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TABLE OF CONTENTS pg. 1.0 EXECUTIVE SUMMARY ................................ ................................ ................................ . 4 2.0 HED RECOMMENDATIONS ................................ ................................ ............................ 7 2.1 Data Deficiencies/Conditions of Registration ................................ ................................ ..... 7 2.2 Tolerance Considerations ................................ ................................ ................................ ..... 7 2.2.1 Enforcement Anal ytical Method ................................ ................................ .............. 7 2.2.2 International Harmonization ................................ ................................ .................... 7 2.2.3 Recommended Tolerances ................................ ................................ ....................... 7 2.2.4 Revisions to Petitioned for Tolerances ................................ ................................ .. 10 2.3 Label Recommendations ................................ ................................ ................................ ... 10 3.0 IN GREDIENT PRO FILE ................................ ................................ ................................ .. 11 3.1 Chemical Identity ................................ ................................ ................................ .............. 11 3.2 Phy sical/Chemical Properties ................................ ................................ ............................ 11 3.3 Pesticide Use Pattern ................................ ................................ ................................ .......... 11 3.4 Anticipated Exposure Pathway s ................................ ................................ ........................ 13 3.5 Environmental Justice ................................ ................................ ................................ ........ 14 4.0 HAZARD CHARACTERIZATION/ASSESSMENT ................................ ....................... 14 4.1 Toxicology

S tudies Available for Analy sis ................................ ................................ ....... 14 4.2 Absorption, Distributi on, Metabolism, & Elimination ................................ ...................... 15 4.3 Toxicological Effects ................................ ................................ ................................ ......... 16 4.4 Safety

fa ctor for Infants and Children ................................ ................................ ............... 18 4.4.1 Completeness of the Toxi cology Database ................................ ............................ 18 4.4.2 Evidence of Neurotoxicity ................................ ................................ ..................... 1 9 4.4.3 Evidence of Sensitivity /Su sceptibility

in the Developing or Young Animal ........ 19 4.4.4 Residual Uncertainty in the Exposure Database ................................ .................... 19 4.5 Toxicity

Endpoint and Point of Departure Selections ................................ ....................... 20 4. 5.1 Dose - Response Assessment ................................ ................................ ................... 20 4.5.2 Recommendation for Combining Exposure Routes ................................ .............. 20 4.5.3 Cancer Classification ................................ ................................ ............................. 21 4.5.4 Summary

of Points of Departure Used in Risk Assessment ................................ .. 22 5.0 DIETARY AND D RI NKING WATER RI SK ASSESSMENT ................................ ........ 23 5.1 Metabol ite/Degradate Residue Profile ................................ ................................ ............... 23 5.1.1 Summary

of Plant and Animal Metabolism Studies ................................ .............. 23 5.1.2 Summary

of Environmental Degradation ................................ .............................. 23 5.1. 3 Comparison of Metabolic Pathway s ................................ ................................ ...... 24 5.1.4 Residues of Concern Summary and Rationale ................................ ....................... 24 5.2 Food Residue Profile ................................ ................................ ................................ .......... 25 5.2.1 Residues in Crops ................................ ................................ ................................ .. 25 5.2.2 Residues in Meat, Milk, Poultry and Eggs ................................ ............................ 25

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5.2.3 Residues in Processed Commodities ................................ ................................ ..... 2 6 5.2.4 Storage Stability ................................ ................................ ................................ ..... 26 5.3 Water Residue Profile ................................ ................................ ................................ ........ 26 5.4 Dietary and Drinking Water Exposure and Risk ................................ ............................... 27 5.4 .1 Acute Dietary

and Drinking Water Exposure and Risk Estimates ........................ 27 5.4 .2 Chronic Dietary

and Drinking Water Exposure and Risk Estimates ..................... 27 6.0 RESIDENT IA L EXPOSURE/RI SK CHARACTERIZATION ................................ ........ 28 6.1 Residential By stander Postapplication Inhalation Exposure ................................ ............. 28 6.2 Spray

Drift ................................ ................................ ................................ ......................... 28 7.0 AGGREGATE EXPOSURE/RI SK CHARACTERIZATION ................................ .......... 29 8.0 CUMULAT IVE RISK ................................ ................................ ................................ ....... 29 9.0 OCCUPATI ONAL EXPOSURE/RI SK CHARACTERIZATION ................................ ... 30 9.1 Exposure Scenarios ................................ ................................ ................................ ........... 30 9.2 Handler Exposure ................................ ................................ ................................ ............... 30 9.2.1 Handler Exposure Scenarios ................................ ................................ .................. 30 9.2.2 Handler Exposure Data ................................ ................................ .......................... 32 9.2.3 Handler Exposure Assumptions ................................ ................................ ............. 32 9.2 .4 Handler Exposure and Risk ................................ ................................ ................... 33 9.3 Post - App lication Exposure ................................ ................................ ................................ 36 10.0 REFERENCES ................................ ................................ ................................ .................. 37 Appendix A. Toxicity

Pr ofile and Executive Summaries ................................ .............................. 38 A.1 Tox icity

Data Requirements ................................ ................................ .................. 38 A.2 Toxicity

Profiles ................................ ................................ ................................ ..... 39 A.3 Hazard Identifi cation and Endpoint Selection ................................ ....................... 50 A.4 Executive Summaries ................................ ................................ ............................. 53 Appendix B. Metabolism ................................ ................................ ................................ .............. 69 Appendix C. Physical/Chemical Properties ................................ ................................ ................... 83 Appendi x D. Review of Human Research ................................ ................................ ..................... 83

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**1.0 EXECUTIVE SUMMARY**  This assessment provides information to support a Section 3 registration for the use of the new active ingredi ent , fluxapy roxad on cereal grains, legume vegetables, oil seed crops, peanuts, pome fruit, stone fruit, root and tuber vegetables, fruiting vegetables, and cotton. This document addresses the exposures and estimated risk associated with the proposed new uses of fluxapy roxad . Itprovides an assessment of proposed tolerances (pesticide residue limits in food) to ensure that they

meet the safety standard established by the Food Quality Protection Act (FQPA) of 1996. This assessment was conducted as part o f a global review involving the U.S., Canada, and Australia. **Use Profile**  Fluxapy roxad (3 - (difluoromethyl) - 1 - methyl -N - (3 ′,4′ ,5′ - trifluoro[1,1 ′ - biphenyl] - 2 - yl ) - 1 Hpy razole - 4 - carboxamide) is a fungicide belonging to the carboxamide class of chemicals. It is a new active ingredient proposed for use on a wide range of crops to control a broad spectrum of fungal diseases . Fluxapyroxad is a py razole carboxamide. The mode of pesticidal action as a fungicide is inhibition of succinate dehydrogenase in comp lex II of the mitochondrial respiratory chain, resulting in inhibition of spore germination, germ tubes, and myc elial growth. Applications may

be made using groundboom, airblast, aerial, and standard slurry or mist - ty pe seed treatment equipment. There are no fluxapy roxad products proposed for homeowner use and there are no products proposed for application to residential areas. Recommended tolerances for combined residues of fluxapy roxad and its major metabolites in/on plant and animal commodities range from 0.0 03 ppm to 20 ppm. BASF Corporation is requesting a Section 3 registration of four fluxapy roxad products . The products are proposed for use on various seed and food crops. The technical product to be registered is XEM IUM Technical (7969 - GRE). The proposed formulations are BAS 700 01 F Fungicide (7969 - GNA, an emulsifiable concentrate (EC) containing 5. 96% fluxapy roxad); BAS 700 02 F (7969 - GNT, for seed treatment, 28.78% ai); BAS 700 03 F (7969 - GNI, for seed treatment, 28.70%; BAS 700 04 F (79 69 - GNO, EC formulatio n with 26.55% ai ); and two co active ingredient products with py raclostrobin: BAS 703 01 F (7969 - GRN, with fluxapy roxad at 21.26% (2.09 lb ai/gal) and py raclostrobin at 21.26 %) and BAS 703 02 F (7969 - GRR, with fluxapy roxad 14.33% and py

raclostrobin at 28.58%). Crop a pplications may

be begin at emergence, but typical applications begin as plants touch across rows. Maximum single application rates range from 0.09 lbs ai/A for most crops to 0.18 lb ai/A for dry shelled beans . Maximum seasonal application rates range from 0.18 to 0.36 lb ai/A. Proposed p re - harvest intervals (PHIs) are 0 day s for pome and stone fruit crops , 21 day s for cereal grains and 7 day s for other commodities. A 365 day plant back interval (PBI) is required for all crops that are not on the label.

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**Hazard Identification** An extensive toxicity

database for fluxapy

roxad was submitted to the Agency for registration of fluxapy

roxad. This database is sufficient for hazard characterization and end point 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 fluxapy

roxad exposure via the oral route is the liver with secondary toxicity

in the thy

roid for rats onl y. Liver toxicity was observed in rats, mice, and dogs , with species differences in both the time of onset, sensitivity, and nature of effects. Rats were the most sensitive species for all durations of exposure. In rats, adaptive effects of hepatocellular hyp ertrophy and increased liver weights and changes in liver enzy me activities were first observed. As the dose or duration of exposure to fluxapy roxad increased, clinical chemistry changes related to liver functio n also occurred, foll owed b y hepatocellular necrosis, neoplastic changes in the liver, and tumors. Thyr oid effects were observed only in rats. These effects were secondary

to changes in liver enzy

me regulation, which increased metabolism of thy roid horm one, resulting changes in thy roid hormones, thy

roid follicular hy

pertrophy and hy perplasia, 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 likel y” to cause tumors in humans based on convincing evidence that carcinogenic effects are not likely below a defined dose range . This classification was based on a full panel of in vitro and in vivio studies that showed no evidence of genotox icity, together with mechanistic studies in the liver and thy roid of rats that satisfied stringent criteria for establishing tumorgenic modes of action. No evidence of neurotoxicity was observed in response to repeated administration of fluxapy roxad. An acute neurotoxicity study showed decreased rearing and motor activity . This occurred on the day

of dosing onl y in the absence of histopathological effects or alterations in brain weights. This indicated that any neurotoxic effects of fluxapy roxad are likely

to be transient and reversible due to alterations in neuropharmacology and not from neuronal damage. No evidence of reproductive toxicity was observed. Developmental effects observed in both rats and mice (thyr oid follicular hy pertrophy and hy pe rplasia in rats and decreased defecation, food consumption, body

weight/body

weight gain, and increased litter loss in rabbits) occurred at the same doses as those that caused adverse effects in maternal animals, indicating no quantitative susceptibility. Since the maternal toxicities of thy roid hormone perturbation in rats and sy stemic 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 fluxapy roxad. 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 fluxapy roxad . Fluxapy roxad acute toxicity

to mammals is low by all routes of exposure. No hazards were identified for exposures via the dermal route in dermal toxicity studies. Oral

### Page 6 of 83

studies were extrapolated for assessment of inhalation hazards, since no repeated - dose inhalation studies were availab le. However, an inhalation study is not required at this time. **Dose Response Assessment** Toxicological points of departure (PODs) were selected for dietary /drinking water and occupational exp osure 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 b y the additional FQPA S afety Factor, which was reduced to 1X. An acute RfD/PAD for all populations was selected from a n acute neurotoxicity study in rats based on decreased motor activity and decreased rearing. A chronic RfD/PAD for all populations was selected from a chronic toxicity /carcinogenicity study in rats based on non - neoplastic changes in the liver (foci, masses). A POD for short - term inhalation exposure was selected from 28 day dietary study in rats based on thy

roid effects (thy roid follicular hy

pertrophy /hy perplasi a) . A POD for intermediate - term inhalation exposure was selected from a 90 day dietary study in rats based also on thy

roid effects. PODs for short and intermediate - term dermal exposure were not selected because there was no sy stemic toxicity up to the l imit dose in the 2 8 - day dermal toxicity

study in rats. An uncertainty

factor of 100x was applied to endpoints selected for all exposure routes (10x for interspecies extrapolation, 10x for intraspecies variation). **Exposure/Risk Assessment and Risk Chara cterization**  D ietary (food and water) and occupational exposure and risk assessment s w ere conducted for cereal grains, legume vegetables, oil seed crops, peanuts, pome fruit, stone fruit, root and tuber vegetables, fruiting vegetables, and cotton . Worker inhalation exposures were assessed for handler and post - application activities. Screening level acute and moderately refined chronic dietary and drinking water ri sk assessments for fluxapy roxad show that dietary

and drinking water exposure estimate s for the proposed uses are below HED’s level of concern for the general population and all population subgroups. Occupational exposure and risk estimates indicate that worker handler and post - application exposures are not of concern at the maximum allowa ble application rates for the proposed new uses. **Use of Human Studies** This risk assessment relies in part on data from studies in which adult human subjects were intentionall y exposed to a pesticide or other chemical. These studies, listed in Appendix D , have been determined to require a review of their ethical conduct. Some of these studies are also subject to review b y the Human Studies Review Board. All of the studies used have received the appropriate review.

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**2.0 HED RECOMMENDATIONS**  **2.1 Dat**  **a Deficiencies /Conditions of Registration**  A revised Section F must be submitted. The Agency is denying the registrant’s requested tolerance for subgroup 1A. For future consideration of a tolerance for subgroup 1A, f ield trials on carrot and radish must be submitted . BASF Methods L 0137/01 and L0140/02 will be submitted to the Analy

tical Chemistry

L aboratory

(ACL), and to FDA for updating PAM II, and to USDA for enforcement of tolerances in livestock commodities. The label must be revised as indicated in Section 2.3 below. **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  The residue anal ytical methods available for enforcement of fluxapy roxad tolerances include the L C/MS/MS method used for data gathering and proposed for enforcement. This method uses reversed - phase HPL C with gradient elution, and includes 2 ion transition s to be monitored for the parent fluxapy roxad. **2.2.2 International Harmonization**  There are no Codex MRLs established for residues of fluxapy roxad in any commodities. International harmonization is not an issue at this time. **2.2.3 Recommended**  **Tolerances** Pending submission of a revised Section B (see requirements under Directions for Use), and a revised Section F (see requirements under Proposed Tolerances), there are no residue chemistry issues that would preclude granting a Section 3 registration for the requested uses of fluxapy roxad, or establishment of tolerances for residues of fluxapy roxad as follows: Tolerances are established for residues of fluxapy roxad, including its metabolites and degradates, in or on the commodities in Table 1 . Compliance with the tolerance levels specified below is to be determined b y measuring only fluxapyroxad [ 3 - (difluoromethyl) - 1 - methyl -N - (3 ′,4′,5′ - trifluoro[1,1 ′ - biphenyl ] - 2 - yl ) - 1 H - pyrazole - 4 - carboxamide ] in or on the commodity . **Table 1. Proposed and Re**  **commended Tolerances for Fluxapyroxad Crop Group or**  **Comm odity**  **Proposed**

**Tolerance (ppm)**  **Recommended**

**Tolerance (ppm) Comments;**  **Correct Commodity Definition** Apple, wet pomace 3.5 2 Barley, bran 6 -- Calculated tolerance level (3.0 ppm) is the same as the Grain, Cereal, Group 15 tolerance,

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**Table 1. Proposed and Re**  **commended Tolerances for Fluxapyroxad Crop Group or**  **Comm odity**  **Proposed**

**Tolerance (ppm)**  **Recommended**

**Tolerance (ppm) Comments;**  **Correct Commodity Definition**

so it is not needed. Beet, sugar -- 0.1 Although there are not sufficient data to establish a tolerance on crop group 1A, there are no data deficiencies that would preclude the unconditional registration of sugar beets. Beet , sugar, dried pulp 0.16 0.1 Beet, sugar , tops 4 7 Cattle, fat 0.1 0.0 5 Rounded to 0.05 ppm. Cattle, kidney 0.01 -- Covered by tolerance in/on meat byproducts Cattle, liver 0.1 -- Covered by tolerance in/on meat byproducts Cattle, meat 0.01 0.01 Cattle, meat byproducts 0.1 0.03 Corn, field, grain 0.1 0.01 Corn, oil, refined 0.05 0.03 Corn, oil Corn, pop, grain -- 0.01 Separate tolerance is needed because there is mo re than a 10x difference between the needed tolerance and the crop group tolerance. Corn, sweet, kernels plus cobs with husks removed -- 0.015 Separate tolerance is needed because there is mo re than a 10x difference between the needed tolerance and the crop group tolerance. Cotton , undelinted seed 0.01 0.01 Cotton , gin byproducts 0.01 0.01 Egg 0.01 0.002 F ruit , pome, group 11 0.7 0.8 F ruit , stone, group 1 2 1.4 2 G oat, fat 0.1 0.05 G oat, kidney 0.01 -- Covered by tolerance in/on meat byproducts G oat, liver 0.1 -- Covered by tolerance in/on meat byproducts Goat , meat 0.01 0.01 G oat , meat byproducts 0.1 0.03 Grain, aspirated fractions 16.0 6 Grain, cereal, group 15, except field corn grain 2.5 3 Grain, cereal, group 15 (except field corn , except wheat

) More than 10x difference: wheat 0.3 ppm, sorghum 0.7 ppm, barley 2 ppm, rice 3 ppm, sweet corn 0.15 ppm; wheat will be excluded from crop group as well. Grain, cereal, forage, fodder and straw , group 16 25 20 More than 10x difference

– corn forage 2 ppm, corn stover 5 ppm, wheat forage 10 ppm, wheat hay 15 ppm, wheat straw , 15 ppm, sorghum forage 4 ppm, stover 2 ppm, barley hay 15 ppm , barley straw 20 ppm, rice straw 2 ppm . However, crop group tolerance will be set as is. Hog, fat 0.01 -- Swine, fat

– not needed

– Category 3 Hog, liver 0.01 -- Swine, liver

– not needed

– Category 3 Hog , meat 0.01 -- Swine, meat

– not needed

– Category 3

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**Table 1. Proposed and Re**  **commended Tolerances for Fluxapyroxad Crop Group or**  **Comm odity**  **Proposed**

**Tolerance (ppm)**  **Recommended**

**Tolerance (ppm) Comments;**  **Correct Commodity Definition** Hog, meat byproducts 0.01 -- Swine, meat byproducts

– not needed

– Category 3 H orse, fat 0.1 0.05 Horse , kidney 0.01 -- Covered by tolerance in/on meat byproducts Horse , liver 0.1 -- Covered by tolerance in/on meat byproducts Horse , meat 0.01 0.01 Horse , meat by

products 0. 1 0.03 Milk 0.02 0.005 Milk, fat 0.1 -- A milk tolerance was established to harmonize with PMRA. A milk fat tolerance is/is not required because milk fat is account for through the milk tolerance. Oilseeds, group 20 0.6 0.9 Highest residue in canola was 0.84 ppm, rounded to 0.9 ppm Peanut 0.02 0.01 Peanut , refined oil 0.06 0.02 Peanut, meal 0.03 -- Not needed, only 1.5x concentration Plum, prune 4 3 Potato, wet peel 0.2 0.1 Poultry, byproducts 0.01 -- Not needed

– estimated residues more than 10x lower than LOQ (Category 3) Poultry , fat 0.01 -- Not needed

– estimated residues more than 10x lower than LOQ (Category 3) Poultry , liver 0.01 -- Not needed

– estimated residues more than 10x lower than LOQ (Category 3) Poultry , meat 0.01 -- Not needed

– estimated residues more than 10x lower than LOQ (Category 3) Poultry, skin 0.01 -- Not needed

– estimated residues more than 10x lower than LOQ (Category 3) Rapeseed, (cultivars/varieties and/or hybrids including canola and crambe 0.60 -- not needed, included in oilseeds, group 20 Rice, bran 4.5 4.5 Rice hull s 10 8 Rice, hulls S heep, fat 0.1 0.03 S heep, kidney 0.01 0.01 Covered by tolerance in/on meat byproducts S heep, liver 0.1 0.02 Covered by tolerance in/on meat byproducts S heep , meat 0.01 0.01 Sheep, meat by

products 0.1 0.03 Soy bean, hulls 6.5 0.3 Soy bean , seed 0.2 0.15 Sunflower, seed 0.6 0 -- Not needed, included in oilseed, group 20 Vegetable, Foliage of legume , group 7 18 30 V egetables , Fruiting, 0.6 0.7

### Page 10 of 83

**Table 1. Proposed and Re**  **commended Tolerances for Fluxapyroxad Crop Group or**  **Comm odity**  **Proposed**

**Tolerance (ppm)**  **Recommended**

**Tolerance (ppm) Comments;**  **Correct Commodity Definition** group 8 Vegetable, l egume , dried shelled (except soybean) subgroup 6C 0.35 0.4 Pea and bean, dried shelled, except soybean, subgroup 6C Vegetable, legume, edible podded, subgroup 6A 1.4 2 Vegetable, legume, succulent shelled, subgroup 6B 0.45 0.5 Pea and bean, succulent shelled, subgroup 6B Vegetable, root, subgroup 1A 0.1 -- Beet, sugar. Data was only submitted for sugar beets. No data were submitted for the other two representative commodities of the crop subgroup (carrot and radish). A crop subgroup tolerance is not possible. Field trial data for carrot and radish are also required to establish a crop group tolerance. Vegetable, tuberous and corm, subgroup 1C 0.04 0.02 Vegetable, tuberous and corm, except potato, subgroup 1 D 0.04 -- Tolerance on this subgroup is not needed since all commodities are included in subgroup 1C Wheat, bran 6 0.6 Wheat, germ 3 -- Not needed, concentration is only 1.5x Wheat, grain -- 0.3 Tolerance is set separately from crop group tolerance because residues in wheat grain are mo re than 5x lower than the highest residue. 

