UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION 

MEMORANDUM 

20-April-2016 

SUBJECT: Fluxapyroxad. Hwnan Health Risk Assessment for Use of Fluxapyroxad on 

Citrus Crop Group 10-10, Grass Crop Group 17, and Non-Grass Crop Group 18. 

PC Code: 138009 OP Barcode: 0425590 

Decision No.: 498952 Registration No.: 7969-312, 7969-306, 7969-

309, 7969-311 

Petition No.: 5F8344 Regulatory Action: Section 3 Registration 

Risk Assessment Type: Single Chemical Ae.g:regate Case No.: 3125 

TXR No.: NA CAS No.: 907204-31-3 

MRIO No.: NA 40 CFR: 180.666 ~ 

FR OM: Mohsen Sahafeyan, Chemist and Risk Assessor ./~ ~;: ~ 

Mon

Evisabel 

ica Hawkins, 

Craig, Ph.D.

Ph.D.

, Toxic

, M.P.H

ologi

., 

s

E

t 

nvironmental 

~AA Heal~cie~~t -; ...rl JA ~ <b~ Risk Assessment Branch 6 (RAB6) 

Health Effects Division (HED, 7509P) 

THROUGH: Donna Davis. Branch Chief 

Risk Assessment Branch 6, HED (7509P) 

TO: Driss Benmhend, Risk Manager Reviewer 

Shaja Joyner, Risk Manager 

Rachel Holloman, Branch Chief 

Fungicide and Herbicide Branch (FHB) 

Registration Division (RD) (7505P) 

This document provides the Health Effects Division's (HED's) risk assessment for the proposed 

new uses of the active ingredient fluxapyroxad on the citrus crop group l 0- 10, grass crop group 

17, and non-grass crop group 18. 

Page I of 81 
1.0 EXECUTIVE SUMMARY ................................................................................................ 5 

2.0 HED RECOMMENDATIONS .......................................................................................... 8 

2.1 Data Deficiencies/Conditions of Registration ................................................................ 8 

2.2 Tolerance Considerations ............................................................................................... 8 

2.2.1 Enforcement Analytical Method ............................................................................. 8 

2.2.2 International Harmonization ................................................................................... 8 

2.2.3 Recommended Tolerances ........................................................................................ 9 

2.2.4 Revisions to Petitioned-For Tolerances ................................................................ 10 

2.3 Label Recommendations ............................................................................................... 11 

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

3.1 Chemical Identity .......................................................................................................... 1"1 

3.2 Physical/Chemical Characteristics ............................................................................... 11 

3.3 Pesticide Use Pattern ..................................................................................................... 12 

3.4 Anticipated Exposure Path,vays ................................................................................... 14 

3.5 Considerations of Environmental Justice .................................................................... 14 

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

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

4.2 Absorption, Distribution, Metabolism and Excretion ................................................ 15 

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

4.4 Safety Factor for Infants and Children (FQPA Safe ty Factor) ................................. 18 

4.4. l Completeness of the Toxicology Database ............................................................ 19 

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

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

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

4.5.2 Recommendations for Combining Exposure Routes ........................................... 20 

4.5.3 Classification of Carcinogenic Potential ............................................................... 21 

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

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

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

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

Page 2of81 
Page 3 of 81

5.1.2 Comparison of Metabolic Pathways...................................................................... 23

5.1.3 Environmental Fate and Transport ...................................................................... 24

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

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

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

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

5.3.1 Estimated Drinking Water Concentrations.......................................................... 26

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

5.4.1 Acute Dietary (Food and Drinking Water) Analysis........................................... 27

5.4.2 Chronic Dietary (Food and Drinking Water) Analysis....................................... 28

5.4.3 Cancer Dietary (Food and Drinking Water) Analysis......................................... 29

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .............................. 29

6.1 Residential Handler Exposure...................................................................................... 29

6.1.1 Handler Exposure Data.......................................................................................... 29

6.1.2 Residential Handler Exposure Assumptions........................................................ 30

6.2 Post-Application Exposure ........................................................................................... 31

6.3 Residential Risk Estimates for Use in Aggregate Assessment................................... 33

6.4 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk 

Estimates ................................................................................................................................. 34

6.5 Non-Occupational Spray Drift Exposure and Risk Estimates.................................. 34

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT............................................ 34

7.1 Acute Aggregate Risk.................................................................................................... 35

7.2 Short- Term Aggregate Risk ........................................................................................ 35

7.3 Intermediate-Term Aggregate Risk............................................................................. 35

7.4 Chronic, Non-Cancer, Aggregate Risk........................................................................ 35

7.5 Cancer Aggregate Risk ................................................................................................. 35

8.0 CUMULATIVE RISK...................................................................................................... 36

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION.............................. 36

9.1 Occupational Handler Exposure/Risk Estimates ....................................................... 36

9.3 Post-Application Exposure ........................................................................................... 39

9.3.1 Dermal PostApplication Risk................................................................................. 39

9.3.2 Inhalation Post Application Risk........................................................................... 40
Page 4 of 81

9.3.3 Restricted Entry Interval ....................................................................................... 40

10. REFERENCES.................................................................................................................. 41

APPENDIX A: TOXICOLOGY DATA SUMMARY ......................................................... 42

A.1 Guideline Data Requirements ...................................................................................... 42

A.2 Toxicity Profiles............................................................................................................. 42

A.3 Toxicological Endpoints................................................................................................ 54

A.3.2 Chronic Reference Dose (cRfD)-All Populations................................................ 54

A.3.3 Incidental Oral Exposure (Short-Term (1-30 days)).......................................... 55

A.3.4 Incidental Oral Exposure (Intermediate-Term (1-6 months))........................... 55

A.3.5 Occupational and Residential Dermal Exposure (Short- and IntermediateTerm) 55

A.3.6 Occupational and Residential Inhalation Exposure (Short-Term)................. 56

A.3.7 Occupational and Residential Inhalation Exposure (Intermediate-Term) ...... 56

A.4 EXECUTIVE SUMMARIES........................................................................................ 57

A.4.1 Subchronic Toxicity................................................................................................ 57

A.4.2 Prenatal Developmental Toxicity .......................................................................... 59

A.4.3 Reproductive Toxicity ............................................................................................ 61

A.4.4 Chronic Toxicity...................................................................................................... 61

A.4.5 Carcinogenicity ....................................................................................................... 62

A.4.6 Mutagenicity........................................................................................................... 65

A.4.7 Neurotoxicity ........................................................................................................... 68

A.4.8 Metabolism .............................................................................................................. 69

A.4.9 Immunotoxicity ....................................................................................................... 72

APPENDIX B. Chemical Names And Structures Of Metabolites......................................... 74

APPENDIX C. Physical/Chemical Properties.......................................................................... 79

APPENDIX D. Studies Reviewed for Ethical Conduct.......................................................... 80

APPENDIX E. Proposed Use Directions for Fluxapyroxad ................................................... 81
Page 5 of 81

1.0 EXECUTIVE SUMMARY

This assessment provides information to support a Section 3 registration and establishment of 

permanent tolerances for the use of fluxapyroxad on citrus (crop group 10-10), grass (crop group 

17) including grass grown for seed, and non-grass animal feed (crop group 18). Due to an 

increase in livestock dietary burdens, HED is also recommending new tolerances for poultry 

tissues (fat, meat, and meat byproduct) and milk fat, and increasing the current tolerances on 

milk, ruminant fat, and meat byproduct (to include fat and meat byproduct of cattle, goat, horse 

and sheep).

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 

registered 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.

BASF Corporation is requesting a Section 3 registration of three fluxapyroxad products for use 

on citrus (crop group 10-10), grass (crop group 17) including grass grown for seed, and nongrass animal feed (crop group 18). The proposed maximum use rate for foliar application on 

citrus (crop group 10-10) is 4 applications, each at 0.122 lb ai/A, with a total maximum 

application rate of 0.488 lb ai/A and 0-day pre-harvest interval (PHI). The proposed maximum 

use rate for foliar application on grass (crop group 17) including grass grown for seed, and nongrass animal feed (crop group 18) is 3 applications, each at 0.089 lb ai/A, with a total maximum 

rate of 0.267 lb ai/A and a 14-day PHI. 

The toxicology database for fluxapyroxad is complete and considered 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. There was one 28-day dermal toxicity study in rats that 

showed no effects up to the limit dose and one dermal penetration study in rats that estimated a 

dermal absorption factor of 8.38%. No inhalation toxicity studies were submitted, and the 28-

day subchronic inhalation study was waived by the Agency. Liver toxicity was observed in 

rats, mice, and dogs, with rats being the most sensitive species for all durations of exposure. 

