### UNITED STATES ENV I RONMENTAL PROTECTION AGENCY WASH I NGTON, D

. C

. 20460

OFFICE OF CHEM I CAL SAF E TY AND POLLU T ION PREV E NTION



### MEMORANDUM

July 25, 2013



### SUBJECT: Human Health Risk Assessment for Use ofFluxaproxad on Numerous Crops.

PC Code: 1380 09 DP Barcode:

, 403912

, 41092 3,4 10925, &
410964
Decision N o.: 466686

, 475980

, 4 66653 Registration No.: 7969

- 306

, 7969

- 307, 7969- 308,7969

- 309 ,7 969-310,7969-311

, 7969-312

, 7969-GLE, 7969-GUO, 7969-GLN
Petition No.: 2F8 053

, 2 F 8058

, & 3F 8161 Regulatory Action: Section 3 Registration
Risk Assessment Type: Single C hemical Aggre g ate Case No

. : 3125

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

MRIDNo. : NA 40 CFR : 18,0.666 

### /

# ~/**~** 

# ..**h** ROM: Thurston G. Morton, Chemist \ / "7p-l 

### F



### James S. Miller

, Environmental

# S~tist**~** Angela Howard, PhD., Toxico l ogist

## ~~ Ri s k Assessment Branch 4

Health Effects Division (7509P)



### THROUGH: "'n 6 nna S. Da v i s, Acting Chief 

# #**~** Susan V. Hummel, Branch Senior Scientist

Risk Assessment Branch 4

, HED ( 7 509P)



### TO: O l ga Odiott

, Ri sk Manager Fungicide Branch Registrat i on Division (7505P) . ..



### This document provides the Health Effects D i vision ' s (HED's) risk assessment fo r the propos e d

new uses ofthe active ingredient fluxapyroxad on a wide range of food and seed commodities.

In addition, there is a pe t ition in for an amended stone fruit group tolerance.

Pag e 1 of89

### 1

. 0 EXECUTIVE SUMMARY

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



## 2.0 HED RECOMMENDATIONS

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

2.1 Data Deficiencies/Conditions of Registration

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

2.2 Tolerance Considerations

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

2.2.1 Enforcement Analytical Method

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

2

. 2.2 International Harmonization

.. ...................................... .. .. ... . .. .. . . . . . . ... . ... . . .. . ... .. ........ 9

2.2.3 Recommende

- d Tolerances

. .. .. .. .. .. . ... . ... .. .. .. . ...... ... .. .... . . .. . ... .. .. . ... . ... . .......... . .... . .. .. ... . .. 9

2.2.4 Revisions to Petitioned

- For Tolerances

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

2

. 3 Label Recommendat ion s

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

3.0 ING:REDIENT PROFILE

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

3.1 Chemical Identity

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

3.2 Physical/Chemical Characteristics

........... . . . ... . .. .. .. . . .. .. ....... . ......... . .. •..

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

3

. 3 

### Pesticide Use 

### Pattern

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



### 3.3.1 Registered Products

.. . ... . .. .. .. . ..... . ....... .......................... ...... . ..... . .•.

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

3.3.2 Proposed New Uses

. . . . .. .. .. .. .. . ... . . . . . ..... . .. .. .. .. . ... .. ... ... . . .. ... . .. .. ....... •

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

3.4 Anticipated Exposure Pathways

. ........ .•

.. ...... .. .... .... .. .. .. ... . .. .. ......... . . •.

. ... . ... . ... . .... ... .. .. .. . 16

3

. 5 

### Considerations of 

### Env i ronmental Justice

...... . . .. .. .. .. .. ... . .. . ... . ..... .. .. ....................... .. .. .... 16

4.0 HAZARD CHARACTERIZATION/ASSESSMENT

.............. .. .. ..... .. .. .. .. .................... 17

4 .1 Toxicolog)' Studies Available for Analysis

.. . ...... . .. ... . . ... .. .. .. .. .. .. .. ........ . .... .. ... . ... .. ... . ... . . 17

4.2 Absorption, Distribution, Metabolism and Excretion

.. .. .. .. .. ...... .. .. .. .. .. .. .... .. .............. 17

4

. 3 Toxicological Effects

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

4

. 4 Safety Factor for Infants and Children (FQPA Safety Factor)

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

4.4.1 Completeness of the Toxicology Database

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

4.4

. 2 

### Evidence of 

### Neurotoxicity

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



### 4.4

. 3 Evidence of Sensitivity/Susceptibility in the Devel o ping or Young Animal

.. .. .. 21

4

. 4.4 Residual Uncerta i nty in the Exposure Database

...... .. ... . .. .. .. .. .. ...... .. .. .................. 22

4

. 5 Toxicity Endpoint and Point of Departure

.. .. .. .................. ........ .. .. .. .. .. ........ .. .. ....... .... . 22

4.5.1 Dose

- Response Assessment

. . . .. .. . . . .. ............... .. . ... . ......... . . . . . .. .. .. .. . . ... .. .. .. ... .......... .... 22

4

. 5

. 2 Recommendations for Combining Exposure Routes

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

4

. 5.3 Classification of Carcinogenic Potential

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

4

. 5.4 Summary of Points of Departure Used in Risk Assessment

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

5.0 DIETARY AND DRINKING WATER EXPOSU:RE AND RISK ASSESSMENT

.... 26

5 .1 Metabolite/Degradate Residue Profile

. . .. .. .... .. .. .. ... . . .. . .... .. .. ... . .. ... . ..•

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

5.1.1 Summary of Plant and Livestock Metabolism Studies

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

Page 2 o f89Page 3 of 89



### 5.1.2 Comparison of Metabolic Pathways

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

5.1.3 Environmental Fate and Transport

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

5.1.4 Residues of Concern Summary and Rationale

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

5.2 Food Residue Profile

................................ ................................ ................................ ..... 28

5.2.1 Residues in Crops

................................ ................................ ................................ .... 28

5.3 Water Residue Profile

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

5.3.1 Estimated Drinking Water Concentrations

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

5.4 Dietary and Drinking Water Exposure and Risk

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

5.4.1 Acute Dietary (Food and Drinking Water) Analysis

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

5.4.2 Chronic Dietary (Food and Drinking Water) Analysis

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

5.4.3 Cancer Dietary (Food and Drinking Water) Analysis

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

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

6.1 Residential Handler Exposure

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

6.1.1 Handler Exposure Data

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

6.1.2 Residential Handler Exposure Assumptions

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

6.2 Post

- Application Exposure

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

6. 2.1 Residential Post

- appliction Scenarios

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

6.2.2 Residential Post

- application Exposure Data and Assumptions

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

6.3 Residential Risk Estimates for Use in Aggregate Assessment

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

6.4 Residential Bystander Post

- application Inhalation Exposure

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

6.5 Spray Drift

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

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT

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

7.1 Acute Aggregate Risk

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

7.2 Sh ort

- Term Aggregate Risk

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

7.3 Intermediate

- Term Aggregate Risk

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

7.4 Chronic, Non

- Cancer, Aggregate Risk

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

7.5 Cancer Aggregate Risk

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

8.0 CUMULATIVE RISK

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

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

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

9.1 Exposure Scenarios

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

9.2 Handler Exposure

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

9.2.1 Handler Exposure Scenarios

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

9.2.2 Handler Exposure Data

................................ ................................ .......................... 43

9.2. 3 Handler Exposure Assumptions

................................ ................................ ............ 43Page 4 of 89



### 9.2.4 Handler Exposure and Risk Estimates

................................ ................................ . 45

9.3 Post Application Exposure

................................ ................................ ............................ 50

9. 3.1 Post Application Exposure Scenarios

................................ ................................ ... 50

9.3.2 Restricted Entry Interval

................................ ................................ ....................... 51

10. REFERENCES

................................ ................................ ................................ .................. 51

APPENDIX A: TOXICOLOGY DATA SUMMARY

................................ ......................... 52

A.1 Guideline Data Requirements

................................ ................................ ...................... 52

A.2 Toxicity Profiles

................................ ................................ ................................ ............. 53

A.3 Toxicological Endpoints

................................ ................................ ................................ 64

A.3. 1 Acute Reference Dose (aRfD)

– All populations (General Population, including infants and children and females ages 13

- 49)

................................ ................................ .... 64

A.3.2 Chronic Reference Dose (cRfD)

- All Populations

................................ ................ 64

A.3.3 Incidental Oral Exposure (Short

- Term (1

- 30 days))

................................ .......... 65

A.3.4 Incidental Oral Exposure (Intermediate

- Term (1

- 6 months))

........................... 65

A.3.5 Occupational and Residential Dermal Exposure (Short

- and Intermediate

Term) 65

A.3.6 Occupational and Residential Inhalation Exposure (Short

- Term)

................. 66

A.3.7 Occupational and Reside ntial Inhalation Exposure (Intermediate

- Term)

...... 66

A.4 EXECUTIVE SUMMARIES

................................ ................................ ........................ 67

A.4.1 Subchronic Toxicity

................................ ................................ ................................ 67

A.4.2 Prenatal Developmental Toxicity

................................ ................................ .......... 69

A.4.3 Reproductive Toxicity

................................ ................................ ............................ 71

A.4.4 Chronic Toxicity

................................ ................................ ................................ ...... 71

A.4.5 Carcinogenicity

................................ ................................ ................................ ....... 72

A.4.6 Mutagenicity MRIDs 47923572, 47923579, 47923577, 47923584

...................... 75

A.4.7 Neurotoxicity

................................ ................................ ................................ ........... 77

A.4.8 Metabolism

................................ ................................ ................................ .............. 78

A.4.9 Immunotoxicity

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

APPENDIX B. Chemical Names And Structures Of Metabolites

................................ ......... 84

APPENDIX C. Physical/Chemical Properties

................................ ................................ .......... 89

APPENDIX D. Studies Reviewed for Ethical Conduct

................................ .......................... 89Page 5 of 89



### 1.0 EXECUTIVE SUMMARY

This assessment provides information to support a Section 3 registration for the use of fluxapyroxad for seed and foliar uses on bulb vegetables, leafy vegetables, brassica vegetables, cucurbit vegetables, and root a nd tuber vegetables ( subgroup 1B ) . Also, for foliar uses on the caneberry subgroup, bushberry subgroup, small fruit vine climbing subgroup, low growing berry subgroup, t urf, tree nuts and sugarcane

. In addition, the registrant is amending the tolerance for the stone fruit crop group, and amending the use on rice. This document addresses the exposures and estimated risk associated with the proposed new and amended uses o f fluxapyroxad.

Use Profile

Fluxapyroxad (3

- (difluoromethyl)

- 1

- methyl

- N

- (3′,4′,5′

- trifluoro[1,1′

- biphenyl]

- 2

- yl)

- 1 H

pyrazole

- 4

- carboxamide) is a fungicide belonging to the carboxamide class of chemicals. It is registered for use on a wide range of c rops to control a broad spectrum of fungal diseases. Fluxapyroxad is a pyrazole carboxamide. The mode of pesticidal action as a fungicide is inhibition of succinate dehydrogenase in complex II of the mitochondrial respiratory chain, resulting in inhibiti on of spore germination, germ tubes, and mycelial growth. Applications may be made using groundboom, airblast, aerial, chemigation, mechanically pressurized handgun

, and standard slurry or mist

- type seed treatment equipment. The new registrations include products proposed for homeowner use on turf to residential areas.

T olerances for combined residues of fluxapyroxad and its major metabolites in/on plant and animal commodities range from 0.00 2 ppm to 3 0 ppm.

Proposed New Uses

BASF Corporation i s requesting a Section 3 registration of four fluxapyroxad products. The products are proposed for use on various seed and food crops. BASF has proposed new uses of the fungicide fluxapyroxad (BAS 700F; 3

- (difluoromethyl)

- 1

- methyl

- N

- (3′,4′,5′

- trifluoro[1, 1′

- biphenyl]

- 2

- yl)

- 1 H

- pyrazole

- 4

- carboxamide) on Root vegetables (except sugar beet) subgroup 1B, Bulb vegetables Crop Group 3

- 07, Leafy vegetables (except Brassica) Crop Group 4, Brassica leafy vegetables Crop group 5, Cucurbit vegetables Crop group 9, Ca neberry Crop subgroup 13

- 07A, Bushberry Crop subgroup 13

- 07B, Small fruit vine climbing Crop subgroup
13

- 07F, Low growing berry Crop subgroup 13

- 07G, almonds, pecans, sugarcane, rice (amended use), rotational mint, and rotational Non

- grass animal feed Crop group 18, along with an increased tolerance on Stone fruit Crop group 12. The formulations are Imbrex Xemium Brand Fungicide ( ( 7969

- 306, an emulsifiable concentrate (EC) containing 5.96% fluxapyroxad, 0.52 lb ai/gal with application rates ranging from 0 .09 to 0.18 lb ai per acre and a pre

- harvest interval ( PHI ) range of 0

- 28 days. ) ); Xemium 2.78 Fungicide ST (7969

- 307, for seed treatment, 28.78%
ai , 2.78 lbs ai/gal with application rates ranging from 0.02 to 0.25 lb ai per 100 lb of seed );
Xemium 2.72 Fu ngicide ST (7969

- 308, for seed treatment, 28.70% ai, 2.72 lbs ai/gal with application rates ranging from 0.02 to 0.25 lb ai per 100 lb of seed); Sercadis Xemium Brand Fungicide (7969

- 309, EC formulation with 26.55% ai, 2.47 lb ai/gal with application rates ranging from 0.09 to 0.18 lb ai per acre and a PHI range of 0

- 28 days ); and two co

- active ingredient products with pyraclostrobin: Merivon Xemium Brand Fungicide (7969

- 310, with
f luxapyroxad at 21.26% ai, 2.09 lb ai/gal with applica tion rates ranging from 0.09 to 0.18 lb aiPage 6 of 89



### per acre and a PHI range of 0

- 14 days ) and ( pyraclostrobin at 21.26 % ai), and Priaxor Xemium Brand Fungicide ( 7969

- 311, with f luxapyroxad at 14.33% ai, 1.39 lb ai/gal with application rates ranging from 0.06 to 0 .10 lb ai per acre and a PHI range of 0

- 29 days ) and pyraclostrobin at
28.58% ai ); along with a new product Xemium 703 Fungicide ST (7969

- GLE, for seed treatment, 21.26% ai , 2.09 lbs ai/gal with application rates ranging from 0.01 to 0.08 lb ai per
100 lb of seed ). In addition, there are two proposed new products for turf use. These products are Xzemplar Fungicide ( (7969

- GUO, 26.55% ai, 2.47 lb ai/gal with application rates ranging from 0.14 to 0.22 lb ai per acre and a re

- treatment interval ( RTI ) of 14 days ) ) and Lexicon Intrinsic Fungicide (7969

- GLN, 14.33% ai, 1.39 lb ai/gal with application rates ranging from 0.16 to 0.23 lb ai per acre and a RTI of 14 days ).

Hazard Identification

An extensive toxicity database for fluxapyroxad was submitted to the Agency for registration of fluxapyroxad. This database is complete and considered sufficient for hazard characterization and endpoint selection for the anticipated routes (oral, dermal, and inhalation) and durations of exposure (acute, subchronic, and chr onic) for the proposed uses.

The primary target organ for fluxapyroxad exposure via the oral route is the liver with secondary toxicity in the thyroid for rats only. There was one 28

- day dermal toxicity study in rats that showed no effects up to the l imit dose and one dermal penetration study in rats that estimated a dermal absorption factor of 8.38%. No inhalation toxicity studies were submitted, and the 28

- day subchronic inhalation study was waived at the January 17, 2013 HASPOC meeting (see
discuss ion in Section 4.1). 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 effect s of hepatocellular hypertrophy and increased liver weights and changes in liver enzyme activities were first observed. As the dose or duration of exposure to fluxapyroxad increased, clinical chemistry changes related to liver function also occurred, foll owed by hepatocellular necrosis, neoplastic changes in the liver, and tumors. Thyroid effects were observed only in rats. These effects were secondary to changes in liver enzyme regulation, which increased metabolism of thyroid hormone, resulting changes in thyroid hormones, thyroid follicular hypertrophy and hyperplasia, and thyroid tumor formation. Tumors were not observed in species other than rats or in organs other than the liver and thyroid. The Agency classified fluxapyroxad as “not likely” to be carcinogenic to humans below a defined dose range and has determined that the quantification of risk using a non

- linear approach (i.e., RfD) will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to fl uxapyroxad. This classification was based on a full panel of in vitro and in vivio studies that showed no evidence of genotoxicity, together with mechanistic studies in the liver and thyroid of rats that satisfied stringent criteria for establishing tumorgenic modes of action.

No evidence of neurotoxicity was observed in response to repeated administration of fluxapyroxad. However, a n acute neurotoxicity study showed decreased rearing and motor activity. This occurred on the day of dosing only in the absence of histopathological effects or alterations in brain weights. This indicated that any neurotoxic effects of fluxapyroxad are l ikely to be transient and reversible due to alterations in neuropharmacology and not from neuronal damage. No evidence of reproductive toxicity was observed in rats

. Developmental toxicity inPage 7 of 89



### rats in a two

- generation study was limited to decreased body weight and body weight gain in offspring of the F 1 

### generation (with decreased body weight observed in the F 2 

### generation after lactation day 7) and was observed at the same dose levels that caused thyroid follicular hypertrophy/hyperplasia in parental anim als. Developmental toxicity in rabbits was limited to paw hyperflexion which was significantly increased at the highest dose, where decreased body weight in maternal animals was also observed. Since the maternal toxicities of thyroid hormone perturbation in rats and systemic toxicity in rabbits likely contributed to the observed developmental effects there is low concern for qualitative susceptibility. An immunotoxicity study in mice showed no evidence of immunotoxic effects from fluxapyroxad.

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

No hazards were identified for exposures via the dermal route in a 28

- day dermal toxicity stud y at the limit dose and the dermal absorption study indicates that there is low absorption (8.38%)
via the dermal route in rats

. Further, a lthough developmental toxicity was not assessed in the dermal toxicity study, the Agency has low concern for developmental toxicity for fluxapyroxad.

Oral studies were extrapolated for assessment of inha lation hazards, since no repeated

- dose inhalation studies were available. The HASPOC met on January 17, 2013 to discuss the need for a subchronic inhalation study for fluxapyroxad (TXR # 0056561). The decision was made that this requirement could be waiv ed and a subchronic inhalation study is not required. The weight of the evidence used to support this decision included: the low acute inhalation toxicity of fluxapyroxad, the low volatility of fluxapyroxad and the large margin of exposure demonstrated
in the exposure assessment.

Dose Response Assessment

Toxicological points of departure (PODs) were selected for dietary (food and drinking water) , residential, and occupational exposure scenarios for this assessment. Acute and chronic reference doses ( RfDs) were selected for assessment of food and drinking water exposures. The population adjusted dose (PAD) is equivalent to the reference dose (RfD) divided by the additional FQPA Safety Factor, which was reduced to 1X ; therefore, the acute and chronic R fDs are equivalent to the acute and chronic PADs, respectively

. The rational for reduction of the FQPA Safety to 1X is based on the availability of a complete toxicity database with clear NOAELs for characterizing neurotoxicity and sensitivity during devel opment, supplemental
studies that characterize the effects of fluxapyroxad on thyroid hormones, and no residual uncertainties in the exposure data base.

An acute RfD/PAD for all populations was selected from an acute neurotoxicity study in rats
based on decreased motor activity and decreased rearing. A chronic RfD/PAD for all populations was selected from a chronic toxicity/carcinogenicity study in rats based on non

neoplastic changes in the liver (foci, masses). A POD for short

- term inhalation exposur e was selected from the 28

- day dietary study in rats based on thyroid effects ( thyroid follicular hypertrophy/hyperplasia)

. A P O D for intermediate

- term inhalation exposure was selected from a
90

- day dietary study in rats based also on thyroid effects. PO Ds for short

- and intermediate

- term dermal exposure were not selected because fluxapyroxad does not pose a dermal hazard. AnPage 8 of 89



### uncertainty factor of 100x was applied to endpoints selected for all exposure routes (10x for interspecies extrapolation, 10x for intraspecies variation).

Exposure/Risk Assessment and Risk Characterization

Dietary (fo od and water), occupational handler and post application, and residential handler and post application exposure and risk assessments were conducted for the requested new uses.

Screening level acute and moderately refined chronic dietary and drinking water risk assessments for fluxapyroxad show that dietary and drinking water exposure estimates for the proposed uses are below HED’s level of concern for the general population and all population subgroups.

Occupational exposure and risk estimates for all likely scenarios, including seed treaters and planters are not of concern at the maximum allowable application rates for the proposed new

uses. Although a quantitat ive occupational post

- application inhalation exposure assessment was not performed, an occupation inhalation exposure assessment was performed. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

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

- application inhalation exposure scenarios.

Residential handler and incidental oral exposures were assessed for homeowner applications to
turf. Residential handler and incidental oral exposures are not of concern at the maximum allowable application rates for the proposed new uses.