### 2.2.4 **Revisions to Petitioned -**  **For Tolerances** As noted in section 2.2.3 HED has recommended for different tolerances than proposed by the registrant. HED has used the OECD calculator to determine the appropriate tolerances. **2.3 Label Recommendations**  The label must be revised to delete use on root and tuber vegetables , subgroup 1A. Only use on sugar beets from subgroup 1A is allowed. The petitioner must clarify the PHI for peanuts . The 365 day

plant back interval must remain on the label.

### 3 **.0 INGREDIENT PROFILE** 

**3 .1**  **Chemical Identity TABLE**  **2 .**  **Fluxapyroxad Test Compound Nomenclature.** Chemical structure

Common name Fluxapyroxad (ISO, proposed) Company experimental name BAS 700 F IUPAC name 3 - (difluoromethyl) CAS name 3 - (difluoromethyl) carboxamide CAS # 907204 Molecular Formula C 18 H 12 End -use product/EP Xemium Technical, BAS 700 01F, BAS 700 02F, BAS 700 03F, BAS 700 04F 

### 3.2 **Physical/Chemical Characteristics** A detailed description of the physiciochemical properties of fluxapyroxad is provided in Appendix C. Fluxapy

roxad exhibits relatively

low solubility

in water and higher solubility in organic solvents. It has a v ery low vapor pressure persistent in terrestrial and aquatic environments and is moderatel y to slightly mobile in soil. Fluxapy roxad does not present significant concerns for bioaccumulation based on the lipophilicity

of the compound and on results of bioconce **3.3 Pesticide Use Pattern**  Fluxapy roxad is a fungicide belonging to the carboxamide class of chemicals. I t is a new active ingredient proposed for use on a wide range of crops to control a broad spectrum of fungal diseases. P roduct registrations and proposed use patterns and form Table 3.

Page 11 of 83 **INGREDIENT PROFILE**
**Fluxapyroxad Test Compound Nomenclature.**

Fluxapyroxad (ISO, proposed) BAS 700 F (difluoromethyl) - 1 - methyl -N - (3 ′,4 ′,5 ′ - trifluorobiphenyl - 2 - yl)pyrazole (difluoromethyl) - 1 - methyl -N - (3',4',5' - trifluoro[1,1' - biphenyl] - 2 - yl) - 1 carboxamide 907204 - 31 - 3 12 F 5 N 3 O Xemium Technical, BAS 700 01F, BAS 700 02F, BAS 700 03F, BAS 700 04F 

### Physical/Chemical Characteristics A detailed description of the physiciochemical properties of fluxapyroxad is provided in Appendix C. Fluxapy

roxad exhibits relatively

low solubility

in water and higher solubility in ery low vapor pressure ( 6.1 x 10 - 11 

### Torr at 25  ̊ C ) . Fluxapy roxad is persistent in terrestrial and aquatic environments and is moderatel y to slightly mobile in soil. Fluxapy roxad does not present significant concerns for bioaccumulation based on the lipophilicity

of the compound and on results of bioconce ntration studies in fish. Fluxapy roxad is a fungicide belonging to the carboxamide class of chemicals. I t is a new active ingredient proposed for use on a wide range of crops to control a broad spectrum of fungal

roduct registrations and proposed use patterns and form ulations are provided in yl)pyrazole - 4 - carboxamide 1 H - pyrazole - 4 -

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

### A detailed description of the physiciochemical properties of fluxapyroxad is provided in Appendix C. Fluxapy

roxad exhibits relatively

low solubility

in water and higher solubility in Fluxapy roxad is persistent in terrestrial and aquatic environments and is moderatel y to slightly mobile in soil. Fluxapy roxad does not present significant concerns for bioaccumulation based on the Fluxapy roxad is a fungicide belonging to the carboxamide class of chemicals. I t is a new active ingredient proposed for use on a wide range of crops to control a broad spectrum of fungal lations are provided in

### Page 12 of 83

**Table 3. Summary of Directions for Use of Fluxapyroxad Applic. Timing,**  **Type, and Equip. Form** **ulation Applic. Rate**  **(lb ai/A) Max. No.** 

**Applic. per Season**  **Max. Seasonal**

**Applic. Rate (lb ai/A)**  **PHI**

**(days) Cereal Grains**  Foliar spray Ground, Aerial or Chemigation 5.96% EC 26.55% EC 21.26% EC 14.33% EC 0.09 2 0.18 21 Use Directions and Limitations: A minimum 7 - day RTI is specified. Applications may be begin at emergence, but typical applications begin as plants touch across rows. A 7 day PHI is allowed for sweet corn only. Seed Treatment 28.7% SC 0.01 Not provided Not applicable Not applicable Use Directions and Limitations: Rate is expressed in lb ai/100 lb seed. Apply in enough water to ensure adequate coverage, but without damaging the seed. A higher rate of 0.02 lb ai/100 lb seed is allowed on sweet corn and sorghum seed. A higher rate of 0.05 lb ai/100 lb seed is allowed on wheat seed. **Cotton , Sunflower**  Seed Treatment 28.7% SC 0.0103 Not provided Not applicable Not applicable Use Directions and Limitations: Rate is expressed in lb ai/100 lb seed. Apply in enough water to ensure adequate coverage, but without damaging the seed. A higher rate of 0.02 lb ai/100 lb seed is allowed on sweet corn and sorghum seed. A higher rate of 0.05 lb ai/100 lb seed is allowed on wheat seed. **Oilseeds, Dried Shelled Peas, Soybeans** Foliar spray Ground, aerial or chemigation 5.96% (0.52 lb/gal) EC 26.55% (2.47 lb/gal) EC 21.26% (2.09 lb/gal) EC 14.33% (1.39 lb/gal) EC 0.09 2 0.18 7 Use Directions and Limitations: A minimum 7 - day RTI is specified. Applications may be begin at emergence, but typical applications begin as plants touch across rows. DO NOT harvest for forage, green chop, vines, or hay within 7 days of last application (14 days for 1.39 and 2.09 lb/gal EC). Do not feed soybean hay for 14 days after application (21 days for 2.09 lb/gal EC). No livestock feeding restrictions for oils eeds. **Dried Shelled Beans** Foliar spray Ground, aerial or chemigation 5.96% (0.52 lb/gal) EC 26.55% (2.47 lb/gal) EC 21.26% (2.09 lb/gal) EC 14.33% (1.39 lb/gal) EC 0.18 2 0.36 7 Use Directions and Limitations: A minimum 7 - day RTI is specified. Applications may be begin at emergence, but typical applications begin as plants touch across rows. DO NOT harvest for forage, green chop, vines, or hay within 7 days of last application (14 days for 1.39 and 2.09 lb/gal EC). **Edible Podded Legume Vegetables, Succulent Shelled Beans and Peas** Foliar spray Ground, aerial or chemigation 5.96% (0.52 lb/gal) EC 26.55% (2.47 lb/gal) EC 21.26% (2.09 lb/gal) EC 14.33% (1.39 lb/gal) EC 0.09 2 0.18 7 Use Directions and Limitations: A minimum 7 - day RTI is specified. Applications may be begin at emergence, but typical applications begin as plants touch across rows. DO NOT harvest for forage, green chop, vines, or hay within 7 days of last application (14 days for 1.39 and 2.09 lb/gal EC).

**Fruiting Vegetables Group, Sugar Beets, Tuberous & Corm Vegetables Subgroup**  Foliar spray 5.96% (0.52 lb/gal) EC 0.09 3 0.27 7

### Page 13 of 83

**Table 3. Summary of Directions for Use of Fluxapyroxad Applic. Timing,**  **Type, and Equip. Form** **ulation Applic. Rate**  **(lb ai/A) Max. No.** 

**Applic. per Season**  **Max. Seasonal**

**Applic. Rate (lb ai/A)**  **PHI**

**(days)** Ground, aerial or chemigation 26.55% (2.47 lb/gal) EC 21.26% (2.09 lb/gal) EC 14.33% (1.39 lb/gal) EC Use Directions and Limitations: A minimum 7 - day RTI is specified (14 days for sugar beets). Apply a minimum of 20 gallons of spray volume per acre, and increase the spray volume as the plants grow during the season. Spray volume should be proportional to the amount of plant tissue to be covered such that 100 gallons of spray per acre is used on mature plants. DO NOT make more than two (2) consecutive applications of fluxapyroxad before alternating to a labeled fungicide with a different mo de of action. Sugar beet leaves, roots and tops may be fed no sooner than 7 days after last application. Use of the 2.09 lb/gal EC on sugar beets is not permitted. **Peanut** Foliar spray Ground, aerial or chemigation 5.96% (0.52 lb/gal) EC 26.55% (2.47 lb/gal) EC 14.33% (1.39 lb/gal) EC 0.09 3 0.27 7 Use Directions and Limitations: A minimum 14 - day RTI is specified. DO NOT make more than two (2) consecutive applications of fluxapyroxad before alternating to a labeled fungicide with a different mode of action. Do not graze or harv est for peanut forage. The 1.39 lb/gal EC label states that a 7 day PHI is required in the crop specific use directions, and 14 d ays in the overview table. **Pom e Fruit Group**  Foliar spray Ground, aerial or chemigation 5.96% (0.52 lb/gal) EC 26.55% (2.47 lb/gal) EC 21.26% (2.09 lb/gal) EC 14.33% (1.39 lb/gal) EC 0.09 4 0.36 0 Use Directions and Limitations: Do not use less than 10 gallons of spray solution per acre. A minimum 7 - day RTI is specified. DO NOT make more than two (2) consecutive applications of fluxapyroxad before alternating to a labeled fungicide with a different mode of action. No restriction on livestock grazing or feeding. **Stone Fruit Group** Foliar spray Ground, aerial or chemigation 5.96% (0.52 lb/gal) EC 26.55% (2.47 lb/gal) EC 21.26% (2.09 lb/gal) EC 14.33% (1.39 lb/gal) EC 0.11 3 0.33 0 Use Directions and Limitations: Do not use less than 10 gallons of spray solution per acre. A minimum 7 - day RTI is specified. DO NOT make more than two (2) consecutive applications of fluxapyroxad before alternating to a labeled fungicide with a different mode of action. 

### 3.4 **Anticipated Exposure Pathways** Dietary (food and water) and occupational exposures via dermal and inhalation pathway s are expected based on proposed uses of fluxapy roxad on a variety of food commodities . Acute and chronic dietary exposure and risk assessment s were conducted for the proposed uses. HED assessed occupational exposure and risk from proposed uses of fluxapy roxad for seed and foliar applications on cereal grains, sorghum, legume vegetables (succulent and dry), oil seed crops (canola and sunflower), peanuts, pome fruit, stone fruit, root and tuber vegetables (potatoes and sugar beets), fruiting vegetables, and cotton. Worker exposures were assessed for handler and

### Page 14 of 83

post - application activities. There are no residential uses for fluxapy roxad so residential exposure to children via incidental oral activities is not anticipated. **3.5 Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 128 98, "Federal Actions to Address Environmental Justice in Minority Populations and Low - Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ). As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy , HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Whenever appropriate, non - dietary exposures based on home use of pesticide products and associated risks for ad ult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development, as OPP has committed resources and expertise to the development of specialized so ftware and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. **4 .0**  **HAZARD CHARACTERIZATION/ASSESSMENT 4.1**  **Toxicology Studies Available for Analysis** An extensive toxicity

database for fluxapy

roxad was submitted to the Agency for registration of fluxapy

roxad . Submitted studies via the oral route cover durations and endpoints relevant for hazard characterization for acute and chronic dietary assessments. These studies include metabolism and pharmacokinetic studies, subchronic and chronic dietary studies in rats, mice, and dogs; prenatal developmental studies in rats and rabbits, a 2 - generation reproduction and fertility

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

study in mice, a complete battery of in vitro and in vivo genotoxicity studies, and carcinogenicity studies in rats and mice. Supplemental studies were submitted to further investigate the mode of action of fluxapy roxad on the liver and thyroid. These studies, together with a dermal toxicity

study and dermal penetration study , are also appropriate for hazard characterization for short - term to intermediate - term exposures via the dermal route. Occupational exposures are also anticipated via the inhalation route, but no subchronic inhalation study was submitted. Therefore, extrapolation from oral studies appropriate for short - term to intermediate - term exposures will be used for inhalation hazard characterization. A subchronic inhalation study

is not required at this time. There are no toxicity studies availabl e for fluxapy roxad in the general literature, as it is a new active ingredient. Acute toxicity

studies (acute oral, dermal, and inhalation studies in rats, eye irritation and dermal irritation studies in rabbits, and a skin sensitization study in guinea pigs) were also

### Page 15 of 83

submitted for each formul ation for labeling purposes that can also inform hazard characterization. There are three metabolites of fluxapy roxad: two soil metabolites (M700F001 and M700F002) and a metabolite found on food crops (M700F04 8). There are no toxicity studies of these metabolites in the general literature. However, subchronic dietary studies in rats, prenatal developmental studies in rabbits, and a complete battery of in vitro and in vivo genotoxicity studies were submitted to the Agency for these metabolites. Metabolism and pharmacokinetic studies were also submitted for the M700F048 plant metabolite. These studies are sufficient for hazard characterization. **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  Pharmacokinetic and metabolism studies with radiolabeled fluxapy roxad in rats show that plasma levels of radiolabel scaled with dose, indicating that uptake was not saturated up to dose levels of 500 mg/kg. There were no sex differences observed in the rate or extent of absorption. The time to peak plasma levels (tMAX

### ) was dependent upon on dose, and ranged from 1 hour (at 5 mg/kg) to 24 hours (at 500 mg/kg) with maximum mean plasma concentrations (C MAX

### ) 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 m g/kg) in males/females. Mass balance, tissue distribution and biliary excretion studies were performed in rats at doses of 150 mg/kg and 7.5 mg/kg. These studies indicated that radioactivity was widel y distributed in both sexes within 16 hours, with bi oavailability 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, thy roid, 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 fec es indicated the excretion occurred predominantl y within three day s 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 ex creted 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. Resid ue chemistry

studies in ruminants indicated that fluxpy roxad and metabolites are excreted in milk. Metabolism studies revealed that the main biotransformation steps of BAS 700 F in rats are hydrox yl ation at the biphenyl ring s ys tem (sometimes repeatedl y) , N - demethylation at the py razole ring s ys tem, loss of a fluorine atom at the biphenyl ring s ys tem, and conjugation with glucuronic acid or sulfate, and conjugation with glutathione derivatives. These reactions produced approximately

51 different metaboli tes. Minor biotransformation steps produced

### Page 16 of 83

additional metabolites, including M700F001 (from hydrol ys is of the amide bond between the py razole and biphenyl rings) and M700F002 (from N - demethyl ation 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 M 700F001 or impurities. Pharmacokinetic studies in rats showed that the soil metabolite M700F002 was sy stemically 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 sy stemic bioavailability with distribution to the bone marrow, blood, and liver after administration via th e oral route. Excretion was primaril y 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 fluxapy roxad and py

raclostrobin (BAS 500F). The Agency calculated a dermal absorption factor of 8.4% at dose of 5.6 μg/cm2 

### for potential use in future risk assessments. **4.3 Toxicological Effects**  In mammals, the primary target organ for fluxapy roxad exposure via the oral route is the liver. Liver toxicity

in response to fluxapy

roxad via the oral route was observed in several species: rats, mice, and dogs. The sensitivity to liver toxicity

and the development and manifestations of liver toxicity over time varied with species. In rats, the most sensitive species, adaptive effects of hepatocellular hypertrophy and increased liver weights and changes in liver enzy me activities were first observed. As the dose or duration of exposure to fluxapy roxad increased, clinical chemistry changes related to liver function were observed, followed by hepatocellular necrosis and neoplastic liver changes (foci, masses), which were considered adverse effect s . Liver toxicity was also observed in mice and dogs. In subchronic studies in mice, increased liver weights were observed along with fatty changes in the liver, with few observations of hepatocellular hy pertrophy . At higher doses, liver necrosis was also observed. Liver effects in subchronic studies in dogs were limited to incre ased liver weights at high doses. However, in chronic studies, increased liver weights were observed in conjunction with fibrosis and cirrhosis . Fluxapy roxad administration via the oral route resulted in toxic effects in the thy roid. These thyroid effects occurred secondary to the effects on the liver and were seen onl y in rats. Thy roid effects in rats were observed throughout the toxicity datab ase and included changes in serum thy roid hormone levels, enlarged thy roid, increased thyroid weights, and/or microscopic effects of thyroid follicular hypertrophy and hyperplasia. These effects showed a clear threshold, were evident within weeks and were observed out to two years. Although these effects were observed in male and female rats, males were usually more sensitive. Threshold doses at which thy roid effects occurred in the rat were accompanied by changes in the liver that were considered adaptive or potentiall y adverse. These changes included increased liver weights, hepatocellular hy pertrophy , and changes in liver- associated clinical chemistry parameters. These results

### Page 17 of 83

suggested that the effects in the thy roid were secondary

to fluxapy

roxad - induced changes in thy roid hormone metabolism by the liver and not due to direct action of fluxapy roxad on the thy roid. Supplementary

studies (including a perchlorate discharge assay and measurement of T 4 

### - metaboilizing Phase II enzy me activities) confirmed indirect thy roid effects. The most sensitive of these thyroid effects are perturbations in thy roid hormone levels, which occur temporally before histopathological alternations in the thy roid. Chronic oral administration of fluxapy roxad resulted in tre atment - related liver tumors in male and female rats and thy roid 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 assay s, and no evidence of chromosomal damage was observed in a guideline mouse ery

throcy te micronucleus study in vivo . Together, these data indicated that the thy roid 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 thy roid tumors also indicated clear thresholds protective for tumorgenic effects. Although the primary effects of oral fluxapy

roxad exposure were on the thy roid and liver, effects in other organ s ys tems 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 moto r 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 g eneral malaise. There were no neurotoxic effects observed in the subchronic dietary toxicity study . Fluxapy

roxad did not cause reproductive toxicity in rats. Developmental toxicity in rats was limited to decreased body weight and body

weight gain in of

fspring and was observed at the same dose levels that caused thyro id dy sregulation in parental animals. Developmental toxicity

in rabbits was limited to paw hy perflexion, a malformation that usually reverses as the animal matures, and was observed at the s ame dose levels that caused reduced maternal body weight. There were clear NOAELs for these developmental effects. An unusual effect of tooth whitening was observed was observed in rats in several studies. This effect was observed with increasing oral doses of fluxapy roxad. 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 depos ition of Perl’s Prussian Blue stain (indicative of iron) in other bone tissues. These effects in the teeth and bones suggested treatment - related changes in iron storage, but there was no evidence of microscopic damage to these tissues or clinical evidence of compromised tissue function. . The Agency considered the potential for flurosis to result from any fluoride released during metabolism of fluxpyroxad. The Agency concluded that it is unlikely that fluxapy

roxad would cause fluorosis because detailed histopathological evaluation of the teeth did not show changes consistent withfluorosis at the highest dose in parental and F1 males of the rat 2 - generation reproduction and fertility effects study .

