UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON

, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### MEMORANDUM

20-April-2016

SUBJECT: 

### Fluxapyroxad. Hwn an Health Risk Assessment for Use of Fl uxapyroxad on Citrus Crop Group 10-10

, G r ass Crop Group 17

, and Non-Grass Crop Group 18.

P C C ode : 138009 OP Barcode: 0425590

D ec i s ion No.: 498952 Re g i s t ratio n No.: 7969-312

, 7969-306

, 7969-
309

, 7969-311

Petition No. : 5F8344 Regulator y Action: Section 3 Registration

Ri sk A ssess m e nt T y p e: Single C hemical Ae.g:regate Case No.: 3125

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

MRIO No.: NA 40 CF R: 180.666**~**



### FR OM: Mohsen Sahafeyan, Chem i s t and Risk Assessor

# ./~**~;: ~** 
Evisabel Craig

, Ph.D.

, Toxic o logi s t

# ~AA**-;** JA

# <b**~** Mon i ca Hawkins, Ph.D.

, M.P.H

., E n v ironm e nt al

## Heal~cie~~t**...rl ~**  R isk Assessment Branch 6 (RAB6)

H ea lth Effec ts Division (HE D

, 7509P)

THROUGH: Donna Davi s. Br a nch C hief

Risk Assessment Branch 6, HED (7509 P )

TO: Driss B e nmhend

, Risk Manager R ev i ewe r Shaja Joyner

, Ri sk Manager

Rachel H olloman

, Bran c h C hief Fungicide and H erbicide Br anch ( FHB )

R egist ration Divi s i on ( RD ) ( 7505P)

This document provides the Health Effects Divi sio n ' s (HED's) risk assessment for the proposed

new u ses of the active ing r edient fluxapyroxad on the citrus crop group l 0- 10

, grass crop group 17, and non- g ras s crop group 18.

Page I of 81

### 1.0 EXECUT IV E SUMMA R Y

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

2.0 HED RECOMM EN DATIONS

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

2.1 Data D efic i e n cies/Co nditi o n s o f R eg i s tration

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

2.2 Tol e r a n ce Co n s iderati o n s

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

2.2.1 E nforcement A n a l y tical Method

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

2.2.2 Int er national Harmon iza tion

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

2.2.3 R ecommended Tole ranc es

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

2

. 2.4 Re v i s ion s to Pe ti t ion ed-Fo r To l e ran ces

.. . .. ... . .... ..... . . . ... ...... .. .... .... . . . ..... . .. .. ... ..... . .. 10

2

. 3 L a b e l R ecom mendati ons

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

3.0 I NG R E DI ENT PROFIL E

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

3.1 C h emica l Id e nti ty

.. .. .... ..... .. .......... ....... .. .... .. ............ .. ... . ....... . ... . .. .. .. . ............ .... . ............ 1 " 1

3.2 Ph ys ical/ C h e mical C h a r acteristics

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

3.3 Pesticide Use Patt er n

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

3.4 A nticip a ted Ex p os ur e Path,vays

........................ . ........ . ....... . .................... . ..... . .............. 14

3

. 5 Co n s i derations of E n v ironm e n ta l Ju st i ce

.. .. ....... .. ... ... ..... .. .......................... .. ... ..... . ..... 14

4.0 HAZARD CHARACTE RI ZAT IO N/ASSESSMENT

. .. . ........................... . ... .. . . .. ... . ...... 14

4.1 Toxico l ogy St udi es Ava il ab l e for A n a l ys i s

. . ... ..... ..... ..... .. .. .. . ... .. . .. .. . ...... . . . ..... . ..... .. ...... 14

4.2 A b sor ption

, Di s tribution

, Metabolism a nd Exc retion

.... . ... . .............. . ..... .... .. .. ..... . ..... 1 5

4.3 Toxico l ogica l E ffect s

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

4.4 Safety Factor for In fants and C hildren (F Q PA Sa fe ty Fac tor )

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

4.4

. l 

### C omplet e ne ss of t he Toxico l ogy D a t a b ase

. ... ... .. . ....... . ......... ... . .. .. . ... . .................... 1 9

4.4.2 Ev iden ce of Ne u rotoxicity

..... ........... .. ..... .. . .. ... .... . .......... .. .. . .. .. ..... .. . ................ . ..... . 1 9

4.4 .3 Ev i dence of Se n s i tivity / Su s ceptib ili ty in the Dev e l oping or Young Animal..

