F

N

O

N

N

H

F

F

H

F

F

O-GlcA

F

N

O

N

N

F

F

H

F

F

O-GlcA

F

N

O

N

N

H

F

F

H

F

F

O-GlcA

F

N

O

N

N

F

F

H

F

O-GlcA

F

N

O

N

N

F

F

H

F

F

SCH3

OH
Page 72 of 83

M700F019

3-(difluoromethyl)-1-methyl-N-((1-glucuronyl)oxy-3',4',5'-

trifluoro-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 573

M700F020

3-(difluoromethyl)-1-methyl-N-(hydroxy-(1-glucuronyl)oxy3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-

carboxamide

M = 589

M700F021

3-(difluoromethyl)-N-((1-glucuronyl)oxy-3',[4' or 5']-difluoro-

[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 541

M700F022

3-(difluoromethyl)-N-((1-glucuronyl)oxy-3',4',5'-trifluoro-[1,1'-

biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 559

M700F023

3-(difluoromethyl)-N-((1-glucuronyl)oxy-3',4',5'-trifluoro[1,1'-

biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 559

M700F024

3-(difluoromethyl)-1-methyl-N-(hydroxy-3',[4' or 5’]-

difluoro[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 379

M700F025

3-(difluoromethyl)-N-((hydroxysulfonyl)oxy-3',4',5’-

trifluoro[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 463

M700F026

3-(difluoromethyl)-1-methyl-N-((hydroxysulfonyl)oxy-3',4',5’-

trifluoro[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 477

F

N

O

N

N

F

F

H

F

F

O-GlcA

F

N

O

N

N

F

F

H

F

F

O-GlcA

OH

F

N

O

N

N

H

F

F

H

F

O-GlcA

F

N

O

N

N

H

F

F

H

F

F

O-GlcA

F

N

O

N

N

H

F

F

H

F

F

O-GlcA

F

N

O

N

N

F

F

H

F

OH

F

N

O

N

N

H

F

F

H

F

F

OSO3H

F

N

O

N

N

F

F

H

F

F

OSO3H
Page 73 of 83

M700F027

3-(difluoromethyl)-1-methyl-N-((hydroxysulfonyl)oxy-3',[4' or 

5’]-difluoro[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 459

M700F028

3-(difluoromethyl)-1-methyl-N-(methylthio-(1-glucuronyloxy)-

3',4',5'-trifluoro-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-

carboxamide

M = 619

M700F029

3-(difluoromethyl)-N-(methylthio-(1-glucuronyl)oxy- 3',4',5'-

trifluoro-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 605

M700F032

3-(hydroxycarbonyl)-N-(hydroxy-3',4',5'-trifluoro[1,1'-

biphenyl]-2-yl)-1H-pyrazole-4-carboxamide or tautomer

M = 361

M700F042

3-(difluoromethyl)-1-methyl-N-(hydroxy-3',4',5'-trifluoro[1,1'-

biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 397

M700F048

3-(difluoromethyl)-1-(-D-glucopyranosyl)-N-(3',4',5'-

trifluoro[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M700F050

3-(difluoromethyl)-N-((1-glucuronyl)oxy-3',4',5'-trifluoro[1,1'-

biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 559

F

N

O

N

N

F

F

H

F

OSO3H

F

N

O

N

N

F

F

H

F

F

O-GlcA

SCH3

F

N

O

N

N

F

F

H

F

F

O-GlcA

SCH3

F F

F

N

O

N

N H

HOOC

F F

F

N

O

N

N

F

F

H

OH

F

N

O

N

N

H

F

F

H

F

F

O-GlcA
Page 74 of 83

M700F061

3-(difluoromethyl)-5-(1-glucuronyl)oxy-N-(3',4',5'-

trifluoro[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 559

M700F063

3-(difluoromethyl)-1-methyl-N-((S-cysteinyl)-hydroxy-3',[4' or 

5']-difluoro-[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 498

F F

F

N

O

N

N

H

F

F

H

O-GlcA

F

N

O

N

N

F

F

H

F

OH

COOH

NH2

S
Page 75 of 83

B.2 METABOLISM SUMMARY TABLE

Table B.2 Tabular Summary of Fluxapyroxad Metabolites and Degradates

Chemical Name 

(other names in 

parenthesis) and 

Structure

Matrix Percent TRR (PPM) 1

Matrices - Major Residue 

(>10%TRR)