### Page 18 of 83

Immunotoxicity

was investigated via the oral route in male mice. No immunotoxic effects of fluxapy

roxad were observed at doses up to and including the limit dose. A dermal toxicity

study in rats was the onl y route - specific study that was submitted for occupational assessments. No toxic effects of fluxapy roxad were observed at doses up to and including the limit dose. Acute toxicity

studies show that fluxapy roxad 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 fluxapy roxad metabolites F700F001, M700F002, and M700F048. The Agency con siders these studies sufficient for hazard identification and characterization. Like fluxapy roxad, no genotoxic effects were observed for any of these metabolites. All three metabolites displayed lower subchronic toxicity via the oral route than fluxapy

roxad, with evidence of non - specific toxicity (decreased body

weight) observed onl y for M700F0048 at the limit dose. Only M700F0048 exhibited developmental toxicity at doses similar to those that caused developmental effects in rabbits with fluxapy roxad treatment. However, these effects (abortions and resorptions) were of a different nature than for fluxapy roxad (paw hyp erflexion) and are likel y secondary to maternal toxicity. These data are sufficient for the Agency to conclude that these metabolites do not have hazards that exceed those of fluxap y

roxad in nature, severity , or potency . The complete toxicity

profile for fluxapy

roxad 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 fluxapy roxad on thy

roid ho rmones, and no residual uncertainties in the exposure data base. The information used to reduce uncertainties in hazard and exposure of infants and children is described in detail below. **4.4.1 Completeness of the Toxicology Database**  The Agency

considers the toxicity

database used to characterize the hazards of fluxapy roxad 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 fluxapy

roxad. Inaddition to these lifestage - specific studies, a full toxicity database of guideline and supplemental studies available in adult animals to evaluate neurotoxicity, immunotoxicity, genotoxicity , and thyroid effects.

### Page 19 of 83

**4.4.2 Evidence of**  **Neurotoxicity** Acute and subchronic neurotoxicity studies are available for fluxapy roxad. Treatment related effects of decreased rearing and motor activity were observed onl y 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 fluxapy

roxad. Ho wever, the Agency has considered the potential for fluxapy

roxad to cause developmental neurotoxicity as a result of thy

roid hormone disruption, which is more sensitive than the endpoints used in a developmental neurotoxicity study . The Agency

has evaluate d supplemental thy roid hormone data submitted by the registrant and considered the ontogeny of thy roid 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 fluxapy roxad at any life stage. **4.4.3 Evidenc**  **e 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 ob served at the same dose levels that caused thyroid follicular hypertrophy/hy perplasia in parental animals. However, low birth weights, which can result from thy

roid dy sregulation 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 hy perflexion, 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 significantl y 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 likel y secondary

to matern al toxicity, and demonstrated clear NOAELs . Nonetheless, the risk assessment is protective of paw hyp erflexion because this effect occurs at dose levels higher than the points of departure selected for risk assessment for repeat - exposure scenarios . **4.4.4 Resid**  **ual 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 fluxapy

roxad. There are no residential uses proposed for fluxapy roxad.

### Page 20 of 83

**4.5 Toxicity Endpoint**  **and Point of Departure Selection**  **4.5.1 Dose**  **- Response Assessment**  Acute and chronic dietary endpoints were selected from acute, subchronic, and chronic oral toxicity

studies in the database for fluxapy roxad. The endpoint of decreased motor activity and decreased rearing identified in the acute neurotoxicity study in rat s was chosen for the acute dietary endpoint because it is clearly adverse and clearl y results from a single exposure. Paw hy perflexion was not considered to be a single - dose effect and thus was not selected for an acute endpoint. No other endpoints in th e toxicity database for fluxapy

roxad 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. Th e duration of exposure in this study is appropriate for a chronic dietary endpoint and the point of departure at this endpoint is protective for all adverse effects in rats and other species that occur at higher doses and/or for shorter durations of exposure. There are no residential uses for fluxapy roxad and so residential risks will not be assessed. However, endpoints were chosen for occupational exposure scenarios. A dermal toxicity study was selected for short - term and intermediate - term dermal scenarios because it is a route - specific study

that also assessed all of the endpoints used in the other exposure scenarios and durations of exposure (e.g. neurological endpoints, thyroid and liver histopathology). Although developmental toxicity was not asses sed in the dermal toxicity study , the Agency

has low concern for developmental toxicity because the only

observed effect, paw hy

perflexion, was likely secondary

to maternal toxicity

and is not considered severe, since this effect is usually reversible as the animal matures. No hazard was identified at the limit dose in the dermal toxicity study . No inhalation studies were available for short - term and intermediate - term inhalation scenarios. Therefore, endpoints from oral studies were evaluated. The endpoint of changes in thyroid hormones and thyroid follicular hypertrophy/hy perplasia from the 28 - day oral study in rats was identified for short - term inhalation. This is the most sensitive endpoint in the most sensitive species for an adverse effect for a duration of exposure ranging from 1 - 30 day s. The endpoint of thyroid follicular hypertrophy/hy perplasia was identified from the 90 day oral toxicity study in rats for intermediate - term inhalation. This endpoint was chosen because the duration of exposure is relevant to a 1 - 6 month intermediate - term exposure and this was the most sensitive endpoint in the most sensitive species. Although thyroid hormones were not measured in the dermal study , calculation of dermal equivalency dose from the developmental study and dermal absorption data indicates that a dermal endpoint is not required for this effect. **4.5.2 Recommendation for Combining Exposure Routes**  Under FQPA, when there are potential residential exposures to a pesticide, HED must aggregate exposures fro m three major sources: oral, dermal and inhalation exposures. These combined residential exposures must then be aggregated with exposure from food and water to determine aggregate risk. Since there are no residential incidental oral exposures to fluxapy roxad , aggregate exposure from food and non - food oral exposures is not required.

### Page 21 of 83

**4.5.3 Cancer**  **Classifi cation**  Tumors related to fluxapyroxad treatment were observed in the liver of male and female rats and in the thyroid in male rats onl y. Males were more sensitive than females to the tumorgenic effects of fluxapy roxad in the liver. The combined incidence of liver adenomas and carcinomas in males ranged from 10% at 11 mg/kg bw/day to 43% at 145 mg/kg bw/day compared to 2% in controls. For females, the combined incidence of adenomas and carcinomas ranged from 8% at 82 mg/kg bw/day to 14% at 182 mg/kg bw/day compared to 2% in controls. Dose and temporal concordance data supported a non - genotoxic mitogenic MOA for liver adenomas and carcinomas in rats. This MOA is based on earl y changes in liver enzyme regulation and increased cell proliferation that lead to micro scopic and macroscopic foci and then to adenoma and carcinoma formation. The endpoint of changes in liver enzy me 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 thy roid follicular adenomas and carcinomas in male rats ranged from 15% at 68 mg/kg bw/day to 18% at 145 mg/kg bw/day compared to 5% in controls. Dose and temporal concordance data supported a MOA for thy roid tumo rgenesis in rats in which early

changes in liver enzy

me regulation lead to dy sregulation of thy roid hormone homeostasis, thy

roid follicular hypertrophy/hy perplasia, and thy

roid tumors. The endpoint of changes in liver enzy

me regulation at 2.1/2.7 mg/kg bw/day in males/females provides a clear threshold for thyroid tumors. In accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment (March, 2005), the CARC classified fluxapy roxad 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 tes ted 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 - relate d thy roid follicular cell tumors were seen in male rats only at doses > 1500 ppm (68 mg/kg/day) ; (iv) There is no mutagenicity concern from in vivo or in vitro assays; (v) The hy

pothesized mode of action (i.e, a non - genotoxic) for each tumor typ e (i.e., the liver and thy

roid) was supported by

adequate studies that clearl y identified the sequence of key

events, dose - response concordance and temporal relationship to the tumor ty pes. The mode of action met the criteria established by the Agency. The Agency does not have cancer concerns for workers because the proposed use patterns indicate that workers will not be expos ed to fluxapyroxad for long enough periods at levels sufficient to induced liver and/or thyroid tumors.

### Page 22 of 83

**4.5.4 Summary of**  **Points of Departure Used in**  **Risk Assessment** Toxicological doses/endpoints selected for the fluxapy roxad risk assessment are provided in Tables 4 and 5 . **Table 4**  **. Summary of Toxicological Doses and Endpoints for Fluxapyroxad for Use in Dietary and Non**   ** Occupational Hum** **an Health Risk Assessments**  **Exposure/ Scenario Point of** 

**Departure Uncertainty/** 

**FQPA Safety Factors**  **RfD, PAD, Level**

**of Concern for Risk Assessment**  **Study and Toxicological Effects** Ac ute Dietary (General Population, including Infants and Children and Females 13 - 49 years of age) NOAEL= 125 mg/kg/day UF A= 10 x

UF H=10 x FQPA SF= 1x Ac ute RfD = 1.25

mg/kg/day aPAD= 1.25 mg/kg/day Ac ute neurotoxicity study in rats

LOAEL = 500 mg/kg/day based on decreased motor activity (both sexes) and decreased rearing (males only) Chronic Dietary (All Populations) NOAEL= 2.1 mg/kg/day UF A= 10 x

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

0.021 mg/kg/day cPAD = 0.021 mg/kg/day Chronic toxicity/carcinogenicity study

in rats LOAEL = 11 mg/kg/day based on non - neoplastic changes in the liver (foci, masses) Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans at doses sufficient to induce liver and/or thyroid tumors. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOA=mode of action. **Table 5. Summary of Toxicological Doses and Endpoints for Fluxapyroxad for Use in Occupational Hum an**  **Health Risk Assessments Exposure/**  **Scenario Point of** 

**Departure Uncertainty** 

**Factors Level of**  **Concern**

**for Risk Assessment**  **Study and Toxicological Effects** Dermal Short Term (1 - 30 days) NOAEL=

1000 mg/kg/day UF A=10x

UF H=10x NA: No hazard

identified 28 - day dermal toxicity study in rats

LOAEL = Not observed Dermal Intermediate Term (1 - 6 mo nths) NOAEL=

1000 mg/kg/day UF A=10x

UF H=10x NA: No hazard

identified 28 - day dermal toxicity study in rats

LOAEL = Not observed Inhalation Short - Term

(1 - 30 days) NOAEL=

9 mg/kg/day UF A=10x

UF H=10x Occupational

LOC for MOE = 100 28 - day oral toxicity study in rats

LOAEL = 176 mg/kg/day based on changes in thyroid hormones and thyroid follicular hypertrophy/hyperplasia Inhalation Intermediate term (1 - 6 mo nths) NOAEL=

7.3 mg/kg/day UF A=10x

UF H=10x Occupational

LOC for MOE = 100 LOAEL = 35.1 mg/kg/day based on

thyroid follicular hypertrophy/hyperplasia

### Page 23 of 83

**Table 5. Summary of Toxicological Doses and Endpoints for Fluxapyroxad for Use in Occupational Hum an**  **Health Risk Assessments Exposure/**  **Scenario Point of** 

**Departure Uncertainty** 

**Factors Level of**  **Concern**

**for Risk Assessment**  **Study and Toxicological Effects** Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans at doses sufficient to induce liver and/or

thyroid tumors. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable. 

### 5.0 **DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT 5.1**  **Metabolite/Degradate Residue Profile 5.1.1**  **Summary of Plant and Animal Metabolism Studies** The nature of the residue in plants and animals is adequatel y understood . Fluxapy roxad metabolism studies were conducted using an aniline label and a p yrazole label in soy beans, 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 fluxapy roxad parent. Metabolite residues to be included in the risk assessment are M700F008 and M700F010 for milk residues only . **5.1.2 Summary of Environmental Degradation**  Fluxapy roxad does not readily

undergo aerobic or anaerobic degradation in soil, with half - lives ranging from 213 to 1,827 day s. In terrestrial field dissipation studies, dissipation halflives ranged from 17 to 436 day s and fluxapy roxad was detected infre quently below the top 6 inches of the soil . Fluxapy roxad is moderatel y to slightly mobile based on adsorption KOC 

### values ( 496 to 1,424 mL/g oc 

### ) in studies conducted on U.S. and foreign soils. Fluxapy roxad is stable to hydrol ys is (pH values of 5, 7 and 9) and to soil and aqueous photoly sis. Fluxapy roxad has the potential to leach to ground water, particularl y where high water tables are present, high rainfall/irrigation occurs, and where sandy soils with low organic matter exist. As previously noted , fluxa

py roxad was detected infrequentl y at depths greater than 6 inches in terrestrial field dissipation studies . However, given its persistence and mobility , the terrestrial field dissipation studies, which only

lasted a maximum of 472 days, may not have been long enough to capture leaching over time. Fluxapy roxad does not readily

undergo aerobic or anaerobic degradation in aquatic s ys tems, with half - lives of 420 to 731 days. Fluxapy roxad is not expected to volatilize (vapor pressure 6.1 x 10 - 11 

### Torr at 25  ̊ C ). It will not likely bioaccumulate based on results of bioconcentration studies in fish.

### Page 24 of 83

**5.1. 3**  **Compa r** **ison of Metabolic Pathways** Submitted data shows that fluxapy roxad is metabolized mainly by hydroxylation at the biphenyl moiety (sometimes repeatedly), loss of a fluorine atom at the biphenylring (presumabl y by substitution with a hydroxyl - group), N - demethylation at the py razole moiety , hydrol ys is 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 fluxapy

roxad is similar in primary and rotational crops but with some variation in metabolite levels. In general, the parent compound is the main residue f ollowed by

the metabolites M700F008, M700F002 and M700F048. For livestock, the parent, M700F008, M700F005, M700F004, M700F010 and dimer of the parent were observed as major residues in fat, muscle, milk, liver, kidney and/or egg commodities. In the rat, the parent was the main residue followed b y M700F008, and their corresponding metabolites hydrox yl ated in the biphenyl moiety (M700F009, M700F005, and M700F006). Other reactions led to the formation of a large number of minor metabolites. Metabolite str uctures are provided in Appendix B. **5.1. 4**  **Residues of Concern Summary and Rationale** HED has concluded that the residue of concern for tolerance expression for all commodities is parent only based on the recommendation of the Residues of Concern Knowledgebase Subcommittee (ROCKS) . Although there was concern expressed about metabolites in livestock commodities (particularly M700F008 being present at greater levels than parent in most matrices), for tolerance setting the parent compound alone is adequate as an indicator for misuse. The ROCKS recommend ed inclusion of parent fluxapy roxad and M700F008 for risk assessment for primary

and rotational crops . While the parent is generall y 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. Th e 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 fluxapy roxad and M700F008, M700F002 and M700F048. The metabolite M700F002 was observed as a major residue in rotational spinach onl y 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 met abolites are not likely to be more toxic than the parent. For livestock commodities, except milk, the ROCKS recommended that fluxapy roxad and M700F008 be included for risk assessment purposes based on results from metabolism and feeding studies which sho w that parent fluxapy roxad and M700F008 are the major residues in ruminant and poultry commodities . For milk only, the ROCKS recommended that fluxapy roxad, 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 highl y consumed commodity b y children. M700F010 is

### Page 25 of 83

hydrox yl ated parent and likely to have comparable toxicity to the parent. For water, the ROCKS committee recommended including parent flux apyroxad only in the risk assessment . Parent fluxapy roxad and M700F001 were the only two major residues identified in the environmental fate studies. Although M700F001 was identified as a major degradate , available evidence suggest s that this degradate h as lower toxicity than the parent and will be present in low concentrations relative to the parent in drinking water. **Table 6**  **: Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance**  **Expression Matrix**  **Residues of Concern**  1 **For Risk Assessment For Tolerance Expression**  Plants Primary Crop Fluxapyroxad and M700F008 Fluxapyroxad

Rotational Crop Fluxapyroxad and M700F008 Fluxapyroxad Livestock Ruminant Fluxapyroxad, M700F008 and M700F010 2 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) - 1 H - pyrazole - 4 - carboxamide. M700F008 is 3 - (difluoromethyl) -N - (3 ′,4 ′,5 ′- trifluorobiphenyl - 2 - yl)pyrazole - 4 - carboxamide. M700F010 is 3 - (difluoromethyl) -N - (hydroxy3',4',5' - trifluoro[1,1' - biphenyl] - 2 -yl) - 1H - py razole - 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 trial s conducted in appropriate ly representative locations are available for fluxapy roxad for the majority

of crop applications and use patterns (application rate and PHI) submitted on the label. However, f ield trials on carrot and radish must be submitted in order to allow use on root and tuber vegetables, subgroup 1A. S ubmitted field trial data for fluxapy

roxad on cereal grains, legume vegetables (succulent and dry), oil seed crops (canola and sunflower), peanuts, pome fruit, stone fruit, root and tuber vegetables (potatoes and sugar beets), and fruiting vegetables reflect the use of 2 - 4 fo liar applications of an emulsifiable concentrate formulation. Decline studies were submitted for each commodity , as required. Seed treatment studies for fluxapy roxad on cotton reflect the use of an SC formulation. Adequate c onfined and field rotational c rop data were provided for fluxapy roxad. The field rotational crop studies show finite residues at 30, 60, 90, and 120 day plant back intervals (PBIs) except for wheat, which is also a primary crop . The confined rotational crop studies show no quantifiab le residues at a 365 day

plant back interval. Detailed information on residue data from crop field trials on flux a

py roxad and its metabolites is provided in the Residue Chemistry Chapter . (D 390223 ) **5.2.2 Residues in Meat, Milk, Poultry, and Eggs**  The magnitude of the residue of fluxapy roxad and metabolites M700F002 and M700F008 in dairy