Environmenta l Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populat ions and Low

- Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies/Conditions of Registration

A revised Section F must be submitted which reflects the commodity definitions and tolerance levels specified in Section 2.2.3, below

.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The residue analytical methods available for enforcement of fluxapyroxad tolerances include the LC/MS/MS method used for data gathering and proposed for enforcement. This method uses
reversed

- phase HPLC with gradient elution, and includes 2 ion transitions to be monitored for the parent fluxapyroxad.Page 9 of 89



### 2.2.2 Inter national Harmonization

No Codex, or Mexican maximum residue limits (MRLs) have been established for residues of fluxapyroxad on any commodity. Maximum residue limits (MRLs) for some of the commodities in this petition are established in Canada, however, harmonization on MRLs other than hog, meat byproducts cannot be accomplished due to higher application rate requested for rice in this petition along with the submission of two additional cherry field trials which required a higher
stone fruit tolerance to be established

.

2.2.3 Recommended Tolerances

Pending submission of a revised Section F (see Section 2.1) , there are no residue chemistry
issues that would preclude granting a Sectio n 3 registration for the requested new and amended uses of fluxapyroxad, or establishment of tolerances for residues of fluxapyroxad (per 2009 HED issued guidance on tolerance expressions (S. Knizner, 2009 ) ) is as follows:

Tolerances are established for residues of fluxapyroxad, including its metabolites and degradates, in or on the commodities in Table 1. Compliance with the tolerance levels specified below is to be determined by measuring only fluxapyroxad [ 3

- (difluoromethyl)

- 1

- methyl

- N

- (3′,4′,5′

- trif

luoro[1,1′

- biphenyl]

- 2

- yl)

- 1 H

- pyrazole

- 4

- carboxamide ] in or on the commodity.Page 10 of 89

Table 2.2.3.1 . Proposed and Recommended Tolerances for Fluxapyroxad

Crop Group or Commodity Proposed

Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity Definition

almond, nut 0.05 0.02 Almond, nut
almond, hulls 4.0 4.0 Almond, hulls berry, low growing, subgroup 13

- 07G 4.0 4.0 Berry, low growing, subgroup 13

- 07G

bushberry, subgroup 13

- 07B 6.0 7.0 Bushberry, subgroup 13

- 07B

caneberry, subgroup 13

- 07A 6.0 5.0 Caneberry, subgroup 13

- 07A

fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F 2.0 2.0 Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F

grapes 2.0 none Fruit, small, vine climbing, except fuzzy kiwifruit, subgroup 13

- 07F will cover grape. grapes, raisin 5.7 5.7 Grapes, raisin

pecans 0.05 0.06 Pecans rice, bran 8.5 8.5 Rice, bran rice, grain 5.0 5.0 Rice, grain rice, hulls 15.0 15 Rice, hulls

rice, straw 20.0 none Covered by existing tolerance on Grain, cereal, forage, fodder and straw, group 16

Strawberry 4.0 none Berry, low growing, subgroup 13

- 07G will cover strawberry.

sugarcane, cane 3.0 3.0 Sugarcane, cane Vegetable, brassica leafy, group 5 3.0 4.0

vegetable, bulb, group 3

- 07 0.8 1.5 Vegetable, bulb, group 3

- 07

vegetable, cucurbit, group 9 0.4 0.50 Vegetable, cucurbit, group 9

vegetable, leafy, except brassica, group 4 15.0 30 Vegetable, leafy, except brassica, group 4

vegetable, root, except sugarbeet, subgroup 1B 0.7 0.90 Vegetable, root, except sugarbeet, subgroup 1B

Fruit, stone, group 12 0.3 3.0 Hog, meat byproducts

--- 0.01 Hog, meat byproducts

Fish

- freshwater finfish

--- 0.01 Fish

- freshwater finfish

Fish

- shellfish,

crustacean --- 0.01 Fish

- shellfish, crustacean

Inadvertent Tolerances nongrass animal feeds, group 18 0.5 

### 0.30 Nongrass animal feeds, group 18

mint 0.05 

### 0.01 Peppermint and SpearmintPage 11 of 89



### Note to PM: Concurrent with the establishment of the proposed tolerance for Rice, grain at 5.0 ppm

under 180.666(a), the tolerances for

Grain, cereal, group 15, (except corn, field, grain; except corn, pop, grain; except corn, kernels plus cobs with husks removed; except wheat)

listed under 180.666(a) should be amended as follows:

Grain, cere al, group 15, (except corn, field, grain; except corn, pop, grain; except corn, kernels plus cobs with husks removed; except rice; except wheat).

In addition, the registrant has proposed tolerances for almond and pecan but use directions
are for the tree nut crop group. The Notice of Filing has individual tolerances. Use directions for the tree nut crop group must be replaced with the individual crops of almond and pecan.

RD should note that the additional stone fruit trials do not exceed the established crop

group tolerance of 2 ppm, but when put into the OECD MRL C alculator a tolerance of 3

ppm is calculated . PMRA to expected to receive a submission requesting a tolerance
increase and that when PMRA have the additional data, HED expect s they will concur with 3 ppm, and this harmonizes the US with the EU action.

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 calculat i o n procedures to determine the appropriate
tolerances. While the registrant also used the OECD calculation procedures to determine proposed tolerances levels, the registrant combined all the data for multiple crops in a crop group in a single calculation. HED’s current policy is to use the OECD calculation procedures to calculate individual tolerances for each crop in a crop group, and then to select the highest tolerance output from the calculation procedures to cover the entire crop group.

2.3 Label Recommendations

The submitted proposed labels were acceptable and adequately supported by field trial data. Use directions for the tree nut crop group must be changed to almonds and pecans. The registrant requested almond and pecan tolerances.Page 12 of 89



### 3 .0 INGREDIENT PROFILE

3.1 Chemical Identity

Structure and nomenclature are reported in Table 3.1.1

.

TABLE 3.1.1 Fluxapyroxad Test Compound Nomenclature.

Chemical structure

Common name Fluxapyroxad (ISO, proposed)

Company experimental name BAS 700 F

IUPAC name 3

- (difluoromethyl)

- 1

- methyl

- N

- (3′,4′,5′

- trifluorobiphenyl

- 2

- yl)pyrazole

- 4

- carboxamide

CAS name 3

- (difluoromethyl)

- 1

- methyl

- N

- (3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1 H

- pyrazole

- 4

- carboxamide

CAS # 907204

- 31

- 3

Molecular Formula C 18 H 12 F 5 N 3 O

End

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



### 3.2 Physical/Chemical Characteristics

A detailed description of the physicochemical properties of fluxapyroxad is provided in Appendix C. Fluxapyroxad exhibits relatively low solubility in water and higher solubility in organic solvents. It has a very low vapor pressure. Fluxapyroxad is pe rsistent in terrestrial and aquatic environments and is moderately to slightly mobile in soil. Fluxapyroxad does not present significant concerns for bioaccumulation based on the lipophilicity of the compound and
on results of bioconcentration studies in fish.

3.3 Pesticide Use Pattern

3.3.1 Registered Products

There are 9 active fluxapyroxad registrations, 7 Section 3s and 2 Section 18 Emergency Exemption s.

3.3.2 Proposed New Uses

Fluxapyroxad is proposed for the following uses ( Table 3 .3.2.1 ).Page 13 of 89

Table 3. 3.2.1 Summary of Directions for Use of Fluxapyroxad

Appl . Timing, Type, and Equip. Formulation Applic. Rate (lb ai/A) (lb ai/100lb seed) for seed

treatment Max. No.

Applic. per
Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days)

Berries and Small Fruits (inc caneberries, bushberries, strawberries, etc)

Foliar spray Ground, Aerial or Chemigation 5.96% EC (7969

- 306)

26.55% EC (7969

- 309) 21.26% EC (7969

- 310) 14.33% EC (7969

- 311) 0.18 3 0.54 0 (caneberry, bushberry, low

growing berry)

14 (grape and small
fruit vine climbing subgroup)

Use Directions and Limitations: A minimum 7

- day RTI is specified. Mix Imbrex (7969

- 306), Sercadis (7969

- 309), Merivon (7969

- 310), Priaxor (7969

- 311) with water only for crops in the caneberry and bushberry crop group. Do not make more than 2 sequential applications before alternating to a labeled non

- Group 7 fungicide. Not registered in CA.
Brassica Vegetables

Foliar spray Ground, Aerial
or C hemigation 5.96% EC (7969

- 306)

26.55% EC (7969

- 309) 21.26% EC (7969

- 310) 14.33% EC (7969

- 311) 0.09 3 0.27 3

Use Directions and Limitations: A minimum 7

- day RTI is specified. Do not make more than 2 sequential applications before alternating to a labeled non

- Group 7 fungicide. Not registered in
CA.

Seed Treatment 28.78% SC (7969

- 307)

28.7% SC (7969

- 308) 21.26% (7969

- GLE) 0.04 0.08 (GLE) Not

applicable 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. Bulb Vegetables

Foliar spray Ground, Aerial
or C hemigation 5.96% EC (7969

- 306)

26.55% EC (7969

- 309) 21.26% EC (7969

- 310) 14.33% EC (7969

- 311) 0.18 3 0.54 7

Use Directions and Limitations: A minimum 7

- day RTI is specified. Do not make more than 2 sequential applications before alternating to a labeled non

- Group 7 fungicide. Not registered in
CA.

Seed Treatment 28.78% SC (7969

- 307)

28.7% SC (7969

- 308) 21.26% (7969

- GLE) 0.04 (0.25 for onion smut) 0.08 (GLE) Not

applicable 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.Page 14 of 89

Table 3. 3.2.1 Summary of Directions for Use of Fluxapyroxad

Appl . Timing, Type, and Equip. Formulation Applic. Rate (lb ai/A) (lb ai/100lb seed) for seed

treatment Max. No.

Applic. per
Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days)

Cucurbit Vegetables

Foliar spray Ground, Aerial
or C hemigation 5.96% EC (7969

- 306)

26.55% EC (7969

- 309) 21.26% EC (7969

- 310) 14.33% EC (7969

- 311) 0.09 3 0.27 0

Use Directions and Limitations: A minimum 7

- day RTI is specified. Mix Imbrex (7969

- 306), Sercadis (7969

- 309), Merivon (7969

- 310), Priaxor (7969

- 311) with water only. Do not make more than 2 sequential applications before alternating to a labeled non

- Group 7 fungicide. Not registered in CA.

Seed Treatment 28.78% SC (7969

- 307)

28.7% SC (7969

- 308) 21.26% (7969

- GLE) 0.04 0.06 (GLE) Not

applicable 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.

Grapes

Foliar spray Ground, Aerial
or C hemigation 5.96% EC (7969

- 306)

26.55% EC (7969

- 309) 21.26% EC (7969

- 310) 14.33% EC (7969

- 311) 0.09 (0.18) 6 (3) 0.54 14

Use Directions and Limitations: A minimum 10

- day RTI is specified. The safety of all possible tank mixtures with Imbrex (7969

- 306), Sercadis (7969

- 309), Merivon (7969

- 310), Priaxor (7969

- 311) has not been tested. Safety should be confirmed prior to appl ication. Do not make more than 2 sequential applications before alternating to a labeled non

- Group 7 fungicide. Not registered in CA. Leafy Vegetables

Foliar spray Ground, Aerial
or C hemigation 5.96% EC (7969

- 306)

26.55% EC (7969

- 309)
21.26% EC (7969

- 310) 14.33% EC (7969

- 311) 0.18 3 0.54 1

Use Directions and Limitations: A minimum 7

- day RTI is specified. Do not apply Imbrex, Sercadis, Merivon, Priaxor to spinach as a tank mix. The safety of all possible tank mixtures with Imbrex (7969

- 306), Sercadis (7969

- 309), Merivon (7969

- 310), Priaxor (7969

- 311) has not been tested on leafy vegetables. Safety should be confirmed prior to application. Do not make more than 2 sequential applications before alternating to a labeled non

- Group 7 fungicide. Not registered in CA except for lettuce drop on leaf and head lettuce.

Seed Treatment 28.78% SC (7969

- 307)

28.7% SC (7969

- 308) 21.26% (7969

- GLE) 0.04

- 2 depending on target disease 0.06 (GLE) Not

applicable 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.Page 15 of 89

Table 3. 3.2.1 Summary of Directions for Use of Fluxapyroxad

Appl . Timing, Type, and Equip. Formulation Applic. Rate (lb ai/A) (lb ai/100lb seed) for seed

treatment Max. No.

Applic. per
Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days)

Rice
Foliar spray Ground, Aerial
or C hemigation 5.96% EC (7969

- 306)

26.55% EC (7969

- 309) 0.13 2 0.27 28

Use Directions and Limitations: A minimum 7

- day RTI is specified. Do not make more than 2 sequential applications before alternating to a labeled non

- Group 7 fungicide. Not registered in
CA.

Seed Treatment 28.78% SC (7969

- 307)

28.7% SC (7969

- 308) 0.05 Not applicable 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.
Root Vegetables Crop Subgroup 1B

Foliar spray Ground, Aerial
or C hemigation 5.96% EC (7969

- 306)

26.55% EC (7969

- 309) 21.26% EC (7969

- 310) 14.33% EC (7969

- 311) 0.09 3 0.27 7

Use Directions and Limitations: A minimum 7

- day RTI is specified. Do not make more than 2 sequential applications before alternating to a labeled non

- Group 7 fungicide. Not registered in
CA.

Seed Treatment 28.7% SC (7969

- 308)

21.26% (7969

- GLE) 0.04 0.06 (GLE) Not

applicable 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.

Sugarcane Foliar spray Ground, Aerial
or C hemigation 5.96% EC (7969

- 306)

26.55% EC (7969

- 309) 14.33% EC (7969

- 311) 0.11 2 0.22 14

Use Directions and Limitations: A minimum 7

- day RTI is specified. Do not make more than 2 sequential applications before alternating to a labeled non

- Group 7 fungicide. Not registered in
CA.

Tree Nuts

Foliar spray Ground, A erial

o r C hemigation 5.96% EC (7969

- 306)

26.55% EC (7969

- 309) 21.26% EC (7969

- 310) 14.33% EC (7969

- 311) 0.11 3 0.33 14

Use Directions and Limitations: A minimum 7

- day RTI is specified except for pistachio which has an RTI of 10 days. Do not make more than 2 sequential applications before alternating to a
labeled non

- Group 7 fungicide. For aerial do not use less than 10 gallons of spray solution per

acre. N ot registered in CA.

Turf
Ground, Aerial, Chemigation,
and/or Mechanically
Pressurized
Hand Gun 26.55% SC (7969

- GUO )

14.33% SC (7969

- GLN ) 0.23 N/A 0.80 N/APage 16 of 89

Table 3. 3.2.1 Summary of Directions for Use of Fluxapyroxad

Appl . Timing, Type, and Equip. Formulation Applic. Rate (lb ai/A) (lb ai/100lb seed) for seed

treatment Max. No.

Applic. per
Season Max.

Seasonal Applic. Rate (lb ai/A) PHI

(days)

Use Directions and Limitations: A 14

- 28 day RTI is specified for turf applications. Do not make more 2 sequential applications in the Fall and Spring, or more than 0.80 lbs ai/Acre per Acre per season. Do not make more than 2 sequential applications before alternating to a
labeled non

- Grou p 7 fungicide. Aerial applications are to be conducted for Sod farms only with
a 100 ft. buffer in the State of NY.



### 3.4 Anticipated Exposure Pathways

Humans may be exposed to fluxapyroxad in food and drinking water, since fluxapyroxad may be applied directly to growing crops and application may result in fluxapyroxad reaching surface and ground water sources of drinking water. Additionally humans may b e exposed to fluxapyroxad in residential settings, since it may be applied to ornamental plantings in residences, public areas, and recreational sides, as well as on lawns and turf and to residential berries and fruit and nut trees. In an occupational set ting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is a potential for
post

- application exposure for workers re

- entering treated fields.

Risk assessments have been previously prepared for the existing uses of fluxapyroxad. This risk assessment considers all of the aforementioned exposure pathways based on the proposed new
and amended uses of fluxapyroxad, as well as the existing uses as well.

3.5 Considerations of Environmental Jus tice

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

- Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on pat terns 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.Page 17 of 89



### 4.0 HAZARD CHARACTERIZATION/ASSESSMENT

4.1 Toxicology Studies Available for Analysis

An extensive toxicity database for fluxapyroxad was submitted to the Agency for registration of fluxapyroxad. Submitted studies via the oral route cover durations and endpoints relevant for hazard characterization for acute and chronic dietary assessments . These studies include metabolism and pharmacokinetic studies, subchronic and chronic dietary studies in rats, mice, and dogs; prenatal developmental studies in rats and rabbits, a 2

- generation reproduction and fertility effects study in rats, acute and subchronic neurotoxicity studies in rats, an immunotoxicity study in mice, a complete battery of in vitro and in vivo genotoxicity studies, and carcinogenicity studies in rats and mice. Supplemental studies were submitted to further investigate the mode o f action of fluxapyroxad on the liver and thyroid. These studies, together
with a 28

- day dermal toxicity study and dermal penetration study, are also appropriate for hazard
characterization for short

- term to intermediate

- term exposures via the dermal rou te. 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 was used for inhalation hazar d characterization. The HASPOC met on January 17, 2013 to discuss the need for a subchronic inhalation study for fluxapyroxad (TXR #0056561). The decision was made that this requirement could be waived and a subchronic inhalation study was not required. The weight of the evidence used to support this decision included: the low acute inhalation toxicity of fluxapyroxad, the low volatility of fluxapyroxad and the large margin of exposure demonstrated in the exposure assessment. There are no toxicity
studi es available for fluxapyroxad in the general literature.

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 submit ted for each formulation for labeling purposes that can also inform hazard characterization.

There are three metabolites of fluxapyroxad: two soil metabolites (M700F001 and M700F002) and a metabolite found on food crops (M700F048). There are no toxic ity studies on these metabolites in the general literature. However, subchronic dietary studies in rats, prenatal developmental studies in rabbits, and a complete battery of in vitro and in vivo genotoxicity studies were submitted to the Agency for these metabolites. Metabolism and pharmacokinetic studies were also submitted for the M700F048 plant metabolite. These studies are sufficient for
hazard characterization.

4.2 Absorption, Distribution, Metabolism and Excretion

Pharmacokinetic and metabolism studies with radiolabeled fluxapyroxad in rats show that plasma levels of radiolabel scaled with dose, indicating that uptake was not saturated up to dose levels of 500 mg/kg. There were no sex differences observed in the rate or extent of absorption.
Th e time to peak plasma levels (t MAX 

### ) was dependent up 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) inPage 18 of 89



### males/females. The initial half

- life of elimination ranged from 14.5/12.0 h (at 5 mg/kg) to 27.3/24.5 h (at 500 mg/kg) in males/females.

Mass ba lance, tissue distribution and biliary excretion studies were performed in rats at doses of 150 mg/kg and 7.5 mg/kg. These studies indicated that radioactivity was widely distributed in both sexes within 16 hours, with bioavailability estimated to be betw een 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 live r, thyroid, adrenal glands, kidney, pancreas, testes/uterus, and brain. For both male and female rats, radioactivity declined in all tissues over time. The time course of the amount of radioactivity found in urine and feces indicated the
excretion occurre d predominantly within three days after dosing, indicating a low potential for bioaccumulation. For both dose groups, the majority of the radioactivity (84

- 94%) was excreted via the feces within 168 hours. The amount excreted via the urine during this t ime was 3

- 17%. Bile duct cannulation experiments showed that the bile was a major route of excretion, with 51

- 64% of radioactivity eliminated via this route. Negligible amounts were excreted as expired air
in rats.

Metabolism studies revealed that the main biotransformation steps of BAS 700 F in rats are hydroxylation at the biphenyl ring system (sometimes repeatedly), N

- demethylation at the pyrazole ring system, loss of a fluorine atom at the biphenyl ring system, and conjugation with glucuronic acid or sulfate, and conjugation with glutathione derivatives. These reactions produced approximately 51 different metabolites. Minor biotransformation steps produced additional metabolites, including M700F001 (from hydrolysis of the amide bond between the

py razole and biphenyl rings) and M700F002 (from N

- demethylation of M700F001). These metabolites were also found in soil, as described below.