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 be carcinogenic to humans below a defined 

dose range and 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 
Page 6 of 81

from exposure to fluxapyroxad.

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

fluxapyroxad. However, 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 in rats. Developmental toxicity in 

rats in a two-generation study was limited to decreased body weight and body weight gain in 

offspring of the F1 generation (with decreased body weight observed in the F2 generation after 

lactation day 7) and was observed at the same dose levels that caused thyroid follicular 

hypertrophy/hyperplasia in parental animals. Developmental toxicity in rabbits was limited to 

paw hyperflexion which was significantly increased at the highest dose, where decreased body 

weight in maternal animals was also observed. 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. 

Fluxapyroxad acute toxicity to mammals is low by all routes of exposure. No hazards were 

identified for exposures via the dermal route in a 28-day dermal toxicity study at the limit dose 

and the dermal absorption study indicates that there is low absorption (8.38%) via the dermal 

route in rats. . 

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

residential, 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; therefore, the acute and chronic RfDs 

are equivalent to the acute and chronic PADs, respectively. The rational for reduction of the 

FQPA Safety to 1X 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 of fluxapyroxad on thyroid hormones, and no residual 

uncertainties in the exposure data base. 

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 nonneoplastic changes in the liver (foci, masses). A POD for short-term and intermediate-term 

inhalation exposure was selected from a 90-day dietary study in rats based also on thyroid 

effects. PODs for short- and intermediate-term dermal exposure were not selected because 

fluxapyroxad does not pose a dermal hazard. An uncertainty factor of 100x was applied to 

endpoints selected for all exposure routes (10x for interspecies extrapolation, 10x for intraspecies

variation).
Page 7 of 81

Screening level acute and moderately refined chronic dietary (food and drinking water) risk 

assessments for fluxapyroxad show that dietary exposure estimates for the established and 

proposed uses are below HED’s level of concern for the general population and all population 

subgroups.

There are no residential exposure associated with the proposed uses in this action; however, there 

are residential exposure from existing turf uses that were previously assessed for fluxapyroxad. 

An updated turf assessment was completed in this document due to a correction in the single 

maximum application rate from 2.47 lb ai/gallon to 0.005 lb ai/gallon. The residential handler 

exposure and risk estimates indicate that the short-term inhalation margin of exposures (MOEs) 

for adult handlers are greater than HED’s LOC (i.e., MOEs are ≥ 100) and therefore are not of 

concern; the MOEs range from 170,000 to 5,300,000. Residential post-application dermal 

exposure for adults was not quantitatively assessed because there is no identified dermal hazard. 

Residential post-application incidental oral exposure for children indicate that the MOEs are 

greater than HED’s LOC (i.e., MOEs are ≥ 100) and therefore are not of concern; the MOEs 

range from 2,100 to 940,000. The corrected turf assessment will impact the human health 

aggregate risk assessment for fluxapyroxad.

The aggregate risk assessment includes residential adult handler exposure from turf use and 

incidental oral for children 1<2 plus background dietary exposure for both groups. The MOEs 

for both adult and children 1<2 are greater than HED’s LOC and therefore are not of concern.

Occupational handler short- and intermediate-term exposure is anticipated from the proposed

uses. The occupational handler exposure and risk estimates indicate that the short- and 

intermediate-term inhalation MOEs are not of concern to HED (i.e., MOEs ≥ 100) at the baseline 

attire (i.e., no gloves and no respirator). The MOEs range from 25,000 to 9,900,000,000. 

Occupational post-application dermal exposure was not quantitatively assessed since there is no 

dermal hazard for fluxapyroxad. 

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler 

Exposure Task Force (AHETF) database, and the Agricultural Reentry Task Force (ARTF) 

database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, 

and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review 

may have included review by the Human Studies Review Board. Descriptions of data sources, 

as well as guidance on their use, can be found at the following Agency websites: 

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

http://www.epa.gov/pesticides/science/post-app-exposure-data.html. 

Environmental Justice
Page 8 of 81

Potential environmental justice concerns were considered, to the extent possible, in this humanhealth risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to 

Address Environmental Justice in Minority Populations and Low-Income Populations.1” 

2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies/Conditions of Registration 

 A revised Section F must be submitted which reflects the commodity definitions and 

tolerance levels specified in Section 2.2.3, below. 

 The following analytical standards will need to be replenished as soon as possible as the 

Repository is out of stock:

o Fluxapyroxad

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

There are suitable residue analytical methods available for enforcement of fluxapyroxad 

tolerances (BASF Methods L0137/01 for plants and L0140/02 for animal matrices) which have 

been radiovalidated and have underwent successful validation by an independent laboratory. 

These are liquid chromatography with tandem mass spectrometry (LC/MS/MS) methods and 

monitor two ion transitions. The Limit of Quantitation (LOQ) for BASF method L0137/01 is 

0.01 mg/kg for various matrices. The LOQ for BASF method L0140/02 is 0.01 ppm for liver 

and muscle, and 0.001 ppm for milk and eggs.

2.2.2 International Harmonization

There are no Codex or Canadian MRLs for citrus, grass and non-grass animal feed at present. 

US-recommended tolerances for residues in ruminant meat byproduct, milk, and milk fat are 

generally much lower than Codex and therefore cannot be harmonized. US-recommended 

tolerances for those tissues plus ruminant fat are slightly higher than Canadian MRLs; however, 

they cannot be lowered for harmonization with Canada since it would result in over-the-tolerance 

residues in those commodities. US-recommended tolerances for residues in poultry tissues are 

harmonized with Canada.

 

1 http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf
Page 9 of 81

2.2.3 Recommended Tolerances

Tolerances for residues of fluxapyroxad in/on citrus, grass, and non-grass animal feed were 

derived using the Organization for Economic Cooperation and Development Maximum Residue 

Level (OECD MRL) Calculation Procedures. The rounding system in OECD MRL spreadsheet 

calculator was used for rounding the expected residues in livestock tissues and recommending

livestock tolerances. 

Pending submission of a revised Section F (see Section 2.1) and analytical reference standards 

(see deficiencies), there are no residue chemistry issues that would preclude granting a Section 3 

registration for the requested new uses of fluxapyroxad. The current tolerance expression 

complies with the 2009 Knizner guidance on tolerance expressions. Tolerances should be 

established under 40 CFR 180.666 as follows:

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

degradates. 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 2.2.3.1 Tolerance Summary for Fluxapyroxad

Established 

Tolerances 

(ppm)

Proposed 

Tolerances 

(ppm)

HEDRecommended 

Tolerance 

(ppm)

Comments 

Cattle, fat

0.05 --- 0.06

Increase in established 

tolerance not proposed, 

but required. 

Cattle, meat byproduct

0.03 --- 0.04

Increase in established 

tolerance not proposed, 

but required.

Citrus, dried pulp --- 2.7 3.0

Citrus, oil --- 19 40

Egg

0.002 0.01 0.01

Fruit, citrus, group 10-10 --- 1.0 1.0

Grass, forage, fodder and 

hay, group 17

--- 30 40

Goat, fat

0.05 --- 0.06

Increase in established 

tolerance not proposed, 

but required.

Goat, meat byproduct

0.03 --- 0.04

Increase in established 

tolerance not proposed, 

but required.

Horse, fat

0.05 --- 0.06

Increase in established 

tolerance not proposed, 

but required.
Page 10 of 81

Table 2.2.3.1 Tolerance Summary for Fluxapyroxad

Established 

Tolerances 

(ppm)

Proposed 

Tolerances 

(ppm)

HEDRecommended 

Tolerance 

(ppm)

Comments 

Horse, meat byproduct

0.03 --- 0.04

Increase in established 

tolerance not proposed, 

but required.

Milk

0.005 --- 0.01

Increase in established 

tolerance not proposed, 

but required.

Milk, fat ---- --- 0.15

Nongrass animal feed, 

group 18

--- 30 30

Poultry, fat --- 0.005 0.01

Poultry, meat --- --- 0.01

Poultry, meat byproduct --- --- 0.01

Sheep, fat

0.05 --- 0.06

Increase in established 

tolerance not proposed, 

but required.

Sheep, meat byproduct

0.03 --- 0.04

Increase in established 

tolerance not proposed, 

but required.

Note to PM:

Tolerance for nongrass animal feeds, group 18 under 40 CFR §180.666 section (d) Indirect 

or inadvertent residues should be revoked.