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

cattle and laying hen s. Based on these studies, tolerances are needed for

### Page 26 of 83

cattle meat, fat , milk products and eggs . Tolerances are not needed for cattle liver and kidney or for any poultry tissues because estimated residues are more than 10x lower than the level of quantitation (L OQ). **5 .2.3**  **Residues in Processed Co mmodities**  Processing studies were provided for processed commodities associated with cereal grains, oil seed crops (canola and sunflower), peanuts, pome fruit, stone fruit, root and tuber vegetables (potatoes and sugar beets), and fruiting vegetables. Co ncentration was observed in some processed commodities and tolerances are being set in those commodities (see Table 1). **5.2.4 Storage Stability**  Adequate storage stability data for fluxap yroxad, per se, are available to support the storage conditions and durations of field trial samples for raw agricultural commodities. The available data indicate that residues of fluxapy roxad are relativel y stabl e for up to 24 months in/on apple (fruit), tomato (fruit), triticale (whole plant), soy bean (seed), avocado (fruit), dried pea (seed), cereal (grain), potato (tuber), grape (fruit), lemon (fruit), and wheat (straw) stored at - 20 C. Storage stability

of metabolite M700F008 was investigated for 24 months. Some instability was seen for the metabolite M700F008 in oily and starchy commodities. Residues of M700F008 have been corrected to account for the 57% recovery in the storage stability

studies in oily commodities. **5.3 Water Residue Profile**  Drinking water residues were incorporated directly into the acute and chronic dietary anal ys es as “ water, direct, all sources” and “water, indirect, all sources.” Estimated Drinking Water Concentrations (EDWCs) for fluxapy roxad were provided b y the Environmental Fate and Effects Division (EFED) (D138009, C. Peck, 9/21/11). EFED generated the surface water estimates using the Tier I aquatic model FIRST (FQPA Index Reservoir Screening Tool). Ground water estimates were calculated using the Tier 1 Screening Concentration in Ground Water model (SCI GROW). EDWCs for fluxapyroxad (parent onl y) were derived based on fluxapy roxad use on dry

shelled beans (except soybeans) at 0.18 lbs ai/acre/application, applied 2 times per year with a 7 - day reapplication interval for a maximum total annual application rate of 0.36 lb ai/A/y

r. S 

### urface and groundwater EDWCs for fluxapy roxad are provided in Table 3. E stimated drinking water residues for peak concentration of 0. 014 mg/L (ppm) were used in the acute assessment . Estimated 30 year annual average drinking water concentrations of 0. 0067 mg/L (pp m) were used the chronic assessment . **Table 7**  **. EDWCs for the Fluxapyroxad Human Health Risk Assessment Drinking Water Source**  **Peak (μg/L) Annual Mean**  **(μg/L)** Surface Water 14.1 6.7 Ground Water 0.087 0.087

### Page 27 of 83

**5.4 Dietary and Drinking Water**  **Exposure and Risk** HED conducted screening - level acute and chronic dietary and drinking water exposure and risk assessments using the Dietary Exposure Evaluation Model with the Food Commodity Intake Database (DEEM - FCIDTM). Dietary risk assessment incorporates both exposure and toxicity of a given pesticide. For acute and chronic dietary assessments, the risk is expressed as a percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result in no unreasonable adverse health effec ts). This dose is referred to as the population adjusted dose (PAD). The PAD is equivalent to the reference dose (RfD) divided b y the additional FQPA Safety Factor, if applied. For acute and non - cancer chronic exposures, HED is concerned when estimated dietary

risk exceeds 100% of the PAD. **5.4.1 Acute Dietary and Drinking Water Exposure and Risk**  **Estimates** A conservative acute dietary exposure anal ys is was performed for the general population and all population subgroup s . Tolerance level residues adjusted to account for the metabolites of concern (M700F008, M700F010) and 100 % crop treated assumptions were used. DEEM default and empirical processing factors were used to modify the tolerance values. The acute anal ys is inco rporated the 1 in 10 year peak surface drinking water estimate from application of fluxapy roxad to dry

shelled beans . The resulting 95th percentile acute exposure estimates are not of concern for the general population or for any sub group population. The 95 th 

### percentile acute population adjusted dose (aPAD) for children 1 - 2 years old, the subgroup with the highest risk estimate, is 6 %. The 95 th 

### percentile aPAD for the general population is 2 %. **Table 8. Summary of Acute Dietary Exposure and Risk for Fluxapyroxad**  **Population Subgroup aPAD (m**  **g/kg/day) Acute (95th Percentile)**  **Exposure (mg/kg/day) % aPAD**  General U.S. Population
1. 25 0.023310 2 All Infants (< 1 year old) 0.074082 6 Children 1 - 2 years old 0.068058 5 Children 3 - 5 years old 0.047241 4 Children 6 - 12 years old 0.026755 2 Youth 13 - 19 years old 0.015850 2 Adults 20 - 49 years old 0.016730 1 Adults 50+ years old 0.013855 1 Females 13 - 49 years old 0.014264 1 

### 5.4.2 **Chronic Dietary and Drinking Water Exposure and Risk**  **Estimates** A moderatel y refined chronic dietary exposure analy sis was performed for the general U.S. population and various population subgroups. Highest average field trial (HAFT) residues for parent plus metabolite were used for all plant comm odities. 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 anal ys is. DEEM default and empirical processing factors were used to modify the tolerance values. The chronic anal ys is incorporated the 10 year average surface drinking water

### Page 28 of 83

estimate from application of fluxapy roxad to dry

shelled beans . Chronic dietary risk estimates are not of concern for general population or other population subgroups. The population subgroup with the highest risk estimate is children 1 - 2 years old with a % chronic PAD (cPAD) of 48 %. The % cPAD for the general U.S. population is 1 4 %. **Table 9. Summary of Chronic Dietary Exposure and Risk for Fluxapyroxad**  **Population Subgroup cPAD (m**  **g/kg/day) Chronic**  **Exposure (mg/kg/day) % cPAD**  General U.S. Population
0.022 0.002923 14 All Infants (< 1 year old) 0.008474 40 Children 1 - 2 years old 0.010055 48 Children 3 - 5 years old 0.007369 35 Children 6 - 12 years old 0.004011 19 Youth 13 - 19 years old 0.002217 11 Adults 20 - 49 years old 0.002204 11 Adults 50+ years old 0.002007 10 Females 13 - 49 years old 0.001986 10 

### 6.0 **RESIDENTIAL EXPOSURE/RISK CHARACTERIZATION** A residential assessment is not required because there are no fluxapy roxad products proposed for registration for homeowner use and there are no products proposed for application to residential areas. **6.1 Residential Bystander Postapplication**  **Inhalation Exposure** Based on the Agency's current practices, a quantitative residential b ys tander postapplication inhalation exposure assessment was not performed for fluxapy roxad at this time. However, volatilization of pesticides may be a potential source of postapplication inhalation exposure to individuals nearb y to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may , as appropriate, deve lop policies and procedures, to identify

the need for and, subsequently , the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment for fluxapy

roxad . **6.2 Spray Drift**  Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for fluxapy roxad . The Agency

has been working with the Spray Drift Task Force, EPA Regional

### Page 29 of 83

Offices and State Lead Agencies for pesticide regulatio n and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring int erim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by

the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy

on how to appropriatel y apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast and ground hydraulic methods. After the policy

is in place, the Agency

may impose further refinements in spray drift management practices to reduce off - target drift with specific products with significant risks associated with drift. **7 .0**  **AGGREGATE EXPOSURE/RISK CHARACTERIZATION**  In accordance with the FQPA, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major routes: oral, dermal, and inhalation. There are three sources for these types of exposures: food, drinking water, and residential uses. In an aggregate assessment, exp osures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. The proposed/registered fluxapy roxad uses are not expected to result in residential exposure. Therefore, the acute and chronic exposure estimates provided in the Dietary Exposure Section represent aggregate exposure. **8 .0**  **CUMULATIVE RISK** Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify , or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide's residues and “o ther substances that have a common mechanism of toxicity .” EPA does not have, at this time, available data to determine whether fluxapy roxad 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 fluxapy

roxad and any

other substances and, fluxapy

roxad does not appear to produce a toxic metabolite produced by other substance s which have tolerances in the U. S. For the purposes of this tolerance reassessment action, therefore, EPA has not assumed that fluxapy roxad has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by

EPA’s OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/fedrgstr/EPA_PEST/2002/January /Day _16/ .

### Page 30 of 83

**9 .0**  **OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION**  **9 .1**  **Exposure Scenarios** Occupational handler and post - application exposure scenarios are assessed for the risk assessment of the proposed crop and seed commodities . Based on the product labels and information provided b y the registrant, short - and intermediate - term exposure is assessed for occupational handlers and post - application activities. Chronic exposure is not expected for the proposed use patterns. Only inhalation exposures are assessed for proposed new uses of fluxapy roxad. Dermal exposures are not assessed because PODs for short - and intermediate term dermal exposure were not selected as there was no sy stemic toxicity up to the limit dose in the subchronic dermal toxicity study in rats . Labels for fluxapy roxad formulations require that mixers, loaders, applicators and other handlers (seed treatment activities) wear long - sleeved shirt and long pants, chemical resistant gloves, protective eyewear, and shoes plus socks . **9 .2**  **Handler Exposure** The term “handler” applies to individuals who mix, load, and apply the pesticide product. There is a potential for exposure to fluxapy roxad during mixing, loading, and app lication activities through inhalation routes only . Occupational handler exposure is expected for individuals involved in commerc ial seed treatment (primary handlers), and planting treated seeds (secondary

handlers) as well as aerial, flagging, airblast, and groundboom applicators. According to proposed labels, applications may be begin at plant emergence, but ty pical applications begin as plants touch across rows. The following handler exposure scenarios evaluated for this assessment are based on information provided in the proposed labels. **9 .2.1**  **Handler Exposure Scenarios 9**  **.2.1.1 Mixing and**  **Loading Scenarios**

• Open mixing/loading for aerial application; • Open mixing/loading for groundboom application; • Open mixing/loading for airblast applicati on. **9 .2.1.2**  **Appl ication**  **Scenarios**

• Applying spray s with aerial equipment ; • Applying spray s with groundboom equipment ; • Applying spray s with airblast equipment

. **9.2.1.3 Flagging** The Agency

has evaluated scenarios that may be limited in nature such as flagging during aerial applications because engineering controls (i.e. Global Positioning Satellite technology) are

### Page 31 of 83

now predominantly

used as indicated by

the 1998 National Agricultural Aviation Association (NAAA) survey

of their membership. It appears, however flaggers are still used in approximately

10 to 15 percent of aerial application operations. In cases like these, the Agency strongl y encourages the use of the engineering control sy stem, but will continue to evaluate risks for flaggers and any other population where a clear exposure pathway exists until the potential for exposure is eliminated. The Agency is aware that NAAA is conducting another survey of its membership on exp osure issues and will consider those results as is timely and appropriate. For pesticide handlers, HED presents estimates of dermal exposure for “baseline” (i.e. workers wearing a single layer of work clothing consisting of a long sleeved shirt, long pants , shoes, plus socks and no protective gloves, as well as for “baseline” and the use of protective gloves or other personal protective equipment (PPE), as might be nece ssary . However, dermal exposures were not assessed for this analysis because there was n o sy stemic toxicity up to the limit dose in the subchronic dermal toxicity study in rats . The fluxapy

roxad product labels for foliar treatments recommend applicators and other handlers to wear long - sleeved shirt and long pants, and shoes plus socks. **9.2.1.4 Seed Treatment** Occupational seed treatment handlers may experience short - and intermediate - term exposure to fluxapy

roxad while performing seed treatment activities in commercial settings. In addition, occupational secondary handlers may

experienc e short - and intermediate - term exposure while planting fluxapy

roxad - treated seeds. No chemical - specific handler exposure data were submitted in support of this use pattern. For assessing commercial seed treatment and seed planting activities, unit exposure data were taken from HED ExpoSAC Policy 14: SOPs for Seed Treatment and MRID 47054702 . The amount of active ingredient handled depends on the application rate (lb ai/lb seed) and the pounds of seed treated in a day (or the pounds of seed that can be pl anted in a day), all of which vary depending upon the seed type. Values for the amount of seed treated and planted per day were obtained from HED ExpoSAC Policy 15. The results are presented in Table 5. Treating Seed (Primary

Handler) P otential occupational exposure scenarios from the use of fluxapy roxad as a commercial seed treatment include:

 Mixing, loading, appl ying liquid formulations;  Bagging treated seed;  Sewing bags; and  Multiple activities . Ty pically , for large - scale commerci al seed treatments, workers perform only those specific individual tasks listed above; however, it is assumed that workers also may perform multiple activities throughout the day . As a result a “multiple activities” scenario (i.e. where one worker perform s all seed treatment tasks such as loading/appl ying, sewing, bagging, cleaning,

### Page 32 of 83

calibration, repair, forklift driver, etc.) w as addressed. Planting Treated Seed (Secondary Handler) P otential occupational exposure scenarios from the use of flux a py roxad as a commercial seed treatment include p lanting treated seed (secondary handler) . Planting treated seed consists of the farmer purchasing bags of treated seed, placing the seed in the h oppe r and appl ying seed to fields ( considered a secondary handler exposure scenario ) . The fluxapy roxad product labels discuss inhalation exposures exclusively for mixers, loaders, applicators and other handlers (seed treatment activities) to wear long - sleeved shirt and long pants, chemical resistant glove s , protective eyewear, and shoes plus socks . **9 .2.**  **2 Handler Exposure Data**  No chemical - specific handler exposure data were submitted in support of this registration. It is HED’s policy t o use data from the USEPA OPP Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (5/4/11). http://www.epa.gov/pesticides/science/handler- exposure - data.html ). **9.2.3 Handler Exposure Assumptions** 

• Average body weight of an adult handler is 8 0 kg. • Exposure duration s hort - term (1 - 30 day s), intermediate - term (1 - 6 months) • Maximum label application rates for aerial, groundboom and airblast :

- 0.09

– 0.18 lb ai/A • Maximum label application rates for seed treatment :

- 0.01 - 0.05 lb ai/100 lb seed • Area treated for aerial, groundboom and airblast application :

- 1200 acres per day

for aerial application

- 200 acres per day

for groundboom application to corn, s oy bean and wheat

- 80 acres per day

for groundboom application to all other crops

- 20 acres per day

for airblast application to stone fruit • Amount (pounds) of Seed Treated per Day (Primary Handler)

- Beans and Peas (CG6 and CG7)

– 194,000

- Soy bean , Sorghum - 718,000

- Sunflower and safflower - 718,000

- Cereal Grains (CG 15 and 16)

– 718,000

- Corn (field, sweet, pop)

– 550,000

- Cotton

– 160,000

- Peanut

– (Loader/Applicator) = 120,000), (Sewer, Bagger, and Multiple activities = 718,000) • Amount (pounds) of Seed Treated per Day (Secondary

Handler)

- Beans and Peas (CG6 and CG7)

– 194,000

- Soy bean

– 20,000

### Page 33 of 83

- Sunflower and safflower

– 7,700

- Barley

– 19,000

- Oat - 26,000

- Triticale

– 20,000

- Rye - 24,000

- Wheat

– 30,000

- Corn (field, sweet, pop)

– 3,000

- Sorghum

– 800

- Cotton

– 3,600

- Peanut

– 11,000

- **9 .2.**  **4 Handler**  **Exposure and Risk Estimates**  A target LOC or MOE of 100 is considered adequate for inhalation. All worker exposures are assessed as short - and intermediate - term based on label prescribed uses and expected exposure durations. Exposure and risk estimates indicate non - cancer risks are not of concern for occupational handler activities for the proposed new uses (MOEs > 100). Summaries of occupational handler e xposure and risk calculations, assumptions, an d results are provided in Table s 10 , 11 and 12 . **Table 10**  **: Short and Intermediate -**  **Term Risk Assessment For Agricultural Uses of Fluxapyroxad**  **Exposure Scenario**  **Inhalation**

**Unit Exposure**  **(μg/lb ai) 1**  **Crops Application**  **Rate (lb ai/A)**  **2 Area** 

**Treated (A/day)**  **3 MOE**  **5**

**Short -**  **Term Intermed**  **- Term** 

**Inhalation Mixer/Loader**  Aerial Fixed Wing (enclosed cockpit) 0.219 Fruiting vegetables, oilseed crops (flax, rape, and sunflower seed), pome fruits, stone fruits, sugar beet, tuberous and corn vegetables (incl. Potatoes),oat, peanut, rye, triticale 0.09 350 100,000 85,000 Dried shelled beans 0.18 52,000 42,000 corn, soybean, wheat 0.09 1200 30,000 25,000
Groundboom (open Cab) 0.219 Dried shelled beans 0.18 80 230,000 190,000 Fruiting vegetables, oilseed crops (flax, rape, and sunflower seed), pome fruits, stone fruits, sugar beet, tuberous and corn vegetables (incl. Potatoes),oat, peanut, rye, triticale 0.09 460,000 370,000 corn, soybean, wheat 200 180,000 150,000 Airblast (open cab) stone fruits 0.11 40 750,000 610,000 **Applying**

### Page 34 of 83 **Table 10**  **: Short and Intermediate -**  **Term Risk Assessment For Agricultural Uses of Fluxapyroxad**  **Exposure Scenario**  **Inhalation**

**Unit Exposure**  **(μg/lb ai) 1**  **Crops Application**  **Rate (lb ai/A)**  **2 Area** 

**Treated (A/day)**  **3 MOE**  **5**

**Short -**  **Term Intermed**  **- Term** 

**Inhalation** Aerial Fixed Wing (enclosed cockpit) 0.068 Fruiting vegetables, oilseed crops (flax, rape, and sunflower seed), pome fruits, stone fruits, sugar beet, tuberous and corn vegetables (incl. Potatoes),oat, peanut, rye, triticale 0.09 350 340,000 270,000 Dried shelled beans 0.18 170,000 140,000 corn, soybean, wheat 0.09 1200 98,000 80,000 Groundboom (open Cab) (Chemigation) 6 0.068 Dried shelled beans 0.18 80 150,000 120,000 Fruiting vegetables, oilseed crops (flax, rape, and sunflower seed), pome fruits, sugar beet, tuberous and corn vegetables (incl. Potatoes),oat, peanut, rye, triticale 0.09 290,000 240,000 corn, soybean, wheat 200 120,000 95,000 Airblast (open cab) Stone fruits 0.11 20 36,000 29,000 **Flagging** Aerial Fixed Wing (enclosed cockpit) 0.35 corn, soybean, wheat4 0.09 1200 33,000 26,000 1 Inhalation unit exposure values represent no respirator. 2 Application rates are based on maximum values found in proposed labels 3 Daily area treated is based on the area that can be reasonably applied in a single day for each exp osure scenario of concern based on the application method and formulation/packaging type. (standard EPA/OPP/HED values). 4 Corn, Soybeans, and Wheat have the most conservative MOEs, therefore representative for Flagging activities. 5 Short - /Intermediate - Term MOE = Inhalation NOAEL ( 9.0 mg/kg/day or 7.3 mg/kg/day ) / Daily Inhalation Dose). The LOC is 100. 6 Chemigation: Aerial applicator MOEs are protective. * Daily Dose (mg/kg/day) was calculated by Unit Exposure * 100 % Inhalation a bsorption factor * A

ppl ication rate * Area treated} / 7 0 kg. {Where: inhalation absorption is assumed to be 100 %}