.... 1 9

4.4.4 R es idu a l Uncerta in ty in th e Ex po s ure Database

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

4.5 Toxicity E ndpoin t and Point o f Departur e

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

4.5.1 Dose-Re s ponse Assessme nt

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

4.5.2 Recommendations for Co mbinin g Expos ur e Ro ut es

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

4.5.3 C la ss ifi cat ion of Carci no ge ni c Pot e ntial

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

4.5.4 S umm ary of Points of Dep a rture Use d in Ri s k Assess ment

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

5.0 DI ETARY AND DRINKING WATER EX PO SURE AND RI SK ASSESSM ENT

.... 23

5. 1 Met a bolite/De g radat e Re s idu e Profile

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

5.1.1 S umma ry of P l a nt a nd Livestock Me taboli s m St udi es

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

P age 2o f81

### Page 3 of 81

5.1.2 Comparison of Metabolic Pathways

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

5.1.3 Environmental Fate and Transport

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

5.1.4 Residues of Concern Summary and Rationale

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

5.2 Food Residue Profile

................................ ................................ ................................ ..... 25

5.2.1 Residues in Crops

................................ ................................ ................................ .... 25

5.3 Water Residue Profile

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

5.3.1 Estimated Drinking Water Concentrations

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

5.4 Dietary and Drinking Water Exposure and Risk

................................ ....................... 27

5.4.1 Acute Dietary (Food and Drinking Water) Analysis

................................ ........... 27

5.4.2 Chronic Dietary (Food and Drinking Water) Analysis

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

5.4.3 Cancer Dietary (Food and Drinking Water) Analysis

................................ ......... 29

6.0 Reside ntial (Non

- Occupational) Exposure/Risk Characterization

.............................. 29

6.1 Residential Handler Exposure

................................ ................................ ...................... 29

6.1.1 Handler Exposure Data

................................ ................................ .......................... 29

6.1.2 Residential Handler Exposure Assumptions

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

6.2 Post

- Application Exposure

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

6.3 Residential Risk Estimates for Use in Aggregate Assessment

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

6.4 Non

- Occupational Bystander Post

- Application Inhalation Exposure and Risk
Estimates

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

6.5 Non

- Occupational Spray Drift Exposure and Risk Estimates

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

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT

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

7.1 Acute Aggregate Risk

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

7.2 Short

- Term Aggregate Risk

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

7.3 Intermediate

- Term Aggregate Risk

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

7.4 Chronic, Non

- Cancer, Aggregate Risk

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

7.5 Cancer Aggregate Risk

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

8.0 CUMULATIVE RISK

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

9.0 OCCU PATIONAL EXPOSURE/RISK CHARACTERIZATION

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

9.1 Occupational Handler Exposure/Risk Estimates

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

9.3 Post

- Application Exposure

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

9.3.1 Dermal PostApplication Risk

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

9.3.2 Inhalation Post Application Risk

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

### Page 4 of 81

9.3.3 Restricted Entry Interval

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

10. REFERENCES

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

APPENDIX A: TOXICOLOGY DATA SUMMARY

................................ ......................... 42

A.1 Guideline Data Requirements

................................ ................................ ...................... 42

A.2 Toxicity Profiles

................................ ................................ ................................ ............. 42

A.3 Toxicological Endpoints

................................ ................................ ................................ 54

A.3.2 Chronic Reference Dose (cRfD)

- All Populations

................................ ................ 54

A.3.3 Incidental Oral Exposure (Short

- Term (1

- 30 days))

................................ .......... 55

A.3.4 Incidental Oral Exposure (Intermediate

- Term (1

- 6 months))

........................... 55

A.3.5 Occupational and Residential Dermal Exposure (Short

- and Intermediate

Term) 55

A.3.6 Occupational and Residential Inhalation Exposure (Short

- Term)

................. 56

A.3.7 Occupational and Residential Inhalation Exposure (Intermediate

- Term)

...... 56

A.4 EXECUTIVE SUMMARIES

................................ ................................ ........................ 57

A.4.1 Subchronic Toxicity

................................ ................................ ................................ 57

A.4.2 Prenatal Developmental Toxicity

................................ ................................ .......... 59

A.4.3 Reproductive Toxicity

................................ ................................ ............................ 61