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

M 700F001 or impurities. Pharmacokinetic studies in rats showed that the soil metabolite
M700F002 was systemically bioavailable and distributed to the bone marrow, blood and liver after oral administration. Pharmacokinetic and metabolism in rats on the plant metabolite
M700F048 also showed systemic bioavailability with distribution to the bone marrow, blood, and liver after administration via the oral route. Excretion was primarily via the feces in both sexes, and was rapid (within 12

- 24 hours of dosing). A dermal penetration study was submitted by the registrant that utilized the BAS 703 02 F formulation, which contains both fluxapyroxad and pyraclostrobin (BAS 500F). The Agency calculated a dermal absorption factor of 8.4% at dose of 5.6 μg/cm 2 

### for poten tial use in future
risk assessments.

4.3 Toxicological Effects

In mammals, the primary target organ for fluxapyroxad exposure is the liver. There was one 28

- day dermal toxicity study in rats that showed no effects up to the limit dose and one dermal

p enetration study in rats that estimated a dermal absorption factor of 8.38%. No inhalation toxicity studies were submitted, and the 28

- day subchronic inhalation study was waived at the January 17, 2013 HASPOC meeting (see discussion in Section 4.1). Live r toxicity in response toPage 19 of 89



### fluxapyroxad exposure 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 s pecies, adaptive effects of hepatocellular hypertrophy and increased liver weights and changes in liver enzyme activities were first observed. As the dose or duration of exposure to fluxapyroxad increased, clinical chemistry changes related to liver
funct ion were observed, followed by hepatocellular necrosis and neoplastic liver changes (foci, masses), which were considered adverse effects. Liver toxicity was also observed in mice and dogs. In subchronic studies in mice, increased liver weights were obs erved along with fatty changes in the liver, with few observations of hepatocellular hypertrophy. At higher doses, liver necrosis was also observed. Liver effects in subchronic studies in dogs were limited to increased liver weights at high doses. Howev er, in chronic studies, increased liver weights were observed in conjunction with fibrosis and cirrhosis.

Fluxapyroxad administration via the oral route resulted in toxic effects in the thyroid. These thyroid effects occurred secondary to the effects on the liver and were seen only in rats. Thyroid effects in rats were observed throughout the toxicity database and included changes in serum thyroid hormone levels, enlarged thyroid, increased thyroid weights, and/or microscopic effects of thyroid follicul ar 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 whi ch thyroid effects occurred in the rat were accompanied by changes in the liver that were considered adaptive or potentially adverse. These changes included increased liver weights, hepatocellular hypertrophy, and changes in liver

- associated clinical chem istry parameters. These results suggested that the effects in the thyroid were secondary to fluxapyroxad

- induced changes in thyroid hormone metabolism by the liver and not due to direct action of fluxapyroxad on the thyroid. Supplementary studies (includi ng a perchlorate discharge assay and measurement of T 4 

### - metaboilizing Phase II enzyme activities) confirmed indirect thyroid effects. The most sensitive of these thyroid effects are perturbations in thyroid hormone levels, which occur temporally
before his topathological alterations in the thyroid.

Chronic oral administration of fluxapyroxad resulted in treatment

- related liver tumors in male and female rats and thyroid tumors in male rats only. No tumors were observed in male or female mice. Also, no ev idence of mutations or chromosomal damage were observed in a panel of guideline in vitro assays, and no evidence of chromosomal damage was observed in a guideline mouse erythrocyte micronucleus study in vivo . Together, these data indicated that the thyro id and liver tumors observed in rats were due to non

- genotoxic and/or species

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

- genotoxic modes of action for liver and thyroid tumors also indicated clear thresholds prot ective for tumorgenic
effects.

Although the primary effects of oral fluxapyroxad exposure were on the thyroid and liver, effects in other organ systems were also noted. However, the doses at which these other effects
occurred exceeded those of the liver and thyroid effects. Treatment

- related effects of decreased rearing (in males only) and decreased motor activity (in both sexes) were observed after dosing via oral gavage in the acute neurotoxicity study. These effects were considered equivocal for

neu rotoxcity, since they may indicate transient and reversible neurotoxicity from a bolusPage 20 of 89



### exposure and/or general malaise. There were no neurotoxic effects observed in the subchronic dietary toxicity study. Fluxapyroxad did not cause reproductive toxicity in rats. Developmental toxicity in rats was limited to decreased body weight and body weight gain in offspring and was observed at the same dose levels that caused thyroid dysregulation in parental animals. Developmental toxicity in rabbits was limited to paw hyperflexion, a malformation that usually reverses as the animal matures, and was observed at the same dose levels that caused reduced maternal body weight. There were clear NOAELs for these developmental effects.

An unusual effect of tooth whiten ing was observed in rats in several studies. This effect was observed with increasing oral doses of fluxapyroxad. This was likely due to decreased deposition of a yellow iron

- containing pigment in the "outer outer enamel” layer of the teeth.
Bone thicke ning and white discoloration of the skull bones were also observed, as was increased deposition of Perl’s Prussian Blue stain (indicative of iron) in other bone tissues. These effects in the teeth and bones suggested treatment

- related changes in iron stor age, but there was no evidence of microscopic damage to these tissues or clinical evidence of compromised tissue function. The Agency considered the potential for flu o rosis to result from any fluoride released during metabolism of fluxpyroxad. The Agency concluded that it is unlikely that fluxapyroxad
would cause fluorosis because detailed histopathological evaluation of the teeth did not show changes consistent with fluorosis at the highest dose in parental and F1 males of the rat 2

- generation reproducti on and fertility effects study.

Immunotoxicity was investigated via the oral route in male mice. No immunotoxic effects of fluxapyroxad were observed at doses up to and including the limit dose.

A dermal toxicity study in rats was the only route

- specific study that was submitted for occupational assessments. No toxic effects of fluxapyroxad were observed at doses up to and including the limit dose.

Acute toxicity studies show that fluxapyroxad exhibits low acute toxicity by all exposure routes (EPA Toxicity Category III or IV) and is not a dermal sensitizer.

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

in vivo genotoxicity studies were p erformed for fluxapyroxad metabolites F700F001, M700F002, and M700F048. The Agency considers these studies sufficient for hazard identification and characterization. Like fluxapyroxad, no genotoxic effects were observed for any of these
metabolites. All three metabolites displayed lower subchronic toxicity via the oral route than fluxapyroxad, with evidence of non

- specific toxicity (decreased body weight) observed only for
M700F0048 at the limit dose. Only M700F0048 exhibited developmental toxicity at doses similar to those that caused developmental effects in rabbits with fluxapyroxad treatment. However, these effects (abortions and resorptions) were of a different nature than for fluxapyroxad (paw hyperflexion) an d are likely secondary to maternal toxicity. These data are sufficient for the Agency to conclude that these metabolites do not have hazards that exceed those of fluxapyroxad in nature, severity, or potency.

The complete toxicity profile for fluxapyrox ad is provided in Appendix A.Page 21 of 89



### 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 wi th clear NOAELs for characterizing neurotoxicity and sensitivity during development, supplemental studies that characterize the effects fluxapyroxad on thyroid hormones, and no residual uncertainties in the exposure data base. The information used to
reduc e uncertainties in hazard and exposure of infants and children is described in detail below.

4.4.1 Completeness of the Toxicology Database

The Agency considers the toxicity database used to characterize the hazards of fluxapyroxad to
infants and childre n 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 fluxap yroxad. In addition to these lifestage

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

4.4.2 Evidence of Neurotoxicity

Acute and subchronic neurotoxicity studies are available for fluxapyroxad. Treatment

- related effects of decreased rearing and motor activity were observed only in the acute neurotoxicity study and only on the day of dosing. These effects a re equivocal, as they may indicate transient and reversible neurotoxicity and/or general malaise. No developmental neurotoxicity study is available for fluxapyroxad. However, the Agency has considered the potential for fluxapyroxad to cause developmenta l neurotoxicity as a result of thyroid hormone disruption, which is more sensitive than the endpoints used in a developmental neurotoxicity study. The Agency has evaluated supplemental thyroid hormone data submitted by the registrant and considered the

on togeny of thyroid hormone metabolism to determine that adverse thyroid hormone disruptions in the young are unlikely to occur at dose levels similar to the points of departure chosen for risk assessment. The Agency has low concern for neurotoxic effects o f fluxapyroxad at any life
stage.

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

No evidence of quantitative susceptibility was observed in a reproductive and developmental toxicity study in rats or in developmental toxi city studies in rats and rabbits. Developmental toxicity in rats in a 2 generation study was limited to decreased body weight and body weight gain in offspring and was observed at the same dose levels that caused thyroid follicular hypertrophy/hyperplasi a in parental animals. However, low birth weights, which can result from thyroid dysregulation in maternal animals, was observed in the first generation only, with no decreased body weights observed in the second generation until lactation day 7. Developm ental toxicity in rabbits was limited to paw hyperflexion, a malformation that is not considered to result from a single exposure and that usually reverses as the animal matures. This effect was observed in untreated controls and all treatment groups but was significantly increased only at the high dose at which reduced maternal body weight was also observed. Although thesePage 22 of 89



### developmental effects differed from the maternal effects and so indicate qualitative susceptibility, these developmental effects are of low concern to the Agency. The Agency’s rationale for low concern for developmental toxicity is that these effects were of low severity, were likely secondary to maternal toxicity, and demonstrated clear NOAELs. Nonetheless, the risk assessment is pro tective of paw hyperflexion because this effect occurs at dose levels higher than the points of departure selected for risk assessment for repeat

- exposure scenarios.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The residue data base is adequate. The dietary risk assessment is conservative and will not underestimate dietary exposure to fluxapyroxad. There are residential uses proposed for fl uxapyroxad and the assessment will not underestimate residential exposure via handler for adults and incidental oral for children.

4.5 Toxicity Endpoint and Point of Departure

4.5.1 Dose

- Response Assessment

Acute and chronic dietary points of departure and endpoints were selected from acute, subchronic, and chronic oral toxicity studies in the database for fluxapyroxad. The endpoint of decreased motor activity and decreased rearing identified in the acute neurotoxicity study in rats
was chosen for the acute dietary endpoint because it was considered adverse and results from a single exposure. Paw hyperflexion was not considered to be a single

- dose effect and thus was not selected for an acute endpoint. No other endpoints in the toxicity database for fluxap yroxad were identified that were likely to result from a single exposure. The endpoint of liver foci and masses identified in the chronic toxicity/carcinogenicity study in rats was chosen for the chronic dietary endpoint. The duration of exposure in this study is appropriate for a chronic dietary endpoint and the point of departure at this endpoint is protective for all adverse effects in rats and other species that occur at higher doses and/or for shorter durations of exposure.

The proposed/registered fluxapyroxad uses are expected to result in residential exposure via inhalation for residential handlers and incidental oral exposure for toddlers

. The endpoint of changes in thyroid hormones and thyroid follicular hypertrophy/hyperplasia from the 28

- day oral study in rats was identified for the short

- term incidental oral endpoint . This is the most sensitive endpoint in the most sensitive species for an adverse effect for a duration of exposure ranging
from 1

- 30 days. The following endpoints were chosen for occupational exposure scenarios.
PODs for short

- and intermediate

- term dermal exposure were not selected because there was no systemic toxicity up to the limit dose in the 28

- day dermal toxicity study in rats. Although developmental toxicity was not a ssessed in the dermal toxicity study, the Agency has low concern for developmental toxicity because the only observed effect, paw hyperflexion, was likely secondary to maternal toxicity and is not considered severe, since this effect is usually
reversible as the animal matures. No inhalation studies were available for short

- term and
intermediate

- term inhalation scenarios. The HASPOC met on January 17, 2013 to discuss the need for a subchronic inhalation study for fluxapyroxad (TXR #0056561). The decision was made that this requirement could be waived and a subchronic inhalation study was not required. The weight of the evidence used to support this decision included: the low acute inhalationPage 23 of 89



### toxicity of fluxapyroxad, the low volatility of fluxapyroxad and the large margin of exposure demonstrated in the exposure assessment. Therefore, endpoints from oral studies were evaluated. The endpoint of changes in thyroid hormones and thyroid follicular hypertrophy/hyperplasia
from the 28

- day oral study in rats was identified for short

- term inhalation. This is the most sensitive endpoint in the most sensitive species for an adverse effect for a duration of exposure ranging from 1

- 30 days. The endpoint of thyroid follicular hypertrophy/hyperplasia was
identified fr om 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 spec ies.

4.5.2 Recommendations for Combining Exposure Routes

Under FQPA, when there are potential residential exposures to a pesticide, HED must aggregate exposures from the three routes of exposure : oral, dermal and inhalation exposures There is no
derm al hazard posed by fluxapyroxad. Oral and inhalation endpoints, and points of departure for regulation were selected from the same 28

- day oral toxicity study; therefore oral and inhalation exposures should be combined.

4.5.3 Classification of Carcinogen ic Potential

Tumors related to fluxapyroxad treatment were observed in the liver of male and female rats and in the thyroid in male rats only. Males were more sensitive than females to the tumorgenic effects of fluxapyroxad in the liver. 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 carcino mas 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 mode of action ( MOA ) for liver adenomas and carcinomas in rats. This MOA is based on early changes in liver enzyme regulation and increased cell proliferation that lead to microscopic and macroscopic foci and then to adenoma and carcinoma formation. The endpoint of changes in liver enzyme regulation at 2.1/2.7 mg/kg bw/day in males/females pro vides a clear threshold for liver tumors.

The incidence of treatment

- related combined thyroid follicular adenomas and carcinomas in male rats ranged from 15% at 68 mg/kg bw/day to 18% at 145 mg/kg bw/day compared to 5% in controls. Dose and temporal conc ordance data supported a MOA for thyroid tumorgenesis in rats in which early changes in liver enzyme regulation lead to dysregulation of thyroid hormone homeostasis, thyroid follicular hypertrophy/hyperplasia, and thyroid tumors. The endpoint of changes i n liver enzym e regulation at 2.1/2.7 mg/kg bw /day in males/females provides a clear threshold for thyroid tumors.Page 24 of 89



### In accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment (March, 2005), the CARC classified fluxapyroxad as “Not likely to be Carcinogenic to Humans” based on convincing evidence that carcinogenic effects are not likely below a defined dose range (J. Kidwell, June 9, 2011, TXR 0055930). This decision was based on the following considerations:

(i) No treatment

- re lated tumors were seen in male or female mice when tested at doses that were adequate to assess carcinogenicity (including the Limit Dose);

(ii) Treatment

- related liver tumors were seen in male rats at doses > 250 ppm (11 mg/kg/day) and in female rats at d oses > 1500 ppm (82 mg/kg/day);

(iii) Treatment

- related thyroid follicular cell tumors were seen in male rats only at doses > 1500 ppm (68 mg/kg/day);

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

(v) The hypothesized mode of action (i.e, a non

- genotoxic) for each tumor type (i.e., the liver and thyroid) was supported by adequate studies that clearly identified the

sequence o f key events, dose

- response concordance and temporal relationship to the tumor types. The mod e of action met the criteria established by the Agency.

Therefore, the Agency has determined that the quantification of risk using a non

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

4.5.4 Summary of Points of Departure Used in Risk Assessment

Toxicological doses/endpoints selected for the fluxapyroxad risk assessment are provided in
Tables 4 .5.4.1 and 4.5.4.2

.Page 25 of 89

Table 4. 5.4.1 Summary of Toxicological Doses and Endpoints for Fluxapyroxad for Use in Dietary and Non

Occupational Human Health Risk Assessments

Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety

Factors RfD, PAD, Level

of Concern for
Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population, including Infants and
Children and Females
13

- 49 years of age) NOAEL=
125 mg/kg/day UF A = 10 x

UF H =10 x FQPA SF=

1x Acute RfD = 1.25

mg/kg/day

aPAD= 1.25 mg/kg/day Acute neurotoxicity study in rats

LOAEL = 500 mg/kg/day based on decreased motor activity (both sexes) and decreased rearing (males only)

Chronic Dietary (All Populations) NOAEL=

2.1 mg/kg/day 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 below a defined dose range.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL
= no observe d 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 4.5.4.2 Summary of Toxicological Doses and Endpoints for Fluxapyroxad for Use in Residential and Occupational Human Hea lth Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk
Assessment Study and Toxicological Effects

Dermal Short

and
Intermediate

Term 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 /Resi

dential 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 months) NOAEL=

7.3 mg/kg/day UF A =10x

UF H =10x Occupational /Resi

dential LOC for
MOE = 100 90

- day dietary study in rats

LOAEL = 35.1 mg/kg/day based on thyroid follicular hypertrophy/hyperplasia

Incidental Oral
Short

- Term (1

- 30 days) NOAEL=

9 mg/kg/day UF A =10x

UF H =10x Residential 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 Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans below a defined dose range.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL
= no observed adverse effect level. LOAEL = lowest observed ad verse 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.Page 26 of 89



### 5.0 DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Livestock Metabolism Studies

The nature of the residue in plants and animals is adequately understood. Fluxapyroxad metabolism studies were conducted using an aniline label and a pyrazole label in soybeans, tomato, and wheat; in the rotational crops spinach, radish, and wheat; and in animal studies in goats, hens. The primary residue found in plant and livestock commodities is fluxapyroxad parent. Metabolite residues to be included in the risk assessment are M700F008 and M700F010 for milk residues only.

5.1.2 Comparison of Metabolic Pathways

Submitted data shows that fluxapyroxad is metabolized mainly by hydroxylation at the biphenyl moiety (sometimes repeatedly), loss of a fluorine atom at the biphenyl ring (presumably by substitution with a hydroxyl

- group), N

- demethylation at the pyrazole moiety, hydrolysis of the amide bond, and oxidation of t he difluoromethyl group. Conjugation of the hydroxyl

- groups in addition to these reactions led to the observed large number of metabolites. The metabolic pathway of fluxapyroxad is similar in primary and rotational crops but with some variation in
metabo lite levels. In general, the parent compound is the main residue followed by the metabolites M700F008, M700F002 and M700F048. For livestock, the parent, M700F008, M700F005, M700F004, M700F010 and dimer of the parent were observed as major residues in
fat , muscle, milk, liver, kidney and/or egg commodities. In the rat, the parent was the main residue followed by M700F008, and their corresponding metabolites hydroxylated in the biphenyl moiety (M700F009, M700F005, and M700F006). Other reactions led to th e formation of a large number of minor metabolites. Metabolite structures are provided in Appendix B.

5.1.3 Environmental Fate and Transport

Fluxapyroxad degrades slowly under aerobic or anaerobic conditions in soil, with single first

order half

- lives ranging from 213 to 1,827 days. Fluxapyroxad also degrades slowly under aerobic or anaerobic conditions in aquatic systems, with single first

- order, whole system half

lives ranging from 420 to 731 days. Fluxapyroxad is classified as moderately to slightly mobile (FAO soil mobility classification) based on adsorption K OC 

### values in two U.S. soils ranging from 725 to 1,200 mL/g
oc 

### . Fluxapyroxad has the potential to leach to ground water, particularly where high water tables are present, high rainf all/irrigation occurs, and where sandy soils with low organic matter exist. Fluxapyroxad will not likely bioaccumulate.

5.1.4 Residues of Concern Summary and Rationale

HED has concluded that the residue of concern for tolerance expression for all comm odities is parent only based on the recommendation of the Residues of Concern KnowledgebasePage 27 of 89



### Subcommittee (ROCKS , D 390225, 7/4/11 ). Although there was concern expressed about metabolites in livestock commodities (particularly M700F008 being present at greater levels than parent in most matrices), for tolerance setting the parent compound alone is adequate as an
indicator for misuse.

The ROCKS recommended inclusion of parent fluxapyroxad and M700F008 for risk assessment for primary and rotational crops. While the parent is generally the most significant residue in plants, results from crop field trials with cherries and peppers show a higher relative level of M700F008 with respect to the parent at longer PHIs. The M700F008 metabolite is demethylated parent and is expected to have comparable toxicity to the parent. The major residues observed
in the confined rotational studies are parent fluxapyroxad and M700F008, M700F002 and M700F048. The metabolite M700F002 was observed as a major residue in rotational spinach only and was not detected at all in the field studies of accumulation in rotational crops. The
metabolite M700F048 was observed as a major residue in radish tops in the confined study, but was seen at much lower levels than the parent and M700F008 in the field studies. Toxicity studies with M700F002 and M700F048 show that these two metabolites are not likely to be more

to xic than the parent. For livestock commodities, except milk, the ROCKS recommended that fluxapyroxad and M700F008 be included for risk assessment purposes based on results from metabolism and feeding studies which show that parent fluxapyroxad and M700F0 08 are the major residues in ruminant and poultry commodities. For milk only, the ROCKS recommended that fluxapyroxad, M700F008 and M700F010 be included for risk assessment purposes based on the metabolism study in goat showed the presence of M700F010 at 12

- 15% TRR in milk which is highly consumed commodity by children. M700F010 is hydroxylated parent and likely to have comparable toxicity to the parent. For water, the ROCKS committee recommended including parent fluxapyroxad only in the risk assessment. Parent fluxapyroxad and M700F001 were the only two major residues identified in the environmental fate studies. Although M700F001 was identified as a major degradate, available evidence suggests that this degradate has lower toxicity than the parent and will be present in low concentrations relative to the parent in drinking water.