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

**UE** a **mg/lb Max App Rate**  b

**lb ai/lb seed Am** **t Treated** c

**lb seed/day Inhal Dose**  d

**mg/kg/day Short**  **- Term** 

**Inhal MOE** e **Intermediate -**  **Ter m** 

**Inhal MOE** f **Loader/Applicator (No Respirator)** Peanuts 0.00034 0.0001 5,500 0.000058 180,000 140,000 Dried Shelled Beans 0.00034 0.0001 194,000 0.000094 110,000 89,000 Soy bean 0.00034 0.0001 718,000 0.00035 29,000 24,000 Cereal Grains 0.00034 0.0005 718,000 0.00017 5,900 4,800

### Page 35 of 83 **Table 11**  **. Short**  **- and Intermediate**  **- Term**  **Primary Handler Exposures and Risks for Fluxapyroxad Seed Treatment**  **Seed Type Inhal** 

**UE** a **mg/lb Max App Rate**  b

**lb ai/lb seed Am** **t Treated** c

**lb seed/day Inhal Dose**  d

**mg/kg/day Short**  **- Term** 

**Inhal MOE** e **Intermediate -**  **Ter m** 

**Inhal MOE** f Corn 0.00034 0.0005 550,000 0.0013 7,700 6,200 Cotton 0.00034 0.0002 160,000 0.00016 66,000 54,000 Sunflower and safflower 0.00034 0.0002 718,000 0.00 1 7 15,000 12,000 Sorghum 0.00034 0.0002 718,000 0.0007 15,000 12,000 **Sewer (No Respirator)** Peanuts 0.00023 0.0001 718,000 0.00024 44,000 35,000 Dried Shelled Beans 0.00023 0.0001 194,000 0.000064 160,000 130,000 Soy bean 0.00023 0.0001 718,000 0.00024 44,000 35,000 Cereal Grains 0.00023 0.0005 718,000 0.0012 8,700 7,100 Corn 0.00023 0.0005 550,000 0.0009 11,000 9,200 Cotton 0.00023 0.0002 160,000 0.00011 98,000 79,000 Sunflower and safflower 0.00023 0.0002 718,000 0.00047 22,000 18,000 Sorghum 0.00023 0.0002 718,000 0.00047 22,000 18,000 **Bagger (No Respirator)** Peanuts 0.00016 0.0001 718,000 0.00016 63,000 51,000 Dried shelled Beans 0.00016 0.0001 194,000 0.000044 230,000 190,000 Soy bean 0.00016 0.0001 718,000 0.00016 63,000 51,000 Cereal Grains 0.00016 0.0005 718,000 0.00082 13,000 10,000 Corn 0.00016 0.0005 550,000 0.00063 16,000 13,000 Cotton 0.00016 0.0002 160,000 0.000073 140,000 110,000 Sunflower and safflower 0.00016 0.0002 718,000 0.00033 31,000 25,000 Sorghum 0.00016 0.0002 718,000 0.00033 31,000 25,000 **Multiple Activities (No Respirator)** Peanuts 0.0016 0.0001 718,000 0.0016 6,300 5,100 Dried Shelled Beans 0.0016 0.0001 194,000 0.00044 23,000 19,000 Soy bean 0.0016 0.0001 718,000 0.0016 6,300 5,100 Cereal Grains 0.0016 0.0005 718,000 0.0082 1,300 1,200 Corn 0.0016 0.0005 550,000 0.0063 1,600 1,300 Cotton 0.0016 0.0002 160,000 0.00073 14,000 11,000 Sunflower and safflower 0.0016 0.0002 718,000 0.0033 3,100 2,500 Sorghum 0.0016 0.0002 718,000 0.0033 3,100 2,500 Planters Peanuts 0.0034 0.0001 11,000 0.000047 190,000 210,000 Dried Shelled Beans 0.0034 0.0001 8,000 0.000034 260,000 190,000 Soy bean 0.0034 0.0001 20,000 0.000085 110,000 86,000 Cereal Grains 0.0034 0.0005 26,000 0.00011 81,000 66,000 Corn 0.0034 0.0005 3,000 0.000064 140,000 110,000 Cotton 0.0034 0.0002 3,600 0.000031 290,000 240,000 Sunflower and safflower 0.0034 0.0002 800 0.000068 1,300,000 1,100,000 Sorghum 0.0034 0.0002 800 0.000068 1,300,000 1,100,000 a Unit Exposures from HED Exposure Science Advisory Council Policy 14: Standard Operating Procedures for Seed Treatment. b Application Rates based on proposed label uses for fluxapyroxad .

### Page 36 of 83

c HED default for lb seed planted per day from HED Exposure Science Advisory Council Policy 15, d Daily Inhalation Dose (mg/kg/day) = daily inhalation unit exposure (mg/ lb ai) x application rate (lb ai/lb seed) x amount planted (lb seed/day) x absorption f

actor (100%) / body weight (70 kg adult). e Short - term Inhalation MOE = NOAEL (9.0 mg/kg/day for short - term exposure) / Inhalation Dose (mg/kg/day). Level of concern = 100. f Intermediate - term Inhalation MOE = NOAEL (7.3 mg/kg/day for intermediate - term exposure) / Inhalation Dose (mg/kg/day). Level of concern = 100. * in the case where there are several crops under the crop group assessed, the crop with the highest amount of seeds planted per day was assessed to cover that crop group (i.e., beans and pe as, cereal grains) 

### 9 **.3 Post**  **- Application Exposure**  HED uses the term “post - application” to describe those individuals who can be exposed to pesticides after entering areas previousl y treated with pesticides and performing certain tasks or activities (also often referred to as reentry exposure). Post - appli cation exposures are expected to occur primaril y via the dermal route. Based on the Agency's current practices, a quantitative occupational post - application inhalation exposure assessment was not performed for fluxapy roxad at this time; an inhalation expo sure assessment was performed for occupational handlers. This assessment resulted in risk estimates that did not exceed HED’s level of concern at baseline inhalation PPE. Handler exposure resulting from application of pesticides outdoors is likely to res ult in higher exposure than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational postapplication inhalation exposure scenarios. However, there are multiple potential sources of post application inhalation exposure to individuals performing post - application activities in previously

treated fields. These potential sources include volatilization of pesticides and re suspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final rep ort on March 2, 2010 (http://www.epa.gov/scipoly /SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated b y the Agricultural Reentry Task Force and may , as appropriate, develop policies and procedures, to identify the need for and, subsequently , the way to incorporate occupational post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for fluxapy roxad. The potential for post - application exposures following the planting of fluxapy roxad treated seeds is unlikely

becaus e s ustained levels of contact with treated seed after it has been placed in the soil or other planting media would not be expected because no routine cultural practice required for the production of agricultural commodities involves such an activity as def ined in the no/low contact criteria in the Worker Protection Standard (WPS) . Therefore, no quantitative post - application assessment is required for exposure to treated seeds that have already been planted .

### Page 37 of 83

**10.0 REFERENCES**  Fluxapy roxad; Occupational Exposure Assessment to Support the Request for Registration of Fluxapy roxad on seed and various food crops, J. Miller D3 90242 , 2/8/12 Fluxapy roxad (BAS 700F) on Small Grains, Oilseeds, Corn, Cotton, Sugar Beet, Tubers & Corm Vegetables, Legumes, Fruiting Vegetables except Cucurbits, Pome Fruits and Stone Fruits Evaluation of Anal ytical Methods and Residue Data. S. Hummel, D390223, 2/8/12 Fluxapy roxad

**–** Acute and Chronic Dietary Exposure and Risk Assessments for Proposed Use of New Active In gredient on Small Grains, Oilseeds, Corn, Cotton, Sugar Beet s , Tuber & Corm Vegetables, Legumes, Fruiting Vegetables except Cucurbits, Pome Frui t and Stone Fruit. B. Daiss, D390245, 2/8/12 Fluxapy roxad (BAS 700F). Report of the Residues of Concern Knowledgebase Subc ommittee (ROCKS) . I. Negrón - Encarnación, D390225, 7/14/11 Fluxapy roxad (BAS 700F) New Chemical Screen for Toxicology . J. Ry man, D377679, 7/30/10 CARC Report ( J. Kidwell , June 9 , 2011, TXR 0055930 ).

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**APPENDIX A . TOXICOLOGY PROFILE AND EXECUTIVE SUMMARIES**  **A.1 TOXICOLOGY DATA REQUIREMENTS**  The requirements (40 CFR 158.340) for food use for fluxapy roxad are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used. **Guideline No.**  **Study Type Technical**  **MRID No. Required**  **Submitted** 870.3100 870.3150 870.3200 870.3250 870.3465 Subchronic (Oral) Toxicity - Rodent ................................

Subchronic (Oral) Toxicity - Non - Rodent ................................ 21/28 - Day Dermal Toxicity ................................ ................................ 90 - Day Dermal Toxicity 90 - Day Inhalation Toxicity ................................ ................................ Y Y N N Y Y

Y Y N N 47923567

47923568 47923569 47923571

---

--- 870.3700a 870.3700b 870.3800 Prenatal Developmental Toxicity - Rodent ................................

Prenatal Developmental Toxicity - Non - Rodent ................................ Reproduction and Fertility Effects ................................ ................................ Y Y Y Y

Y Y 47923603

47923604 47923602 870.4100a 870.4100b 870.4200a 870.4200b 870.4300 Chronic (Oral) Toxicity - Rodent ................................ ................................

Chronic (Oral) Toxicity - Non - Rodent (Dog) ................................ Carcinogenicity - Rat Carcinogenicity - Mouse Com bined 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 - Ac ute Delayed Neurotox. - Hen ................................

Neurotoxicity - Subchronic - Hen ................................ ................................ Neurotoxicity Screening Battery - Ac ute - Rat ................................ Neurotoxicity Screening Battery - Subchronic - Rat ................................ Developmental Neurotoxicity.................. Immunotoxicity............................. ................................ N N Y Y N Y N

N Y Y N Y ---

--- 47923605 47923606

--- 47923633

### Page 39 of 83

**A.2 TOXICITY PROFILES**  **A.2.1 Acute Toxicity** Table A.2.1.1 Ac ute Toxicity Profile

– Fluxapyroxad Guideline No. Study T ype MRID(s) Results Toxicity Category 870.1100 Ac ute oral

– rat (females) 47923607 LD 50 = >2000 mg/kg III 870.1200 Ac ute dermal

– rat 47923559 LD 50 >2000 mg/kgM & F III 870.1300 Ac ute inhalation

– rat 47923560 LC 50 >5.1 mg/L M & F IV 870.2400 Ac ute eye irritation

– rabbit 47923562 Slightly irritating IV 870.2500 Ac ute dermal irritation

– rabbit 47923561 Slightly irritating IV 870.2600 Dermal sensitization

– guinea pig 47923813 No sensitization - **TableA.2.1.2 Acute Toxicity Profile** 
**– Fluxapyroxad Metabolites**  **Guideline No.**  **Study Type MRID(s)**  **Results Toxicity Category**  870.1100 Ac ute oral

– rat (females) **M -**  **1** 47701678 LD 50 = >2000 mg/kg III 870.1100 Ac ute oral

– rat (females) **M -** **3** 47701679 LD 50 = >2000 mg/kg III 870.1100 Ac ute oral

– rat (females) **M -**  **25** 47701680 LD 50 = >2000 mg/kg III 870.1100 Ac ute oral

– rat (females) **M -**  **28** 47701755 LD 50 = >2000 mg/kg III 870.1100 Ac ute oral

– rat (females) **I -**  **3** 47701681 LD 50 = >2000 mg/kg III 870.1100 Ac ute oral

– rat (females) **I -**  **4** 47701682 LD 50 = >2000 mg/kg III 870.1100 Ac ute oral

– rat (females) **I -**  **5** 47701683 LD 50 = >2000 mg/kg III **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)**  **Guideline No Study Type**  **MRID/Classification Doses**  **Results** 870.3050 28 day dietary in rats 47923564 (2009) Acceptable, guideline 0, 100, 500, 2000, 6000 ppm 0/0, 9/9.4, 43.7/47.8, 176/183, 530/531, mkd M/F **Males** NOAEL=100 ppm ( 9.0 mkd) LOAEL 500 ppm (176 mkd) based on thyroid follicular hypertrophy/hyperplasia and clinical chemistry changes **Fem ales**  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 day s - rat 47923594 (2009) Acceptable, non guideline 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 el imination of circulating thyroxine (T 4 ) 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 day s rat 47923595 (2009) Acceptable, non guideline 0, 3000 ppm The similarities in the behavior of BAS 700 F to phenobarbitol in this perchlorate discharge assay support the hypothesis that BAS 700 F causes increases in thyroid hormones by an indirect mechanism.

### Page 40 of 83

**Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)**  **Guideline No Study Type**  **MRID/Classification Doses**  **Results** 0/0, 283/247 mkd Non - Guideline Enzyme induction 47923599 (20210) Acceptable, non guideline 50 ppm Mechanistic investigations of enzyme induction (thyroid and liver).
Non - Guideline Enzyme induction 47923593 (2010) Acceptable, non guideline 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 day s 47923598 (2010) Acceptable, non guideline 0, 50, 250, 1500, 3000 ppm Mechanistic tnvestigations of hepatocellular proliferation.

Non - Guideline S -phase induction 7 - 28 - 91 days 47923597 (2010) Acceptable, non guideline 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. **Fem ales**  NOAEL=7000 ppm (2100 mkd) LOAEL=Not observed No EPA guideline, OECD 407

–28 day dietary in dogs 47923566 (2009) Acceptable/non - EPA guideline 0, 2500, 7500, 20000 ppm 0/0, 74/85, 211/230, 521/503 mkd M/F NOAEL=2500 ppm (74/85 mkd M/F) LOAEL - =7500 ppm (211/230 mkd M/F) based on vomiting (M/F) and clinical chemistry changes

870.3100 90 - day dietary in mice 47923568 (2009) Acceptable/guideline 0, 100, 400, 2000, 6000 ppm 0/0, 21/32, 77/128, 390/610, and **Males** NOAEL=2000 ppm (390 mkd) LOAEL 6000 ppm (1136 mkd) based on decreased body weight and body weight gain and multifocal necrosis in the liver **Fem ales**  NOAEL=6000 ppm (1657 mkd)

### Page 41 of 83

**Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)**  **Guideline No Study Type**  **MRID/Classification Doses**  **Results** 1136/1657 mkd (M/F) LOAEL=Not observed. 870.3100 90 - Day dietary in rats 47923567 (2009)

Acceptable, guideline 0, 100, 500, 2000, 6000 ppm 0/0, 6.1/7.3, 31.2/35.1, 126/144, and 407/424 mkd (M/F) NOAEL = 500 ppm (31.2 mkd) males; 100 ppm (7.3 mkd) females LOAEL = 2000 ppm (126 mkd) males; 500 ppm (35.1 mkd females) based on changes in thyroid hormone levels and thyroid follicular hypertrophy/hyperplasia
870.3150 90 - Day Oral Toxicity Feeding - dog 47923569 (2009) Acceptable/guideline 0, 300, 1500, 10000/7500 (M/F) 0/0, 9/10, 45/51, 295/238 mkd M/F NOAEL=1500 ppm (45/51 mkd M/F) LOAEL=10000 ppm (295 mkd) males, 7500 ppm (238 mkd) females based on vomiting and clinical chemistry chan ges

870.3200 28 - Day Dermal Toxicity - rat 47923571 (2009) Acceptable, guideline 0, 100, 300, 1000 mkd NOAEL=1000 mkd LOAEL=not observed 870.3465 90 - Day Inhalation Still required, data gap 870.3700a Prenatal Developmental - rat 47923603 (2009) Acceptable, guideline 0, 25, 200 and 1000 mkd (gavage in CMC) **Maternal** NOAEL=200 mkd LOAEL =1000 mkd based on increased absolute and relative thyroid weights and thyroid hypertrophy/hyperplasia **Offspring** NOAEL=1000 mkd LOAEL =Not observed 870.3700b Prenatal Developmental rabbit 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 Perform ance**  NOAEL=300 mkd LOAEL =Not observed. **Offspring**

### Page 42 of 83

**Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)**  **Guideline No Study Type**  **MRID/Classification Doses**  **Results**

NOAEL=10 mkd LOAEL =50 mkd decreased pup body weight/body weight development 870.4100 Chronic Toxicity- dog 47923570 (2009) Acceptable/guideline 0, 300, 1500, 12000/9000 ppm (M/F) 0/0, 8/9, 39/43, 335/257 mkd M/F **Fem ales**  NOAEL=300 ppm ( 9 mkd) LOAEL =1500 ppm (43 mkd) based on hepatic fibrosis and clinical chemistry changes **Males** NOAEL=1500 ppm ( 39m kd) LOAEL=12000 ppm (335 mkd) based on vomiting, heptaic fibrosis and cirrhosis, and clinical chemistry changes (liver enzyme elevation) 870.4300 Chronic toxicity/carcinogenicity in rats 47923591 (2009) Acceptable, guideline 0, 50, 250, 1500, 3000 ppm 0/0, 2.1/2.7, 11/14, 68/82, 145/182 mkd (M/F) **Chronic toxicity** NOAEL=50 ppm (2.1/2.7 mkd in males/females) LOAEL =250 ppm (11/1 mkd) based on neoplastic changes in the liver (foci, masses). **Carcinogenicity -**  **see CARC report** Classified as“ not likely to be carcinogenic to humans” at doses below

those that cause liver enzyme induction in rats. 870.4300 Chronic toxicity/carcinogenicity in mice 47923592 (2009) Acceptable, guideline 0, 150, 750, 3000, 6000 ppm 0/0, 21/33, 107/158, 468/652, 996/1307 mkd (M/F) **Chronic toxicity** NOAEL=750ppm (158/107 mkd M/F) LOAEL =3000 ppm (468/652) mkd M/F based on decrease body weight. **Carcinogenicity** NOAEL=6000 ppm (996/1307 mkd M/F) LOAEL =Not observed Gene Mutation 870.5100 In vitro Bacterial Gene Mutation 47923572 (2008) Acceptable, guideline 0, 20, 100, 500, 2500, 5000 μg/plate  S9 Not mutagenic in the reverse mutation assay in Salmonella typhimurium or Escherichia coli with or without metabolic activation. Gene Mutation 870.5300 In vitro Mammalian Cells Gene Mutation (Chinese Hamster Ovary Cells) 47923579 (2007) Acceptable, guideline 0 - 100 μg/ml  S9 Does not induce forward mutations in CHO cells with or without metabolic activation.
Cy togenetics 870.5375 In vitro Mammalian Cy togenetics Chromosomal Aberration Assay human 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.

Cy togenetics - other 47923584 (2006) Did not lead to any increase in polychromatic erythrocytes.

### Page 43 of 83

**Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)**  **Guideline No Study Type**  **MRID/Classification Doses**  **Results** 870.5395 In Vivo Mammalian Cy togenetics - Erythrocyte Micronucleus - mo use Acceptable, guideline 0, 500, 1000, 2000 mkd 870.6200a Ac ute Neurotoxicity - rat 47923605 (2009) Acceptable, guideline 0, 125, 500, 2000 mkd NOAEL (neurotoxicity) =125 mk LOAEL (neurotoxicity)=500 mk based on decreased motor activity (both sexes) and decreased rearing (males only). 870.6200b Subchronic Neurotoxicity - rat 47923606 (2009) Acceptable, guideline 0, 200, 100, and 5000 ppm 0, 11.5/13.4, 57.7/67.2, 302.2/337.7 mkd M/F NOAEL (neurotoxicity)=5000 ppm (302/338 mkd M/F) LOAEL (neurotoxicity) =Not observed

870.7485 Metabolism and Pharmacokinetics - rat 47923555 (2009) 47923556 (2009) The times to maximum plasma levels (T MAX) 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 day s 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 syste m. 870.7600 Dermal penetration 47923632 (2010) Acceptable, guideline 5.6, 33,4, 1670 μg/cm2 for 8 h exposure and 24 and 120 h termination The dermal absorption factor is 8.38%.