2.2.4 Revisions to Petitioned-For Tolerances

HED is now recommending tolerances for poultry tissues (fat, meat, and meat byproduct); the 

registrant proposed a tolerance for poultry fat only. No tolerances were established on poultry 

tissues previously as it was not expected to find residues in those tissues due to their low dietary 

burden; i.e., category 3 of CFR 180.6(a) applied for those poultry matrices. However, because of 

expectation of higher residues on the feed items associated with the proposed uses (mainly grass 

and nongrass), the livestock dietary burdens in general have increased and residues are now 

expected to be transferred to poultry tissues. Tolerances should now be established for poultry 

tissues; i.e., category 3 of CFR 180.6(a) no longer applies. In addition, due to the higher 

livestock dietary burdens, HED is also recommending for increasing current tolerances on milk, 

ruminant fat and meat byproduct (to include fat and meat byproduct of cattle, goat, horse and 

sheep) and a tolerance for residues in milk fat.

As it is seen in Table 2.2.3.1 above, HED recommended tolerances are higher than proposed 

tolerances for grass (group 17), citrus oil, dried pulp, and poultry fat. This difference in 
Page 11 of 81

tolerance for grass is due to HED using residues from 0-day pre-harvest interval (PHI) from 

grass samples (instead of 14-day used by the registrant) for calculating the tolerance; for citrus 

oil, the difference is due to HED using highest average field trial (HAFT) data, instead of 

median, times processing factor; for dried pulp, the difference is due to HED rounding up the 

calculated tolerance; for poultry fat, the difference is due to recalculating dietary burden for 

livestock, taking into account feed commodities from (0-day PHI) grass, alfalfa and clover which 

resulted in higher than previously calculated dietary burdens and therefore higher tolerances. 

2.3 Label Recommendations

The submitted proposed labels were acceptable and adequately supported by field trial data. 

3.0 INGREDIENT PROFILE 

3.1 Chemical Identity

Structure and nomenclature of fluxapyroxad are reported in Table 3.1.1. For chemical names and 

structures of fluxapyroxad metabolites see Appendix B.

TABLE 3.1.1 Fluxapyroxad Test Compound Nomenclature.

Chemical structure

 

Common name Fluxapyroxad (ISO, proposed)

Company experimental name BAS 700 F

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

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

carboxamide

CAS # 907204-31-3

Molecular Formula C18H12F5N3O

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 physicochemical properties of fluxapyroxad is provided in 

Appendix C. Fluxapyroxad exhibits relatively low solubility in water and higher solubility in 
Page 12 of 81

organic solvents. It has a very low vapor pressure. 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. 

3.3 Pesticide Use Pattern

BASF has petitioned the Agency for foliar use of the fungicide fluxapyroxad on citrus (crop 

group 10-10), grass (crop group 17) including grass grown for seed, and non-grass animal feed 

(crop group 18). The use pattern are shown in Table 3.3.1 below. 
Page 13 of 81

Table 3.3.1 - Proposed Use Directions.

Applic. Timing, 

Type, and Equip. Formulation

Applic. Rate 

(lb ai/A)

(lb ai/100lb 

seed) for seed 

treatment

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. 

Rate

(lb ai/A)

PHI

(days)

Citrus

Foliar ground/aerial 

spray; (timing in 

plant’s growth stages 

not specified)

5.96% EC (7969-306)

26.55% EC (7969-309)

14.33% EC (7969-311)

0.122 4 0.488 0

Use Directions and Limitations: A minimum 10-day RTI is specified. No livestock 

feeding restriction. For aerial application spray volume should be no less than 10 gallons 

of solution per acre. 

Grass forage, fodder, straw, and hay

Foliar ground spray; 

(timing in plant’s 

growth stages not 

specified) 

5.96% EC (7969-306)

26.55% EC (7969-309) 0.089 3 0.267 14

Use Directions and Limitations: A minimum 14-day RTI is specified. “Do not apply 

within 14 days of grazing or harvest for forage and hay.” Not to be used on rangeland.

Non-grass animal feed, including alfalfa and clover

Foliar ground spray; 

(timing in terms of 

plant’s growth stages 

not specified)

5.96% EC (7969-306)

26.55% EC (7969-309) 0.089 3 0.267 14

Use Directions and Limitations: A minimum 14-day RTI is specified. “Do not apply 

within 14 days of grazing or harvest for forage and hay.” Not to be used on rangeland.

Alfalfa

Foliar ground spray; 

(timing in terms of 

plant’s growth stages 

not specified)

14.33% EC (7969-311) 0.075 3 0.225 14

Use Directions and Limitations: A minimum 14-day RTI is specified. “Do not apply 

within 14 days of grazing or harvest for forage and hay.” Not to be used on rangeland.

Grass grown for seed

Foliar ground spray; 

(timing in terms of 

plant’s growth stages 

not specified)

5.96% EC (7969-306)

26.55% EC (7969-309)

14.33% EC (7969-311)

0.089 3 0.267 14

Use Directions and Limitations: A minimum 14-day RTI is specified. 

Priaxor label (7969-311) also specifies: “Do not graze or feed forage or hay to livestock 

within 27 days of last application.”
Page 14 of 81

3.4 Anticipated Exposure Pathways

Humans may be exposed to fluxapyroxad in food and drinking water, since fluxapyroxad may be 

applied directly to growing crops and application may result in fluxapyroxad reaching surface 

and ground water sources of drinking water. Additionally humans may be exposed to 

fluxapyroxad in residential settings, since it may be applied to ornamental plantings in 

residences, public areas, and recreational sides, as well as on lawns and turf and to residential 

berries and fruit and nut trees. In an occupational setting, applicators may be exposed while 

handling the pesticide prior to application, as well as during application. There is a potential for 

post-application exposure for workers re-entering treated fields. 

Risk assessments have been previously prepared for the existing uses of fluxapyroxad. This risk 

assessment considers all of the aforementioned exposure pathways based on the proposed new 

and amended uses of fluxapyroxad as well as the existing uses. 

3.5 Considerations of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://epa.gov/compliance/ej/resources/policy/exec_order_12898.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. Extensive data on food consumption patterns are compiled by the U.S. Department of 

Agriculture (USDA) under the National Health and Nutrition Examination Survey, What We Eat 

in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered 

food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and 

ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized 

subgroups and exposure assessments are performed when conditions or circumstances warrant. 

Whenever appropriate, non-dietary exposures based on home use of pesticide products and 

associated risks for adult applicators and for toddlers, youths, and adults entering or playing on 

treated areas post-application are evaluated. Further considerations are currently in development 

as OPP has committed resources and expertise to the development of specialized software and 

models that consider exposure to bystanders and farm workers as well as lifestyle and traditional 

dietary patterns among specific subgroups.

4.0 HAZARD CHARACTERIZATION/ASSESSMENT

4.1 Toxicology Studies Available for Analysis
Page 15 of 81

The toxicological database for fluxapyroxad is complete and adequate for risk assessment. 

Appendix A is a summary of the fluxapyroxad toxicological database. Based on a weight-ofevidence (WOE) approach and considering of all the available hazard information for 

fluxapyroxad, the HASPOC concluded that a subchronic inhalation study is not required for 

fluxapyroxad at this time (K. Rury, TXR#0056561, 1/17/2013). 

Available mammalian toxicology studies considered in the hazard characterization include:

 Acute oral, dermal, and inhalation toxicity; eye and dermal irritation; and dermal 

sensitization studies

 Acute and subchronic neurotoxicity studies in rats

 Subchronic and chronic oral toxicity studies in rats, mice and dogs

 21-day dermal toxicity study in rabbits

 Developmental toxicity studies in rats and rabbits

 Reproductive and postnatal toxicity study in rats

 Carcinogenicity studies in mice and rats

 Dermal penetration in rats

 Immunotoxicity study in rats

 Metabolism and pharmacokinetic studies in rats

 Supplemental mode of action studies. 

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 on 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 and Excretion

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 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. 
Page 16 of 81

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. 

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 

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 is the liver, with toxicity 

observed in several species: rats, mice, and dogs. In rats, the most sensitive species, effects 

ranged from increased liver weights and changes in liver enzyme activities in subchronic studies 
Page 17 of 81

to hepatocellular necrosis and neoplastic liver changes (foci, masses) in chronic studies. 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 also 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. 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 alterations 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 in rats in several studies. This effect was 
Page 18 of 81

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 fluorosis 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 with fluorosis at the highest dose in parental and F1 males of the rat 2-

generation reproduction and fertility effects study. 