Table 5.1.4.1 : Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

Matrix Residues of 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

- (hydroxy

- 3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide

2 The metabolite M700F010 will be considered a residue of concern for milk only.Page 28 of 89



### 5.2 Food Residue Profile

5.2.1 Residues in Crops

An adequate number and crop field trials conducted in appropriately representative locations are available for fluxapyroxad for the following crops: radish, carrot, green onion, dry bulb onion, spinach, head lettuce, leaf lettuce, celery, broccoli, head ca bbage, mustard greens, cucumber, cantaloupe, summer squash, blueberry, blackberry, raspberry, grape, strawberry, almond, pecan rice, sugarcane, and additional cherry field trials. Decline studies were submitted for each commodity, as required. In additio n, extended field rotational crop studies were conducted for
alfalfa and mint. Detailed information on residue data from crop field trials on fluxapyroxad and its metabolites is provided in the Residue Chemistry Chapter. (D 403993 )

In addition to foliar u ses, BASF has proposed the use of seed treatment on the following commodities: beans and peas, cereal grains, peanuts, soybeans, and sunflower. The field trials conducted did not reflect the use of seed treatment followed by foliar treatment. Historical ly, EPA had not required field trials for seed treatments when foliar treatments were registered. The seed treatment rate (calculated in terms of ai/A) is compared to the foliar application rate in
the table below. The seed treatment rate was less than 25% of the single application rate and less than 10% of the seasonal application rate.Page 29 of 89

Table 5.2.1.1 Summary of Fluxapyroxad Residues

Crop Total

Application

Rate (gr ai/ha) PHI

(days) No of

Field
Trials Matrix Residues (ppm)

Fluxapyroxad M700F008

Radish 296

- 305 7 5 Root 0.03

- 0.1

HAFT= 0.10 <0.01

5 Tops 0.1

- 4.0

HAFT= 4.0 0.1

- 0.9

Carrot 297

- 305 7 7 Root 0.04

- 0.5

HAFT= 0.50 <0.01

Green Onion 607

- 624 7 3 Whole Plant w/o

roots 0.23

- 0.73

HAFT= 0.56 <0.002

Dry Bulb 602

- 685 7 6 Dry bulb 0.03

- 0.28

HAFT= 0.27 <0.002

-

<0.01

Spinach 606

- 623 1 5 * Leaves 5.95

- 19.5

HAFT= 11.5 0.04

- 0.91

Celery 606

- 611 1 6 Stalk 1.01

- 6.08

HAFT= 5.15 <0.002

-

<0.01

Head Lettuce 606

- 609 1 6 Head w/ wrapper
leaves 0.28

- 3.58

HAFT= 1.96 <0.002

-

<0.01

Leaf Lettuce 606

- 612 1 3 * Leaves 3.79

- 9.53

HAFT= 6.46 0.04

- 0.12

Broccoli 300

- 610 3 6 * Flower Head and
Stem 0. 27

- 1. 45

HAFT= 1.22 <0.01

- 0.05

Head Cabbage 303

- 610 3 6 * Head w/ wrapper
leaves 0.05

- 1. 24

HAFT= 1.23 <0.002

- 0.02

Mustard
Greens 303

- 315 3 5 Leaves 0.44

- 1.87

HAFT= 1.87 0.07

- 0.59

Cucumber 606

- 621 0 6 Fruit 0.02

- 0.25

HAFT= 0.24 <0.002

Cantaloupe 601

- 615 0 6 Fruit <0.002

- 0.25

HAFT= 0.24 <0.002

Summer Squash 606

- 624 0 5 Fruit 0.05

- 0.16

HAFT= 0.14 <0.002

Cherry 0.37 0 2 Fruit 0.250

- 1.932

HAFT= 1.86 0.074

- 0.433

Blueberry 599

– 611 0 6 Fruit 1.16

- 3.90

HAFT= 3.77 <0.01

- 0.02

Blackberry 600 0 1 Fruit 1.23

- 1.53

HAFT= 1.38 <0.01

Raspberry 602

– 609 0 2 Fruit 0.86

- 2.05

HAFT= 1.98 <0.002

-

<0.01

Grape 598

- 621 14 12 Fruit 0. 08

- 1. 40

HAFT= 1.36 <0.002

-

<0.01

Strawberry 597

– 624 0 6 Fruit 0.19

- 2.51

HAFT= 2.34 <0.002

-

<0.02

Almond 372

- 375 13

- 14 5 Nutmeat <0.01

- 0.01

HAFT= 0.01 <0.002

5 Hulls 0.74

- 1.67

HAFT= 1.67 <0.002

Pecan 372

- 396 14 5 Nutmeat <0.002

- 0.03

HAFT= 0.03 <0.01

- 0.01

Rice 288

- 309 28

- 29 16 Grain 0.22

- 3.84

HAFT= 3.73 <0.01

- 0.04Page 30 of 89 16 Straw 0.36

- 16.6

HAFT= 14.5 <0.01

- 0.10

Sugarcane 246 14 8 Cane <0.01

- 2.17

HAFT= 1.34 <0.002

- 0.04

*Registrant stated additional trials would be submitted. Summaries of these additional trials have been submitted, however, final reports have not been. HED reviewed the summaries and residues of fluxapyroxad are similar to those residues in field trials submitted with this petition.



### Grape and sugarcane processing studies were conducted to determine the potential for concentration of residues of fluxapyroxad (BAS 700 F) in the processed fractions.

Table 5.2.1.2 Summary of All Fluxapyroxad Processing Factors.

Commodity Average Processing factor

Grape

- juice 0.26

Grape

– raisin 4.1

Grape

- wine 0.17

Sugarcane

- molasses 0.2

Sugarcane

– refined sugar <0.1



### 5.3 Water Residue Profile

5.3. 1 Estimated Drinking Water Concentrations

Monitoring data for fluxapyroxad is not available. Estimated Drinking Water Concentrations (EDWCs) for fluxapyroxad were provided by the Environmental Fate and Effects Division (EFED) (D403944, C. Peck, 3/15/13). EFED generated the surface water estimates using the
Tier I Rice model. Ground water estimat es were calculated using the Pesticide Root Zone Model for Ground Water (PRZM

- GW). EDWCs for fluxapyroxad (parent only) were derived based on fluxapyroxad use on rice and turf. S 

### urface and groundwater EDWCs for fluxapyroxad are

pro vided in Table 5.3.1.1 . The estimated drinking water residue level for peak concentration of 0.203 mg/L (ppm) was used in the acute assessment

. The Average Simulation Breakthrough Time for this concentration to occur was approximately 48 yrs. The 1

- in10 year chronic drinking
water concentration of 0.184 mg/L (ppm) was used the chronic assessment.

Table 5.3.1.1 EDWCs for the Fluxapyroxad Human Health Risk Assessment Drinking Water Source 1

- in

- 10 year acute (μg/L) 1

- in

- 10 year chronic (μg/L)

Surface Water (Rice Model) 127 127

Ground Water (PRZM

- GW) 203 184



### 5

. 4 Dietary and Drinking Water Exposure and Risk

HED conducted screening

- level acute and moderately refined chronic dietary and drinking water exposure and risk assessments using the Dietary Exposure Evaluation Model with the Food Commodity Intake Database (DEEM

- FCIDTM). Dietary risk assessment incorporates bothPage 31 of 89



### exposure and toxicity of a given pesticide. For a cute and chronic dietary assessments, the risk is expressed as a percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result in no unreasonable adverse health effects). This dose is referred to as the population adjusted do se (PAD). The PAD is equivalent to the reference dose (RfD) divided by the additional FQPA Safety Factor, if applied. For acute and non

- cancer chronic exposures, HED is concerned when estimated dietary risk exceeds 100% of the PAD.

5

. 4 .1 Acute Dietary (Food and Drinking Water) Analysis

A conservative acute dietary exposure analysis was performed for the general population and all population subgroups. Tolerance level residues adjusted to account for the metabolites of concern (M700F008, and M700F010 (milk only) ) and 100 % crop treated assumptions were used. DEEM default and empirical processing factors were used to modify the tolerance values. The acute analysis incorporated the 1 in 10 year acute ground water estimate from application of fluxapyro xad to turf

. The resulting 95th percentile acute exposure estimates are not of concern for the general population or for any subgroup population. The 95 th 

### percentile acute population adjusted dose (aPAD) for children 3

- 5 years old, the subgroup with the highest risk estimate, is

12 %. The 95 th 

### percentile aPAD for the general population is 7.7 %.

Table 5.4.1.1 Summary of Acute Dietary Exposure and Risk for Fluxapyroxad

Population Subgroup a PAD (mg/kg/day) Acute (9 5 th Percentile) Exposure (mg/kg/day) % a PAD General U.S. Population

1.25 0.095673 7.7 All Infants (< 1 year old) 0.099197 7.9
Children 1

- 2 years old 0.150445 12
Children 3

- 5 years old 0.15134 9 12
Children 6

- 12 years old 0.085812 6.9
Youth 13

- 19 years old 0.074648 6.0
Adults 20

- 49 years old 0.094052 7.5
Adults 50

- 99 years old 0.092906 7.4
Females 13

- 49 years old 0.099341 8.0



### 5

. 4 .2 Chronic Dietary (Food and Drinking Water) Analysis

A moderately refined chronic dietary exposure analysis was performed for the general U.S. population and various population subgroups. Combined average residue for parent and highest
residue for metabolite M700F008 and 100% crop treated assumptions were used. For livestock commodities tolerance level residues adjusted to account for the metabolites of concern (M700F008, M700F010) were used. An assumption of 100 % crop treated was also used for the chronic dietary analysis. DEEM default and empirical pr ocessing factors were used to modify the tolerance values. The chronic analysis incorporated the 10 year average ground water estimate from application of fluxapyroxad to turf . Chronic dietary risk estimates are not of concern for general population or o ther population subgroups. The population subgroup with the highest risk estimate is all infants <1 year old with a % chronic PAD (cPAD) of 64 %. The % cPAD for the general U.S. population is 31 %.Page 32 of 89

Table 5.4.2.1 Summary of Chronic Dietary Exposure and Risk for Fluxapyroxad

Population Subgroup cPAD (mg/kg/day) Chronic Exposure (mg/kg/day) % cPAD General U.S. Population

0.02 1 0.00 6450 31 All Infants (< 1 year old) 0.013528 64
Children 1

- 2 years old 0.012549 60
Children 3

- 5 years old 0.009987 48
Children 6

- 12 years old 0.006410 31
Youth 13

- 19 years old 0.004608 22
Adults 20

- 49 years old 0.006105 29 Adults 50+ years old 0.006169 29
Females 13

- 49 years old 0.006091 29



### 5.4. 3 Cancer Dietary (Food and Drinking Water) Analysis

Fluxapyroxad has been classified as “not likely to be carcinogenic to humans below a defined dose range ”. T he Agency has determined that the quantification of risk using a non

- linear approach (i.e., RfD) will ad equately account for all chronic toxicity, including carcinogenicity, that could result from exposure to fluxapyroxad. As shown in Section 5.4.2, there are no chronic risks of concern for fluxapyroxad.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

Fluxapyroxad is proposed for uses on residential turf which may result in residential exposures.

6.1 Residential Handler Exposure

HED uses the term “handlers” to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct tasks related to applications and that exposures can vary depending on the specifics of each task. Residential handlers are addressed somewhat differently by HED as homeowners are assumed to complete all ele ments of an application without use of any protective equipment.

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

• Open mixing/loading /applying for a hose

- end sprayer application to turf (homeowner lawns) ;

• Open mixing/loading /applying for a manually pressurized handgun. application to turf (homeowner lawns) ;

• Open mixing/loading /applying for a backpack sprayer application to turf (homeowner lawns)

.

6.1.1 Handler Exposure Data

No chemical

- specific residential handler exposure data were submitted in support of this registration. It is HED’s policy to use data from the HED 2012 Residential SOPs. Available at http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html ).Page 33 of 89



### 6

. 1

. 2 Residential Handler Exposure Assumptions

A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments. Each assumption and factor is detailed below.

Application Rate: Application rates are provided in Table 6.1.2.1 below.

Unit Exposures and Area Treated or Amount Handled: Unit exposure values and estimates for area treated or a mount handled were taken from HED’s
2012 Residential SOPs. Available at http://www.epa.gov/pesticides/science/residential

- exposure

sop.html ). Exposure Duration: Residential handler exposure is expected to be short

- term in duration. Intermediate

- term exposures are not likely because of the intermittent nature of applications by homeowners;

Residential Handler Non

- Cancer Exposure and Risk Estimate Equations
The al gorithms used to estimate exposure and dose for residential handlers can be found in the
2012 Residential SOPs.

Fluxapyroxad does not pose a dermal risk; therefore, only inhalation exposures for handlers were
calculated. For all residential handler expos ure scenarios, inhalation MOEs exceed HED’s LOC ( inhalation LOC = 100), and therefore not of concern to HED. Summaries of the short

- term risk
estimates for residential handlers are included in Table 13.

Summaries of the short

- term risk estimates for res idential post

- application activities are included
in Table 6.1.2.1

.Page 34 of 8 9

Table 6.1.2.1 Short

- Term Residential Handler Exposure and Risk Estimates for Fluxapyroxad.

Exposure Scenario Target

MOE Inhl. Unit

Exposure (ug/lb ai) Maximum Application

Rate a (lb ai/gal)
Or (lb ai/Acre) Area Treated b Inhalation

Dose (mg/kg/day) c MOE d

Mixer/loader/Applicator (Turf

- Lawns)

Hose

- end Sprayer/

100 0.022 0.23 0.5 Acres 0.000032 280,000

Manually

Pressurized
Handwand 0.018

2.47 5 Acres 0.0028 3,200

Backpack Sprayer 0.14 0.022 420

Based on regi stered or proposed label (0.023 lb ai/A) and (2.47 lb ai/gal) : Exposure Science Advisory Council Policy #9.1. Inhalation Dose = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/acre or gal) x Area Tr eated or
Amount Handled (A or gallons/day) / BW (kg). Inhalation MOE = Inhalation NOAEL (mg/kg/day) / Inhalation Dose (mg/kg/day).



### 6.2 Post

- Application Exposure

Post

- application inhalation exposure while engaged in activities on or around previous ly treated turf is generally not quanitatively assessed. The combination of low vapor pressure for chemicals typically used as active ingredients in outdoor residential pesticide products and
dilution in outdoor air is likely to result in minimal inhalation exposure.

A quantitative assessment was conducted for the incidental oral scenarios (i.e., hand

- to

- mouth, object

- to

- mouth and incidental soil ingestion). This combination should be considered a protective es timate of children’s exposure to pesticides used indoors.

As a standard practice, post

- application non

- dietary ingestion exposure (i.e., hand

- to

- mouth, object

- to

- mouth, soil ingestion, etc.) for adults is not assessed

– it is assumed that an adult would

n ot place pesticide

- contaminated hands, objects, or soil in their mouth.

The quantitative oral exposure/risk assessment for residential post

- application exposures is based on the following scenarios:Page 35 of 89



### 6.2.1 Residential Post

- appliction Scenarios

Incidental soil ingestion

The lifestages selected for each post

- application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

exposure

- sop.html ). These lifestages are not the only lifestages that could be potentially exposed for these post

- application scenarios; however, the assessment of these lifestages is health protective for the exposures and risk estimates for any other potentially exposed lifestages. A series of assumptions and exposure factors served as the basis for completing the residential
post

- application risk assessment. Each assumption and factor is detailed in th e 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html )

.

6. 2

. 2 Residential Post

- application Exposure Data and Assumptions

Residential Post

- application Exposure Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the residential
post

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

. Availabl e at : http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html

Residential Post

- application Non

- Cancer Exposure and Risk Equations The algorithms used to estimate residential post

- application exposure and dose can be found in the 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- exposure

sop.html )

.

Residential estimated risks far exceed the level of concern (LOC) of 100, and are, therefore, not of concern. A summary of the residential post

- application exposures and risks are provided
below in Table 6.2.2.1

.

Table 6.2.2.1 Residential Post

- applicati on Non

- cancer Exposure and Risk Estimates for Fluzapyroxad.

Lifestage Post

- application Exposure

Scenario Application

Rate 1
(lb ai/acre) Dose

(mg/kg/day) 2 MOEs 3

Use Site Route of

Exposure

Adult

Turf/Lawns Inhalation N/A: no dermal endpoint

Child Hand to Mouth

0.23 0.0035 2,600

Object to Mouth 0.00011 85,000

Incidental Soil Ingestion 0.0000078 1,200,000

1 Based on registered or proposed label (Reg. No. 7969

- GUO, 7969

- GLN ).
2 Dose (mg/kg/day) equations: HtM: E = [HR * ( F M * SA H ) * (ET * N_Replen) * (1

- (1

- SE ) (Freq_HtM/N

- Replen) /BW )] . OtM: E = [OR* CF1 *
SAM O * (ET * N_Replen) * (1

- (1

- SE O ) (Freq_OtM/N_Replen) /BW )] . ISI: E = [OR* CF1 * SAM O * (ET * N_Replen) * (1

- (1

- SE O ) (Freq_OtM/N_Replen) ) /BW ]
3 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day ).Page 36 of 89



### It is noted that the 0.23 lb ai/acre application rate for turf was modeled to estimate post

application residential exposure of children. As this rate is equal to or higher than many of agricultural application rates, this scenario is protective of any exposure of farm children v ia spray drift from agricultural fluxapyroxad applications.

6.3 Residential Risk Estimates for Use in Aggregate Assessment

The residential doses to be used for the aggregate risk assessment and the source of those exposures are shown in Table 6.3.1 , below.Page 37 of 89

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

2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed from Table 13

. 3 Residential Handler MOE = the MOEs associated with the highest doses identified in Table 13

. 4 Residential Post

- application Dose = the highest post

- application dose for each applicable lifestage of all sce narios assessed from Table 14.
5 Residential Post

- application MOE = the MOEs associated with the highest doses identified in Table 14

6 Lifestage population was combined (BW = 80) due to an inhalation only assessment with MOEs well above 100. 7 For aggregate exposure, HtM will be used , whereas this scenario is the most conservative. Table 6. 3

. 1 Recommendations for the Short

- and Intermediate

- Term Residential Exposures for the Fluxapyroxad Aggregate Assessment 1

Lifestage Handler Exposure

(mg/kg/day) 2 Residential

Handler Total Exposure (mg/kg/day) 3 Residential

Handler
Total MOE 4 Post

- application Exposure (mg/kg/day) 5 Residential Post

application Total Exposure (mg/kg/day) Residential Post

application MOE 6 Dermal Inhalation Dermal Inhalation Oral

Short

- Term

Adult Male N/A 0.022 0.022 420 N/A N/A N/A N/A N/A

Adult Female N/A 0.022 0.022 420 N/A N/A N/A N/A N/A

Child N/A N/A N/A N/A N/A N/A 0.0035 0.0035 2600

Intermediate

- Term

Adult Male

N/A N/A Adult Female

ChildPage 38 of 89



### 6.4 Residential Bystander Post

- application Inhalation Exposure

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

- application inhalation exposure assessme nt was not performed for fluxapyroxad at this time. However, volatilization of pesticides may be a potential source of post

- application inhalation exposure to individuals nearby to pesticide applications. The Agency sought expert advice and input on
issu es related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the
SAP’ s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/ 2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate 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 post

- application inhalation exposure assessment for fluxapyroxad.

6. 5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for fluxapyroxad. The Agency ha s been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at http: //www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, o rchard 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 AND RISK ASSESSMENT

In accordance with the FQPA, when there are potential residential exposures to a pesticide, aggregate risk assessment must consider exposures from three major routes: oral, dermal, and
inhalation. Additionally, ag gregate exposure should consider exp os ure across both the dietary and residential pathways. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the
risk s themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. The proposed/registered fluxapyroxad uses are expected to result in residential exposure via inhalation for residential handlers and incidental oral exposure for toddlers

.Page 39 of 89



### 7.1 Acute Aggregate Risk

Acute aggregate risks for fluxapyroxad include exposure from food and water only. As demonstrated under Section 5.4, acute aggregate risks are not of concern.

7.2 Short

- Term Aggregate Risk

Short term aggregate exposure takes into account residential exposure plus average exposure levels to food and water (considered to be a background exposure level). The short

- term aggregate risks for fluxapyroxad are not of concern and are shown in the t able below.

Table 7.2 .1 Short

- Term and/or Intermediate Term Aggregate Risk Calculations

Population Short

- or Intermediate

- Term Scenario

NOAEL mg/kg/day LOC 1 

### Max

Allowabl

e Exposure

2 

### mg/kg/da

y Average
Food and
Water Exposure mg/kg/day Residential

Exposure mg/kg/day 3 

### Total

Exposure mg/kg/day 4 

### Aggregate

MOE (food, water, and residential)

5



### Adult Male 9 100 0.009 0.006169 0.022 0.028169 320

Adult Female 9 100 0.009 0.006091 0.022 0.028091 320

Child 9 100 0.009 0.012549 0.0035 0.016049 560

1 The LOC of 100 is based on the standard inter

- and intra

- species extrapolation factors.