### Page 44 of 83

**Table A.2.2 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)**  **Guideline No Study Type**  **MRID/Classification Doses**  **Results** *I n a formulation with pyraclostrobin (BAS 500 F) 870.7800 Immunotoxicity - mice (male) 47923633 (2009) Acceptable, guideline 0, 500, 2000 and 6000 ppm 0, 106, 450 and 1323 mg/kg/d Not immunotoxic.

Non - guideline S -phase Response Liver 1, 3, 7, 14 days - rat 47923598 (2009) 0, 50, 250, 1500 and 3000 ppm Cell proliferation in both sexes was dose - dependent at maximal at Day 7 (males) and Days 7& 14 (females). Non - guideline S -phase Response Liver 7, 28, 91 days - rat 47923596 (2009) 0, 50 ppm (nominal) - Acceptable, non guideline 47923596 (2009) Acceptable, non guideline 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 highe r 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, non guideline 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, non guideline 0, 1000, 2000 mkd Does not induce unscheduled DNA synthesis.

**Table A.2.5 Subchronic, Chronic and Other Toxicity**  **Profile Toxicity Profile for**  **Me tabolite M700F001**  **Guideline No Study Type**  **MRID Classification**  **Doses Results**  870.3100 90 - Day dietary in rats 47923608 (2009)

Acceptable, - guideline 0/0, 94.6/98.8, NOAEL=953.6/983.1 mkd in M/F LOAEL=Not observed

### Page 45 of 83 **Table A.2.5 Subchronic, Chronic and Other Toxicity**  **Profile Toxicity Profile for**  **Me tabolite M700F001**  **Guideline No Study Type**  **MRID Classification**  **Doses Results**  285.7/295.1, 953.6/983.1 mkd M/F 870.3700b Prenatal Developmental rabbit 47923613 (2009) Acceptable, guideline 0, 40, 100, and 250 mkd **Maternal** NOAEL=250 mkd LOAEL =Not observed. **Offspring** NOAEL=250 mkd LOAEL =Not observed Gene Mutation 870.5100 In vitro Bacterial Gene Mutation 47923609 (2009) Acceptable, guideline Not mutagenic. Gene Mutation 870.5300 In vitro Mammalian Cells Gene Mutation (Chinese Hamster Ovary Cells) 47923611 (2009) Acceptable, guideline Not mutagenic.

Cy togenetics 870.5375 In vitro Mammalian Cy togenetics Chromosomal Aberration Assay human peripheral blood lymphocytes 47923610 (2009) Acceptable, guideline Not clastogenic.

Cy togenetics - other 870.5395 In Vivo Mammalian Cy togenetics - Erythrocyte Micronucleus - mo use 47923612 (2009) Acceptable, guideline O, 500, 1000, 2000 mkd Did not lead to any increase in polychromatic erythrocytes.

**Table A.2.5 Subchronic, Chronic and Other Toxicity Profile**  **Toxicity Profile for Me** **tabolite M700F002 Guideline No**  **Study Type MRID**  **Classification Doses**  **Results** 870.3050 28 day dietary in rats 47923615 (2009) Acceptable, guideline 0/0, 113/113.4, 275.9/394.8, 1164.8/1253.3 mkd NOAEL= 1164.8/1253.3mkd in M/F LOAEL=Not observed

870.3100 47923616 (2009)

### Page 46 of 83 **Table A.2.5 Subchronic, Chronic and Other Toxicity Profile**  **Toxicity Profile for Me** **tabolite M700F002 Guideline No**  **Study Type MRID**  **Classification Doses**  **Results** 90 - Day dietary in rats Acceptable, - guideline

0/0, 113/113.4, 275.9/394.8, 1164.8/1253.3 mkd 0/0, 95.1/98.0, 285.3/299.5, 958.4/928.7 mkd M/F NOAEL=958.4/928.7 mkg M/F LOAEL=not observed

870.3700b Prenatal Developmental rabbit 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.

Cy togenetics 870.5375 In vitro Mammalian Cy togenetics Chromosomal Aberration Assay human peripheral blood lymphocytes 47923618 (2008) Acceptable, - guideline Not clastogenic.

Cy togenetics - other 870.5395 In Vivo Mammalian Cy togenetics - Erythrocyte Micronucleus - mo use 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, non guideline 1000 m kd, oral (gavage) M700F002 is systemically bio available and its presence in the bone marrow

and blood after an oral application is confirmed.

### Page 47 of 83 **Table A.2.4 Subchronic, Chronic and Other Toxicity Profile**  **Toxicity Profile for Me** **tabolite 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 Developmental rabbit 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.

Cy togenetics 870.5375 In vitro Mammalian Cy togenetics Chromosomal Aberration Assay human peripheral blood lymphocytes 47923626 (2009) Acceptable, guideline Clastogenic with metabolic activation.

Cy togenetics - other 870.5395 In Vivo Mammalian Cy togenetics - Erythrocyte Micronucleus - mo use 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 femal es). Non - OPPTS guideline, 47923630 (2009) M700F048 is 5077265 is systemically bio available and its

### Page 48 of 83 **Table A.2.4 Subchronic, Chronic and Other Toxicity Profile**  **Toxicity Profile for Me** **tabolite M700F048 Guideline No**  **Study Type MRID**  **Classification Doses**  **Results** OECD 417 Acceptable, non guideline 1000 m kd, oral (gavage) presence in the bone marrow , blood and liver after an oral application is confirmed.
Non - OPPTS guideline, OECD 486 47923629 (2009) Acceptable, non guideline 0, 1000, 2000 mkd Does not induce unscheduled DNA synthesis.

**Table A.2.5 Subchronic, Chronic and Other Toxicity Profile**  **Toxicity Profile for Artificial Batch**  **Guideline No Study Type**  **MRID Classification**  **Doses Results**  Gene Mutation 870.5100 In vitro Bacterial Gene Mutation 47923573 (2009) Acceptable, guideline No evidence of mutagenicity. Gene Mutation 870.5300 In vitro Mammalian Cells Gene Mutation (Chinese Hamster Ovary Cells) 47923580 (2009) Acceptable, guideline No evidence of forward mutations.

Cy togenetics 870.5375 In vitro Mammalian Cy togenetics Chromosomal Aberration Assay human peripheral blood lymphocytes 47923578 (2009) Acceptable, guideline Clastogenic in V79 cells in the presence or absence of metabolic activation.

Cy togenetics - other 870.5395 In Vivo Mammalian Cy togenetics - Erythrocyte Micronucleus - mo use 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, non guideline 0, 2.5, 5 mkd Does not induce unscheduled DNA synthesis.

### Page 49 of 83 **Table A.2.5 Subchronic, Chronic and Other Toxicity Profile**  **Toxicity Profile for Impurity B**  **Guideline No Study Type**  **MRID Classification**  **Doses Results**  Gene Mutation 870.5100 In vitro Bacterial Gene Mutation 479 23574 (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.

Cy togenetics - other 870.5395 In Vivo Mammalian Cy togenetics - Erythrocyte Micronucleus - mo use 47923586 (2009) Acceptable, guideline 0, 15, 30, 60 mkd Did not lead to any increase in polychromatic erythrocytes.

**Table A.2.3 Subchronic, Chronic and Other Toxicity Profile**  **Toxicity Profile for Impurity C**  **Guideline No Study Type**  **MRID Classification**  **Doses Results**  Gene Mutation 870.5100 In vitro Bacterial Gene Mutation 479 23576 (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.

Cy togenetics - other 870.5395 In Vivo Mammalian Cy togenetics - Erythrocyte Micronucleus - mo use 47923588 (2008) Acceptable, guideline 0, 500, 1000, 2000 mkd Did not lead to any increase in polychromatic erythrocytes.

### Page 50 of 83

**A.3 HAZARD IDENTIFICATION AND ENDPOINT SELECTION**  **A.3.1 Acute Reference Dose (aRfD)**
**– All populations (General Population, including**  **infants and children and females ages 13**  **- 49)**  **Study Selected:** Acute Neurotoxicity Study in Rats **MRID No.:** 47923606 **Dose and Endpoint for Risk Assessment** : NOAEL= 125 mg/kg/day . The LOAEL of 500 mg/kg/day

was based on decreased motor activity (both sexes) and decreased rearing (males only) seen on the day

of dosing. **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability); FQPA SF = 1X **Acute RfD= acute PAD** = 125 mg/kg/day = **1.25 mg/kg/ day**  100 **Comments about Study/Endpoint/Uncertainty Factors:** The study is appropriate for acute dietary exposure due to the route (oral) and duration (acute) of dosing. The effects are clearl y adverse and result from a single exposure. Endpoints from the developmental rat and rabbit studies as well as the 2 - generation reproduction study were n ot selected since there were no effects seen that were attributable to a singl e 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 ye ars 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. **Unc ertainty Factor:**  100x (10x interspecies extrapolation, 10x intraspecies variability); FQPA SF = 1X

### Page 51 of 83 **Chronic RfD = chronic PAD** = 2.1 mg/kg/day = **0.021 mg/kg/day** 100 **Comments about Study/Endpoint/Uncertainty Factors:**  The study is appropriate for chronic dietary exposure due to the route (oral) and duration (chronic) of dosing. These effects are consistent with the liver being the target organ and are supported b y 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 hy pertrophy /hy perplasia. **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 Incide**  **ntal 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 thy roid hormones and thy

roid follicular hy pertrophy /hy perplasia. **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 der

mal irritation or sy stemic effects were observed up to the limit dose of 1000 mg/kg/day . This is a route - specific study that also assessed all of the endpoints used in the other exposure scenarios and durations of exposure (e.g. neurological endpoints, thyroid and liver histopathology). In addition, no increased susceptibility was seen

### Page 52 of 83

between offspring and adult animals in the developmental toxicity studies in rats and rabbits and in the 2 - generation reproduction study in rats. **Therefore, the quantificat ion 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 thy roid follicular hyp ertrophy /hy perplasia. **Uncertainty Factor:** The occupational and residential level of concern for MOE is 100. **Comments about Study/Endpoint/UF:** No inhalation studies are available for fluxapy roxad; 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 sen sitive species for this duration of exposure. **A.3.7 Occupational and Residential Inhalation Exposure (Intermediate**  **- Term)**  **Study Selected:** 90 - Day Dietary Toxicity Study in the Rat **MRID No:** 47923567 **Dose and Endpoint for Risk Assessment:** NOAEL= 7.3 mg/kg/day (100 ppm). The LOAEL = 500 ppm (35.1 mg/kg/day) based on thy roid follicular hy

pertrophy /hy perplasia. **Uncertainty Factor:** The occupational and residential level of concern for MOE is 100. **Comments about Study/Endpoint/UF:** No inh alation studies are available for fluxapy roxad; 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 fluxapy roxad, occupational long - term inhalation exposure is not anticipated.

### Page 53 of 83

**A. 4 EXECUTIVE SUMMARIES**  **A.4.1 Subchronic Toxicity**  **870.3100 90**  **- Day Oral Toxicity** 
**– Rat**  **MRID 47923567** BAS 700 F (Batch: COD

–000826; Purity : 99.6%) was administered to male and female Wistar rats at dietary

dose levels of 0, 100, 500, 2000, or 6000 ppm (0/0, 6.1/7.3, 31.2/35.1, 126/144, and 407/424 mg/kg bw/day in males/females) for at least 90 days. Significant decreases in body weight and body weight gain were observed in 6000 ppm males and females and were considered adverse. A functional observational battery and motor activity

measurements were performed at the end of the dietary

exposure period. However, no evidenc e of neurotoxicity was observed in these investigations. Also, no signs of neurotoxic i ty were noted in dail y cageside or weekl y 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 hy pertrophy 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 clearl y adverse). The clinical chemistry

changes considered potentiall y i ndicative of adverse effects were increased serum cholest erol and trigl yc erides 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 pp m 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 thy roid follicular cell hy pertrophy /hy per plasia present at ≥2000 ppm. In females, both changes in thy roid hormone levels and thyro id follicular hy pertrophy /hy perplasia were observed at ≥500 ppm. Additionally , an increased tubular deposition of pigment indicative of a mild tubulonephrosis was observed in kidneys of top dose females and was not considered adverse. **The LOAEL is 2000 ppm (126 mg/kg bw/day) in males and 500 ppm (35.1 mg/kg bw/day) in females, based on thyroid follicular hypertrophy and hyperplasia. The NOAEL is 500**  **ppm (31.2 mg/kg bw/day) in males and 100 ppm (7.3 mg/kg bw/day) in females.** This study

is classified as **totally reliable** ( **acceptable/guideline)** and satisfies the guideline requirement for a 90 - day

oral toxicity

study (OPPTS 870.3100; OECD 408) in rats.

### Page 54 of 83

**870.3100 90**  **- Day Oral Toxicity** 
**– Mice MRID 47923568**  BAS 700 F (Batch: COD

–000826; Purity 99.6%) was administered to C57BL/6 J Rj mice (10/sex/dose) at dietary

dose levels of 0, 100, 400, 2000 and 6000 ppm (corresponding to 0/0, 21/32, 77/128, 390/610, and 1136/1657 mg/kg bw/day) for at least 91 days. Sign ificant 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 die tary 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, alanine aminotransfer ase (ALAT) and urea levels in top dose males as well as decreased trigl yc eride (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 enzy mes, was considered potentiall y 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 9 0 - 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 co nsumption in each two high dose males and females. This was accompanied by decreased body

weight development in one high dose female onl y. Furthermore, vomiting was recorded in all male and female dogs of the high dose group during the first two day s 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 potentiall y adverse were increase ALP and GGT in both sexes at the high dose. Increased absolute and/or relative weights in both sexes were considered adaptive and not adverse , since there were not histopathological correlates. **The LOAEL is 10000 ppm (295 mg/kg bw/day) in males and 7500 ppm (238 mg/kg bw/day)**

### Page 55 of 83

**in females, based on vomiting and clinical chemistry changes. The NOAEL is 1500 ppm in both sexes (45 mg/kg bw/day i**  **n 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 carbox ym ethyl cellulose vehicle to 10/sex/dose Wistar rats (6 hours/day ; 5 day s/week, semi occlusive 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** B AS 700 F (Batch COD - 000899, Purity 99.7%) was administered dail y to presumabl y pregnant Crl:WI(Han) Wistar rats by oral gavage in a 0.5% carbox ym ethyl cellulose vehicle during gestation day s 6 - 19 at dose levels of 0, 25, 200 and 1000 mg/kg bw. The high dos e of 1000 mg/kg bw/day

resulted in increased (12 - 16%) absolute and relative thy roid weights (with correlating microscopic effects of thyroid hyp ertrophy and hyp erplasia (considered adverse). Absolute and relative liver weights were increased significantl y, but slightly (9 - 13%) at this dose and occurred in the absence of corroborating effects on serum liver enzy mes (liver hi stopathology

was not examined). This effect was considered as most likely due to hep at ocellular hyp ertrophy (due to extensive evidence of hepatocellular hypertrophy in conjunction with increased liver weights throughout the database for this chemical) and so was not considered adverse. **The LOAEL for maternal toxicity in females is 1000 mg/kg bw/day, based on increased**

### Page 56 of 83

**absolute and relative thyroid**  **weights and thyroid hypertrophy/ hyperplasia**  **. The NOAEL is 200 mg/kg bw/day.**  No treatment - related effects on cesarean section parameters were observed at any dose. No treatment - related external, visceral or skeletal malformations were noted. BAS 700 F was not teratogenic up to the highest dose tested. **The LOAEL for developmental toxicity was not obser ved. 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 Devel opmental Toxicity Study** 
**– Rabbit**  **MRID 47923604 A.4.3**  **Reproductive Toxicity 870.3800 Reproduction and Fertility Effects** 
**– Rat**  **MRID 47923602** BAS 700 F (Batch COD - 000899, Purity 99.7%) was administered dail y to presumabl y pregnant Himalayan rabbits by

stomach tube during gestation day s 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 s igns of maternal toxicity as indicated b y one abortion, decreased food consumption ( - 21.9% during the treatment period) corroborated b y an increased number of animals with reduced or no defecation, body weight loss during gestation day s 9 to 11 and a decre ase of cumulative body weight gain by 49.3% during the treatment period. Body weighs were decreased 12% b y 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 tr eatment related variation was a statistically significant increase in incidence of mean % affected fetuses with paw hy

perflexion 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 consid ered potentiall y adverse. **The LOAEL for developmental toxicity was 60 mg/kg bw/day, based on decreased fetal body weights and an increased incidence of paw hyperflexion, which was considered**  **potentially adverse. The NOAEL is 25 mg/kg bw/day.**

### Page 57 of 83

This study

is classified as **totally reliable (acceptable/guideline)** and satisfies guideline requirements for a prenatal developmental toxicity study (OPPTS 870.3700; OECD 414) in rabbits. **A.4.4 Chronic Toxicity**  **870.4100b Chronic Toxicity**
**– Dog**  **MRID 47923570**  BAS 700 F (Batch: COD

– 001026, purity 99.4%) was administered to Beagle Dogs for 12 months at dietary

dose levels of 0, 300, 1500 and 12000 ppm in males ( 0, 8, 39, and 335 mg/kg bw/day) and 0, 300, 1500 and 9000 ppm in females ( 0, 9, 43, and 257 mg/kg b w/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, trigl yceride and alanine aminotransferase levels as well as decreased total protein, albumin, cholesterol, total bilirubin, creatinine, urea and calcium levels in either or both sexes. Histopathlogical anal ys is of the organ showed an intracy

toplasmic iron deposition in hepatocy tes 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 9000/120 00 ppm. This was accompanied b y 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 atrop y at the high dose were considered potentially adverse. Changes wer e 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 po tentially 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 LOAELin males is 12000 ppm (335 mg/kg bw/day) based on vomiting, clinical chemistry changes, and hepatic fibrosis and cirrhosis. The NOAEL in males is 1500 ppm (39 mg/kg bw/day). This study

is classified as **totally reliable** ( **acceptable/guideline)** and satisfies guideline requirements for a chronic toxicity study (OPPTS 870.4100; OECD 452) in non - rodents.