A.4.4 Chronic Toxicity

................................ ................................ ................................ ...... 61

A.4.5 Carcinogenicity

................................ ................................ ................................ ....... 62

A.4.6 Mutagenicity

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

A.4.7 Ne urotoxicity

................................ ................................ ................................ ........... 68

A.4.8 Metabolism

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

A.4.9 Immunotoxicity

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

APPENDIX B. Chemical Names And Structures Of Metabolites

................................ ......... 7 4

APPENDIX C. Physical/Chemical Properties

................................ ................................ .......... 79

APPENDIX D. Studies Reviewed for Ethical Conduct

................................ .......................... 80

APPENDIX E. Proposed Use Directions for Fluxapyroxad

................................ ................... 81

### Page 5 of 81

1.0 EXECUTIVE SUMMARY

This assessment provides information to support a Section 3 registration and establishment of permanent tolerances for the use of fluxapyroxad on citrus (crop group 10

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

- grass animal feed (crop group 18). Due to an increase in livestock dietary burden s , HED is also recommending new tolerances for poultr y tissues (fat, meat, and meat b yproduct) and mi lk fat, and i ncreasing the cu rrent tolerances on milk, ruminant fat, and meat byproduct (to include fat and meat byproduct of cattle, goat, horse and sheep).

Fluxapyroxad (3

- (difluoromethyl)

- 1

- methyl

- N

- (3′,4′,5′

- trifluoro[1,1′

- biphenyl]

- 2

- yl)

- 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 crops to control a broad spectrum of fungal diseases. Fluxapyroxad is a pyraz ole carboxamide. The mode of pesticidal action as a fungicide is inhibition of succinate dehydrogenase in complex II of the mitochondrial respiratory chain, resulting in inhibition of spore germination, germ tubes, and mycelial growth.

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

on citrus (crop group 10

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

grass animal feed (crop group 18 ). The proposed maximum use rate for foliar applicatio n on citrus (crop group 10

- 10) is 4 applications, each at 0.122 lb ai/A, with a total maximum application rate of 0.488 lb ai/A and 0

- day pre

- harvest interval (PHI). The proposed maximum use rate for foliar application on grass (crop group 17) including g rass grown for seed, and non

grass animal feed (crop group 18) is 3 applications, each at 0.089 lb ai/A, with a total maximum
rate of 0.267 lb ai/A and a 14

- day PHI.

The toxicology database for fluxapyroxad is complete and considered sufficient for hazard characterization and endpoint selection for the anticipated routes (oral, dermal, and inhalation) and durations of exposure (acute, subchronic, and chronic) for the proposed uses.

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

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

- day subchronic inhalation study was waived by the Agency. Liver toxicity was observed in rats, mice, an d dogs, with rats bei n g the most sensitive species for all durations o f exposure. Thyroid effects were observed only in rats. These effects were secondary to changes in liver enzyme regulation, which increased metabolism of thyroid hormone, resulting changes in thyroid hormones, thyroid follicular hypertrophy and hyperplas ia, 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 determi ned that the quantification of risk using a non

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

### Page 6 of 81

from exposure to fluxapyroxad.

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

. Developmental toxicity in

rat s 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 th yroid follicular hypertrophy/hyperplasia in parental animals. Developmental toxicity in rabbits was limited to paw hyperflexion which was significantly increased at the highest dose, where decreased body weight in maternal animals was also observed. Sinc e 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 evid ence of immunotoxic effects from fluxapyroxad.

Fluxapyroxad acute toxicity to mammals is low by all routes of exposure. No hazards were identified for exposures via the dermal route in a 28

- day dermal toxicity 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

. .

Toxicological points of departure (PODs) were selected for dietary (food and drinking water), residential, and occupational exposure scenarios for this as sessment. 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 red uced to 1X ; therefore, the acute and chronic RfDs are equivalent to the acute and chronic PADs, respectively

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

uncerta inties 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 tox icity/carcinogenicity study in rats based on non

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

- term and intermediate

- term inhalation exposure was selected from a 90

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

- and intermediate

- term dermal exposure were not selected because fluxapyroxad does not pose a dermal hazard. An uncertainty factor of 100x was applied to endpoints selected for all exposure routes (10x for interspecies extrapolation, 10x for intraspecies variation).