2 Maximum Allowable Exposure (mg/kg/day) = 9.0 / 100

3 Residential Ex posure values taken from Table 6

. 3 .1.Average food & water exposure taken from Table 5

. 4

. 2

. 1

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

5 Aggregate MOE = [ 9.0



### 7. 3 Intermediate

- Term Aggregate Risk

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

- term exposure to fluxapyroxad ; therefore, an intermediate

- term aggregate risk assessment is not required.

7.4 Chronic, Non

- Cancer, Aggregate Risk

There are no residential use scenarios that would result in potential long

- term (chronic) exposure; therefor e, the chronic aggregate risk is equivalent to the chronic dietary (food and water) risk, and as shown in Section 5.4.2, there are no risks of concern.

7.5 Cancer Aggregate Risk

Fluxapyroxad has been classified as “not likely to be carcinogenic to humans below a defined dose range ”. T he Agency has determined that the quantification of risk using a non

- linear approach (i.e., RfD) will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to fluxapyroxad. A s shown in Section 5.4.2, there are no chronic risks of concern for fluxapyroxad.Page 40 of 89



### 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 in formation” concerning the cumulative effects of a particular pesticide's residues and “other substances that have a common mechanism of toxicity.”

EPA does not have, at this time, available data to determine whether fluxapyroxad has a common
mechanism of toxicity with other substances. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to fluxapyroxad and any other substances and, fluxapyroxad does not appear to produce a toxic metabolite produced by other substances which have tolerances in the U. S. For the purposes of this tolerance reassessment action, therefore, EPA has not assumed that fluxapyroxad has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s OPP concerning c ommon mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on
EPA’s website at http://www.epa.gov/fedrgstr/EPA_PEST/2002/January/Day_16/

.

9 .0 OCCUPATIONAL EXPOSURE / RISK CHARACTERIZATION

9 .1 Exposure Scenarios

Occupational handler and post

- application exposure scenarios were assessed to support proposed

crop , turf, and seed treatment uses . Based on the product labels and information provided by the registrant, short

- and intermediate

- term exposure is assessed for occupational handlers and post

application activities. Chronic exposure is not expected for the proposed use pa tterns. Only inhalation exposures are assessed for proposed new uses of fluxapyroxad. Dermal exposures are
not assessed because PODs for short

- and intermediate

- term dermal exposure were not selected because fluxapyroxad does not pose a dermal hazard (se e Section 4.3). . Labels for fluxapyroxad formulations require that mixers, loaders, applicators and other handlers (seed treatment activities) wear long

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

9

. 2 Handler Exposure

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each t ask. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.Page 41 of 89



### Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupat i onal handlers is based on individuals involved commercial seed treatment (primary handlers), and planting treated seeds (secondary handlers) as well as aerial, flagging, airblast, chemigation, mechanically pressurized handgun, and groundboom applicators. According to proposed labels, applications may be begin at plant emergence, but typical applications begin as plants touch across rows. The following handler exposure scenarios evaluated for this assessment are based on information provided in the propo sed labels.

9.2.1 Handler Exposure Scenarios

9.2.1.1 Mixing and Loading Scenarios

• Open mixing/loading for aerial application;

• Open mixing/loading for groundboom application;

• Open mixing/loading for airblast application.

• Open mixing/loading for chemigation application.

9.2.1.2 Application Scenarios

• Applying sprays with aerial equipment; • Applying sprays with groundboom equipment; • Applying sprays with airblast equipment ;

9.2.1.3 Mixing/Loading/Applying Scenarios

• Open mixing/loading /applying for manually pressurized handgun application

.

9.2.1.4 Flagging

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

appro ximately 10 to 15 percent of aerial application operations. In cases like these, the Agency strongly encourages the use of the engineering control system, but will continue to evaluate risks for flaggers and any other population where a clear exposure pat hway exists until the potential for exposure is eliminated. The Agency is aware that NAAA is conducting another survey of its membership on exposure issues and will consider those results as is timely and appropriate.

For pesticide handlers, HED present s 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 ot her personal protective equipment (PPE), as might be necessary. However, dermal exposures were not assessed for this analysis because fluxapyroxad does not pose a dermal hazard (see SectionPage 42 of 89



### 4.3). The fluxapyroxad product labels for foliar treatments re commend applicators and other handlers wear long

- sleeved shirt

, long pants, and shoes plus socks.

9.2.1.5 Seed Treatment

Occupational seed treatment handlers may experience short

- and intermediate

- term exposure to fluxapyroxad while performing seed treatment activities in commercial settings. In addition, occupational secondary handlers may experience short

- and intermediate

- term exposure while planting fluxapyroxad

- treated seeds. No chemical

- specific handler expo sure 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 . Concerning t he amount of a ctive ingredient handled ; AHETF is currently conducting surveys for use in seed treatment exposure assessment, providing daily seed treatment throughput data along with information on seed treating equipment and worker
activities. The HED Interim Guidance (SOP 15.1) Amount of Commercial Seed Treated Per Day provides updated additional information regarding these throughput data which will ultimately be incorporated into a final revised Seed Treatment SOP 15. Since the AHETF surveys only include informatio n for the five major field crops (canola, corn, rice, soybean and wheat), throughput values for non

- surveyed crops are assigned based on a combination of “best professional judgement;” similarity of seed size to that of the surveyed crops; and general
know ledge of each crop and its production. The amount of seed planted per day is based on information provided in the HED Reviewer’s Aid to Calculating Occupational Exposures from Activities Related to Agricultural Seed Treatment (November 29, 2012) and the B EAD Acres Planted per Day and Seeding Rates of Crops Grown in the United States

. The results are presented in Table 5.

Treating Seed (Primary Handler)

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

treatment include:

Mixing, loading, applying liquid formulations; Bagging treated seed; Sewing bags; and Multiple activities.

Typically, for large

- scale commercial seed treatments, workers perform only those specific individual tasks listed above; however, it is a ssumed that workers also may perform multiple activities throughout the day. As a result a “multiple activities” scenario (i.e. where one worker performs all seed treatment tasks such as loading/applying, sewing, bagging, cleaning, calibration, repair, fo rklift driver, etc.) was addressed.

Planting Treated Seed (Secondary Handler)

Potential occupational exposure scenarios from the use of fluxapyroxad as a commercial seed treatment include planting treated seed (secondary handler). Planting treated seed consists of thePage 43 of 89



### farmer purchasing bags of treated seed, placing the seed in the hopper and applying seed to fields (considered a secondary handler exposure scenario). The fluxapyroxad product labels discuss exposures exclusively for mixers, loaders, applicators and other handlers (seed treatment activities) to wear long

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

9.2.2 Handler Exposure Data

No chemical

- specific handler exposure data were submitted in support of this registration. It is HED’s policy to use data from the USEPA OPP Occupational Pesticide Handler Unit Exposure Surrogate Reference Table (5/4/11). http://www.epa.gov/pesticides/science/handler

- exposure

data.html ).

9.2. 3 Handler Exposure Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational
handle r risk assessments. Application rates, area treated, and the amounts of seed treated as well as seed planted are detailed below

.

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

• Exposure duration short

- term (1

- 30 days), intermediate

- term (1

- 6 months)

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

- 0.09

– 0.23 lb ai/A

• Maximum label application rates for mechanically pressurized handgun:

- 1.39

– 2.47 lb ai/gal

• Maximum label application rates for seed treatment:

- 0.01

- 0.2 5 lb ai/100 lb seed

• Area treated for aerial, groundboom and airblast application:

- 1200 acres per day for aerial application to high acreage field crops

- 350 acres per day for aerial application to typical field crops, grapes, and so d

- 350 acres per day for chemigation application to typical field crops

- 80 acres per day for groundboom application to sod and typical field crops

- 4 0 acres per day for groundboom application to turf (golf course)

- 4 0 acres per day for air blast application to orchards (tree nuts/grapes)

- 5 acres per day for groundboom application to turf (golf course tees and greens only)

- 5 acres per day for mechanically pressurized handgun application to turf (parks, athletic fields, commercial areas)

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

- Brassica vegetables

– 3, 000

- Bulb vegetables

- 3 ,000

- Cucurbit vegetables

- 339,5 000

- Leafy vegetables

– 3 ,000

- Rapeseed

– 125 ,000Page 44 of 89



### - Rice

– 302,5 00

- Root/tuber vegetables

– 800 ,000)

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

- Brassica vegetables

– 112.45

- Bulb vegetables

- 756.88

- Cucurbit vegetables

- 614.60

- Leafy vegetables

– 4.84

- Rapeseed

– 60,550

- Rice

– 17,424

- Root/tuber vegetables

– 418.18

Occupational handler: Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of
chemical

- specific data, include PHED 1.1, the AHETF database, the Outdoor Residential Exposure Task F orce (ORETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handl er exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf ), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler

- exposure

- data.html

. Estimates of inhalation exposure were calculated for various levels of personal protective equipment (PPE). Results are presented for “baseline,” defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc).

Body weight : The standard b ody weight for the general population (80 kg) was used for all exposure scenarios covered in this risk assessment since the endpoints selected were not developmental and/or fetal effects. Furthermore, i nhalation calculations assumed 100%
inhalation absorpt ion

.

Amount of Seed Planted Per Day: The amount of seed planted per day is based on information provided in the HED Reviewer’s Aid to Calculating Occupational Exposures from Activities Related to Agricultural Seed Treatment (November 29, 2012) and the BEA D Acres Planted per Day and Seeding Rates of Crops Grown in the United States,

Seed treatment exposure d uration: Treatment of the proposed seeds is expected to result in short

- and intermediate

- term

exposure.Page 45 of 89



### On

- Farm seed treatment exposure and r isk HED assumes that the commercial seed treatment risk assessment is protective of on

farm seed treatment because the commercial and farm equipment are similar but the on

farm throughput is significantly less than in commercial seed treatment

.

9.2. 4 Handl er Exposure and Risk Estimates

HED is not concerned with inhalation margins of exposure (MOEs) which are not less than the level of concern (LOC) of 100. All worker exposures are assessed as short

- and intermediate

term based on label prescribed uses and expected exposure durations. Exposure and risk
estimates indicate non

- cancer risks are not of concern for occupational handler activities for the proposed new uses (MOEs > 100). Summaries of occupational handler exposure and risk calculations, assumptions, and results are provided in Tables 9.2.4.1

, 9.2.4.2, and 9.2.4.3

.

Table 9.2.4.1 : 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 4

Short

- Term Intermed

- Term

Inhalation

Mixer/Loader

Aerial Fixed Wing (enclosed cockpit) 0.219 Turf (sod farms, golf courses, commercial lawns, parks, rec. areas, cemeteries) 0.23

350 41 ,000 33 ,000

Vegetables: Berries and small fruits, Bulb, Leafy (except Brasica),
Strawberries 0.18 52,000 42,000

Vegetables: Brassica leafy, Cucurbit, Grapes,
Root and tuber (except sugar beet). Sorghum and Millet 0.09

1200 30,000 25,000

Rice 0.135 20,000 16,000

Groundboom (open Cab) 0.219 Sod

0.23 80 18 0,000 14 0,000

Turf (sod farms, golf courses,
commercial lawns, parks, rec. areas, cemeteries) 40 360,000 290,000

Vegetables: Berries and small fruits, Bulb, Leafy (except Brasica), grapes,
and Strawberries 0.18 80 23 0,000 19 0,000Page 46 of 89 Table 9.2.4.1 : 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 4

Short

- Term Intermed

- Term

Inhalation

Sorghum and Millet 0.09 200 180,000 150,000

Airblast (open cab) Orchard (Tree Nuts) 0.11 40 7 0,000 60 0,000

Chemigation Turf (sod farms, golf courses, commercial lawns, parks, rec. areas, cemeteries) 0.23

350 41,000 33,000

Vegetables: Berries and small fruits, Bulb, Leafy (except Brasica), Strawberries and Grapes 0.18 52,000 42,000

Sorghum and Millet 0.09 1200 30,000 25,000

Applying

Aerial Fixed Wing (enclosed cockpit) 5 0.34 Turf (sod farms, golf courses, commercial lawns, parks, rec. areas, cemeteries) 0.23

350 Exposure estimates are expected to be protected by mixer/loader, whereas application is conducted mechanically while the pilot in
inside the aircraft. Vegetables: Berries and small fruits, Bulb, Leafy (except Brasica),
Strawberries 0.18 Vegetables: Brassica leafy, Cucurbit, Grapes, Root and tuber (except sugar

beet).

Sorghum and Millet 0.09

1200

Rice 0.135

Groundboom (open Cab) 0.034 Turf (sod farms, golf courses "fairways", commercial lawns, parks, rec. areas, cemeteries). 0.23

80 110 ,000 93 ,000

Vegetables: Berries and small fruits, Bulb, Leafy (except Brasica), Strawberries, Brassica leafy, Cucurbit, Grapes,
Root and tuber (except sugar

beet). 0.18 15 0,000 120 ,000Page 47 of 89 Table 9.2.4.1 : 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 4

Short

- Term Intermed

- Term

Inhalation

Sorghum and Millet 0.09 20 0 36,000 29,000

Airblast (open cab)

(Chemigation) 5 4.71 Orchard (Grapes and Tree Nuts) 0.18 20 0 21,000 17,000

Mixing/Loading/Applying

Mechanically
Pressurized Handgun 1.9 Turf (sod farms, golf courses "fairways", commercial lawns, parks, rec. areas, cemeteries). 0.23 5 330,000 270,000

Flagging

Aerial Fixed Wing (enclosed cockpit) 0.35 Sorghum and Millit 6 0.09 1200 19 ,000 15 ,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 conc ern based on the application
method and formulation/packaging type. (standard EPA/OPP/HED values).

4 Short

- /Intermediate

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

5 Aerial and Chemigation: Gr oundboom applicator MOEs are protective, whereas areal and chemigation application is done mechanically.

6 So rghum, and Millit have the most conservative MOEs, therefore representative for Flagging activities. * Daily Dose (mg/kg/day) was calculated by Unit Exposure * 100 % Inhalation a bsorption factor * Appl ication rate * Area treated} / 8 0 kg. {Where: inhalation absorption is assumed to be 100 %}



### Seed treatment (primary and secondary handler) occupational handler estimates are summarized
below.Page 48 of 89 Table 9.2.4.2

. Short

- and Intermediate

- Term Primary and Secondary Handler Exposures and Risks for Fluxapyroxad Seed

Treatment

Seed Type Inhal

UE a mg/lb Max App Rate b

lb ai/lb seed Amt Treated c

lb seed/day Inhal Dose d

mg/kg/day Short

- Term

Inhal MOE e Intermediate

- Term

Inhal MOE f

Loader/Applicator (No Respirator) Brassica Vegetables 0.00034 0.000 4 3,000 0.0000051 1 ,800 ,000 1,400 ,000 Bulb Vegetables 0.00034 0.0025 3,000 0.000032 2 80,000 23 0,000 Cucurbit Vegetables 0.00034 0.000 4 339,500 0.00058 16 ,000 13 ,000 Leafy Vegetables 0.00034 0.000 4 3,000 0.0000051 1 ,800 ,000 1,400 ,000 Rapeseed 0.00034 0.000 2 125,000 0.00011 85,000 6 9,0 00

Rice 0.00034 0.000 5 302,500 0.00064 14,000 11,000

Root and Tuber 0.00034 0.000 4 800,000 0.0014 6,6 00 5 ,4 00 Sewer (No Respirator) Brassica Vegetables 0.00023 0.000 4 3,000 0.0000 035 2, 60 0 ,000 2,100,000 Bulb Vegetables 0.00023 0.0025 3,000 0.000 022 4 20 ,000 340,000 Cucurbit Vegetables 0.00023 0.000 4 339,500 0.00 039 23 ,000 19,000 Leafy Vegetables 0.00023 0.000 4 3,000 0.0000 035 2, 60 0 ,000 2,100,000 Rapeseed 0.00023 0.000 2 125,000 0.000072 130,000 100,000

Rice 0.00023 0.000 5 302,500 0.00043 21,000 17,000

Root and Tuber 0.00023 0.000 4 800,000 0.00092 9,800 7,900 Bagger (No Respirator)

Brassica Vegetables 0.00016 0.000 4 3,000 0.0000024 3,800,000 3,000,000

Bulb Vegetables 0.00016 0.0025 3,000 0.000015 600,000 490,000

Cucurbit Vegetables 0.00016 0.000 4 339,500 0.00027 33,000 27,000 Leafy Vegetables 0.00016 0.000 4 3,000 0.0000024 3,800,000 3,000,000 Rapeseed 0.00016 0.000 2 125,000 0.00005 180,000 150,000

Rice 0.00016 0.000 5 302,500 0.0003 30,000 24,000

Root and Tuber 0.00016 0.000 4 800,000 0.00064 14,000 11,000 Multiple Activities (No Respirator)

Brassica Vegetables 0.0016 0.000 4 3,000 0.000024 380,000 300,000

Bulb Vegetables 0.0016 0.0025 3,000 0.0015 60,000 49,000

Cucurbit Vegetables 0.0016 0.000 4 339,500 0.0027 3,300 2,700 Leafy Vegetables 0.0016 0.000 4 3,000 0.000024 380,000 300,000 Rapeseed 0.0016 0.000 2 125,000 0.0005 18,000 15,000

Rice 0.000 5 302,500 0.003 3,000 2,400

Root and Tuber 0.0016 0.000 4 800,000 0.0064 1,400 1,100

Planters

Brassica Vegetables 0.0034 0.000 4 112.45 0.000000024 56 ,000 ,000 45,000,000

Bulb Vegetables 0.0034 0.0025 756.88 0.000001 6 0,000 ,000 49,000

Cucurbit Vegetables 0.0034 0.000 4 614.60 0.00000013 69,000,000 56,000,000 Leafy Vegetables 0.0034 0.000 4 4.84 0.000000001 8,800,000,000 7,100,000,000 Rapeseed 0.0034 0.000 2 60,550 0.000016 560,000 450,000

Rice 0.000 5 17,424 0.0000019 4,900,000 3,900,000

Root and Tuber 0.0034 0.000 4 418.18 0.000000089 100,000,000 82,000,000

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 49 of 89

c HED default for lb seed planted per day from HED Exposure Science Advisory Council Policy 15, and Acres planted per day and seeding rates of crops grown in the United States (3/24/2011)
d Daily Inhalation Dose (mg/kg/day) = daily inhalation unit exposure (mg/ lb ai) x application rate (lb ai/lb seed) x amount planted (lb seed/day) x absorption factor (100%) / body weight (8 0 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.

### Page 50 of 89

9.3 Post Application Exposure

HED uses the term “post

- application” to describe those individuals who can be exposed to pesticides after entering areas previously treated with pesticides and performing certain tasks or activities (also often referred to as reentry exposure). Post

- application exposures are expected to occur primarily via the dermal route.

9.3.1 Post Application Exposure Scenarios

Occupational post

- application dermal exposure was not assessed for fluxapyroxad

, since fluxapyroxad does not pose a dermal ri sk. Based on the Agency's current practices, a quantitative occupational post

- application inhalation exposure assessment was not performed for fluxapyroxad at this time . However, an inhalation exposure assessment was performed for occupational handlers a nd this assessment resulted in risk estimates that did not exceed HED’s
level of concern at baseline inhalation PPE. Since h andler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application expo sure ; these these handler inhalation exposure estimates would be protective of most occupational post

application inhalation exposure scenarios.

The potential for post

- application exposures following the planting of fluxapyroxad

- treated seeds is unlikely because sustained levels of contact with treated seed after it has been placed in the soil or other planting media would not be expected because no routine cultural practice required for the production of agricultural commodities involves such an activity as defined in the no/low contact criteria in the Worker Protection Standard (WPS). Therefore, no quantitative post

application assessment is required for exposure to treated seeds that have already been planted.

9.3. 1

. 2 Spray Drift and Volatilization

T here 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/o r particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the A gricultural 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 polici es or procedures are put into place, the Agency may revisit the need for a quantitative occupational
post

- application inhalation exposure assessment for fluxapyroxad.

### Page 51 of 89

9.3. 2 Restricted Entry Interval

Fluxapyroxad has been classified in Toxicity Category III for acute dermal, Category IV for eye irritation and Category IV for primary skin irritation. Per the Worker Protection Standard (WPS), a 12

- hr restricted entry interval (REI) is required for chemicals classified under Toxicity Category III/IV.

10. REFERENCES

Fluxapyroxad; Occupationa l and Residential Exposure Assessment for a Proposed Use on a wide range of food and
seed commodities. , J. Miller D 403912

, 7 / 23 /1 3

Fluxapyroxad (BAS 700F) Use on Numerous Crops. Evaluation of Analytical Methods and Residue Data.

. T.

Morton , D390223, 7 / 25 /1 3

Fluxapyroxad

– Acute and Chronic Dietary Exposure and Risk Assessments for Proposed New Uses of Fluxapyroxad on Numerous Crops

. T. Morton , D 410920

, 7 / 2 4 /1 3

Fluxapyroxad (BAS 700F). Report of the Residues of Concern Knowledgebase Subc ommittee (ROCKS)

. I. Negrón

- Encarnación, D390225, 7/14/11

Fluxapyroxad (BAS 700F) New Chemical Screen for Toxicology

. J. Ryman, D377679, 7/30/10

CARC Report ( J. Kidwell

, June 9 , 2011, TXR 0055930 ).