### Page 58 of 83

**A.4.5 Carcinogenicity**  **870.4 300**  **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 ye ar to assess chronic toxicity . In the carcinogenicity group (50/sex/dose), body weight decreases after two years of 8% were noted in males at 3000 ppm. In females, body weights were decreased 11.9% or more at ≥ 250 ppm. This indicated that dosing was adequate. Treatment with BAS 700 F did not affect the survival of rats in the carcinogenicity group. Tumors considered a result of treatment were observed in the liver and thy roid onl y. Hepatocellular tumors were in the form of adenomas and carcinomas in both sexes, with a significant increase in the combined incidence of these tumor ty pes in males at ≥ 1500 ppm and in females at 3000 ppm. Significant increases in hepatocell ar carcinomas were observed only in males and onl y 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. Non neoplastic 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 hy pertrophy , spongiosis hepatitis in males at  1500 ppm, increased pigment storage (likel y lipofucsin) in males and females at  1500 ppm, and dark brown liver discoloration at  1500 ppm. Thy roid tumors res ulting from treatment were in the form of follicular cell adenomas and carcinomas. The combined incidence of adenomas and carcinomas was significantly increased for males onl y at 3000 ppm compared to concurrent controls. The incidence was within the hist orical control range, but was still considered an effect of treatment. The individual incidence of thy roid follicular adenomas or carcinomas did not reach statistical significance for males or females. For males onl y, the incidence of carcinomas at 3000 ppm was not significantl y 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 signific ance at any dose compared to concurrent controls and was within the historical control range. These results were consistent with thy roid histopathology , which showed significant thy roid follicular hy

perplasia in males at  1500 ppm. Colloid was also altered in both sexes at 1500 ppm and above. In addition, the bones of animals in the carcinogenicity group were examined by gross and histopathology . In the femora and other bones of affected animals (nasal turbinates, sternae, vertebrae) deposition of Perl's Prussian Blue stain positive material, most probably iron, was

### Page 59 of 83

observed at  250 ppm in both sexes. No changes of the bone structure were identified by light microscop y . Gross pathological evaluation identified white discoloration of skull bones (fro ntal bone, dorsal skull, ty

mpanic cavity) that diagnosed as periosteal hyperostosis (i.e. bone thickening). These effects were considered potentially adverse. Chronic toxicity

(one ye ar duration) was also investigated in this study in satellite animals (10/sex/dose). Adverse effects on body weight were indicated b y 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 hy pertrophy at  1500 ppm in males and females, pigment storage (likel y lipofucsin) in males and females at  1500 ppm, and liver discoloration at 3000 ppm in both sexes. N one of these changes were considered clearl y adverse. Changes in several clinical chemistry parameters were also observed. These consisted of increased serum - glutamyl transferase (considered equivocal) in males and/or females at  1500 ppm, increased albumin and globulin in males and/or females at  1500 ppm, (not considered adverse), increased cholesterol and triglycerides in females at 3000 ppm (considered potentially adverse) decreased glucose in males at  250 ppm (not to a magnitude considered adverse), and decreased total biliribun in males and females at  250 ppm (not considered adverse). In addition, changes of electrol yt e levels (Ca2+ 

### , Cl 

### and inorganic PO 4 3 - 

### ) were observed in females and/or males, at 3000 ppm (PO 4 3 - 

### in males ) and  1500 ppm (Ca2+ 

### , Cl 

### in 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 Fe 3+ 

### ) was observed at ≥ 1500 ppm, which was not considered adverse. The thy roid as well as the femur and other bones were also affected. In the thy roid an increased incidence of follicular cell hy pertrophy/hy

perplasia 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 probabl y iron, was observed. Although there were no light microscopicall y visible changes of the bone structure, this finding was considered to be potentiall y adverse. Discoloration of the teeth (incisors) was also observed in 3000 ppm males and females. This was not considered adverse. Hematological changes were mainl y 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 level s ≥ 250 ppm and in males at ≥ 1500 ppm, which were considered potentially adverse due to possible hy percoagulability . **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 ch**  **anges in the liver (foci, masses) The NOAEL is 50 ppm (2.1 mg/kg bw/day in males and 2.7 mg/kg bw/day in females).**  This study

is classified as **totally reliable (acceptable/guideline)** and satisfies the guideline

### Page 60 of 83

requirement for a combined chronic toxi city /carcinogenicity

study (OPPTS 870.4300; OECD 453) in rats. **870.4 300**  **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) wa s administered to C57BL/6 J Rj mice in the diet for 18 months at doses of 0, 150, 750, 3000 and 6000 ppm (21, 107, 468 and 996 mg/kg bw in males and 33, 158, 652 and 1307 mg/kg bw in females). There were no treatment - related neoplasms. Sy stemic 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 onl y t arget organ as indicated b y 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, respectivel y. 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 rel iable (acceptable/guideline)**  and satisfies the guideline requirement for a chronic toxicity /carcinogenicity study

(OPPTS 870.4300; OECD 451) in mice. **A.4.6 Neurotoxicity**  **870.6100 Delayed Neurotoxicity Study -**  **Hen -**  **NA 870.6200a Acute Neurotoxicity**  **MRID 47923605** The acute neurotoxicity

of BAS 700 F (Batch COD - 001026; Purity : 99.4%) was investigated in groups of 10 male and female Wistar rats ( Crl:WI(Han) after a s ingle administration by gavage at dose levels of 0, 125, 500, and 2000 mg/kg bw/d. No signs of general sy stemic 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 day s 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 indicatio n of neuronal damage.

### Page 61 of 83

**The LOAEL is 500 mg/kg bw in males and females, based on decreased motor activity (in both sexes) and decreased rearing (in males only). The NOAEL is 125 mg/kg bw.**  This study

is classified as **totally reliable** ( **acceptable/guideline)** and satisfies the guideline requirement for a an acute neurotoxicity study (OPPTS 870.6200; OECD 424) in rats. **870.6200b Subchronic Neurotoxicity MRID 47923606**  Dietary administration of BAS 700F (Batch: COD - 001026, Purity : 99.4%) to groups of 10 male and female Wistar Crl:WI(Han) rats at dietary dose levels of 0, 200, 1000, and 5000 ppm (11.5, 57.7, and 302.2 mg/kg body weight /day

in males and 13.4, 67.2 and 337.7 mg/kg body weight/day

in females) for 3 months did not result in any clinical (general clinical observation, FOB and motor activity) or neurohistopathological indication of neurotoxicity . Signs of s ys temic toxicity observed in this study

were consistent with those observed in other repeated dose rat studies with BAS 700 F. These consisted of slightly impaired body

weight development in high dose females, changes of clinical chemistry parameters (increased serum - GT, total protein, albumin, globulin, cholesterol, trigl yc erides, urea, Ca2+ 

### , inorganic PO 4 - 

### and Mg2+ 

### levels as well as decreased AS(A)T, glucose and bilirubin levels), increased liver and thy roid weights as well as centrilobular hy pertrophy of hepatocy

tes. Under the conditions of the present study the no observed adverse effect level (NOAEL) for neurotoxicity

w as 5000 ppm, the highest dose tested, which is equivalent to about 302 mg/kg bw/d in males and 338 mg/kg bw/d in females. **The NOAEL for neurotoxicity is 5000 ppm (302 mg/kg bw/day in males and 338 mg/kg bw/day in females). The LOAEL was not observed.**  This study

is classified as **totally reliable** ( **acceptable/guideline)** and satisfies the guideline requirement for a chronic neurotoxicity study (OPPTS 870.6200; OECD 424) in rats. S **A.4.6 Mutagenicity**  **MRIDs 47923572, 47923579,**  **47923577, 47923584**  **MRID 47923572**  S. 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 use d 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 o f 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 c oncentrations of 500 μg/plate (strain TA1537 in the plate incorporation assay) or above. Precipitation of the test substance was noted at concentrations of  500 μg/plate with and without metabolic activation in both experiments. Neither in the first experiment (plate incorporation test) nor in the second experiment

### Page 62 of 83

(preincubation test) a biologicall y 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 c ontrols induced the appropriate response in the corresponding strains, thus demonstrating the sensitivity

of the test sy stem. According to the results of the study , the test substance BAS 700 F is not mutagenic in the Salmonella typhimurium/ Escherichia c oli reverse mutation assay under the experimental conditions of the study . This study

is classified as **totally reliable** ( **acceptable/guideline)** and satisfies the guideline requirement for a bacterial reverse mutation test (OPPTS 870.5100, OECD 471). **MRID 47923579**  BAS 700 F (Batch COD - 000899; purity 99.7%) was tested in vitro for its ability to induce forward mutations in mammalian cells by assessing the mutation of the HPRT locus in Chinese Hamster CHO cells. Two independent sets of experiments were c onducted in the presence and absence of metabolic activation. Based on the results of a preliminary cy totoxicity assay concentrations of 5 to 100 μg/mLwere employed in the original experiment using a 4 - hour exposure period with and without metabolic activ ation. In the second experiment concentrations of 6.3 to 100 μg/mLwere used without metabolic activation for a 24 hour exposure and with metabolic activation for a 4 hour exposure. Ethyl methanesulfonate (EMS) and methylcholanthrene (MCA) served as positiv e controls in the experiments without and with metabolic activation, respectivel y. After the incubation period treatment media were replaced b y 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. Cy totoxic 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 cy totox icity

### Page 63 of 83

results of a previously

performed HPRT study , concentrations of 6.3 to 400 μg/mLwere 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, respectivel y) were included to demonstrate the sensitivity of the test sy stem. Prior to cell harvest, addition of Colcemid arrested cells in the metaphase. After slide preparation and staining of the cells, at least 200 well spread metaphases per dose and treatment condition were anal yz ed for chromosomal aberrations. At concentrations of 100 μg/mLand 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 orall y 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 administ ered 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 ery throcytes were ev aluated per animal and investigated for micronuclei. The normocy tes with and without micronuclei occurring per 2000 pol yc hromatic ery throcy tes were also recorded. Two oral administrations of BAS 700 F did not lead to any biologically

relevant increase in the number of pol ychromatic ery throcy tes containing either small or large micronuclei. The rate of micronuclei was mostly

close to the concurrent negative control and was within the range of the

### Page 64 of 83

historical control data. Inhibition of ery thropoiesis, determ ined from the ratio of polychromatic to normochromatic ery

throcy tes, did not occur. Signs of s ys temic 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 ery

throcy tes containing small (cyclophosphamide) or small and large (vincristine sulphate) micronuclei, thus demonstrating the sensitivity of the test sy stem. This study

is classified as **totally reliable** ( **acceptable/guideline)** and satisfies the guideline requirement for an ery

throcy te micronucleus test (OPPTS 870.5395, OECD 474). **A.4.7 A.4.8**  **Metabolism 870.7485**  **Metabolism**
**– Rat MRIDs 47923555 and 47923556**  Biokinetic studies with 14 

### C

–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. 14 

### C

–BAS 700 F was administered to male and female Wistar rats (4/sex/dose) via oral gavage in a water/0.5% carbox ym ethylcellulose/1% cremophor vehicle. Plasma kinetics were first characterized by administering a single dose of 5, 50, or 500 mg/kg bw and plasma concentratio ns measured at 1, 2, 4, 8, 24, 48, 72, 96, 120, 144, and 168 hours. The times to maximum plasma levels (T MAX

### ) 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 (C MAX

### ) of 65.3 1/66.08, 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 respectivel y. 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 an d 500 mg/kg bw and the difference in bile excretion pattern. Doses of 150 and 7.5 mg/kg bw 14 

### C

–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 - do se 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 1 4 

### C

–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 widel y distributed in both sexes with a similar pattern : the highest concentrations were found in the gut contents

### Page 65 of 83

and stomach contents. However, lower concentrations were found in numerous other organs/tissues, including the li ver, thy roid, 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 14 

### C

–BAS 700 F was administered orally (b y gavage) to 4/sex/dose with males sacrificed at 1, 8, 28, and 48 hours and females sacrificed at 1, 20, 28, and 48 h after the administration of the test substance. A similar pattern of distribution of the radiolabel was observed as in the high dose group. Radioactivity declined in all tissues over time for the males and females except for the gut contents, which increased in 3 - fold males from 1 hour to 8 hours prior to decreasing. A similar effect occurred in gut content in females, which increased from 1 to 20 hours about 1 .5 fold up to 1.7 - fold at 28 hours prior to decreasing at 48 h. Mass balance and excretion were investigated in males and females in single dose studies with 150 or 7.5 mg/kg 14 

### C

–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 14 

### C 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 Day s 1 - 14 and 14 

### C

–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%. Non relevant portions of the administered radioactivity were excreted as CO 2 

### in exhaled air. The time course of the amount of radioactivity found in urine and feces indicated the excretion occurred predominantly

within three day s 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 14 

### C

–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, respectivel y. Within 72 hours after administration of 14 

### C

–BAS 700 F at a dose level of 7.5 mg/kg bw, excretion via b ile was found to be 50.92% and 55.80% of the administered radioactivity

in males and females, respectivel y. These data also demonstrated a gender

– independent excretion pattern for 14 

### C

–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 14 

### C

–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 th e 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 pharmacokineti cs study (OPPTS 870.7485; OECD 417) in rats. The **metabolic fate** of 14 

### C

–BAS 700 F was investigated in a follow - up study (BASF Reg. Doc. #

### Page 66 of 83

2009/1019789). Material from the biokinetics study was used for investigation of metabolite patterns in urine and feces (dose groups B, C, D) and in bile (dose groups R, S). Three additional groups of animals (designated DX, V, and W) were dosed with 14 

### C

–B AS 700 F specificall y for the metabolism study

(see **Error! Reference source not found. Error! Reference source not**  **found.** ). Urine, plasma, and bile, as well as extracts of feces, liver, fat, and kidney tissue were anal yz ed b y HPL C. Individual metabolite s were detected down to a level of about 0.1% of the dose administered or less. Metabolites were identified by L C

–MS and LC

–MS/MS. The structures and codes of identified BAS 700 F metabolites are shown in **Error! Reference source not found.**  **Error! Reference source not found.**  . In urine , 23 metabolites were identified. The main metabolites were in the range of 0.2% to 8.6% of the applied dose and identified to be M700F004, M700F005/M700F024 (detected onl y in male rats), M700F009/M700F028, M700F014, M700F015, and M700F061 (detected onl y 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 h igh dose levels, i.e. , dose group D, C, and DX (for both labels (19

–44% of the dose applied), and represented onl y a minor part of the extractable radioactivity (3% of the dose applied) at the low dose level (dose group B). The main metabolites were identi fied 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 a s 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 0.1 1% 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, respectivel y. In fat , two components were detected: the metabolite M700F008 (0.05 to 0.29% of the applied do se) 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, respectivel y. The main biotransformation steps of BAS 700 F in rats are hydrox yl ation at the biphenyl ring sy stem, N - demethylation at the py razole ring s ys tem, loss of a fluorine atom at the biphenyl ring

### Page 67 of 83

sy stem, and conjugati on with glucuronic acid or with glutathione derivatives. A further, but negligible transformation route is cleavage at the amide bond between the py razole ring s ys tem and the biphenylring s ys tem. This study

is classified as **totally reliable** ( **acceptable/g uideline)**  and, together with the biokinetic study , satisfies the guideline requirement for a metabolism and pharmacokinetics study (OPPTS 870.7485; OECD 417) in rats. **870.7600 Dermal Absorption** 
**– Rat**  **– MRID 47923632**  14 

### C - BAS 700 F formulated as BAS 703 02 F, which contains both fluxapy roxad and py raclostrobin (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/cm2 

### for 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 remove d 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 o f 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%. Sy stemic absorption of radioactivity (the amount in the urin e, 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 ov er 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 th at the 120 hour post - observation period should be used for quantitative estimations of dermal absorption. The amount of 14 

### C - BAS 700 F that was s ys temically absorbed at the end of the 120 hours post observation period increased with decreasing dose, rang ing 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 sy stemically 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 14 

### C - BAS 700 F on the skin (tape) strips does not changes this value. This study

is classified as **totally reliable** ( **a cceptable/guideline)**  and satisfies the guideline requirement for a dermal penetration study (OPPTS 870.7600, OECD 427) in rats.

### Page 68 of 83

**A.4.9 Immunotoxicity**  **870.7800 Immunotoxicity** 
**– Mouse MRID 47923633**  The immunotoxic potential of BAS 700 F (Batch: COD - 001049; Purity : 99.2%) in male C57BL/6J Rj mice (8/dose) was anal yz ed 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, respectivel y) for 28 day s. Treatment with BAS 7 00 F did not result in sy stemic 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 d etermination of l ymphoid organ weights (spleen and thy mus) and b) the total ly

mphocy te count as well as l ymphocy

te subpopulation distribution including natural killer cells. Furthermore, functional parameters comprising of the anal ys is of the primary humor al (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 b y oral gavage) induced clear signs of immunotoxicity, demonstrating the reliability of the test sy stem under the study conditions employed. Based on the obtained results it can be concluded that BAS 700 F did not have an immunomodulatory

/immunotoxic potential under the conditions of this study . This study

is classified as **totally reliable** ( **acceptable/guideline)** and satisfies the guideline requirement (OPPTS 870.7800) for an immunotoxicity study .

### Page 69 of 83

### Page 70 of 83

**A PPENDIX B. METABOLISM**  **B. 1 Chemical Names and Structures**

**Me tabolite 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 pyrazole - 4 - carboxamide M = 367

**M700F009** 3 - (difluoromethyl) - N - (hydroxy- 3',4',5' - trifluoro[1,1' - biphenyl] - 2 - yl) - 1Hpyrazole - 4 - carboxamide M = 383 F F F N O N N F F H

O N N F F O H

O N N H F F O H

F N O N N F F H
F F O- G l c A

F F F N O N N F F H O H

F F F N O N N F F H O H

F F F N O N N H F F H

F F F N O N N H F F H O H

### Page 71 of 83 **M700F010** 3 - (difluoromethyl) - N - (hydroxy- 3',4',5' - trifluoro[1,1' - biphenyl] - 2 - yl) - 1Hpyrazole - 4 - carboxamide M = 383

**M700F011** 3 - (difluoromethyl) - 1 - methyl - N - (hydroxy- (1 - glucuronyl)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

**M700F016** 3 - (difluoromethyl) - 1 - methyl - N - (methylthio - hydroxy - 3',4',5' - trifluoro - [1,1' - biphenyl] - 2 - yl) - 1H - pyrazole - 4 - carboxamide M = 443 F F F N O N N H F F H O H

F N O N N F F H

F O - G l c A O H

F N O N N H F F H
F FO - G l cA

F N O N N F F H
F F O - G l c A

F N O N N H F F H
F FO - G l cA

F N O N N F F H

F O - G l cA

F N O N N F F H

F F S C H 3 O H

### Page 72 of 83 **M700F019** 3 - (difluoromethyl) - 1 - methyl - N - ((1 - glucuronyl)oxy - 3',4',5' - trifluoro - [1,1' - biphenyl] - 2 - yl) - 1H - pyrazole - 4 - carboxamide M = 573

**M700F020** 3 - (difluoromethyl) - 1 - methyl - N - (hydroxy- (1 - glucuronyl)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

**M700F025** 3 - (difluoromethyl) - N - ((hydroxysulfonyl)oxy - 3',4',5’ - trifluoro[1,1' - biphenyl] - 2 - yl) - 1H - pyrazole - 4 - carboxamide M = 463

**M700F026** 3 - (difluoromethyl) - 1 - methyl - N - ((hydroxysulfonyl)oxy - 3',4',5’ - trifluoro[1,1' - biphenyl] - 2 - yl) - 1H - pyrazole - 4 - carboxamide M = 477 F N O N N F F H
F F O - G l c A

F N O N N F F H

F F O - G l c A O H

F N O N N H F F H

F O - G l cA

F N O N N H F F H
F FO - G l cA

F N O N N H F F H
F FO - G l cA

F N O N N F F H
F O H

F N O N N H F F H
F F O S O 3 H

F N O N N F F H
F F O S O 3 H

### Page 73 of 83 **M700F027** 3 - (difluoromethyl) - 1 - methyl - N - ((hydroxysulfonyl)oxy - 3',[4' or 5’] - difluoro[1,1' - biphenyl] - 2 - yl) - 1H - pyrazole - 4 - carboxamide M = 459