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.
Page 19 of 81

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 are available in adult animals to evaluate neurotoxicity, immunotoxicity, genotoxicity, 

and thyroid effects. 

4.4.2 Evidence of Neurotoxicity

Acute and subchronic neurotoxicity studies are available for fluxapyroxad. Treatment-related 

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 
Page 20 of 81

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 residential uses proposed for fluxapyroxad and the assessment will not 

underestimate residential exposure via handler for adults and incidental oral for children. 

4.5 Toxicity Endpoint and Point of Departure

4.5.1 Dose-Response Assessment

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 was considered 

adverse and results from a single exposure. 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. 

The endpoint of thyroid follicular hypertrophy/hyperplasia from the 90-day oral toxicity study in 

rats was identified for the short-term incidental oral endpoint. This is the most sensitive endpoint 

in the most sensitive species and is appropriate for the population of concern. 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. 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. 

For the inhalation endpoint, no route-specific studies were available, thus oral studies were 

evaluated. The endpoint of thyroid follicular hypertrophy/hyperplasia was identified from the 

90-day oral toxicity study in rats for short-term and intermediate-term inhalation. This endpoint 

was chosen because it was the most sensitive endpoint in the most sensitive species.

4.5.2 Recommendations for Combining Exposure Routes

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

exposures from the three routes of exposure: oral, dermal and inhalation exposures. There is no 

dermal hazard posed by fluxapyroxad. Oral and inhalation endpoints, and points of departure for 

regulation were selected from the same 90-day oral toxicity study; therefore oral and inhalation 

exposures should be combined.
Page 21 of 81

4.5.3 Classification of Carcinogenic Potential

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. Dose and temporal concordance data supported a nongenotoxic mitogenic mode of action (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/day to 18% at 145 mg/kg/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/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 are no mutagenicity concerns 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. 

Therefore, 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. 
Page 22 of 81

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 4.5.4.1 and 4.5.4.2.

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

Non-Occupational Human Health Risk Assessments

Exposure/ Scenario Point of 

Departure

Uncertainty/

FQPA 

Safety 

Factors

RfD, PAD, 

Level of 

Concern for 

Risk Assessment

Study and Toxicological Effects

Acute Dietary 

(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

MIRD 47923605

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

MIRD 47923591

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 below a defined dose range. 

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 4.5.4.2 Summary of Toxicological Doses and Endpoints for Fluxapyroxad for Use in Residential 

and Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal Shortand 

IntermediateTerm No hazard identified 

28-day dermal toxicity study in rats

MIRD 47923571

LOAEL = Not observed 

Inhalation 

Short-Term (1-

30 days) and 

Intermediateterm (1-6 

months)

NOAEL=

7.3

mg/kg/day

UFA=10x

UFH=10x

Occupational/Res

idential LOC for 

MOE = 100

90-day dietary study in rats

MIRD 47923567

LOAEL = 35.1 mg/kg/day based on 

thyroid follicular hypertrophy/hyperplasia 
Page 23 of 81

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Fluxapyroxad for Use in Residential 

and Occupational Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Incidental Oral 

Short-Term (1-

30 days)

NOAEL=

7.3

mg/kg/day

UFA=10x

UFH=10x

Residential LOC 

for MOE = 100

90-day dietary study in rats

MIRD 47923567

LOAEL = 35.1 mg/kg/day based on 

thyroid follicular hypertrophy/hyperplasia

Cancer (oral, 

dermal, 

inhalation)

Classification: Not likely to be carcinogenic to humans below a defined dose range. 

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 Livestock 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; for milk only 

the metabolites of concern for risk assessment are M700F008 and M700F010. The registrant 

requested a waiver from additional nature of the residue studies in fish/shellfish. The waiver 

request was granted by HED since enough information was obtained from the crayfish 

metabolism study and the bluegill bioaccumulation study reviewed by EFED.

5.1.2 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 biphenyl ring (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 
Page 24 of 81

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.

5.1.3 Environmental Fate and Transport

Fluxapyroxad degrades slowly under aerobic or anaerobic conditions in soil, with single firstorder half-lives ranging from 213 to 1,827 days. Fluxapyroxad also degrades slowly under 

aerobic or anaerobic conditions in aquatic systems, with single first-order, whole system halflives ranging from 420 to 731 days. Fluxapyroxad is classified as moderately to slightly mobile 

(FAO soil mobility classification) based on adsorption KOC values in two U.S. soils ranging from 

725 to 1,200 mL/goc. 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. Fluxapyroxad will not likely bioaccumulate.

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, D390225, 7/4/11). 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 hydroxylated parent and likely to 
Page 25 of 81

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 5.1.4.1 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-(hydroxy-3',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 following crops: orange, lemon, grapefruit, alfalfa, clover, and 

grass (4 cultivars). Decline studies were submitted for each commodity, as required. Detailed 

information on residue data from crop field trials on fluxapyroxad and its metabolites is provided 

in the Residue Chemistry Chapter. (D425590)

Table 5.2.1.1 Summary of Fluxapyroxad Residues

Crop

Total 

Application 

Rate

lb ai/A

(g ai/ha)

PHI 

(days)

No of 

Field 

Trials

Matrix

Residues (ppm)1

Fluxapyroxad M700F008

Orange 0.431-0.450

(483-505) 0 12 Whole fruit 0.093-0.583HAFT=0.558 <0.01

Lemon 0.435-0.448

(488-502)

0 8 Whole fruit 0.090-0.426

HAFT=0.380 <0.01

Grapefruit 0.436-0.450

(489-504) 0 6 Whole fruit <0.01-0.269HAFT=0.203 <0.01

Alfalfa2 0.218-0.231 

(0.245-0.258) 12-17 10 Forage <0.01-8.641

HAFT=8.127

<0.01-0.503

HAFT=0.434

Hay 0.176-8.606 <0.01-1.367
Page 26 of 81

Table 5.2.1.1 Summary of Fluxapyroxad Residues

Crop

Total 

Application 

Rate

lb ai/A

(g ai/ha)

PHI 

(days)

No of 

Field 

Trials

Matrix

Residues (ppm)1

Fluxapyroxad M700F008

HAFT=8.569 HAFT=1.284

Clover2 0.218-0.231 

(0.245-0.258)

12-15 9

Forage <0.01-5.007

HAFT=4.205

<0.01-0.139

HAFT=0.135

Hay 0.562-15.13

HAFT=14.98

<0.01-0.294

HAFT=0.274

Grass 0.221-0.229 

(247-257)

0

13

Forage 1.549-11.481

HAFT=10.992

<0.01-0.031

HAFT=0.030

Hay 3.282-29.226 

HAFT=27.650

<0.01-0.503

HAFT=0.444

14

Forage 0.183-6.806

HAFT=5.985

0.011-0.062

HAFT=0.055

Hay 0.666-16.863

HAFT=13.842

0.019-0.133

HAFT=0.133

1 Range of residues refer to individual samples (two samples per trial collected); HAFT = Highest Average Field Trial; Residues of metabolite 

M700F008 is in parent equivalents.

2 For alfalfa and clover, three applications were made, two before first cutting and one after first cutting (after regrowth). The PHIs refer to either 

first cutting or second cuttings; around 14 days before each cutting. Highest residues reported in this table were either from the first or the second 

cuttings depending on the matrix (forage or hay) or crop (alfalfa or clover). 

Citrus processing studies were conducted to determine the potential for concentration of residues 

of fluxapyroxad (BAS 700 F) in the processed fractions.

Table 5.2.1.2 Summary of Fluxapyroxad Processing Factors for 

Citrus.

Commodity Average Processing factor

Wet Pomace 1.2x

Dried Pulp 4.8x

Peel 1.9x

Juice 0.02x

Marmalade 0.04x

Oil 59x

Fluxapyroxad residues concentrate (on average) in wet pomace (1.2x), dried pulp (4.8x), peel 

(1.9x), and oil (59x) and do not concentrate in juice and marmalade. The metabolites 

M700F002, M700F008, and M700F048 generally do not concentrate in any orange processing 

commodities. 