Matrices - Minor Residue (<10%TRR)

Parent -

Fluxapyroxad

Soybean forage

TRR 4.1-6.1 ppm

Parent >92% M700F048 0.6-1.2%

Soybean hay

TRR 61-64 ppm

Parent 88% M700F048 1.6-2.2%

Soybean straw

TRR 0.85-1.2 ppm

Parent 92% M700F048 0.8%

Soybean hull

TRR 2.2-3.3%

Parent 64% M700F048 2.6-3.1%

M700F002 ND-2%

Soybean seed

TRR 0.11-0.24 ppm

Parent 21% (TRR ~0.12)

M700F002 ND-33%

M700F048 9-20%

Tomato leaves

TRR 4.4-6.7 ppm

Parent >90% M700F075/M700F076 <1.4%

M700F048 <0.8%

M700F008 2.8%

Tomato fruit

TRR 0.12-0.16 ppm

Parent >94% M700F008 <1.4%

Wheat forage 

TRR 0.9-1.0 ppm

Parent 87-91% M700F008 et al 4.2-5.8%

Wheat hay 

TRR 10 ppm

Parent 87-89% M700F008 et al 2.4-3.3%

Wheat straw

TRR 17-19 ppm

Parent 84-86% M700F008 et al 2.8-3.7%

Wheat chaff

TRR 6.7-7.4 ppm

Parent 76-82% M700F008 et al 5.8-6.2%

Wheat grain TRR 

0.045-0.057 ppm

Parent 60-63% M700F008 et al 6.5%

Rotational Crops

Rotational spinach

30 day

TRR 0.10/0.18 ppm

Parent 10-22%

M700F002 48%

M700F058 11.5%

M700F074 4.7-16.4%

M700F001 1.0%

M700F008 3.1-4.9%

M700F036 7.8%

M700F042 4.2-8.1%

M700F048/M700F057 4.5%

Rotational Radish 

Top 30 day

TRR 0.069/-- ppm

Parent 18%

M700F008 24%

M700F048/M700F057 13%

M700F059 11%

M700F036 9%

M700F042 0.7%

M700F058 0.9%

M700F074 3.3%

Rotational Radish 

Root 30 day; TRR 

0.015/0.014 ppm

Parent 43-53%

M700F008 26-29%

M700F048/M700F057 4.9-5.9%
Page 76 of 83

Table B.2 Tabular Summary of Fluxapyroxad Metabolites and Degradates

Chemical Name 

(other names in 

parenthesis) and 

Structure

Matrix Percent TRR (PPM) 1

Matrices - Major Residue 

(>10%TRR)

Matrices - Minor Residue (<10%TRR)