### Page 7 of 81

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

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

are residential exposure from existing turf uses that were previously assessed for fluxapyroxad. An update d turf assessment was completed in this document due to a correction in the single maximum application rate from 2.47 lb ai/gallon to 0.005 lb ai/gallon. The residential handler exposure and risk estimates indicate that the short

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

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

- application dermal

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

- application incidental oral exposure for children indicate that the MOEs are greater than HED’s LOC (i.e., MOEs are ≥ 100 ) and therefore are not of concern; t he MOEs range from 2,100 to 940,000. The corrected turf assessment will impact the human health aggregate risk assessment for fluxapyroxad.

The aggregate risk assessment includes residential adult handler exposure from turf use and
incidental oral for ch ildren 1<2 plus background dietary exposure for both groups. The MOEs for both adult and children 1<2 are greater than HED’s LOC and therefore are not of concern.

Occupational handler short

- and intermediate

- term exposure is anticipated from the proposed uses. The occupational handler exposure and risk estimates indicate that the short

- and
intermediate

- term inhalation MOEs are not of concern to HED (i.e., MOEs ≥ 100) at the baseline attire (i.e., no gloves and no respirator). The MOEs range from 25,00 0 to 9,900,000,000. Occupational post

- application dermal exposure was not quantitatively assessed since there is no dermal hazard for fluxapyroxad.

This risk assessment relies in part on data from studies in which adult human subjects were
intentionall y exposed to a pesticide or other chemical. These data, which include studies from the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, and the Agricultural Reentry Task Force (ART F) database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board . Descriptions of data sources, as well as guidance on their use, can be found at the following Agency websites: http://www.epa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- data.html

.

Environmental Justice

### Page 8 of 81

Potential environmental justice concerns were considered, to the extent possible, in this 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. 1 

### ”

2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies/ Conditions of Registration

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

 The following analytical standards wil l need to be replenished as soon as possible as the Repository is out of stock :

o Fluxapyroxad

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

There are suitable residue analytical methods available for enforcement of fluxapyroxad tolerances ( BASF Methods L0137/01 for plants and L0140/0 2 for animal matrices) which have been radiovalidated and have underwent successful validation by an independent laboratory.
These are liquid chromatography with tandem mass spectrometry ( LC/MS/MS) methods and
monitor two ion transitions. The Limit of Qu antitation (LOQ) for BASF method L0137/01 is 0.01 mg/kg for various matrices. The LOQ for BASF method L0140/02 is 0.01 ppm for liver and muscle, and 0.001 ppm for milk and eggs.

2.2.2 International Harmonization

There are no Codex or Canadian MRLs for citrus, grass and non

- grass animal feed at present.
US

- recommended tolerances for residues in ruminant meat byproduct, milk, and milk fat are generally much lower than Codex and therefore cannot be harmonized. US

- r ecommended
tolerances for those tissues plus ruminant fat are slightly higher than Canadian MRLs; however, they cannot be lowered for harmonization with Canada since it would result in over

- the

- tolerance
residues in those commodities. US

- recommended toler ances for residues in poultry tissues are
harmonized with Canada

.

1 http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf

### Page 9 of 81

2.2.3 Recommended Tolerances

Tolerances for residues of fluxapyroxad in/on citrus, grass, and non

- grass animal feed were derived using the Organization for Economic Cooperation and Develo pment Maximum Residue Level (OECD MRL) Calculation Procedures. T he rounding system in OECD MRL spreadsheet
calculator was used for rounding the expected residues in livestock tissues and recommend ing
livestock tolerances.

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

, there are no residue chemistry issues that would preclude granting a Section 3 registration for the requested new uses of fluxapyroxad . The current tolerance expression

co mplies with the 2009 Knizner guidance on tolerance expressions. Tolerances should be
established under 40 CFR 180.666 as follows:

Tolerances are established for residues of fluxapyroxad, including its metabolites and degradates. Compliance with the tolerance levels specified below is to b e determined by measuring only fluxapyroxad [ 3

- (difluoromethyl)

- 1

- methyl

- N

- (3′,4′,5′

- trifluoro[1,1′

- biphenyl]

- 2

- yl)

- 1 H

- pyrazole

- 4

- carboxamide ] in or on the commodity.