5.3 Water Residue Profile

5.3.1 Estimated Drinking Water Concentrations 
Page 27 of 81

Monitoring data for fluxapyroxad is not available. Estimated Drinking Water Concentrations 

(EDWCs) for fluxapyroxad were provided by the Environmental Fate and Effects Division 

(EFED) (C. Peck, D425591, 9/10/2015) which basically confirms that the highest EDWC still 

are from rice and turf uses for which EFED conducted the assessment previously (C. Peck, 

D403944, 3/15/13 and D426700, 4/10/15). EFED generated the surface water estimates using 

the Tier I Rice model. Ground water estimates were calculated using the Pesticide Root Zone 

Model for Ground Water (PRZM-GW). EDWCs for fluxapyroxad (parent only) were derived 

based on fluxapyroxad use on rice and turf. Surface and groundwater EDWCs for fluxapyroxad 

are provided in Table 5.3.1.1. The estimated drinking water residue level for peak concentration 

of 0.203 mg/L (ppm) was used in the acute assessment. The Average Simulation Breakthrough 

Time for this concentration to occur was approximately 48 yrs. The 1-in10 year chronic drinking 

water concentration of 0.188 mg/L (ppm) was used the chronic assessment. 

Table 5.3.1.1 EDWCs for the Fluxapyroxad Human Health Risk Assessment 

Drinking Water Source 1-in-10 year acute (μg/L) 1-in-10 year chronic (μg/L)

Surface Water (Rice Model) 127 127

Ground Water (PRZM-GW) 203 188

5.4 Dietary and Drinking Water Exposure and Risk

HED conducted screening-level acute and moderately refined 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 (Food and Drinking Water) Analysis

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, and M700F010 (milk only)) 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 acute ground water estimate from application of 

fluxapyroxad to turf. 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 

12%. The 95th percentile aPAD for the general population is 7.7%.
Page 28 of 81

Table 5.4.1.1 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

0.096292 7.7

All Infants (< 1 year old) 0.099800 8.0

Children 1-2 years old 0.151501 12

Children 3-5 years old 0.151447 12

Children 6-12 years old 0.086744 6.9

Youth 13-19 years old 0.074856 6.0

Adults 20-49 years old 0.094594 7.6

Adults 50-99 years old 0.093364 7.5

Females 13-49 years old 0.099615 8.0

5.4.2 Chronic Dietary (Food and Drinking Water) Analysis

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

population and various population subgroups. Combined average residue for parent and highest 

residue for metabolite M700F008 and 100% crop treated assumptions were used. 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 ground water 

estimate from application of fluxapyroxad to turf. Chronic dietary risk estimates are not of 

concern for general population or other population subgroups. The population subgroup with the 

highest risk estimate is all infants <1 year old with a % chronic PAD (cPAD) of 66%. The % 

cPAD for the general U.S. population is 32%. 

Table 5.4.2.1 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

0.021

0.006701 32

All Infants (< 1 year old) 0.013859 66

Children 1-2 years old 0.013446 64

Children 3-5 years old 0.010599 51

Children 6-12 years old 0.006756 32

Youth 13-19 years old 0.004805 23

Adults 20-49 years old 0.006305 30

Adults 50-99 years old 0.006365 30

Females 13-49 years old 0.006292 30
Page 29 of 81

5.4.3 Cancer Dietary (Food and Drinking Water) Analysis

Fluxapyroxad has been classified as “not likely to be carcinogenic to humans below a defined 

dose range”. 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. As shown in Section 5.4.2, there are no chronic 

risks of concern for fluxapyroxad.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no residential exposure associated with the proposed uses in this action; however, there 

are existing turf uses that were previously assessed for fluxapyroxad. An updated turf 

assessment was completed in this document due to a correction in the single maximum 

application rate from 2.47 lb ai/gallon to 0.005 lb ai/gallon. The previous turf assessment 

conducted the residential handler and post-application exposure assessment at a rate of 2.47 lb 

ai/gallon. The corrected residential handler and residential post-application scenarios are 

included in Section 6.1.2 and 6.2. below; see Appendix E for rates. The corrected turf 

assessment will impact the human health aggregate risk assessment for fluxapyroxad.

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct tasks related to applications and that 

exposures can vary depending on the specifics of each task. Residential handlers are addressed 

somewhat differently by HED as homeowners are assumed to complete all elements of an 

application without use of any protective equipment.

The quantitative exposure/risk assessment for fluxapyroxad developed for residential handlers is 

based on the following scenarios: 

 Mixing/loading/applying liquids with a manually-pressurized handwand, 

 Mixing/loading/applying liquids with a hose-end sprayer,

 Mixing/loading/applying liquids with a backpack, and

 Mixing/loading/applying liquids with a sprinkler can.

6.1.1 Handler Exposure Data

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

registration. It is HED’s policy to use data from the HED 2012 Residential SOPs. Available at 

http://www.epa.gov/pesticides/science/residential-exposure-sop.html).
Page 30 of 81

6.1.2 Residential Handler Exposure Assumptions

A series of assumptions and exposure factors served as the basis for completing the residential 

handler risk assessments. Each assumption and factor is detailed below.

Application Rate: 

Application rates are provided in Table 6.1.2.1 below.

Unit Exposures and Area Treated or Amount Handled:

Unit exposure values and estimates for area treated or amount handled were taken from HED’s 

2012 Residential SOPs. Available at http://www.epa.gov/pesticides/science/residential-exposuresop.html).

Exposure Duration: 

Residential handler exposure is expected to be short-term in duration. Intermediate-term 

exposures are not likely because of the intermittent nature of applications by homeowners.

Residential Handler Non-Cancer Exposure and Risk Estimate Equations

The algorithms used to estimate exposure and dose for residential handlers can be found in the 

2012 Residential SOPs.

Fluxapyroxad does not pose a dermal risk; therefore, only inhalation exposures for handlers were 

calculated. For all residential handler exposure scenarios, inhalation MOEs exceed HED’s LOC 

(inhalation LOC = 100), and therefore not of concern to HED. Summaries of the short- term risk 

estimates for residential handlers are included in Table 6.1.2.1.

Summaries of the short-term risk estimates for residential post-application activities are included 

in Table 6.1.2.1.

Table 6.1.2.1. Short-Term Residential Handler Exposure and Risk Estimates for Fluxapyroxad

Exposure Scenario

Inhalation 

Unit 

Exposure 

Maximum 

Application

Rate1

Area 

Treated or 

Amount 

Handled 

Daily2

Inhalation

Dose3

MOE4

mg/lb ai mg/kg/day

Mixer/Loader/Applicator for Reassessed Turf Uses

M/L/A Liquids for Hose-End

Sprayer 0.022 0.23 lb ai/A 0.5 acres 0.000032 230,000

M/L/A Liquids for ManuallyPressurized Handwand 0.018 0.005 lb 

ai/gallon 5 gallons 0.0000056 1,300,000

M/L/A Liquids for Sprinkler Can 0.022 0.000005 lb 

ai/ft2 1,000 ft2 0.0000014 5,300,000

M/L/A Liquids for Backpack 0.14 0.005 lb 

ai/gallon 5 gallons 0.000044 170,000
Page 31 of 81

 1. Based on EPA Reg. No. 7960-350 label (D403943, J. Miller, 7/23/13); 

 2. Based on HED’s 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).

 3. Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A/day or 

gallons/day) ÷ BW (80 kg).

 4. Inhalation MOE = Inhalation NOAEL (7.3 mg/kg/day) ÷ Inhalation Dose (mg/kg/day)

6.2 Post-Application Exposure

Residential post-application dermal risk for adults was not quantitatively assessed for 

fluxapyroxad because there is no identified systemic dermal hazard. Incidental oral exposure for 

children for turf uses is anticipated. Post-application inhalation exposure while engaged in 

activities on or around previously treated turf is generally not quantitatively assessed. The 

combination of low vapor pressure for chemicals typically used as active ingredients in outdoor 

residential pesticide products and dilution in outdoor air is likely to result in minimal inhalation 

exposure. 

A quantitative assessment has been conducted previously for the incidental oral scenarios (i.e., 

hand-to-mouth, object-to-mouth and incidental soil ingestion) for the turf use. This combination 

should be considered a protective estimate of children’s exposure to pesticides used indoors.

As a standard practice, post-application non-dietary ingestion exposure (i.e., hand-to-mouth, 

object-to-mouth, soil ingestion, etc.) for adults is not assessed – it is assumed that an adult would 

not place pesticide-contaminated hands, objects, or soil in their mouth.

The quantitative oral exposure/risk assessment for residential post-application exposures is based 

on the incidental oral scenario for children 1<2. 

Residential Post-application Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the residential 

post-application risk assessment. Each assumption and factor is detailed in the 2012 Residential 

SOPs. Available at: http://www.epa.gov/pesticides/science/residential-exposure-sop.html

Residential Post-application Non-Cancer Exposure and Risk Equations

The algorithms used to estimate residential post-application exposure and dose can be found in 

the 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposuresop.html).