Rotational Wheat 

forage 30 day

TRR 0.14/0.28 ppm

Parent 76-84% M700F002 4.2%

M700F008 5.6-6.0%

M700F036 0.6%

M700F048/M700F057 1.0%

M700F074 1.0%

Rotational Wheat 

hay 30 day

TRR 1.08/-- ppm

Parent 81% M700F008 6.2%

M700F042 0.6%

M700F048/M700F057 0.9%

Rotational Wheat 

straw 30 day

TRR 1.88/2.7 ppm

Parent 54-64% M700F002 2.0%

M700F008 4.4-7.6%

M700F042 0.9-6.0%

M700F048/M700F057 1.9-2.2%

M700F074 2.4%

Rotational Wheat 

chaff 30 day

TRR 0.40/1.1 ppm

Parent 54-64% M700F001 0.7%

M700F002 5.9%

M700F008 7.8%

M700F042 0.3-0.5%

M700F058 1.7%

M700F074 3.1%

Rotational Wheat 

grain 30 day

TRR 0.02/0.03 ppm

Parent 24-28% M700F008 4.0-6.4%

M700F042 0.3%

Ruminant milk

TRR 0.011/0.017 

ppm

Parent 13-20%

M700F008 24-25%

M700F010/M700F040 12-

15%

M700F009 5.5-5.7%

Ruminant liver

TRR 0.35/0.56 ppm

M700F008 13-17% Parent 3.2-3.7%

M700F004 1.9-2.6%

M700F005/M700F024 6.4-8.3%

M700F009 2.3-2.5%

M700F010/M700F040 0.7%

Ruminant kidney

TRR 0.036/0.078 

ppm

M700F004 12-13%

M700F008 22-26%

M700F005/M700F024 5.2-

19%

Parent 5.4-7.0%

M700F009 2.0-3.6%

M700F010/M700F040 3.1-4.0%

M700F014 3.0-3.5%

M700F015 4.1-5.2%

M700F034/M700F036 4.9-5.2%

M700F038/M700F039 5.1-9.0%

M700F046/M700F047 3.1-4.4%

Ruminant muscle

TRR 0.007 ppm

Parent 12%

M700F008 55-83%

Ruminant fat Parent 34-44% M700F004 ND-6.1%
Page 77 of 83

Table B.2 Tabular Summary of Fluxapyroxad Metabolites and Degradates

Chemical Name 

(other names in 

parenthesis) and 

Structure

Matrix Percent TRR (PPM) 1

Matrices - Major Residue 

(>10%TRR)

Matrices - Minor Residue (<10%TRR)

TRR 0.021/0.025 

ppm

M700F008 26%

M700F005/M700F024 3.2-

14%

M700F010/M700F040 ND-3.7%

Ruminant urine

TRR 1.9/4.3 ppm

M700F005/M700F024 33-

34%

M700F008 14-36%

M700F046/M700F047 9.3-

10.3%

M700F004 1.3%

M700F009 8.8%

M700F010/M700F040 2.6-3.0%

M700F034/M700F036 1.3-6.2%

M700F038/M700F039 2.5-2.8%

M700F041/-42/-43/-44 2.6-3.6%

Ruminant feces

TRR 1.9/1.8 ppm

M700F005/M700F024 35-

50%

Parent 2.0-4.0%

M700F008 ND-7.8%

M700F033 ND-1.4%

Ruminant bile

TRR 7.3/6.6 ppm

M700F004 55%

M700F014 25%

M700F015 10%

M700F112 0.8%

Poultry liver

TRR 0.21 ppm

Parent 1%

M700F005 4.1%

M700F008 4.1%

M700F008/ M700F038 5.3%

M700F024 6.9%

M700F0047 3.1%

Poultry muscle

TRR 0.010 ppm

Parent 12%

M700F008 17%

Dimer of parent 21%

M700F005 2.8%

Poultry fat 

TRR 0.059 ppm

Parent 38%

M700F008 15%

Dimer of parent 36%

M700F005 1%

Poultry eggs

TRR 0.077 ppm

Parent 12%

M700F008 44%

Dimer of parent 36%

M700F004 4.2%

M700F005 6.6%

M700F009/ M700F038 5.0%

Poultry excreta

TRR 3.64 ppm

M700F005 17%

M700F024 11%

M700F009/ M700F038 12%

Parent 7.4%

M700F008 6.3%

M700F047 3.7%

Dimer of parent 1.1%

Rat liver

Dose 150 mg/kg

Parent 0.16-0.36%

M700F008 0.17-0.45%

M700F006 0.18-0.23%

M700F005 0.10-0.19%

M700F009 0.12-0.17%

M700F010 et al 0.02-0.04%

M700F016 0.01-0.04%

M700F0240.06

Rat kidney

Dose 150 mg/kg

M700F008 0.0-0.5%

Parent 0.03-0.05%

Rat fat Parent 0.35-1.55 M700F006 0.03-0.09%
Page 78 of 83

Table B.2 Tabular Summary of Fluxapyroxad Metabolites and Degradates

Chemical Name 

(other names in 

parenthesis) and 

Structure

Matrix Percent TRR (PPM) 1

Matrices - Major Residue 

(>10%TRR)

Matrices - Minor Residue (<10%TRR)