Table 2.2.3.1 Tol erance Summary for Fluxa pyroxad

Established
Tolerances (ppm) Proposed

Tolerances (ppm) HED

Recommended
Tolerance (ppm) Comments

Cattle, fat
0.05

--- 0.06 Increase in established tolerance not proposed, but required

. Cattle, meat byproduct
0.03

--- 0.04 Increase in established tolerance not proposed, but required

. Citrus, dried pulp

--- 2.7 3.0 Citrus, oil

--- 19 40 Egg

0.002 0.01 0.01

Fruit, citrus, group 10

- 10

--- 1.0 1.0 Grass, forage, fodder and hay, group 17 --- 30 40

Goat, fat
0.05

--- 0.06 Increase in established tolerance not proposed, but required

. Goat, meat byproduct
0.03

--- 0.04 Increase in established tolerance not proposed, but required

. Horse, fat
0.05

--- 0.06 Increase in established tolerance not proposed, but required

.

### Page 10 of 81

Table 2.2.3.1 Tol erance Summary for Fluxa pyroxad

Established
Tolerances (ppm) Proposed

Tolerances (ppm) HED

Recommended
Tolerance (ppm) Comments

Horse, meat byproduct
0.03

--- 0.04 Increase in established tolerance not proposed, but required

. Milk
0.005

--- 0.01 Increase in established tolerance not proposed, but required

. Milk, fat

---- --- 0.15 Nongrass animal feed, group 18 --- 30 30

Poultry, fat

--- 0.005 0.01 Poultry, meat

--- --- 0.01 Poultry, meat byproduct

--- --- 0.01 Sheep, fat
0.05

--- 0.06 Increase in established tolerance not proposed, but required

. Sheep, meat byproduct
0.03

--- 0.04 Increase in established tolerance not proposed, but required

.



### Note to PM:

Tolerance for nongrass animal feeds, group 18 under 40 CFR §180.666 section (d) Indirect
or inadvertent residues should be revoked

.

2.2.4 Revisions to Petitioned

- For Tolerances

HED is now recommending tolerances for poultry tissues (fat, meat, and meat byproduct) ; the registrant propose d a tolerance for poultry fat only

. No to lerances were established on poultry
tissues previously as it was not expected to find residues in those tissues due to their low dietary
burden ; i.e., category 3 of CFR 180.6(a) applied for those poultry matrices

. However, because of expectation of higher residues on the feed items associated with the proposed uses (mainly grass and nongrass), the livestock dietar y burdens in general have increased and residues are now expected to be transferred to poultry tissues. Tolerances should now be established for poultry tissues; i.e., category 3 of CFR 180.6(a) no longer applies. In addition, due to the higher
livestock dietary burdens, HED is also recommending for increasing current tolerances on milk, ruminant fat and meat byproduct (to include fat and meat byproduct of cattle, goat, horse and sheep) and a tolerance for residues in milk fat.

As it is seen in Table 2.2.3.1 above, HED recommended tolerances are higher than proposed tolerances for grass (group 17), citrus oil, dried pulp, and poultry fat. This difference in

### Page 11 of 81

tolerance for grass is due to HED using residues from 0

- day pre

- harvest interval ( PHI ) from grass samples (instead of 14

- day used by the registrant) for calculating the tolerance; for citrus oil, the difference is due to HED using highest average field trial ( HAFT ) data, instead of median, times processing factor; for dried pu lp, the difference is due to HED rounding up the calculated tolerance; for poultry fat, the difference is due to recalculating dietary burden for livestock, taking into account feed commodities from (0

- day PHI) grass, alfalfa and clover which
resulted in h igher than previously calculated dietary burdens and therefore higher tolerances.

2.3 Label Recommendations

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

3 .0 INGREDIENT PROFILE

3.1 Chemical Identity

Structure and nomenclature of fluxapyroxad are reported in Table 3.1.1

. For chemical names and structures of fluxapyroxad metabolites see Appendix B.

TABLE 3.1.1 Fluxapyroxad Test Compound Nomenclature.

Chemical structure

Common name Fluxapyroxad (ISO, proposed)

Company experimental name BAS 700 F

IUPAC name 3

- (difluoromethyl)

- 1

- methyl

- N

- (3′,4′,5′

- trifluorobiphenyl

- 2

- yl)pyrazole

- 4

- carboxamide

CAS name 3

- (difluoromethyl)

- 1

- methyl

- N

- (3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 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

### Page 12 of 81

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

BASF has petitioned the Agency for foliar use of the fungicide fluxapyroxad on citrus (crop group 10

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

- grass animal feed (crop group 18). The use pattern are shown in Table 3 .3 .1 below

.