A summary of the residential post-application exposures and risks are provided below in Table 

6.2.2.1 and reflects hand-to-mouth exposures of children 1<2 years old from playing on turf.

Table 6.2.2.1. Residential Post-application Non-Cancer Exposure and Risk Estimates for Fluxapyroxad Turf Uses

Lifestage Post-application Exposure Scenario Application Rate 1

(lb ai/A) Dose 2

(mg/kg/day) MOE 3

Liquids

Child 1 < 2 year old Oral

Hand-to-Mouth

0.23

0.0035 2,100

Object-to-Mouth 0.00011 69,000

Soil Ingestion 0.0000078 940,000
Page 32 of 81

1 Based on EPA Reg. No. 7960-350 label (D403943, J. Miller, 7/23/13).

2 Dose (mg/kg/day) algorithms provided in 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential-exposure-sop.html).

3 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day).
Page 33 of 81

It is noted that the 0.23 lb ai/acre application rate for turf was modeled to estimate post-application residential exposure of children. 

6.3 Residential Risk Estimates for Use in Aggregate Assessment

The recommended residential exposure for use in the adult aggregate assessment reflects handler inhalation exposure from 

applications to turf via backpack and in children 1<2 years old reflects hand-to-mouth exposures from post-application exposures from 

children playing on turf. The residential doses to be used for the aggregate risk assessment and the source of those exposures are 

shown in Table 6.3.1, below. 

Table 6.3.1 Recommendations for the Short- and Intermediate-Term Residential Exposures for the Fluxapyroxad Aggregate Assessment 1

Lifestage

Handler Exposure 

(mg/kg/day) 2

Residential

Handler Total 

Exposure 

(mg/kg/day) 3

Residential 

Handler 

Total MOE 4

Post-application Exposure 

(mg/kg/day) 5

Residential Postapplication Total 

Exposure 

(mg/kg/day)

Residential Postapplication MOE 6

Dermal Inhalation Dermal Inhalation Oral

Short-Term

Adult Male N/A 0.000044 0.000044 170,000 N/A N/A N/A N/A N/A

Child N/A N/A N/A N/A N/A N/A 0.0035 0.0035 2100

Intermediate-Term

Adult Male

Adult Female N/A N/A

Child

1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 

2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed from Table 6.1.2.1..

3 Residential Handler MOE = the MOEs associated with the highest doses identified in Table 6.1.2.1.

4 Residential Post-application Dose = the highest post-application dose for each applicable lifestage of all scenarios assessed from Table 

5 Residential Post-application MOE = the MOEs associated with the highest doses identified in Table 6.2.2.1.

6 Lifestage population was combined (BW = 80) due to an inhalation only assessment with MOEs well above 100. 
Page 34 of 81

6.4 Non-Occupational Bystander Post-Application Inhalation Exposure and Risk 

Estimates

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The Agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). During Registration 

Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for fluxapyroxad.

6.5 Non-Occupational Spray Drift Exposure and Risk Estimates

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, spray drift can also be a 

potential source of exposure from the ground application methods (e.g., groundboom and 

airblast) employed for fluxapyroxad. The Agency has been working with the Spray Drift Task 

Force (a task force composed of various registrants which was developed as a result of a Data 

Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation 

and other parties to develop the best spray drift management practices (see the Agency’s Spray 

Drift website for more information). 2 The Agency has also developed a policy on how to 

appropriately consider spray drift as a potential source of exposure in risk assessments for 

pesticides. 

The potential for spray drift will be quantitatively evaluated for each pesticide during the 

Registration Review process which ensures that all uses for that pesticide will be considered 

concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures 

For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating 

Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification 

of indirect non-occupational exposure to drift. 

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT 

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. Additionally, aggregate exposure should consider exposure across both the dietary 

and residential pathways. 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 

 

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
Page 35 of 81

sources, HED considers both the route and duration of exposure. The proposed/registered 

fluxapyroxad uses are expected to result in residential exposure via inhalation for residential 

handlers and incidental oral exposure for toddlers. 

7.1 Acute Aggregate Risk

Acute aggregate risks for fluxapyroxad include exposure from food and water only. As 

demonstrated under Section 5.4, acute aggregate risks are not of concern.

7.2 Short- Term Aggregate Risk

Short term aggregate exposure takes into account residential exposure plus average exposure 

levels to food and water (considered to be a background exposure level). The short-term 

aggregate risks for fluxapyroxad are not of concern and are shown in Table 7.2.1 below. 

Table 7.2.1 Short-Term and/or Intermediate Term Aggregate Risk Calculations

Population

Short- or Intermediate-Term Scenario

NOAEL 

mg/kg/day LOC1

Max 

Allowable 

Exposure2

mg/kg/day

Average 

Food and 

Water 

Exposure 

mg/kg/day

Residential 

Exposure 

mg/kg/day3

Total 

Exposure 

mg/kg/day4

Aggregate 

MOE (food, 

water, and 

residential)5

Adult 7.3 100 0.073 0.006365 0.000044 0.006409 1139

Child 7.3 100 0.073 0.013446 0.0035 0.016946 431

1 The LOC of 100 is based on the standard inter- and intra-species extrapolation factors.

2 Maximum Allowable Exposure (mg/kg/day) = 7.3/100

3 Residential Exposure values taken from Table 6.3.1. Average food & water exposure taken from Table 5.4.2.1

4 Total Exposure = Avg Food & Water Exposure + Residential Exposure)

5 Aggregate MOE = [7.3 / (Avg Food & Water Exposure + Residential Exposure)]

7.3 Intermediate-Term Aggregate Risk 

There are no residential use scenarios that would result in potential intermediate-term exposure 

to fluxapyroxad; therefore, an intermediate-term aggregate risk assessment is not required.

7.4 Chronic, Non-Cancer, Aggregate Risk

There are no residential use scenarios that would result in potential long-term (chronic) 

exposure; therefore, the chronic aggregate risk is equivalent to the chronic dietary (food and 

water) risk, and as shown in Section 5.4.2, there are no risks of concern.

7.5 Cancer Aggregate Risk

Fluxapyroxad has been classified as “not likely to be carcinogenic to humans below a defined 

dose range”. The Agency has determined that the quantification of risk using a non-linear 
Page 36 of 81

approach (i.e., RfD) will adequately account for all chronic toxicity, including carcinogenicity, 

that could result from exposure to fluxapyroxad. As shown in Section 5.4.2, there are no chronic 

risks of concern for fluxapyroxad.

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/.

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

9.1 Occupational Handler Exposure/Risk Estimates

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure is expected from the proposed uses. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios: 

 Mixing/Loading liquids for aerial application,

 Mixing/Loading liquids for airblast application,

 Mixing/Loading liquids for chemigation (including overhead track sprayer) application,
Page 37 of 81

 Mixing/Loading liquids for groundboom application,

 Applying sprays for aerial application,

 Applying sprays for airblast application,

 Applying sprays for groundboom application,

 Flagging for liquid aerial application,

 Mixing/Loading/Applying liquids for backpack application,

 Mixing/Loading/Applying liquids using a manually-pressurized handwand, and 

 Mixing/Loading/Applying liquids using a mechanically-pressurized handgun.

Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational 

handler risk assessments. Each assumption and factor is detailed below on an individual basis.

Application Rate: Refer to the proposed use patterns in Appendix E.

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. 

Sources of generic handler data, used as surrogate data in the absence of chemical-specific data, 

include PHED 1.1, the AHETF database, the ORETF database, and the Residential SOPs. Some 

of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of 

FIFRA. The standard values recommended for use in predicting handler exposure that are used 

in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide 

Handler Unit Exposure Surrogate Reference Table3”, which, along with additional information 

on HED policy on use of surrogate data, including descriptions of the various sources, can be 

found at the Agency website4. 

Area Treated or Amount Handled: The area treated or amount handled is based on HED 

ExpoSAC Policy No. 9.1. Refer to Table 9.1.1 for these assumptions for each scenario.

Exposure Duration: HED classifies exposures from 1 to 30 days as short-term and exposures 30 

days to six months as intermediate-term. Exposure duration is determined by many things, 

including the exposed population, the use site, the pest pressure triggering the use of the 

pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is 

reasonable to believe that occupational handlers will not apply the same chemical every day for 

more than a one-month time frame; however, there may be a large agribusiness and/or 

commercial applicators who may apply a product over a period of weeks (e.g., completing 

multiple applications for multiple clients within a region). For fluxapyroxad, based on the 

proposed uses, short- and intermediate-term exposures are expected. Long-term exposures are 

not expected.