Fluxapyroxad (BAS 700F) Summary of Hazard and Science Policy Council (HASPOC) Meeting of January 17, 2013. Recommendations on the need for a subchronic inhalation study. A. Howard, TXR # 0056561, 2/26/13

### Page 52 of 89

A PPENDIX A: TOXICOLOGY DATA SUMMARY

A .1 Guideline Data Requirements The requirements (40 CFR 158.340) for food use for fluxapyroxad are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Guideline
No. Study Type Technical MRID No. Required Submitted

870.3100

870.3150
870.3200
870.3250
870.3465 Subchronic (Oral) Toxicity

- Rodent

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

Subchronic (Oral) Toxicity

- Non

- Rodent

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

- Day Dermal Toxicity

................................ ................................ ............. 90

- Day Dermal Toxicity
90

- Day Inhalation Toxicity

................................ ................................ .............. Y

Y

N

N

Y Y

Y

Y

N

N 47923567

47923568
47923569
47923571

---

--- 870.3700a
870.3700b
870.3800 Prenatal Developmental Toxicity

- Rodent

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

Prenatal Developmental Toxicity

- Non

- Rodent

................................ .............. Reproduction and Fertility Effects

................................ ................................ ... Y

Y

Y Y

Y

Y 47923603

47923604
47923602

870.4100a

870.4100b
870.4200a
870.4200b
870.4300 Chronic (Oral) Toxicity

- Rodent

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

Chronic (Oral) Toxicity

- Non

- Rodent (Dog)

................................ .................. Carcinogenicity

- Rat Carcinogenicity

- Mouse Combined Chronic Toxicity /Carcinogenicity

................................ ................. Y

Y

Y

Y

Y Y

Y

Y

Y

Y 47923591

47923592
47923570
47923591
47923592
47923591
47923592

870.6100a
870.6100b
870.6200a
870.6200b
870.6300
870.7800 Neurotoxicity

- Acute Delayed Neurotox.

- Hen

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

Neurotoxicity

- Subchronic

- Hen

................................ ................................ ... Neurotoxicity Screening Battery

- Acute

- Rat

................................ ................ Neurotoxicity Screening Battery

- Subchronic

- Rat

................................ ........ Developmental Neurotoxicity.................. Immunotoxicity.............................

................................ .......................... N

N

Y

Y

N

Y N

N

Y

Y

N

Y ---

--- 47923605
47923606

--- 47923633

### Page 53 of 89

A .2 Toxicity Profiles

Table A.2.1.1 Acute Toxicity Profile

– Fluxapyroxad

Guideline

No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral

– rat (females) 47923607 LD 50 = >2000 mg/kg III

870.1200 Acute dermal

– rat 47923559 LD 50 >2000 mg/kgM & F III

870.1300 Acute inhalation

– rat 47923560 LC 50 >5.1 mg/L M & F IV

870.2400 Acute eye irritation

– rabbit 47923562 Slightly irritating IV

870.2500 Acute dermal irritation

– rabbit 47923561 Slightly irritating IV

870.2600 Dermal sensitization

– guinea pig 47923813 No sensitization

-

TableA.2.1.2 Acute Toxicity Profile

– Fluxapyroxad Metabolites

Guideline

No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral

– rat (females) M

- 1 47701678 LD 50 = >2000 mg/kg III

870.1100 Acute oral

– rat (females) M

- 3 47701679 LD 50 = >2000 mg/kg III

870.1100 Acute oral

– rat (females) M

- 25 47701680 LD 50 = >2000 mg/kg III

870.1100 Acute oral

– rat (females) M

- 28 47701755 LD 50 = >2000 mg/kg III

870.1100 Acute oral

– rat (females) I

- 3 47701681 LD 50 = >2000 mg/kg III

870.1100 Acute oral

– rat (females) I

- 4 47701682 LD 50 = >2000 mg/kg III

870.1100 Acute oral

– rat (females) I

- 5 47701683 LD 50 = >2000 mg/kg III

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

Guideline No Study Type MRID/Classification

Doses Results

870.3050 28 day dietary in rats 47923564 (2009) Acceptable, guideline 0, 100, 500, 2000, 6000

ppm

0/0, 9/9.4, 43.7/47.8, 176/183, 530/531, mkd
M/F Males NOAEL=100 ppm ( 9.0 mkd) LOAEL 500 ppm (176 mkd) based on thyroid follicular hypertrophy/hyperplasia and clinical chem istry changes

Females NOAEL=500 ppm (47.8 mkd) LOAEL=2000 ppm (531 mkd) based on decreased prothrombin time and clinical chemistry changes

Non

- Guideline Thyroid hormone
levels

- 28 days

- rat 47923594 (2009) Acceptable, 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 conjugati on and elimination 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 days rat 47923595 (2009) Acceptable, non

guideline

0, 3000 ppm 0/0, 283/247 mkd The similarities in the behavior of BAS 700 F to phenobarbitol in this perchlorate discharge assay support the hypothesis that BAS 700 F causes increases in thyroid hormones by an indirect mechanism

.

Non

- Guideline Enzyme induction 47923599 (20210) Acceptable, non

Mechanistic investigations of enzyme induction (thyroid and liver).

### Page 54 of 89

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

Guideline No Study Type MRID/Classification

Doses Results

guideline

50 ppm

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 days 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.

Females NOAEL=7000 ppm (2100 mkd)
LOAEL=Not observed No EPA guideline,
OECD 407

– 28 day dietary in dogs 47923566 (2009) Acceptable/non

- EPA guideline

0, 2500, 7500, 20000

ppm

0/0, 74/85, 211/230,
521/503 mkd M/F NOAEL=2500 ppm (74/85 mkd M/F)

LOAEL

- =7500 ppm (211/230 mkd M/F) based on vomiting (M/F) and clinical chemistry changes

870.3100
90

- day dietary in mice 47923568 (2009) Acceptable/guideline

0, 100, 400, 2000, 6000

ppm

0/0, 21/32, 77/128, 390/610, and 1136/1657 mkd (M/F) Males NOAEL=2000 ppm (390 mkd) LOAEL 6000 ppm (1136 mkd) based on decreased body weight and body weight gain and multifocal necrosis in the
liver

Females NOAEL=6000 ppm (1657 mkd)
LOAEL=Not observed.

870.3100 47923567 (2009) NOAEL = 500 ppm (31.2 mkd) males; 100 ppm (7.3 mkd)

### Page 55 of 89

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

Guideline No Study Type MRID/Classification

Doses Results

90

- Day dietary in rats 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) females

LOAEL = 2000 ppm (126 mkd) males; 500 ppm (35.1 mkd females) based on changes in thyroid hormone levels and thyroid follicular hypertroph y/hyperplasia

870.3150
90

- Day Oral Toxicity Feeding

- dog 47923569 (2009) Acceptable/guideline

0, 300, 1500, 10000/7500 (M/F)

0/0, 9/10, 45/51,
295/238 mkd M/F NOAEL=1500 ppm (45/51 mkd M/F)

LOAEL=10000 ppm (295 mkd) males, 7500 ppm (238 mkd)
females based on vomiting and clinical chemistry changes

870.3200
28

- Day Dermal Toxicity

- rat 47923571 (2009) Acceptable, guideline

0, 100, 300, 1000 mkd NOAEL=1000 mkd

LOAEL=not observed

870.3465
90

- Day Inhalation Waived by HASPOC (TXR# 0056561)

870.3700a
Prenatal Developmental

- rat 47923603 (2009) Acceptable, guideline

0, 25, 200 and 1000 mkd (gavage in CMC) Maternal
NOAEL=200 mkd
LOAEL =1000 mkd based on increased absolute and relative thyroid weights and thyroid hypertrophy/hyperplasia

Offspring
NOAEL=1000 mkd
LOAEL =Not observed

870.3700b
Prenatal 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 Performance
NOAEL=300 mkd
LOAEL =Not observed. Offspring
NOAEL=10 mkd LOAEL =50 mkd decreased pup body weight/body weight development

### Page 56 of 89

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

Guideline No Study Type MRID/Classification

Doses Results

870.4100
Chronic Toxicity

- dog 47923570 (2009) Acceptable/guideline

0, 300, 1500, 12000/9000 ppm (M/F) 0/0, 8/9, 39/43, 335/257
mkd M/F Females NOAEL=300 ppm ( 9 mkd) LOAEL =1500 ppm (43 mkd) based on hepatic fibrosis and clinical chemistry changes

Males NOAEL=1500 ppm ( 39mkd) LOAEL=12000 ppm (335 mkd) based on vomiting, heptaic fibrosis and cirrhosis, and clinical chemistry changes (liver enzyme elevation)

870.4300
Chronic toxicity/carcinogenicity
in rats 47923591 (2009) Acceptable, guideline

0, 50, 250, 1500, 3000

ppm

0/0, 2.1/2.7, 11/14, 68/82, 145/182 mkd (M/F) Chronic toxicity

NOAEL=50 ppm (2.1/2.7 mkd in males/females) LOAEL =250 ppm (11/1 mkd) based on neoplastic changes in the liver (foci, masses).

Carcinogenicity

- see CARC report
Classified as“ not likely to be carcinogenic to humans” at doses below those that cause liver enzyme induction in rats.

870.4300
Chronic toxicity/carcinogenicity
in mice 47923592 (2009) Acceptable, guideline

0, 150, 750, 3000, 6000

ppm

0/0, 21/33, 107/158, 468/652, 996/1307 mkd (M/F) Chronic toxicity NOAEL=750ppm (158/107 mkd M/F) LOAEL =3000 ppm (468/652) mkd M/F based on decrease body weight.

Carcinogenicity NOAEL=6000 ppm (996/1307 mkd M/F)
LOAEL =Not observed

Gene Mutation
870.5100

In vitro Bacterial Gene
Mutation 47923572 (2008) Acceptable, guideline

0, 20, 100, 500, 2500, 5000 μg/plate S9 Not mutagenic in the reverse mutation assay in Salmonella typhimurium or Escherichia coli with or without metabolic
activation.

Gene Mutation
870.5300

In vitro Mammalian
Cells Gene Mutation (Chinese Hamster Ovary Cells) 47923579 (2007) Acceptable, guideline

0

- 100 μg/ml S9 Does not induce forward mutations in CHO cells with or
without metabolic activation.

Cytogenetics
870.5375

In vitro Mammalian Cytogenetics
Chromosomal Aberration 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.

Cytogenetics

- other
870.5395 In Vivo
Mammalian Cytogenetics

- 47923584 (2006) Acceptable, guideline

0, 500, 1000, 2000 mkd Did not lead to any increase in polychromatic erythrocytes.

### Page 57 of 89

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

Guideline No Study Type MRID/Classification

Doses Results

Erythrocyte
Micronucleus

- mouse 870.6200a Acute Neurotoxicity

- rat 47923605 (2009) Acceptable, guideline

0, 125, 500, 2000 mkd NOAEL (neurotoxicity) =125 mk

LOAEL (neurotoxicity)=500 mk based on decreased motor activity (both sexes) and decreased rearing (males only).

870.6200b
Subchronic Neurotoxicity

- rat 47923606 (2009) Acceptable, guideline

0, 200, 100, and 5000

ppm

0, 11.5/13.4, 57.7/67.2,
302.2/337.7 mkd M/F NOAEL (neurotoxicity)=5000 ppm (302/338 mkd M/F)

LOAEL (neurotoxicity) =Not observed

870.7485
Metabolism and
Pharmacokinetics

- rat 47923555 (2009)

47923556 (2009) The times to maximum plasma levels (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 se xes with a similar pattern: the highest concentrations were found in the gut contents and stomach contents. However, lower concentrations were found in numerous other organs/tissues, including the liver, thyroid, adrenal glands, kidney, pancreas,
testes/ uterus, and brain. For males and females, radioactivity
declined in all tissues over time. The time course of the amount of radioactivity found in urine and feces indicated the excretion occurred predominantly within three days after dosing. Bile duct can nulation 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
bi phenyl ring system, and conjugation with glucuronic acid or with glutathione derivatives. A further, but negligible transformation route is cleavage at the amide bond between the pyrazole ring system and the biphenyl ring system.

870.7600
Dermal penetration 47923632 (2010) Acceptable, guideline

5.6, 33,4, 1670 μg/cm 2
for 8 h exposure and 24
and 120 h termination

*In a formulation with pyraclostrobin (BAS 500 F) The dermal absorption factor is 8.38%.

### Page 58 of 89

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

Guideline No Study Type MRID/Classification

Doses Results

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 higher dose groups. All effects were d ose

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) rever sible 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. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for
Metabolite M700F001

Guideline No Study Type MRID
Classification

Doses Results

870.3100
90

- Day dietary in rats 47923608 (2009) Acceptable,

- guideline

0/0, 94.6/98.8, 285.7/295.1,
953.6/983.1 mkd M/F NOAEL=953.6/983.1 mkd in M/F
LOAEL=Not observed

### Page 59 of 89 Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for
Metabolite M700F001

Guideline No Study Type MRID
Classification

Doses Results

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.

Cytogenetics
870.5375

In vitro Mammalian Cytogenetics
Chromosomal Aberration Assay

human peripheral blood lymphocytes 47923610 (2009) Acceptable, guideline Not clastogenic.

Cytogenetics

- other
870.5395 In Vivo
Mammalian Cytogenetics

- Erythrocyte
Micronucleus

- mouse 47923612 (2009) Acceptable, guideline

O, 500, 1000, 2000
mkd Did not lead to any increase in polychromatic erythrocytes.

Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for
Metabolite M700F002

Guideline No Study Type MRID
Classification

Doses Results

870.3050 28 day dietary in rats 47923615 (2009) Acceptable, guideline

0/0, 113/113.4, 275.9/394.8,
1164.8/1253.3 mkd NOAEL= 1164.8/1253.3mkd in M/F
LOAEL=Not observed

870.3100
90

- Day dietary in rats 47923616 (2009) Acceptable,

- guideline NOAEL=958.4/928.7 mkg M/F

### Page 60 of 89 Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for
Metabolite M700F002

Guideline No Study Type MRID
Classification

Doses Results

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 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.

Cytogenetics
870.5375

In vitro Mammalian Cytogenetics
Chromosomal Aberration Assay

human peripheral blood lymphocytes 47923618 (2008) Acceptable,

- guideline Not clastogenic.

Cytogenetics

- other
870.5395 In Vivo
Mammalian Cytogenetics

- Erythrocyte
Micronucleus

- mouse 47923620 (2009) Acceptable, guideline

O, 375, 750, 1500 mkd Did not lead to any increase in polychromatic erythrocytes.

Non

- OPPTS guideline,
OECD 417 47923621 (2009) Acceptable, non

guideline

1000 mkd, oral (gavage) M700F002 is systemically bio a vailable and its presence in
the bone marrow and blood after an oral application is
confirmed.

### Page 61 of 89 Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for
Metabolite M700F048

Guideline No Study Type MRID
Classification

Doses Results

870.3050 28 day dietary in rats 47923624 (2009) Acceptable, guideline \

0, 50, 200, 1000 mkd (nominal)

0/0, 47.l/51.4, 189.3/208.2, not
calculable/1477.8 M/F NOAEL=47.1/51.4 mkd in males, 1477.8 mkd females.
LOAEL= 189.3 in mkd males based on decreased absolute and realtive monocyte counts. The LOAEL was not
observed in females.

870.3700b
Prenatal 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.

Cytogenetics
870.5375

In vitro Mammalian Cytogenetics
Chromosomal Aberration Assay

human peripheral blood lymphocytes 47923626 (2009) Acceptable, guideline Clastogenic with metabolic activation.

Cytogenetics

- other
870.5395 In Vivo
Mammalian Cytogenetics

- Erythrocyte
Micronucleus

- mouse 47923628 (2009) Acceptable, guideline

0, 500, 1000, 2000
mkd Did not lead to any increase in polychromatic erythrocytes.

870.7485
Metabolism and
Pharmacokinetics

- rat 47923557 (2009) Acceptable, guideline In both sexes, the major route of excretion was the feces (85.47% in males and 86.4% in females) with maximum
excretion within 12

- 24 hours after dosing. The minor route of excretion was in the urine (2.4% in males and 6.8% in females).

Non

- OPPTS guidel ine, 47923630 (2009) M700F048 is 5077265 is systemically bio a vailable and its

### Page 62 of 89 Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for
Metabolite M700F048

Guideline No Study Type MRID
Classification

Doses Results

OECD 417 Acceptable, non

guideline

1000 mkd, oral (gavage) presence in the bone marrow, blood and liver after an oral application is confirmed.

Non

- OPPTS guideline,
OECD 486 47923629 (2009) Acceptable, non

guideline

0, 1000, 2000 mkd Does not induce unscheduled DNA synthesis.

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

Guideline No Study Type MRID
Classification
Doses Results

Gene Mutation
870.5100

In vitro Bacterial Gene
Mutation 47923573 (2009) Acceptable, guideline No evidence of mutagenicity.

Gene Mutation
870.5300

In vitro Mammalian
Cells Gene Mutation (Chinese Hamster Ovary Cells) 47923580 (2009) Acceptable, guideline No evidence of forward mutations.

Cytogenetics
870.5375

In vitro Mammalian Cytogenetics
Chromosomal Aberration Assay

human peripheral blood lymphocytes 47923578 (2009) Acceptable, guideline Clastogenic in V79 cells in the presence or absence of
metabolic activation.

Cytogenetics

- other
870.5395 In Vivo
Mammalian Cytogenetics

- Erythrocyte
Micronucleus

- mouse 47023585 (2009) Acceptable, guideline

0, 500, 1000, 2000
mkd Did not lead to any increase in polychromatic erythrocytes

Non

- OPPTS guideline,
OECD 486 47923590 (2009) Acceptable, non

guideline

0, 2.5, 5 mkd Does not induce unscheduled DNA synthesis.

### Page 63 of 89 Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Impurity B

Guideline No Study Type MRID
Classification
Doses Results

Gene Mutation
870.5100

In vitro Bacterial Gene
Mutation 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.

Cytogenetics

- other
870.5395 In Vivo
Mammalian Cytogenetics

- Erythrocyte
Micronucleus

- mouse 47923586 (2009) Acceptable, guideline

0, 15, 30, 60 mkd Did not lead to any increase in polychromatic erythrocytes.

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

Guideline No Study Type MRID
Classification
Doses Results

Gene Mutation
870.5100

In vitro Bacterial Gene
Mutation 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.

Cytogenetics

- other
870.5395 In Vivo
Mammalian Cytogenetics

- Erythrocyte
Micronucleus

- mouse 47923588 (2008) Acceptable, guideline

0, 500, 1000, 2000
mkd Did not lead to any increase in polychromatic erythrocytes.

### Page 64 of 89

A.3 Toxicological Endpoints

A.3.1 Acute Reference Dose (aRfD)

– All populations (General Population, including infants and children and females ages 13

- 49)

Study Selected: Acute Neurotoxicity Study in Rats

MRID No.: 47923606

Dose and Endpoint for Risk Assessment : NOAEL= 125 mg/kg/day. The LOAEL of 500 mg/kg/day was based on decreased motor activity (both sexes) and decreased rearing (males only) seen on the day of dosing.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability); FQPA
SF = 1X

Acute RfD= acute PAD = 125 mg/kg/day = 1.25 mg/kg/day
100

Comments about Study/Endpoint/Uncertainty Factors: The study is appropriate for acute dietary exposure due to the r oute (oral) and duration (acute) of dosing. The effects are clearly adverse and result from a single exposure.

Endpoints from the developmental rat and rabbit studies as well as the 2

- generation reproduction study were n ot selected since there were no effects seen that were attributable to a single

exposure. Therefore, the dose and endpoint from the ACN study was selected and is considered protective of potential acute toxicity for all populations (i.e. the general popul ation, including infants and children and females ages 13 to 49 years old).

A.3.2 Chronic Reference Dose (cRfD)

- All Populations

Study Selected: Chronic Toxicity/Carcinogenicity Study in Rats

MRID No: 47923591

Dose and Endpoint for Risk Assessment : NOAEL= 2.1 mg/kg/day (50 ppm). The LOAEL of 11 mg/kg/day (250 ppm) was based on non

- neoplastic changes (increased liver weight, liver foci, changes in clinical chemistry, including prothromb in time and cholesterol levels) in the liver of
male rats.

Uncertainty Factor: 100x (10x interspecies extrapolation, 10x intraspecies variability); FQPA
SF = 1X

### Page 65 of 89 Chronic RfD = chronic PAD = 2.1 mg/kg/day = 0.021 mg/kg/day
100

Comments about Study/Endpoint/Uncertainty Factors: The study is appropriate for chronic dietary exposure due to the route (oral) and duration (chronic) of dosing. These effects are consistent with the liver being the target organ and are supported by the effects seen in the 28

- and 90

- day studies. This po int of departure is also protective of the liver adenomas occurring at 250 ppm in male rats.