150 mg/kg M700F008 0.040.25%

Rat Feces

150 mg/kg

M700F009 9-11%

Parent 30-31%

M700F005 2.7-5.2%

M700F006 6.2-7.8%

M700F008 0.34%

M700F010 1.7-3.2%

M700F016 4.2-9.5%

Water

Water

Summary of Metabolism Studies

Soybean; PMRA# 1883838. MRID 47923642.; Application Rate: 3 applications x 60 g a.i./ha (0.6x single rate; 0.9x 

seasonal rate) at BBCH 16/17, 51–59 and 71–75; 0.6x compared to single application rate; pre-harvest interval 14 day 

PHI for mature forage (from 2d treatment); 30 day PHI for soybean hay, straw, hull and seed. BASF only attempted to 

identify parent, M700F0002, and M700F048.

Tomato; PMRA# 1883840. MRID 47923641. Application Rate: 3 x 100 g a.i./ha (1x rate). The applications took place 

17, 10 and 3 days before harvest (55, 62 and 69 days after planting). Tomato fruits and leaves were sampled three days 

after the last treatment.

Wheat; PMRA# 1883842. MRID 47923643.2 applications x 125 g a.i./ha (1.25x). Wheat hay was sampled at 4 DALA; 

straw, chaff and grain samples were collected at 34-35 DALA. Wheat forage samples were collected 36 days after the 

first application (forage samples received one application of 125 g a.i./ha only).

Rotational Crops (spinach, radish and wheat); PMRA# 1884199. MRID 47923680; One application 250 g a.i./ha (2.5x 

single rate, 0.83x seasonal rate). The treated soil was aged for 30, 120 and 365 days. 

Lactating Goat ; PMRA# 1883854 (full report). MRID 47923649.; 12 mg/kg Feeding Level; Level of exaggeration 

compared to maximum dietary burden: 2.6x Beef cattle dietary burden; 0.55x dairy cattle dietary burden; 8 days of 

dosing; 24 hour pre-slaughter interval.

Poultry; Study report. PMRA# 1883852 (full report). MRID 47923645 12 mg/kg Feeding Level; Level of exaggeration 

compared to maximum dietary burden: 3.2x poultry dietary burden; 12 days of dosing; 23 hour pre-slaughter interval.

Rat; Strain: Wistar Crl: WI (Han); male/female; MRID 47923556; BASF Reg. Doc. # 2009/1019789; 150 mg/kg 

dosing level; percentages reported are percent of administered dose. Route of Administration: Oral: gavage; Vehicle: 

0.5% aqueous solution of CMC (carboxymethyl cellulose) containing 1% Cremophor
Page 79 of 83

B.3 METABOLIC PATHWAYS 

Proposed metabolic pathways of BAS 700 F (fluxapyroxad) in plants.

2

M700F051

1

M700F00

M700F060

M700F05

F F

F

N

O

N

N

F

F

H

BAS 700 F

F F

F

N

O

N

N

F

F

H

O-Malonylglc

M700F05

OH

O

N

N

H

F

F

M700F002

F F

F

N

O

N

N

F

F

H

OH

F F

F

N

O

N

N

F

F

H

O-Glc

M700F05

F F

F

N

O

N

N

F

F

H

H

M700F00

F F

F

N

O

N

N

F

F

H

OH

F F

F

N

O

N

N

Glc

F

F

H

M700F04

F F

F

N

O

N

N

F

F

H

Malonylglc

F

N

O

N

N

F

F

H

F

F

O-Glc

M700F05

F F

F

N

O

N

N

F

F

H

O-Malonylglc

F

N

O

N

N

F

F

H

O-Malonylglc F

M700F055

F

N

O

N

N

F

F

H

F

Malonylglc

M700F056

F

N

O

N

N

Glc

F

F

H

F

M700F052

F F

F

N

O

N

N

F

F

H

H

O-Malonylglc

F

N

O

N

N

F

F

H

H

F

F

O-Glc

M700F053
Page 80 of 83

Proposed metabolic pathways of BAS 700 F (fluxapyroxad) in rotational crops (aniline label).