Mitigation/Personal Protective Equipment: Estimates of dermal and inhalation exposure were 

 

3 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf

4 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
Page 38 of 81

calculated for various levels of personal protective equipment (PPE). Results are presented for 

“baseline,” defined as a single layer of clothing consisting of a long sleeved shirt, long pants, 

shoes plus socks, no protective gloves, and no respirator. For the proposed use label (EPA Reg. 

No. 7969-306), the label requires applicators and handlers to wear baseline attire with the 

addition of protective eyewear. For the proposed use labels (EPA Reg. No. 7969-309) and (EPA 

Reg. No. 7969-311), the label requires applicators and other handlers to wear baseline attire.

Occupational Handler Non-Cancer Exposure and Risk Estimate Equations

The algorithms used to estimate non-cancer exposure and dose for occupational handlers can be 

found in Appendix A.

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

The occupational handler exposure and risk estimates indicate that the short- and intermediateterm inhalation MOEs are not of concern to HED (i.e., MOEs > 100) with baseline attire. The 

summary of the occupational handler exposure and risk estimates are provided in Table 9.1.1.

Table 9.1.1. Short- and Intermediate- term Occupational Handler Exposure and Risk Estimates for 

Fluxapyroxad.

Exposure Scenario Crop or Target1

Baseline 

Inhalation 

Unit 

Exposure2

μg/lb ai

Maximum

Application 

Rate3

lb ai/A

(unless 

otherwise 

noted)

Area 

Treated 

or 

Amount 

Handled 

Daily4

Acres

(unless 

otherwise 

noted)

Dose5

mg/kg/day

Short- and 

Intermediate-term

Inhalation

MOE6

LOC = 100

Mixer/Loader

M/L Liquids for Aerial 

Application7

Orchard/Vineyard 0.219 0.12 350 0.000115 63,000

M/L Liquids for Aerial 

Application7

Typical Field Crop 0.219 0.089 350 0.0000853 86,000

High-Acreage Field Crop 0.089 1,200 0.000293 25,000

M/L Liquids for Airblast 

Application Orchard/Vineyard 0.219 0.12 40 0.0000131 560,000

M/L Liquids for 

Chemigation Application

Orchard/Vineyard

0.219

0.12 350 0.000115 63,000

Typical Field Crop 0.089 350 0.0000853 86,000

High-Acreage Field Crop 0.089 350 0.0000853 86,000

M/L Liquids for 

Groundboom Application Typical Field Crop 0.219 0.089 80 0.0000195 370,000

M/L Liquids for 

Groundboom Application High-Acreage Field Crop 0.219 0.089 200 0.0000488 150,000

Applicator

Applying Sprays for Orchard/Vineyard 0.0049 0.12 350 0.00000258 2,800,000
Page 39 of 81

Table 9.1.1. Short- and Intermediate- term Occupational Handler Exposure and Risk Estimates for 

Fluxapyroxad.

Exposure Scenario Crop or Target1

Baseline 

Inhalation 

Unit 

Exposure2

μg/lb ai

Maximum

Application 

Rate3

lb ai/A

(unless 

otherwise 

noted)

Area 

Treated 

or 

Amount 

Handled 

Daily4

Acres

(unless 

otherwise 

noted)

Dose5

mg/kg/day

Short- and 

Intermediate-term

Inhalation

MOE6

LOC = 100

Aerial Application7(EC)

Applying Sprays for 

Aerial Application7

Typical Field Crop 0.0049

(EC)

0.089 350 0.00000191 3,800,000

High-Acreage Field Crop 0.089 1,200 0.00000654 1,100,000

Applying Sprays 

for Airblast Application Orchard/Vineyard 4.71 0.12 40 0.000283 26,000

Applying Sprays for 

Groundboom Application Typical Field Crop 0.34 0.089 80 0.0000303 240,000

Applying Sprays for 

Groundboom Application High-Acreage Field Crop 0.34 0.089 200 0.0000756 97,000

Flagger for Aerial 

Application for Liquids

Orchard/Vineyard

0.35

0.12 350 0.000184 40,000

Typical Field Crop 0.089 350 0.000136 54,000

High-Acreage Field Crop 0.089 350 0.000136 54,000

1 “Typical field crops” include grass grown for seed; “High-acreage field crops” include grass forage, fodder, straw, and hay, alfalfa, and clover; 

“Orchard/Vineyard” include citrus fruit.

2 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline, Eng. 

Controls.

3 Based on proposed label (See Appendix E).

4 Exposure Science Advisory Council Policy #9.1.

5 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/A or gallon) x Area treated or Amount Handled (A/day or 

gallons/day) / Body Weight (80 kg).

6 Inhalation MOE = Inhalation NOAEL (7.3 mg/kg/day)/Inhalation Dose (mg/kg/day).

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. 

9.3.1 Dermal PostApplication Risk

Occupational post-application dermal risk was not assessed for fluxapyroxad because there is no 

identified systemic dermal hazard. 

Dislodgeable Foliar Residue (DFR): In accordance with the updated Part 158 data requirements 
Page 40 of 81

(2007), one or more DFR studies are required when a pesticide has residential or occupational 

uses that could result in post-application dermal exposure. Since there is no hazard via the 

dermal route of exposure, a non-cancer dermal post-application risk assessment was not 

performed for fluxapyroxad. Therefore, DFR studies are not needed for fluxapyroxad at this 

time. If the PODs change, the need for DFR studies may be reevaluated in the future to refine 

the post-application assessment.

9.3.2 Inhalation Post Application Risk

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The Agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

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

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During Registration Review, the Agency will utilize this analysis to determine 

if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is 

required for fluxapyroxad.

In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the Agency's risk assessments.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

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

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting 

workers from inhalation exposures during and after greenhouse applications through the use of 

ventilation requirements.[40 CFR 170.110, (3) (Restrictions associated with pesticide 

applications)]

9.3.3 Restricted Entry Interval

The REI specified on the proposed label is based on the acute toxicity of fluxapyroxad. 

Fluxapyroxad is classified as Toxicity Category III via the dermal route and Toxicity Category 
Page 41 of 81

IV for skin irritation potential. It is not a skin sensitizer. Under 40 CFR 156.208 (c) (2) (iii), ai’s 

classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are 

assigned a 12-hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim 

REI of 12 hours is adequate to protect agricultural workers from post-application exposures to 

fluxapyroxad. 

10. REFERENCES

Fluxapyroxad. Occupational and Residential Exposure Assessment for Proposed Uses On Ornamentals, Citrus 

Fruit, Grasses, Alfalfa, and Clover. M. Hawkins, D424427, 2/18/2016

Fluxapyroxad (BAS 700F) Section 3 Registration And Establishment of Permanent Tolerances For Citrus Crop 

Group 10-10, Grass Crop Group 17, Non-Grass Crop Group 18, And Poultry Fat; Tolerance Amendment for Egg. 

Summary of Analytical Chemistry and Residue Data. M. Sahafeyan, D425590, D425592, D425597, D425600, 

D425601, 4/20/16

Fluxapyroxad – Revised Acute and Chronic Dietary Exposure and Risk Assessments for Proposed New Uses of 

Fluxapyroxad on Citrus, Grass, Nongrass. M. Sahafeyan, D425592, 4/20/16

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).

Fluxapyroxad (BAS 700F) Summary of Hazard and Science Policy Council (HASPOC) Meeting of January 17, 

2013. Recommendations on the need for a subchronic inhalation study. A. Howard, TXR # 0056561, 2/26/13

Fluxapyroxad (BAS 700F) Waiver Request for Requirement of Additional Fish/Shellfish Nature of the Residue 

Studies. T. Morton, D416489, 12/5/13
Page 42 of 81

APPENDIX A: TOXICOLOGY DATA SUMMARY

A.1 Guideline Data Requirements

The requirements (40 CFR 158.340) for food use for fluxapyroxad are in Table A.1. Use of the 

new guideline numbers does not imply that the new (1998) guideline protocols were used. 

Table A.1. Guideline Data Requirements for Fluxapyroxad

Guideline 

No. Study Type Technical MRID 

Required Submitted No.

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

N1

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

1

Study requirement waived by the HASPOC (TXR#0056561, 1/17/2013)

A.2 Toxicity Profiles

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
Page 43 of 81

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.3 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 

0/0, 283/247 mkd

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. 