**M700F028** 3 - (difluoromethyl) - 1 - methyl - N - (methylthio - (1 - glucuronyloxy) - 3',4',5' - trifluoro - [1,1' - biphenyl] - 2 - yl) - 1H - pyrazole - 4 - carboxamide M = 619

**M700F029** 3 - (difluoromethyl) - N - (methylthio - (1 - glucuronyl)oxy - 3',4',5' - trifluoro - [1,1' - biphenyl] - 2 - yl) - 1H - pyrazole - 4 - carboxamide M = 605

**M700F032** 3 - (hydroxycarbonyl) - N - (hydroxy- 3',4',5' - trifluoro[1,1' - biphenyl] - 2 - yl) - 1H - pyrazole - 4 - carboxamide or tautomer M = 361

**M700F042** 3 - (difluoromethyl) - 1 - methyl - N - (hydroxy- 3',4',5' - trifluoro[1,1' - biphenyl] - 2 - yl) - 1H - pyrazole - 4 - carboxamide M = 397

**M700F048** 3 - (difluoromethyl) - 1 - ( - D - glucopyranosyl) - N - (3',4',5' - trifluoro[1,1' - biphenyl] - 2 - yl) - 1H - pyrazole - 4 - carboxamide

**M700F050** 3 - (difluoromethyl) - N - ((1 - glucuronyl)oxy - 3',4',5' - trifluoro[1,1' - biphenyl] - 2 - yl) - 1H - pyrazole - 4 - carboxamide M = 559 F N O N N F F H

F O S O 3 H

F N O N N F F H

F F O - G l c A S C H 3

F N O N N F F H

F F O - G l cA S C H 3

F F F N O N N H H O O C

F F

F N O N N F F H O H

F N O N N H F F H
F FO - G l cA

### Page 74 of 83 **M700F061** 3 - (difluoromethyl) - 5 - (1 - glucuronyl)oxy - N - (3',4',5' - trifluoro[1,1' - biphenyl] - 2 - yl) - 1H - pyrazole - 4 - carboxamide M = 559

**M700F063** 3 - (difluoromethyl) - 1 - methyl - N - ((S - cysteinyl) - hydroxy - 3',[4' or 5'] - difluoro - [1,1' - biphenyl] - 2 - yl) - 1H - pyrazole - 4 - carboxamide M = 498 F F F N O N N H F F H

O - G l c A

F N O N N F F H

F O H C O O H N H 2 S

### Page 75 of 83

**B. 2**  **METABOLISM SUMMARY TABLE Table B.**  **2 Tabular Summary of Fluxapyroxad Metabolites and Degradates**  **Chemical Name (other nam**  **es in parenthesis) and**  **Structure Matrix**  **Percent TRR (PPM) 1**  **Matrices -**  **Major Residue (>10%TRR)**  **Matrices -**  **Minor Residue (<10%TRR)** Parent - Fluxapyroxad Soy bean forage TRR 4.1 - 6.1 ppm Parent >92% M700F048 0.6 - 1.2% Soy bean hay TRR 61 - 64 ppm Parent 88% M700F048 1.6 - 2.2% Soy bean straw TRR 0.85 - 1.2 ppm Parent 92% M700F048 0.8% Soy bean hull TRR 2.2 - 3.3% Parent 64% M700F048 2.6 - 3.1% M700F002 ND - 2% Soy bean seed TRR 0.11 - 0.24 ppm Parent 21% (TRR ~0.12)

M700F002 ND - 33% M700F048 9 - 20% Tomato leaves TRR 4.4 - 6.7 ppm Parent >90% M700F075/M700F076 <1.4% M700F048 <0.8% M700F008 2.8% Tomato fruit TRR 0.12 - 0.16 ppm Parent >94% M700F008 <1.4% Wheat forage TRR 0.9 - 1.0 ppm Parent 87 - 91% M700F008 et al 4.2 - 5.8% Wheat hay TRR 10 ppm Parent 87 - 89% M700F008 et al 2.4 - 3.3% Wheat straw TRR 17 - 19 ppm Parent 84 - 86% M700F008 et al 2.8 - 3.7% Wheat chaff TRR 6.7 - 7.4 ppm Parent 76 - 82% M700F008 et al 5.8 - 6.2% Wheat grain TRR 0.045 - 0.057 ppm Parent 60 - 63% M700F008 et al 6.5% **Rotational Crops**  Rotational spinach 30 day TRR 0.10/0.18 ppm Parent 10 - 22%

M700F002 48% M700F058 11.5% M700F074 4.7 - 16.4% M700F001 1.0% M700F008 3.1 - 4.9% M700F036 7.8% M700F042 4.2 - 8.1% M700F048/M700F057 4.5% Rotational Radish Top 30 day TRR 0.069/ -- ppm Parent 18%

M700F008 24% M700F048/M700F057 13% M700F059 11% M700F036 9% M700F042 0.7% M700F058 0.9% M700F074 3.3% Rotational Radish Root 30 day; TRR 0.015/0.014 ppm Parent 43 - 53%

M700F008 26 - 29% M700F048/M700F057 4.9 - 5.9%

### Page 76 of 83

**Table B. 2**  **Tabular Summary of Fluxapyroxad Metabolites and Degradates Chemical Name**  **(other nam es in**  **parenthesis) and Structure**  **Matrix Percent TRR (PPM)**  **1 Matrices**  **- Major Residue**  **(>10%TRR) Matrices**  **- Minor Residue (<10%TRR)**  Rotational Wheat forage 30 day TRR 0.14/0.28 ppm Parent 76 - 84% M700F002 4.2% M700F008 5.6 - 6.0% M700F036 0.6% M700F048/M700F057 1.0% M700F074 1.0% Rotational Wheat hay 30 day TRR 1.08/ -- ppm Parent 81% M700F008 6.2% M700F042 0.6% M700F048/M700F057 0.9% Rotational Wheat straw 30 day TRR 1.88/2.7 ppm Parent 54 - 64% M700F002 2.0% M700F008 4.4 - 7.6% M700F042 0.9 - 6.0% M700F048/M700F057 1.9 - 2.2% M700F074 2.4% Rotational Wheat chaff 30 day TRR 0.40/1.1 ppm Parent 54 - 64% M700F001 0.7% M700F002 5.9% M700F008 7.8% M700F042 0.3 - 0.5% M700F058 1.7% M700F074 3.1% Rotational Wheat grain 30 day TRR 0.02/0.03 ppm Parent 24 - 28% M700F008 4.0 - 6.4% M700F042 0.3% Ruminant milk TRR 0.011/0.017 ppm Parent 13 - 20%

M700F008 24 - 25% M700F010/M700F040 12 - 15% M700F009 5.5 - 5.7%

Ruminant liver TRR 0.35/0.56 ppm M700F008 13 - 17% Parent 3.2 - 3.7% M700F004 1.9 - 2.6% M700F005/M700F024 6.4 - 8.3% M700F009 2.3 - 2.5% M700F010/M700F040 0.7% Ruminant kidney TRR 0.036/0.078 ppm M700F004 12 - 13%

M700F008 22 - 26% M700F005/M700F024 5.2 - 19% Parent 5.4 - 7.0% M700F009 2.0 - 3.6% M700F010/M700F040 3.1 - 4.0% M700F014 3.0 - 3.5% M700F015 4.1 - 5.2% M700F034/M700F036 4.9 - 5.2% M700F038/M700F039 5.1 - 9.0% M700F046/M700F047 3.1 - 4.4% Ruminant muscle TRR 0.007 ppm Parent 12%

M700F008 55 - 83% Ruminant fat Parent 34 - 44% M700F004 ND - 6.1%

### Page 77 of 83

**Table B. 2**  **Tabular Summary of Fluxapyroxad Metabolites and Degradates Chemical Name**  **(other nam es in**  **parenthesis) and Structure**  **Matrix Percent TRR (PPM)**  **1 Matrices**  **- Major Residue**  **(>10%TRR) Matrices**  **- Minor Residue (<10%TRR)**  TRR 0.021/0.025 ppm M700F008 26%

M700F005/M700F024 3.2 - 14% M700F010/M700F040 ND - 3.7% Ruminant urine TRR 1.9/4.3 ppm M700F005/M700F024 33 -

34% M700F008 14 - 36% M700F046/M700F047 9.3 - 10.3% M700F004 1.3% M700F009 8.8% M700F010/M700F040 2.6 - 3.0% M700F034/M700F036 1.3 - 6.2% M700F038/M700F039 2.5 - 2.8% M700F041/ - 42/ - 43/ - 44 2.6 - 3.6% Ruminant feces TRR 1.9/1.8 ppm M700F005/M700F024 35 -

50% Parent 2.0 - 4.0% M700F008 ND - 7.8% M700F033 ND - 1.4% Ruminant bile TRR 7.3/6.6 ppm M700F004 55%

M700F014 25% M700F015 10% M700F112 0.8% Poultry liver TRR 0.21 ppm Parent 1% M700F005 4.1% M700F008 4.1% M700F008/ M700F038 5.3% M700F024 6.9% M700F0047 3.1% Poultry muscle TRR 0.010 ppm Parent 12%

M700F008 17% Dimer of parent 21% M700F005 2.8% Poultry fat TRR 0.059 ppm Parent 38%

M700F008 15% Dimer of parent 36% M700F005 1% Poultry eggs TRR 0.077 ppm Parent 12%

M700F008 44% Dimer of parent 36% M700F004 4.2% M700F005 6.6% M700F009/ M700F038 5.0% Poultry excreta TRR 3.64 ppm M700F005 17%

M700F024 11% M700F009/ M700F038 12% Parent 7.4% M700F008 6.3% M700F047 3.7% Dimer of parent 1.1% Rat liver Dose 150 mg/kg Parent 0.16 - 0.36%

M700F008 0.17 - 0.45% M700F006 0.18 - 0.23% M700F005 0.10 - 0.19% M700F009 0.12 - 0.17% M700F010 et al 0.02 - 0.04% M700F016 0.01 - 0.04% M700F0240.06 Rat kidney Dose 150 mg/kg M700F008 0.0 - 0.5% Parent 0.03 - 0.05% Rat fat Parent 0.35 - 1.55 M700F006 0.03 - 0.09%

### Page 78 of 83

**Table B. 2**  **Tabular Summary of Fluxapyroxad Metabolites and Degradates Chemical Name**  **(other nam es in**  **parenthesis) and Structure**  **Matrix Percent TRR (PPM)**  **1 Matrices**  **- Major Residue**  **(>10%TRR) Matrices**  **- Minor Residue (<10%TRR)**  150 mg/kg M700F008 0.040.25% Rat Feces 150 mg/kg M700F009 9 - 11%

Parent 30 - 31% M700F005 2.7 - 5.2% M700F006 6.2 - 7.8% M700F008 0.34% M700F010 1.7 - 3.2% M700F016 4.2 - 9.5% Water Water Summary of Metabolism Studies Soy bean; PMRA# 1883838. MRID 47923642. ; Application Rate: 3 applications x 60 g a.i./ha (0.6x single rate; 0.9x seasonal rate) at BBCH 16/17, 51

– 59 and 71

– 75 ; 0.6x compared to single application rate; pre - harvest interval 14 day PHI for mature forage (from 2d treatment); 30 day PHI for s oybean hay, straw, hull and seed . BASF only attempted to identify parent, M700F0002, and M700F048. To mato; PMRA# 1883840. MRID 47923641. Application Rate: 3 x 100 g a.i./ha (1x rate). The applications took place 17, 10 and 3 days before harvest (55, 62 and 69 days after planting). Tomato fruits and leaves were sampled three days after the last treatment. Wheat; PMRA# 1883842. MRID 47923643.2 applications x 125 g a.i./ha (1.25x). Wheat hay was sampled at 4 DALA; straw , chaff and grain samples were collected at 34 - 35 DALA. Wheat forage samples were collected 36 days after the first application (forage samples received one application of 125 g a.i./ha only). Rotational Crops (spinach, radish and wheat); PMRA# 1884199. MRID 47923680; One application 250 g a.i./ha (2.5x single rate, 0.83x seasonal rate). The treated soil was aged for 30, 120 and 365 days. Lactating Goat ; PMRA# 1883854 (full report). MRID 47923649 .; 12 mg/kg Feeding Level; Level of ex aggeration compared to maximum dietary burden: 2.6x Beef cattle dietary burden; 0.55x dairy cattle dietary burden; 8 days of dosing; 24 hour pre - slaughter interval. Poultry; Study report. PMRA# 1883852 (full report). MRID 47923645 12 mg/kg Feeding Level; Level of exaggeration compared to maximum dietary burden: 3.2x poultry dietary burden; 12 days of dosing; 23 hour pre - slaughter interval. Rat; Strain: Wistar Crl: WI (Han); male/female; MRID 47923556; BASF Reg. Doc. # 2009/1019789; 150 mg/kg dosing le vel; percentages reported are percent of administered dose. Route of Administration: Oral: gavage; Vehicle: 0.5% aqueous solution of CMC (carboxymethyl cellulose) containing 1% Cremophor

### Page 79 of 83

**B. 3**  **METABOLIC PATHWAYS Proposed metabolic pathways of BAS**  **700 F (fluxapyroxad) in plants.**

2

M700F051 1

M700F00

M700F060 M700F05 F F F N O N N F F H **BA S 700 F**  F F F N O N N F F H
O - M a l o n y l g l c M700F05 O H O N N H F F M700F002 F F F N O N N F F H O H

F F

F N O N N F F H O - G l c M700F05

F F F N O N N F F H H M700F00

F F F N O N N F F H O H

F F F N O N N G l c F F H M700F04

F F F N O N N F F H M a l o n y l g l c F N O N N F F H
F F O - G l c M700F05

F F F N O N N F F H O - M a l o n y l g l c

F N O N N F F H

F O - M a l o n y l g l c M700F055

F N O N N F F H

F M a l o n y l g l c M700F056

F N O N N G l c F F H

F

M700F052 F F F N O N N F F H H O - M a l o n y l g l c

F N O N N F F H H F F

O - G l c M700F053

### Page 80 of 83

**Proposed metabolic pathways of BAS 700 F (fluxapyroxad) in rotational crops (aniline label).**

2



### M700F04

M700F060 1 

### M700F05 M700F005 1 

### M700F041 1

F F F N O N N G l c F F H 

### M700F04

F F F N O N N F F H M a l o n y l g l c F F F N O N N F F

H H O H 

### M700F03

F N O N N F F H
F F O - G l c 

### M700F07

F F F N O N N F F H O - M a l o n y l g l c 

### M700F043 1 F N O N N F F H

F O H 

### M700F024 1

F F F N O N N F F H 

### BA**S 700** F F F N O N N F F H
O - M a l o n y l g l c 

### M700F05 F F F N O N N F F H O H

F F

F N O N N F F H O - G l c 

### M700F05 F F F N O N N O O H H

F F F N O N N F F H H 

### M700F00 F F F N O N N F F H O H

### Page 81 of 83

**Proposed m etabolic pathways for BAS 700 in lactating goats.** 

F F F N O N N F F H

F F F N O N N H F F H

F F F N O N N F F H G l cA F F F N O N N H F F H O H F F F N O N N F F H O H

F N O N N H F F H O H F N O N N H F F H
F F O - G l cA F F F N O N N H H O 2 C

F F N O N N F F H O H

F F N O N N F F H O - G l cA F F F N O N N H H O 2C O H

F F F N O N N H H H O 2 C

F F F N O N N H O H O H F F

F F

F N O N N F F H O - G l cA F O H

F

F F N O N N H F F H **BA S 700 F**  M700F043

M700F008

M700F034 M700F111 M700F009 M700F010 M700F036 M700F005 M700F006 M700F041 M700F042

M700F033 M700F047

M700F014 M700F038 M700F015 M700F024 M700F040 M700F044

M700F032 M700F046

M700F031 M700F039

M700F004

### Page 82 of 83

**Proposed metabolic pathways of BAS 700 F in laying hens.**

1 M700F005 is hydroxylated in para-position to the amide group, established by 1 H NMR spectroscopy 2 Proposed intermediate, not identified in the current study 3 Th ese metabolites were identified by LC - MS/MS, but they could not unambiguously be assigned to a distinct HPLC peak. They occurred at minor quantities, but they were not listed in metabolite quantification tables, because the correlation to a distinct HPLC peak was not given. F F F N O N N F F H

F F F N O N N H F F H

F F F N O N N H F F H O H F F F N O N N F F H O H

F N O N N H F F H O H F F N O N N F F H O H F F F N O N N H O H O H F F

F F

F N O N N F F H O - G l c A F O H

F N O N N F F H

F S O H N H 2 O H

O

F N O N N F F H

F S H O H F F F N O N N F F H O H S C H 3

F F N O N N H F F H

F F N O N N F F H
F F O S H O H

C H 3

**BA S 700 F** 

M700F008

M700F009 M700F005 1 M700F006 2

M700F047

M700F038 M700F024 M700F039 3

M700F004

M700F063

M700F094 3 M700F016 M700F086 3

### Page 83 of 83

**Proposed Metabolic Pathway of BAS 700**  **F in the Rat**

F F F N O N N F F H **BA S 700 F**  O N N F F O H M700F001 O N N H F F O H M700F002

F F F N O N N H F F H M700F008 F F F N O N N H H O O C

M700F032 F F F N O N N H F F H

O - G l cA M700F061

F F F N O N N H F F H O H M700F009 M700F010 F N O N N H F F H

F F S C H 3 O H O H M700F102 M700F104

F N O N N H F F H

F O- G l c A

M700F021 F N O N N F F H
F O H
M700F024 F N O N N F F H

F O- G l c A O H M700F011 F N O N N F F H

F F O - G l c A O H M700F020 F N O N N F F H

F F O O H M700F105

F N O N N F F H
F F Cys
M700F120 F N O N N H F F H
F F Cys
M700F122 F N O N N F F H
F F O H Cys

M700F118

F N O N N H F F H
F F O H Cys

M700F116 F N O N N F F H

F F S C H 3 O H M700F016 M700F107

F N O N N H F F H

F F S C H 3 O H M700F103

F N O N N F F H

F F O - G l cA S C H 3 M700F029 F N O N N F F H

F F O- G l c A S C H 3 M700F028 F N O N N F F H

F O - G l c A

M700F015 F N O N N F F
H

F O H C y s G l y
M700F113 M700F115

F N O N N F F H

F S C H 3 O H M700F106 M700F108 F

N O N N F F H

F O - G l cA Cys

M700F114 F N O N N F F H
F F O S O 3 H M700F026 F N O N N H F F H
F F O S O 3 H M700F025

F N O N N F F H

F O S O 3H
M700F027

F N O N N F F H
F F O - G l cA M700F004 M700F125 and regioisomers F F F N O N N F F H O H

M700F006 M700F005 and regioisomer

F N O N N F F H

F O H Cys

M700F063 M700F117 and regioisomers F N O N N H F F H
F FO - G l c A M700F014 M700F124 and regioisomers/anomers

Remark: CysGlyc = cysteineglycine,Cys = cysteine; GlcA = glucuro nic acid

### Page 84 of 84

**APPENDIX C. PHYSICAL/CHEMICAL PROPERTIES** TABLE 2. Physicochemical Properties of Fluxapyroxad Parameter Value Reference Melting point/range 156.8 o C Product Chemistry monograph B. pH of 1% solution in water 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 

### ] **APPENDIX D. REVIEW OF HUMAN RESEARCH** The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency , and the National Agricultural Chemicals Association, released February , 1995. Agricultural Re - entry

Task Force (ARTF) data base (SOP #3.1)