2

M700F04

M700F060 1

M700F05

M700F005 1

M700F041 1

F F

F

N

O

N

N

Glc

F

F

H

M700F04

F F

F

N

O

N

N

F

F

H

Malonylglc

F F

F

N

O

N

N

F

F

H

H

OH

M700F03

F

N

O

N

N

F

F

H

F

F

O-Glc

M700F07

F F

F

N

O

N

N

F

F

H

O-Malonylglc

M700F043 1

F

N

O

N

N

F

F

H

F

OH

M700F024 

1

F F

F

N

O

N

N

F

F

H

BAS 700 

F F

F

N

O

N

N

F

F

H

O-Malonylglc

M700F05

F F

F

N

O

N

N

F

F

H

OH

F F

F

N

O

N

N

F

F

H

O-Glc

M700F05

F F

F

N

O

N

N

O

HO

H

F F

F

N

O

N

N

F

F

H

H

M700F00 F F

F

N

O

N

N

F

F

H

OH
Page 81 of 83

Proposed metabolic pathways for BAS 700 in lactating goats.

F F

F

N

O

N

N

F

F

H

F F

F

N

O

N

N

H

F

F

H

F F

F

N

O

N

N

F

F

H

GlcA

F F

F

N

O

N

N

H

F

F

H

OH

F F

F

N

O

N

N

F

F

H

OH

F

N

O

N

N

H

F

F

H

OH

F

N

O

N

N

H

F

F

H

F

F

O-GlcA

F F

F

N

O

N

N H

HO2C

F

F

N

O

N

N

F

F

H

OH

F

F

N

O

N

N

F

F

H

O-GlcA

F F

F

N

O

N

N

H

HO2C

OH

F F

F

N

O

N

N

H

H

HO2C

F F

F

N

O

N

N H

OH OH

F

F

F F

F

N

O

N

N

F

F

H

O-GlcA

F

OH

F

F

F

N

O

N

N

H

F

F

H

BAS 700 F

M700F043

M700F008

M700F034

M700F111 

M700F009

M700F010

M700F036

M700F005 

M700F006 

M700F041 

M700F042 

M700F033

M700F047

M700F014 M700F038 M700F015

M700F024

M700F040

M700F044

M700F032

M700F046

M700F031

M700F039

M700F004
Page 82 of 83

Proposed metabolic pathways of BAS 700 F in laying hens.

1

 M700F005 is hydroxylated in para-position to the amide group, established by 1H NMR spectroscopy

2

 Proposed intermediate, not identified in the current study

3

 These metabolites were identified by LC-MS/MS, but they could not unambiguously be assigned to a distinct HPLC peak. They occurred at minor 

quantities, but they were not listed in metabolite quantification tables, because the correlation to a distinct HPLC peak was not given.