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 

Mechanistic tnvestigations of hepatocellular proliferation. 
Page 44 of 81

Table A.3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)

Guideline No

Study Type

MRID/Classification

Doses Results

ppm 

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 

1136/1657 mkd (M/F)

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)

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)

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
Page 45 of 81

Table A.3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)

Guideline No

Study Type

MRID/Classification

Doses Results

0/0, 9/10, 45/51, 

295/238 mkd M/F

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

Waived by HASPOC (TXR# 0056561)

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 

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 

47923591 (2009)

Acceptable, guideline

Chronic toxicity 

NOAEL=50 ppm (2.1/2.7 mkd in males/females)
Page 46 of 81

Table A.3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)

Guideline No

Study Type

MRID/Classification

Doses Results

in rats 0, 50, 250, 1500, 3000 

ppm 

0/0, 2.1/2.7, 11/14, 

68/82, 145/182 mkd 

(M/F) 

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

870.5395 In Vivo

Mammalian 

Cytogenetics -

Erythrocyte 

Micronucleus-mouse

47923584 (2006)

Acceptable, guideline

0, 500, 1000, 2000 

mkd 

Did not lead to any increase in polychromatic erythrocytes. 

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 

NOAEL (neurotoxicity)=5000 ppm (302/338 mkd M/F)

LOAEL (neurotoxicity) =Not observed 
Page 47 of 81

Table A.3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)

Guideline No

Study Type

MRID/Classification

Doses Results

ppm

0, 11.5/13.4, 57.7/67.2, 

302.2/337.7 mkd M/F 

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

*In a formulation with 

pyraclostrobin (BAS 

500 F) 

The dermal absorption factor is 8.38%.

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. 
Page 48 of 81

Table A.3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)

Guideline No

Study Type

MRID/Classification

Doses Results

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 

dose-dependent. 

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.3 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, 

285.7/295.1, 

953.6/983.1 mkd M/F 

NOAEL=953.6/983.1 mkd in M/F

LOAEL=Not observed 

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 
Page 49 of 81

Table A.3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for 

Metabolite M700F001 

Guideline No

Study Type 

MRID 

Classification

Doses 

Results 

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.3 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

90-Day dietary in rats

47923616 (2009)

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, 

NOAEL=958.4/928.7 mkg M/F

LOAEL=not observed 
Page 50 of 81

Table A.3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for 

Metabolite M700F002 

Guideline No

Study Type 

MRID 

Classification

Doses 

Results 

958.4/928.7 mkd M/F

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 51 of 81

Table A.3 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). 
Page 52 of 81

Table A.3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for 

Metabolite M700F048 

Guideline No

Study Type 

MRID 

Classification

Doses 

Results 

Non-OPPTS guideline, 

OECD 417

47923630 (2009)

Acceptable, nonguideline

1000 mkd, oral 

(gavage) 

M700F048 is 5077265 is systemically bioavailable and its 

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.3 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 53 of 81

Table A.3 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.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 54 of 81

A.3 Toxicological Endpoints

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 55 of 81

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 
Page 56 of 81

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 

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 (IntermediateTerm)

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 57 of 81

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 58 of 81

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. 
Page 59 of 81

The LOAEL is 10000 ppm (295 mg/kg bw/day) in males and 7500 ppm (238 mg/kg bw/day) 

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. 
Page 60 of 81

The LOAEL for maternal toxicity in females is 1000 mg/kg bw/day, based on increased 

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

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. 

This study is classified as totally reliable (acceptable/guideline) and satisfies guideline 
Page 61 of 81

requirements for a prenatal developmental toxicity study (OPPTS 870.3700; OECD 414) in 

rabbits. 

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. 

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 
Page 62 of 81

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. 

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 
Page 63 of 81

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 

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 
Page 64 of 81

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 

-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 

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 
Page 65 of 81

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 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 

(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 
Page 66 of 81

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 

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 
Page 67 of 81

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 

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 
Page 68 of 81

requirement for an erythrocyte micronucleus test (OPPTS 870.5395, OECD 474). 

A.4.7 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.

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 

-

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 
Page 69 of 81

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. 

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 

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 
Page 70 of 81

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. # 

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. 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 
Page 71 of 81

0.1% of the dose administered or less. Metabolites were identified by LC–MS and LC–MS/MS. 

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 

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. 
Page 72 of 81

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. 

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, 
Page 73 of 81

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 74 of 81

APPENDIX B. Chemical Names And Structures Of Metabolites

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)-1H-pyrazole4-carboxamide

M = 367

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
Page 75 of 81

M700F009

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

1Hpyrazole-4-carboxamide

M = 383

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)oxy-3',[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

F F

F

N

O

N

N

H

F

F

H

OH

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
Page 76 of 81

M700F016

3-(difluoromethyl)-1-methyl-N-(methylthio-hydroxy-3',4',5'-trifluoro-

[1,1'-biphenyl]-2-yl)-1H-pyrazole-4-carboxamide

M = 443

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)oxy-3',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

F

N

O

N

N

F

F

H

F

F

SCH3

OH

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
Page 77 of 81

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

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

F

N

O

N

N

H

F

F

H

F

F

OSO3H

F

N

O

N

N

F

F

H

F

F

OSO3H

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
Page 78 of 81

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

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

N

O

N

N

H

F

F

H

F

F

O-GlcA

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 79 of 81

APPENDIX C. Physical/Chemical Properties

TABLE C1. 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-1

cm-1]
Page 80 of 81

APPENDIX D. Studies Reviewed for Ethical Conduct

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) 
Page 81 of 81

APPENDIX E. Proposed Use Directions for Fluxapyroxad 

Table E1. Summary of Proposed Use Directions for Fluxapyroxad.

Use Site Application Equipment Formulation Application Rate Use Directions and 

Limitations

Grass grown for seed

Ground,

Aerial, 

Chemigation

Imbrex Xemium 

Brand Fungicide

EPA Reg. No. 7969-

306

Emulsifiable 

Concentrate

(5.96 % a.i.)

(0.52 lb ai/gallon)

0.089 lb ai/A

For optimal disease control, 

begin applications of Imbrex 

prior to disease development 

and continue on a 14 to 21 

day interval.

Grass forage, fodder, 

straw, and hay, 

alfalfa, and clover

0.075 lb ai/A Do not use on rangeland.

Citrus fruit Aerial,

Chemigation,

Airblast

0.12 lb ai/A

(0.0012 lb ai/gallon)3

For aerial application to citrus 

orchards, Do Not use less than 

10 gallons of spray solution 

per acre.

Grass grown for seed

Ground,

Aerial,

Chemigation,

Sercadis Xemium 

Brand Fungicide

EPA Reg. No. 7969-

309

Suspension

Concentrate

(26.55 % a.i.)

(2.47 lb ai/gallon)

0.089 lb ai/A

For aerial application to citrus 

orchards, Do Not use less than 

10 gallons of spray solution 

per acre.

Grass forage, fodder, 

straw, and hay, 

alfalfa, and clover

Do not use on rangeland.

Citrus fruit

Aerial, 

Chemigation,

Airblast

0.12 lb ai/A

(0.0012 lb ai/gallon)3

For optimal disease control, 

begin applications of Imbrex 

prior to disease development 

and continue on a 14 to 21 

day interval.

Grass grown for seed

Ground,

Aerial,

Chemigation

Priaxor Xemium 

Brand Fungicide

EPA Reg. No. 7969-

311

Suspension 

Concentrate

(14.33% a.i.)

(1.39 lb ai/gallon)

0.075 lb ai/A

For optimal disease control, 

begin applications of Imbrex 

prior to disease development 

and continue on a 14 to 21 

day interval.

Alfalfa Do not use on rangeland.

Citrus fruit

Aerial, 

Chemigation,

Airblast

0.12 lb ai/A

(0.0012 lb ai/gallon)3

For aerial application to citrus 

orchards, Do Not use less than 

10 gallons of spray solution 

per acre.

1 HED received written information from the registrant to clarify that 50- 700 gallons of solution/A are used for outdoor ornamentals. Therefore: 

0.00002 lb ai/gallon in 700 gallons/acre = 0.014 lb ai/A

2 HED received written information from the registrant to clarify that 50-400 gallons of solution/A are used for indoor ornamentals. Therefore: 

0.00002 lb ai/gallon in 400 gallons/acre = 0.008 lb ai/A

3

 HED received written information from the registrant to clarify that 100- 400 gallons of solution/A are used for citrus fruit. Therefore: 0.12 lb 

ai/A in 100 gallons of solution/A = 0.0012 lb ai/gallon