A.3.3 Incidental Oral Exposure (Short

- Term (1

- 30 days))

Study Selected: 28

- Day Dietary Toxicity Study in the Rat

MRID No: 47923564

Dose and Endpoint for Risk Assessment: NOAEL = 9 mg/kg/day (100 ppm) in males. The LOAEL in males of 176 mg/kg/day (500 ppm) was based on changes in thyroid follicular hypertrophy/hyperplasia.

Uncertainty Factor: The residential level of concern for MOE is 100 (10X inter

- spe cies, 10X
intra

- species factor) (proposed)

Comments about Study/Endpoint/UF: The selected endpoint is the most sensitive endpoint and most sensitive species for this route and duration of expsoure.

A.3.4 Incidental Oral Exposure (Intermediate

- Term (1

- 6 months))

Study Selected: 90

- Day Dietary Toxicity Study in the Rat

MRID No: 47923567

Dose and Endpoint for Risk Assessment: NOAEL = 7.3 mg/kg/day (100 ppm). The LOAEL =
500 ppm (35.1 mg/kg/day) based on thyroid hormones and thyroid follicular hypertrophy/hyperplasia.

Uncertainty Factor: The residential level of concern for MOE is 100.

Comments about Study/Endpoint/UF: The selected endpoint is the most sensitive endpo int and most sensitive species for this route and duration of expsoure.

A.3.5 Occupational and Residential Dermal Exposure (Short

- and
Intermediate

- Term)

In a 28

- day dermal toxicity study in rats, no dermal irritation or systemic effects were observe d up to the limit dose of 1000 mg/kg/day. This is a route

- specific study that also assessed all of the

### Page 66 of 89

endpoints used in the other exposure scenarios and durations of exposure (e.g. neurological endpoints, thyroid and liver histopathology). In addition, n o increased susceptibility was seen between offspring and adult animals in the developmental toxicity studies in rats and rabbits and
in the 2

- generation reproduction study in rats. Therefore, the quantification of dermal risk is not required since no haz ard was identified.

A.3.6 Occupational and Residential Inhalation Exposure (Short

- Term)

Study Selected: 28

- Day Dietary Toxicity Study in the Rat

MRID No: 47923564

Dose and Endpoint for Risk Assessment: NOAEL = 9 mg/kg/day (100 ppm) in males. The LOAEL in males of 176 mg/kg/day (500 ppm) was based on changes in thyroid hormones and thyroid follicular hypertrophy/hyperplasia.

Uncertainty Factor: The occupational and residential level of concern for MOE is 100.

Comments about Study/Endpoint/UF: No inhalation studies are available for fluxapyroxad; therefore, a 28

- day oral toxicity study in rats was used for inhalation risk assessment. The selected endpoint is the most sensitive endpoint and most sensitive species for this duration of

exposure.

A.3.7 Occupational and Residential Inhalation Exposure (Intermediate

Term)

Study Selected: 90

- Day Dietary Toxicity Study in the Rat

MRID No: 47923567

Dose and Endpoint for Risk Assessment: NOAEL = 7.3 mg/kg/day (100 ppm). The LOAEL =
500 ppm (35.1 mg/kg/day) based on thyroid follicular hypertrophy/hyperplasia.

Uncertainty Factor: The occupational and residential level of concern for MOE is 100.

Comments about Study/Endpoint/UF: No inhalation studies are available for fluxapyroxad;

t herefore, 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 fluxap yroxad, occupational long

- term inhalation exposure is not anticipated.

### Page 67 of 89

A.4 EXECUTIVE SUMMAR IES

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 we ight gain were observed in 6000 ppm males and females and were
considered adverse.

A functional observational battery and motor activity measurements were performed at the end of the dietary exposure period. However, no evidence of neurotoxicity was obs erved in these investigations. Also, no signs of neurotoxicity were noted in daily cageside or weekly clinical examinations and no opthamoscopic changes were noted.

In the liver, a number of changes were observed. These included changes of a number of clinical chemistry parameters, increased absolute and relative liver weights at ≥ 500 ppm as well as histopathological changes (increased incidence and severity of centrilobular hepatocyte hypertrophy in both sexes at ≥ 500 ppm (which is considered adaptiv e and not adverse), and hepatocellular single cell necrosis in top dose males (which is considered clearly adverse). The clinical chemistry changes considered potentially indicative of adverse effects were increased serum cholesterol and triglycerides in females at ≥ 2000 ppm and in males at 6000 ppm and decreased prothrombin time in females at ≥ 500 ppm, which indicated potential for increased blood clotting. The increase of γ

- glutamyltransferase activities in males at ≥2000 ppm and the top dose group o f both sexes was regarded equivocal, since elevated GGT can be associated with both adaptive and adverse effects

Changes in thyroid hormone levels were observed in males at ≥100 ppm with thyroid follicular cell hypertrophy/hyperplasia present at ≥ 2000 ppm. In females, both changes in thyroid hormone levels and thyroid follicular hypertrophy/hyperplasia were observed at ≥500 ppm.

Additionally, an increased tubular deposition of pigment indicative of a mild tubulonephrosis was observed in kidneys of top dose females and was not considered adverse.

The LOAEL is 2000 ppm (126 mg/kg bw/day) in males and 500 ppm (35.1 mg/kg bw/day) in females, based on thyroid follicular hypertrophy and hyperplasia. The NOAEL is 500 ppm (31.2 mg/kg bw/day) in ma les 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 68 of 89

870.3100 90

- Day Oral Toxicity

– Mice MRID 47923568

BAS 700 F (Batch: COD

– 000826; Purity 99.6%) was administered to C57BL/6 J Rj mice (10/sex/dose) at dietary dose levels of 0, 100, 400, 2000 and 6000 ppm (corresponding to 0/0, 21/32, 77/128, 390/610, and 1136/1657 mg/kg bw/day) for at least 91 days. Significant decreases in body weight (

- 12.6%) and body weight gain (

- 32.5%) were observed in top dose
males were considered adverse.

The liver was identified as a target organ as indicated by changes of a number of clinic al chemistry parameters down to a dietary dose level of 400 ppm in males as well as statistically significant increases of absolute and relative liver weights at 2000 ppm or higher in both sexes. The clinical chemistry changes consisted of increased alkali ne phosphatase, alanine

aminotransferase (ALAT) and urea levels in top dose males as well as decreased triglyceride (males only) and albumin, total protein and cholesterol levels in both sexes. An increased
incidence of multifocal necrosis was observed in the liver of 5/10 6000 pm males and, in conjunction with increased liver enzymes, was considered potentially adverse.

The LOAEL is 6000 ppm (1136 mg/kg bw/day) in males, based on decreased body weight and body weight gain and multifocal necrosis in the liver. The LOAEL in females was not observed. The NOAEL is 2000 ppm (390 mg/kg bw/day) in males and 6000 ppm (1657 mg/kg bw/day) in females.

This 90

- day oral toxicity study in the mouse is classified as totally reliable (acceptable/guideline) and sat isfies guideline requirements for a 90

- day oral toxicity study (OPPTS 870.3100; OECD 408) in mice.

870.3150 90

- Day Oral Toxicity

– Dog MRID 47923569

Administration of BAS 700 F (Batch: COD

– 000899; Purity: 99.7%) to groups of 5 Beagle dogs/sex/dose at dietary dose levels of 0, 300, 1500 and 10000 ppm in males (0, 9, 45, and 295 mg/kg bw/day) and 0, 300, 1500 and 7500 ppm in females (0, 10, 51, and 238 mg/kg bw/day) for at least 90 days resulted in impaired food co nsumption in each two high dose males and females. This was accompanied by decreased body weight development in one high dose female only. Furthermore, vomiting was recorded in all male and female dogs of the high dose group during the first two days of tr eatment.

The liver was identified as the major target organ as indicated by changes in a number of clinical chemistry parameters at 1500 and/or 10000/7500 ppm as well as statistically significant changes of absolute and/or relative liver weights at 10000 ppm in males and 7500 ppm in females. The clinical chemistry changes considered potentially adverse were increase ALP and GGT in both sexes at the high dose. Increased absolute and/or relative weights in both sexes were considered adaptive and not adverse , since there were not histopathological correlates.

The LOAEL is 10000 ppm (295 mg/kg bw/day) in males and 7500 ppm (238 mg/kg bw/day) in females, based on vomiting and clinical chemistry changes. The NOAEL is 1500 ppm in

### Page 69 of 89

both sexes (45 mg/kg bw /day in males and 51 mg/kg bw/day in females).

This study is classified as totally reliable ( acceptable/guideline) and satisfies guideline requirements for a 90

- day oral toxicity study (OPPTS 870.3150; OECD 409) in non

- rodents.

870.3200 21/28

- Day D ermal Toxicity

– Rat MRID 47923571

Dermal Administration of BAS 700 F (Batch: COD

- 001049; Purity: 99.2%) in a carboxymethylcellulose vehicle to 10/sex/dose Wistar rats (6 hours/day; 5 days/week, semi

occlusive dressing) for 4 weeks at dose levels of 0, 10 0, 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 Toxi city Study

– Rat 47923603

BAS 700 F (Batch COD

- 000899, Purity 99.7%) was administered daily to presumably pregnant Crl:WI (Han) Wistar rats by oral gavage in a 0.5% carboxymethylcellulose vehicle during gestation days 6

- 19 at dose levels of 0, 25, 200 and 1000 mg/kg bw. The high dose of 1000 mg/kg bw/day resulted in increased (12

- 16%) absolute and relative thyroid weights (with correlating microscopic effects of thyroid hypertrophy and hyperplasia (considered adverse). Absolute and relative liver weights were increased significantly, but slightly (9

- 13%) at this dose and occurred in the absence of corroborating effects on serum liver enzymes (liver histopathology was not examined). This effect was considered as most likely due to hepatocellular hypertroph y (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 o n increased absolute and relative thyroid weights and thyroid hypertrophy/hyperplasia. The NOAEL

### Page 70 of 89

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 skel etal malformations were noted. BAS 700 F was not teratogenic up to the highest dose tested.

The LOAEL for developmental toxicity was not observed. The NOAEL is 1000 mg/kg bw/day.

This study is classified as totally reliable (acceptable/guideline) and satisfies guideline requirements for a prenatal developmental toxicity study (OPPTS 870.3700; OECD 414) in rats.

870.3700b Prenatal Developmental Toxicity Study

– Rabbit MRID 47923604

BAS 700 F (Batch COD

- 000899, Purity 99.7%) was administered daily to presumably pregnant Himalayan rabbits by stomach tube during gestation days 6

- 28 post insemination (p.i.) at dose levels of 0, 10, 25 and 60 mg/kg bw. The high of 60 mg/kg dose elicited signs of maternal toxicity as indicated by one abortion, decr eased food consumption (

- 21.9% during the treatment period) corroborated by an increased number of animals with reduced or no defecation, body weight loss during gestation days 9 to 11 and a decrease of cumulative body weight gain by 49.3% during the treat ment period. Body weighs were decreased 12% by Day 29, which was considered adverse. No maternal toxicity was observed at dose levels ≤ 25 mg/kg.

The LOAEL for maternal toxicity in males is 60 mg/kg bw/day, based on decreased body weight. The NOAEL is 25 mg/kg bw/day.

No treatment

- related effects on cesarean section parameters were observed at any dose. No

treatment

- related external, visceral or skeletal malformations were noted. The only treatment

related variation was a statistically significant in crease in incidence of mean % affected fetuses with paw hyperflexion at the high dose level (10.3%). This variation is frequently observed in control fetuses (up to 6.7% affected fetuses per study) and may reverse since tendons stretch postnatally as limbs grow and are being used. Although this variation occurred in presence of substantial maternal toxicity and so may be secondary to maternal toxicity, it was an effect of treatment and so is considered potentially adverse.

The LOAEL for developmental toxi city was 60 mg/kg bw/day, based on decreased fetal body weights and an increased incidence of paw hyperflexion, which was considered potentially adverse. The NOAEL is 25 mg/kg bw/day.

This study is classified as totally reliable (acceptable/guideline) and satisfies guideline requirements for a prenatal developmental toxicity study (OPPTS 870.3700; OECD 414) in
rabbits.

### Page 71 of 89 A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects

– Rat MRID 47923602

BAS 700 F (Batch COD

- 000899, Puri ty 99.7%) was administered daily to presumably pregnant Himalayan rabbits by stomach tube during gestation days 6

- 28 post insemination (p.i.) at dose levels of 0, 10, 25 and 60 mg/kg bw. The high of 60 mg/kg dose elicited signs of maternal toxicity as indi cated by one abortion, decreased food consumption (

- 21.9% during the treatment period) corroborated by an increased number of animals with reduced or no defecation, body weight loss during gestation days 9 to 11 and a decrease of cumulative body weight gai n by 49.3% during the treatment period. Body weighs were decreased 12% by Day 29, which was considered adverse. No maternal toxicity was observed at dose levels ≤ 25 mg/kg.

The LOAEL for maternal toxicity in males is 60 mg/kg bw /day, based on decreased body weight. The NOAEL is 25 mg/kg bw/day.

No treatment

- related effects on cesarean section parameters were observed at any dose. No

treatment

- related external, visceral or skeletal malformations were noted. The only treatment

related variation was a statistically significant increase in incidence of mean % affected fetuses with paw hyperflexion at the high dose level (10.3%). This variation is frequently observed in control fetuses (up to 6.7% affected fetuses per study) and ma y reverse since tendons stretch postnatally as limbs grow and are being used. Although this variation occurred in presence of substantial maternal toxicity and so may be secondary to maternal toxicity, it was an effect of treatment and so is considered pot entially adverse.

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

This study is c lassified as totally reliable (acceptable/guideline) and satisfies guideline requirements for a prenatal developmental toxicity study (OPPTS 870.3700; OECD 414) in
rabbits.

A.4.4 Chronic Toxicity

870.4100b Chronic Toxicity

– Dog MRID 47923570

BAS 700 F (Batch: COD

– 001026, purity 99.4%) was administered to Beagle Dogs for 12 months at dietary dose levels of 0, 300, 1500 and 12000 ppm in males ( 0, 8, 39, and 335 mg/kg bw/day) and 0, 300, 1500 and 9000 ppm in females ( 0, 9, 43, and 257 mg/kg bw/ day). Vomiting was observed in the all high dose animals at the beginning and midway through the study, and
was considered adverse.

### Page 72 of 89

In the liver, changes in a number of clinical chemistry parameters at 1500 and/or 12000/9000 ppm as well as statisticall y significant changes of absolute and/or relative liver weights at 12000 ppm in males and 9000 ppm in females were observed. The clinical chemistry changes consisted of increased alkaline phosphatase, serum γglutamyl transferase, triglyceride and alanine

a minotransferase levels as well as decreased total protein, albumin, cholesterol, total bilirubin, creatinine, urea and calcium levels in either or both sexes. Histopathlogical analysis of the organ showed an intracytoplasmic iron deposition in hepatocytes as well as multifocal fibrosis (considered adverse) at dose levels of 1500 ppm and higher. One high dose male displayed a slight cirrhosis.

In the spleen, fine granular iron storage (distinct from hemosiderin) was observed at 1500 and 9000/12000 ppm. This was accompanied by a diffuse atrophy of the red pulp At 9000/12000 ppm. No histopathological changes were observed in the white pulp. The findings of iron storage and atropy at the high dose were considered potentially adverse.

Changes were also obser ved in the gall bladder (epithelial storage of granular brown pigment of

males and females at 1500 ppm, not considered adverse ) and the prostate (reduced weight and atrophy without change of the glandular structure at 12000 ppm, considered potentially ad verse).

The LOAEL is 1500 ppm in females (43 mg/kg bw/day) based on hepatic fibrosis and clinical chemistry changes. The NOAEL in females in 9 mg/kd bw/day. The LOAEL in males is 12000 ppm (335 mg/kg bw/day) based on vomiting, clinical chemistry change s, 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) i n non

- rodents.

A.4.5 Carcinogenicity

870.4300 Carcinogenicity/Chronic Study

– Rat 47923591

BAS 700 F (Batches COD

– 000899 up to study day 454 and COD

- 001049 from study day 455 to termination; Purity: 99.7% and 99.2%, respectively) was administered to Wistar rats at dietary
dose levels of 0, 50, 250, 1500 and 3000 ppm (0/0, 2.1/2.7, 11/14, 68/82, or 145/182 mg/kg bw/day in males/females) for 2 years to assess carcinogenicity. A satellite group of animals was sacrificed at one year to assess chronic toxicity.

In the carcinogenicity group (50/sex/dose), body weight decreases after two years of 8% were noted in males at 3000 ppm. In females, body weights were decreased 11.9% or more at ≥ 250 ppm. This indicated that dosing was adequate. Treatment with BAS 700 F did not affect the survival of rats in the carcinogenicity group. Tumors considered a result of treatment were observed in the liver and thyroid only. Hepatocellular tumors were in the form of adenomas and
carcinomas in both sexes, with a significant increase in the combined incidence of these tumor

### Page 73 of 89

types in males at ≥ 1500 ppm and in females at 3000 ppm. Significant increases in hepatocellar carcinomas were observed only in males and only at 3000 ppm. Adenomas were observed in both sexes at a higher incidence than carcinomas and at lower doses. Significant increases in adenomas were observed in males at ≥ 1500 ppm and in females at 3000, ppm. However, adenoma incidence was greater than the upper limit of historica l 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 hypertrophy, spongiosis hepatitis in males at 1500 ppm, increased pigment storage (likely lipofucsin) in males and females at 1500 ppm, and dark brown liver discoloration at 1500

ppm.

Thyroid tumors 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 only 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 thyroid follicular adenomas or carcinomas did not reach statistical significance for males or females. For males only, the incidence of carcinomas at 3000 ppm was not significantly different from concurrent controls, but was greater than the upper limit of the historical control values and so was considered treatment related. In males and females, the incidence of adenomas did not reach statistical signific ance at any dose compared to concurrent controls and was within the historical control range. These results were consistent with thyroid histopathology, which showed significant thyroid follicular hyperplasia in males at 1500 ppm.
Colloid was also alter ed 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 Per l's Prussian Blue stain positive material, most probably iron, was

observed at 250 ppm in both sexes. No changes of the bone structure were identified by light microscopy. Gross pathological evaluation identified white discoloration of skull bones (fro ntal bone, dorsal skull, tympanic cavity) that diagnosed as periosteal hyperostosis (i.e. bone thickening). These effects were considered potentially adverse.

Chronic toxicity (one year duration) was also investigated in this study in satellite animals (10/sex/dose). Adverse effects on body weight were indicated by terminal body weights in both sexes at 3000 ppm that were decreased more than 10% relative to untreated controls. Increased absolute and relative liver weights were observed at 250 ppm in males and 500 ppm in females in conjunction with centrilobular hepatocellular hypertrophy at 1500 ppm in males and females, pigment storage (likely lipofucsin) in males and females at 1500 ppm, and liver discoloration at 3000 ppm in bot h sexes. None of these changes were considered clearly adverse. Changes in several clinical chemistry parameters were also observed. These consisted

- glutamyl transferase (considered equivocal) in males and/or females at 1500 ppm, increased albumin and globulin in males and/or females at 1500 ppm, (not considered adverse), increased cholesterol and triglycerides in females at 3000 ppm (considered

### Page 74 of 89

potentially adverse) decreased glucose in males at 250 ppm (not to a magnitude considered adverse), and decreased total biliribun in males and females at 250 ppm (not considered adverse). In addition, changes of electrolyte levels (Ca 2+ 

### , Cl 

### and inorganic PO 4 3

- 

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

- 

### in males ) and 1500 ppm (Ca 2+ 

### , 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 thyroid as well as the femur and other bones were also affected. In the thyroid an increased incidence of follicular cell hypertrophy/hyperplasia was observed in males at ≥ 1500 ppm. This was observed in conjunction with enlarged thyroid in all males a t 3000 ppm. These thyroid effects were considered adverse. In the femora, deposition of Perl's Prussian Blue stain positive material, most probably iron, was observed. Although there were no light microscopically visible changes of the bone structure, t his finding was considered to be potentially adverse. Discoloration of the teeth (incisors) was also observed in 3000 ppm males and females. This
was not considered adverse.

Hematological changes were mainly restricted to female rats and consisted of slightly decreased hemoglobin, mean corpuscular volume and mean corpuscular hemoglobin concentrations at 1500 ppm and/or 3000 ppm. None of these effects were considered adverse. However, shorter prothrombin times were recorded for females at dose level s ≥ 250 ppm and in males at ≥ 1500 ppm, which were considered potentially adverse due to possible hypercoagulability.

The LOAEL for chronic toxicity in males is 250 ppm (11 mg/kg bw/day in males and 14 mg/kg bw/day in females) based on non

- neoplastic 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 requirement for a combined chronic toxi city/carcinogenicity study (OPPTS 870.4300; OECD 453) in rats.