F F

F

N

O

N

N

F

F

H

F F

F

N

O

N

N

H

F

F

H

F F

F

N

O

N

N

H

F

F

H

OH

F F

F

N

O

N

N

F

F

H

OH

F

N

O

N

N

H

F

F

H

OH

F

F

N

O

N

N

F

F

H

OH

F F

F

N

O

N

N H

OH OH

F

F

F F

F

N

O

N

N

F

F

H

O-GlcA

F

OH

F

N

O

N

N

F

F

H

F

S

OH

NH2

OH

O

F

N

O

N

N

F

F

H

F

SH

OH

F F

F

N

O

N

N

F

F

H

OH S CH3

F

F

N

O

N

N

H

F

F

H

F

F

N

O

N

N

F

F

H

F

F

O

SH

OH

CH3

BAS 700 F

M700F008

M700F009

M700F005 1

M700F006 2 

M700F047

M700F038

M700F024 

M700F039 3

M700F004

M700F063 

M700F094 3

M700F016

M700F086 3
Page 83 of 83

Proposed Metabolic Pathway of BAS 700 F in the Rat

F F

F

N

O

N

N

F

F

H

BAS 700 F

O

N

N

F

F

OH

M700F001

O

N

N

H

F

F

OH

M700F002

F F

F

N

O

N

N

H

F

F

H

M700F008

F F

F

N

O

N

N H

HOOC

M700F032

F F

F

N

O

N

N

H

F

F

H

O-GlcA

M700F061

F F

F

N

O

N

N

H

F

F

H

OH

M700F009

M700F010

F

N

O

N

N

H

F

F

H

F

F

SCH3

OH OH

M700F102

M700F104

F

N

O

N

N

H

F

F

H

F

O-GlcA

M700F021

F

N

O

N

N

F

F

H

F

OH

M700F024

F

N

O

N

N

F

F

H

F

O-GlcA

OH

M700F011

F

N

O

N

N

F

F

H

F

F

O-GlcA

OH

M700F020

F

N

O

N

N

F

F

H

F

F

O

OH

M700F105

F

N

O

N

N

F

F

H

F

F

Cys

M700F120

F

N

O

N

N

H

F

F

H

F

F

Cys

M700F122

F

N

O

N

N

F

F

H

F

F

OH

Cys

M700F118

F

N

O

N

N

H

F

F

H

F

F

OH

Cys

M700F116

F

N

O

N

N

F

F

H

F

F

SCH3

OH

M700F016

M700F107

F

N

O

N

N

H

F

F

H

F

F

SCH3

OH

M700F103

F

N

O

N

N

F

F

H

F

F

O-GlcA

SCH3

M700F029

F

N

O

N

N

F

F

H

F

F

O-GlcA

SCH3

M700F028

F

N

O

N

N

F

F

H

F

O-GlcA

M700F015

F

N

O

N

N

F

F

H

F

OH

CysGly

M700F113

M700F115

F

N

O

N

N

F

F

H

F

SCH3

OH

M700F106

M700F108

F

N

O

N

N

F

F

H

F

O-GlcA

Cys

M700F114

F

N

O

N

N

F

F

H

F

F

OSO3H

M700F026

F

N

O

N

N

H

F

F

H

F

F

OSO3H

M700F025

F

N

O

N

N

F

F

H

F

OSO3H

M700F027

F

N

O

N

N

F

F

H

F

F

O-GlcA

M700F004

M700F125

and regioisomers

F F

F

N

O

N

N

F

F

H

OH

M700F006

M700F005

and regioisomer

F

N

O

N

N

F

F

H

F

OH

Cys

M700F063

M700F117

and regioisomers

F

N

O

N

N

H

F

F

H

F

F

O-GlcA

M700F014

M700F124

and regioisomers/anomers

Remark: CysGlyc = cysteineglycine, Cys = cysteine; GlcA = glucuronic acid
Page 84 of 84

APPENDIX C. PHYSICAL/CHEMICAL PROPERTIES

TABLE 2. Physicochemical Properties of Fluxapyroxad

Parameter Value Reference

Melting point/range 156.8 oC Product Chemistry monograph 

pH of 1% solution in water B. 5.8

Density 1.47

Water solubility ( 20°C) 3.88 mg/L at pH 5.8 (not buffered)

3.78 mg/L at pH 4

3.44 mg/L at pH 7

3.84 mg/L at pH 9

Solvent solubility (g/L at 20°C) acetone >250

acetonitrile 167.6 ± 0.2

dichloromethane 146.1 ± 0.3

ethylacetate 123.3 ± 0.2

methanol 53.4 ± 0.0

toluene 20.0 ± 0.0

n-octanol 4.69 ± 0.01

n-heptane 0.106 ± 0.001

Vapor pressure at 25 °C 8.1 x 10-9

Pa

Dissociation constant (pKa) 12. 58 (calculated)

Octanol/water partition coefficient Log(KOW) 3.08 (deionized water)

3.09 at pH 4

3.13 at pH 7

3.09 at pH 9

UV/visible absorption spectrum pH λmax ε

1.4 199 35913

230 24137

290 1145

5.9 193 44100

230 24010

290 978

12.2 215 23227

229 23473

290 2405

ε: molar absorption coefficient, [L

mol-1cm-1]

APPENDIX D. REVIEW OF HUMAN RESEARCH

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task 

Force members Health Canada, U.S. Environmental Protection Agency, and the National 

Agricultural Chemicals Association, released February, 1995.

Agricultural Re-entry Task Force (ARTF) data base (SOP #3.1)