870.4300 Carcinogenicity/Chronic Study

– Mouse MRID 47923592

BAS 700 F (Batch COD

– 000899, Purity 99.7% up to study day 349; Batch COD

- 001049, Purity 99.2% from day 350 to end of study) was administered to C57BL/6 J Rj mice in the diet for 18 months at doses of 0, 150, 750, 3000 and 6000 ppm (21, 107, 468 and 996 mg/ kg bw in males and 33, 158, 652 and 1307 mg/kg bw in females). There were no treatment

- related neoplasms.

Systemic toxicity was observed as indicated by effects on body weight development in males at

≥ 3000 ppm and females at 6000 ppm. The liver was iden tified as the only target organ as indicated by increases of relative and/or absolute liver weights in males at ≥ 750 ppm and in females at ≥ 3000 ppm. Histopathological examination of the liver revealed mainly periportal (males; Zone 3) or peripheral (fem ales; Zone 1) hepatocellular hypertrophy at 6000 ppm and

≥ 3000 ppm, respectively. This effect is not considered adverse. In addition, an increased

### Page 75 of 89

severity and/or incidence of fatty changes in hepatocytes was observed at dose levels ≥ 750 ppm.

The LO AEL for chronic toxicity is 3000 ppm (468 mg/kg/day in males and 652 mg/kg/day in females) based on decreased body weight. The NOAEL is 750 ppm (158 mg/kg bw/day in males and 107 mg/kg bw/day in females).

This study is classified as totally reliable (acceptable/guideline) and satisfies the guideline requirement for a chronic toxicity/carcinogenicity study (OPPTS 870.4300; OECD 451) in mice.

A.4.6 Mutagenicity MRIDs 47923572, 47923579, 47923577, 47923584

MRID 47923572 S. typhimurium and E. coli w ere exposed to BAS 700 F (Batch COD

- 001026; purity 99.4%) using dimethylsulfoxide (DMSO) as a solvent in the presence and absence of metabolic activation in two independent sets of experiments. Triplicate plates were used per dose and per test condition. V ehicle and positive controls were included in each experiment.

In the plate incorporation assay as well as in the preincubation test, BAS 700 F was tested up to the limit concentration of 5000 μg/plate. Concentrations of 20, 100, 500, 2500 and 5000 μg/plate were used with and without metabolic activation. In both the plate incorporation assay and the preincubation assay a weak bac teriotoxic effect was occasionally observed depending on the
strain and test conditions at concentrations of 500 μg/plate (strain TA1537 in the plate incorporation assay) or above. Precipitation of the test substance was noted at concentrations of

500 μg /plate with and without metabolic activation in both experiments.

Neither in the first experiment (plate incorporation test) nor in the second experiment (preincubation test) a biologically relevant increase in the number of revertant colonies was
noticed in any of the strains tested in presence or absence of metabolic activation. The positive controls induced the appropriate response in the corresponding strains, thus demonstrating the sensitivity of the test system.

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

This study is classified as totally reliable ( acceptable/guideline) and satisfies the gu ideline requirement for a bacterial reverse mutation test (OPPTS 870.5100, OECD 471).

MRID 47923579
BAS 700 F (Batch COD

- 000899; purity 99.7%) was tested in vitro for its ability to induce forward mutations in mammalian cells by assessing the mutation of the HPRT locus in Chinese Hamster CHO cells. Two independent sets of experiments were conducted in the presence and
absence of metabolic activation. Based on the r esults of a preliminary cytotoxicity assay
concentrations of 5 to 100 μg/mL were employed in the original experiment using a 4

- hour exposure period with and without metabolic activation. In the second experiment concentrations
of 6.3 to 100 μg/mL were used without metabolic activation for a 24 hour exposure and with

### Page 76 of 89

metabolic activation for a 4 hour exposure. Ethylmethanesulfonate (EMS) and methylcholanthrene (MCA) served as positive controls in the experiments without and with metabolic activation, respect ively. After the incubation period treatment media were replaced by culture medium and the cells were incubated for about one week for expression of mutant cells. This was followed by a 6 to 8 day incubation of cells in selection medium containing 6

- thiogu anine.

Cytotoxic effects indicated by reduced cloning efficiencies of below 20 % of the respective vehicle control were observed in both experiments with or without metabolic activation.

An increase in the mutant frequency was not observed neither in the original nor in the confirmatory study. The positive control substances, however, resulted in a marked increase in mutant frequency.

BAS 700 F does not induce forward mutations in mammalian cells in vitro , under the conditions of this study.

This study is classified as totally reliable ( acceptable/guideline) and satisfies the guideline requirement for an in vitro gene mutation test (OPPTS 870.5300, OECD 476).

MRID 47923577
BAS 700 F (Batch COD

- 000899; purity 99.7%) was tested in vitro for the ability to induce chromosome and numerical aberrations in Chinese Hamster V79 cells in two independent experiments in the presence and absence of metabolic activation. Based on the cytotoxicity results of a previously performed HPRT study, concentrations of 6.3 to 400 μg/mL were tested for clastogenic effects with and without metabolic activation in experiments with a pulse treatment of 4 hours or continuous treatment of 18 hours. The preparation intervals used were 18 h or 28 h after the beginning of treatment . Ve hicle (DMSO) and positive controls (cyclophosphamide (CPP) and ethylmethanesulfonate (EMS) for the experiment with and without metabolic activation, respectively) were included to demonstrate the sensitivity of the
test system.

Prior to cell harvest, addi tion of Colcemid arrested cells in the metaphase. After slide preparation and staining of the cells, at least 200 well spread metaphases per dose and treatment condition were analyzed for chromosomal aberrations.

At concentrations of 100 μg/mL and above a sufficient number of metaphases was not available for evaluation. Therefore, the highest concentration to be scored was 50 μg/mL. A relevant increase in the number of aberrant cells was not observed at any of the tested concentrations with
or without meta bolic 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 s light 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.

### Page 77 of 89

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 s pindle poison effects (aneugenic activity) in NMRI mice using the micronucleus test method. For this purpose, the test substance suspended in corn oil was administered twice orally within a 24

- hour period to groups of 5 male mice at dose levels of 500, 100 0, and 2000 mg/kg body weight in a volume of 10 mL/kg body weight. The vehicle served as negative and cyclophosphamide and vincristine sulfate as positive controls. The vehicle was administered twice at a 24 h interval and the positive controls once. The a nimals
were sacrificed 24 hours after the last administration and the bone marrow of the two femora was prepared. After staining of the preparations, 2000 polychromatic erythrocytes were evaluated per animal and investigated for micronuclei. The normocytes with and without micronuclei occurring per 2000 polychromatic erythrocytes were also recorded.

Two oral administrations of BAS 700 F did not lead to any biologically relevant increase in the number of polychromatic erythrocytes containing either small or large micronuclei. The rate of micronuclei was mostly close to the concurrent negative control and was within the range of the historical control data. Inhibition of erythropoiesis, determined from the ratio of polychromatic to normochromatic erythrocytes , did not occur. Signs of systemic toxicity were not observed up to the highest tested dose of 2000 mg/kg bw.

Both of the positive control chemicals, i.e. cyclophosphamide for clastogenic effects and vincristine for induction of spindle poison effects, le d to the expected increase in the rate of polychromatic erythrocytes containing small (cyclophosphamide) or small and large (vincristine sulphate) micronuclei, thus demonstrating the sensitivity of the test system.

This study is classified as totally reli able ( acceptable/guideline) and satisfies the guideline requirement for an erythrocyte micronucleus test (OPPTS 870.5395, OECD 474).

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study

- Hen

- NA

870.6200a Acute Neurotoxicity MRID 47923605 The acute neurotoxicity of BAS 700 F (Batch COD

- 001026; Purity: 99.4%) was investigated in groups of 10 male and female Wistar rats ( Crl:WI(Han) after a s ingle administration by gavage at dose levels of 0, 125, 500, and 2000 mg/kg bw/d.

### Page 78 of 89

No signs of gener al systemic toxicity were observed. Treatment

- related neurobehavioral effects were noted in mid and high dose animals only on the day of treatment. These consisted of slight, but statistically significant increase of the landing foot

- splay in high dose mal es, reduction in the number of rearings in males at ≥ 500 mg/kg bw/d as well as impaired motor activity in high and mid dose males and females. No effects on these parameters were observed on study days 7 and 14. Additionally, no treatment

- related neuropat hological findings were noted, i.e. no brain weight changes or neurohistopathological findings were observed. Therefore, the affected clinical parameters were considered an indication of a neuropharmacological effect rather than
an indication of neuronal d amage.

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 satisfie s 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 Wi star 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 obser vation, FOB and motor activity) or neurohistopathological indication of neurotoxicity.

Signs of systemic toxicity observed in this study were consistent with those observed in other repeated dose rat studies with BAS 700 F. These consisted of slightly im paired body weight

- GT, total protein, albumin, globulin, cholesterol, triglycerides, urea, Ca 2+ 

### , inorganic PO 4 - 

### and Mg 2+ 

### levels as well as decreased AS(A)T, gluco se and bilirubin levels), increased liver and thyroid weights as well as centrilobular hypertrophy of hepatocytes.

Under the conditions of the present study the no observed adverse effect level (NOAEL) for neurotoxicity was 5000 ppm, the highest dose tested, which is equivalent to about 302 mg/kg
bw/d in males and 338 mg/kg bw/d in females.

The NOAEL for neurotoxicity is 5000 ppm (302 mg/kg bw/day in males and 338 mg/kg bw/day in females). The LOAEL was not observed.

This study is classified as totally reliable ( acceptable/guideline) and satisfies the guideline requirement for a chronic neurotoxicity study (OPPTS 87 0.6200; OECD 424) in rats.

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

### Page 79 of 89

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% carboxymethylcellulose/1% cremophor vehicle. Plasma kinetics were first characterized by administering a single dose of 5, 50, or 500 mg/kg bw and plasma concentrations measured at 1, 2, 4, 8, 24, 48, 72, 96, 120, 144, and 168 hours. The times to maximum plasma levels (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 65.31/66.08, 13.35/11.83, and 1.85/1.57 μg Eq/g in males/females, respectively. Areas Under Curve (AUCs) were 4215.2/5667.4, 434.6/532.4, 45.4/35.7 μg E q h/g in males, females respectively. Importantly, no sex differences in the rate or extent of absorption was observed. Also, AUCs scaled with dose, indicating that absorption was not saturated and was most probably the result of passive diffusion. Although, the rates of elimination were the same in males and females in the time intervals following the Tmax, they were slightly reduced in females in the time interval immediately following the t
max 

### . This could be due to the slight
differenc e in tissue distribution between males and females and would explain the slightly higher AUCs in females at doses of 150 and 500 mg/kg bw and the difference in bile excretion pattern.

Doses of 150 and 7.5 mg/kg bw 14 

### C

– BAS 700 F were chosen for mass bala nce, tissue distribution, and biliary excretion studies, based on the results of the plasma kinetic studies and repeated

- dose toxicological studies. The duration of these studies (time to sacrifice) was based on the times of maximum plasma concentration ( MPC), 1⁄2 MPC, 1⁄4 MPC, and 1/8 MPC in each sex. In a tissue distribution study with single high and low doses, 150 mg/kg bw 14 

### 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 sacrific ed at 16, 56, 80, and 104 hours. The highest tissue concentrations of radioactivity in males and females were found at 16 hours. Radioactivity was widely distributed in both sexes with a similar pattern: the highest concentrations were found in the gut contents and stomach contents. However, lower concentrations were found in numerous other organs/tissues, including the liver, thyroid, adrenal glands, kidney, pancreas, testes/uterus, and brain. For males and females, radioactivity declined in all tissu es over time. In the single, low dose study, 7.5 mg/kg bw 14 

### C

– BAS 700 F was administered orally (by gavage) to 4/sex/dose with males sacrificed at 1, 8, 28, and 48 hours and females sacrificed at 1, 20, 28, and 48 h after
the administration of the test s ubstance. 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 ou t 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 7 00 F one per day on Days 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

### Page 80 of 89

were > 89% in males and females for all dose groups. For all dose groups, the majority of the
admi nistered 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 

### i n exhaled air. The time course of the amount of radioactivity found in urine and feces indicated the excretion occurred predominantly within three days after dosing, indicating low potential for bioaccumulation. Bile duct cannulation experiments showed tha t 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, respectively. W ithin 72 hours after administration of 14 

### C

– BAS 700 F at a dose level of 7.5 mg/kg bw, excretion via bile was found to be 50.92% and 55.80% of the administered radioactivity in males and females, respectively. These data also demonstrated a gender

– independ ent 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% an d 67% of the applied dose for males and females at a dose of
150 mg/kg bw and about 68% and 80% of the applied dose for males and female rats at a dose level of 7.5 mg/kg bw.

This study is classified as totally reliable ( acceptable/guideline) and, togeth er with the metabolism study, satisfies the guideline requirement for a metabolism and pharmacokinetics study (OPPTS 870.7485; OECD 417) in rats.

The metabolic fate of 14 

### C

– BAS 700 F was investigated in a follow

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

### C

– BAS 700 F speci fically for the metabolism study (see Error! Reference source not found. ). Urine, plasma, and bile, as well as extracts of feces, liver, fat, and kidney tissue were analyzed by HPLC. Individual
metabolites were detected down to a level of about 0.1% of the dose administered or less. Metabolites were identified by LC

– MS and LC

– MS/MS. The structures and codes of identified
BAS 700 F metabolites are shown in Error! Reference source not found.

.

In urine , 23 metabolites were identified. The main metabolites were in the range of 0.2% to 8.6%
of the applied dose and identified to be M700F004, M700F005/M700F024 (detected only in male rats), M700F009/M700F028, M700F014, M700F015, and M700F061 (detected only in female rats). For all dose groups and both genders, no amounts of the unchanged parent

com pound were detectable at any of the time intervals investigated.

In feces , the unchanged parent compound was found to be the main constituent of the extracts at high dose levels, i.e. , dose group D, C, and DX (for both labels (19

– 44% of the dose applied)

, and represented only a minor part of the extractable radioactivity (3% of the dose applied) at the low dose level (dose group B). The main metabolites were identified as M700F009 (8

– 53% of the dose applied), M700F005 (ranging from 3

– 9% of the dose applie d), and its isomer

### Page 81 of 89

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, M700F0 14 and its isomer M700F123, M700F005, M700F024, and M700F122.

In liver , the main metabolites were in the range of 0.1 to 0.9% of the applied dose and identified as M700F005, M700F006, M700F008, and M700F009. The parent compound was identified at
levels u p to 3.7 and 0.4% of the dose applied for the low and the high dose group, respectively.

In kidney, the main metabolite was identified to be M700F008 (0.02 to 0.11% of the applied dose). The active substance was present at levels up to 0.50 and 0.05% of the dose applied for the low and the high dose group, respectively.

In fat , two component s were detected: the metabolite M700F008 (0.05 to 0.29% of the applied dose) and unchanged BAS 700 F (0.35 to 2.72% of the applied dose).

In plasma , the main metabolite was identified to be M700F006 (0.03 to 0.11% of the applied dose). The parent compoun d was present at levels up to 0.13 and 0.01% of the dose applied for the low and the high dose group, respectively.

The main biotransformation steps of BAS 700 F in rats are hydroxylation at the biphenyl ring system, N

- demethylation at the pyrazole ring s ystem, loss of a fluorine atom at the biphenyl ring system, and conjugation with glucuronic acid or with glutathione derivatives. A further, but negligible transformation route is cleavage at the amide bond between the pyrazole ring system and the biphenyl ring system.

This study is classified as totally reliable ( acceptable/guideline) and, together with the biokinetic study, satisfies the guideline requirement for a metabolism and pharmacokinetics study (OPPTS 870.7485; OECD 417) in rats.

870.7600 De rmal Absorption

– Rat

– MRID 47923632

14 

### C

- BAS 700 F formulated as BAS 703 02 F, which contains both fluxapyroxad and pyraclostrobin (BAS 500F) was applied to the backs of male Crl:WI (Han) rats (4/dose/group) at nominal doses of 1670, 33.4, and 5.6 μg/cm 2 

### 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 sa crificed and surface radioactivity removed with 2 tape strips prior to isolation of application site and surrounding skin and quantification of radioactivity in the carcass. For two post

- observation groups, clean dressing was applied and the experiment

co ntinued out to 24 hours or 120 hours with continued collection of excreta. At the end of the
post

- observational period, dressings were removed and skin was washed and surface radioactivity removed with 2 tape strips prior to isolation of application site and surrounding skin and quantification of radioactivity in the carcass.

### Page 82 of 89

Average recoveries in all groups were acceptable and ranged from 88

- 105%. The majority of the radioactivity in all treatment groups was removed in the first skin wash, and ranged from 89

- 94%. Systemic absorption of radioactivity (the amount in the urine, feces cagewash, blood cells, plasma, and carcass) increased during over the post

- observation period of 24

- 120 hours for all dose groups. Similarly, the amount of radioactivity in the skin at the application site and in the surrounding skin decreased over the post

- observation period of 24

- 120 hours for all dose groups. Together, this indicates that skin

- bound residue (pesticide that was not removed after the first wash, or that laterally diffused into the surrounding skin layers) was bioavailable and that the 120 hour post

- observation period should be used for quantitative estimations of dermal absorption.

The amount of 14 

### C

- BAS 700 F that was systemically absorbed at the end of the 120 hours post

observation period increased with decreasing dose, ra nging from an average of 0.35% at 1670 μg/cm 2 

### to 7.81% at 5.6 μg/cm 2 

### . Values at 5.6 μg/cm 2 

### were used to calculate a dermal absorption factor, which included the amount systemically absorbed (7.81%), the amount in the application site skin (0.50%), and the amount in the surrounding skin (0.07%) for a total dermal absorption
factor that rounds to 8.4%. Inclusion or exclusion of the amount of 14 

### C

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

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

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

– Mouse MRID 47923633 The immunotoxic potential of BAS 700 F (Batch: COD

- 001049; Purity: 99.2%) in male C57BL/6J Rj mice (8/dose) was analyzed using dietary dose levels of 0, 500, 2000 and 6000 ppm (corresponding to approximate mean intake levels of 106, 450 and 1323 mg/kg/d, respectively) for 28 days.

Treatment with BAS 7 00 F did not result in systemic toxicity as assessed by clinical signs, food consumption and body weight development. The parameters used for detection of potential test substance related alterations in the morphology of the immune system included a) the
d etermination of lymphoid organ weights (spleen and thymus) and b) the total lymphocyte count as well as lymphocyte subpopulation distribution including natural killer cells. Furthermore, functional parameters comprising of the analysis of the primary 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 trea tment with positive control substance, cyclophosphamide (12 mg/kg bw/d by oral gavage) induced clear signs of immunotoxicity, demonstrating the reliability of the test system under the study conditions employed.

### Page 83 of 89

Based on the obtained results it can be co ncluded 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 immunotox icity study.

### Page 84 of 89

APPENDIX B. Chemical Names And Structures Of Metabolites

B. 1 Chemical Names and Structures

Metabolite Designation (Code)
Chemical Name Molecular Mass Structure

BAS 700 F
=M700F000

3

- (difluoromethyl)

- 1

- methyl

- N

- (3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1Hpyrazole

- 4

- carboxamide M = 381

M700F001

3

- (difluoromethyl)

- 1

- methyl

- 1H

- pyrazole

- 4

- carboxylic acid M = 176

M700F002

3

- (difluoromethyl)

- 1H

- pyrazole

- 4

- carboxylic acid M = 162

M700F004

3

- (difluoromethyl)

- 1

- methyl

- N

- ((1

- glucuronyl)oxy

- 3',4',5'

- trifluoro

- [1,1'

- biphenyl]

- 2

- yl

- 1H

- pyrazole

- 4

- carboxamide M = 573

M700F005

3

- (difluoromethyl)

- 1

- methyl

- N

- (4

- hydroxy

- 3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 397

M700F006

3

- (difluoromethyl)

- 1

- methyl

- N

- (hydroxy

- 3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 397

M700F008

3

- (difluoromethyl)

- N

- (3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

pyrazole

- 4

- carboxamide M = 367

M700F009

3

- (difluoromethyl)

- N

- (hydroxy

- 3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1Hpyrazole

- 4

- carboxamide M = 383

### Page 85 of 89 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

M700F019

3

- (difluoromethyl)

- 1

- methyl

- N

- ((1

- glucuronyl)oxy

- 3',4',5'

- trifluoro

- [1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 573

### Page 86 of 89 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

### Page 87 of 89 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

### Page 88 of 89 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

### Page 89 of 89

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 (pK

a ) 12. 58 (calculated) Octanol/water partition coefficient Log(K OW ) 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. Studies Reviewed for Ethical Conduct

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.

Agricultural Re

- entry Task Force (ARTF) data ba se (SOP #3.1)