### Page 13 of 81

Table 3 .3 .1

- Proposed Use Directions.

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

treatment Max. No.

Applic. per
Season Max.

Seasonal Applic.

Rate (lb ai/A) PHI

(days)

Citrus Foliar ground/aerial spray; (timing in plant’s growth stages not specified) 5.96% EC (7969

- 306)

26.55% EC (7969

- 309) 14.33% EC (7969

- 311) 0.122 4 0.488 0

Use Directions and Limitations: A minimum 10

- day RTI is specified. No livestock feeding restriction. For aerial application spray volume should be no less than 10 gallons of solution per acre.

Grass forage, fodder, straw, and hay Foliar ground spray; (timing in plant’s growth stages not specified) 5.96% EC (7969

- 306)

26.55% EC (7969

- 309) 0.089 3 0.267 14

Use Directions and Limitations: A minimum 14

- day RTI is specified. “Do not apply within 14 days of grazing or harvest for forage and hay.” Not to be used on rangeland.

Non

- grass animal feed, including alfalfa and clover Foliar ground spray; (timing in terms of plant’s growth stages not specified) 5.96% EC (7969

- 306)

26.55% EC (7969

- 309) 0.089 3 0.267 14

Use Directions and Limitations: A minimum 14

- day RTI is specified. “Do not apply within 14 days of grazing or harvest for forage and hay.” Not to be used on rangeland.

Alfalfa Foliar ground spray; (timing in terms of plant’s growth stages not specified) 14.33% EC (7969

- 311) 0.075 3 0.225 14

Use Directions and Limitations: A minimum 14

- day RTI is specified. “Do not apply within 14 days of grazing or harvest for forage and hay.” Not to be used on rangeland.

Grass grown for seed

Foliar ground spray; (timing in terms of plant’s growth stages not specified) 5.96% EC (7969

- 306)

26.55% EC (7969

- 309) 14.33% EC (7969

- 311) 0.089 3 0.267 14

Use Directions and Limitations : A minimum 14

- day RTI is specified.

Priaxor label (7969

- 311) also specifies: “Do not graze or feed forage or hay to livestock within 27 days of last application.”

### Page 14 of 81

3.4 Anticipated Exposure Pathways

Humans may be exposed to fluxapyroxad in food and drinking water, since fluxapyroxad may be applied directly to growing crops and application may result in fluxapyroxad reaching surface and ground water sources of drinking water. Additionally humans may 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 w ell as the existing uses

.

3.5 Considerations of Environmental Justice

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

- Income Populations," (http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf). As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to
well

- established procedures. In line with OPP poli cy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture (USDA) under the National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered
food uses of a pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumsta nces warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns amon g specific subgroups.

4.0 HAZARD CHARACTERIZATION/ASSESSMENT

4.1 Toxicology Studies Available for Analysis

### Page 15 of 81

The toxicological database for fluxapyroxad is complete and adequate for risk assessment. Appendix A is a summary of the fluxapyroxad toxicological database. Based on a weight

- of

evidence (WOE) approach and considering of all the available hazard information for fluxapyroxad , the HASPOC concluded that a subchronic inhalation study is not required for fluxapyroxad at this time (K. Rury, TXR# 0056561 , 1/17/2013 )

.

Available mammalian toxicology studies considered in the hazard characterization include:



##  A cute oral, dermal, and inhalation toxicity; eye and dermal irritation; and dermal
sensitization studies



##  Acute and subchronic neurotoxici ty studies in rats



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



##  21

- day dermal toxicity study in rabbits



##  Development al toxicity studies in rats and rabbits



##  Reproductive and postnatal toxicity study in rats



##  Ca rcinogenicity studies in mice and rats



##  Dermal penetration in rat s



##  Immunotoxicity study in rats



##  Metabolism and pharmacokinetic studies in rats



##  Supplemental mode of action studies.

There are three metabolites of fluxapyroxad: two soil metabolites (M700F001 and M700F002)
and a metabolite found on food crops (M700F048). There are no toxicity studies on these metabolites in the general literature. However, subchronic dietary studies in rats, prenatal developmental studies in rabbits, and a complete battery of in vitro and in vi vo 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, Distribu tion, 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 se x differences observed in the rate or extent of absorption. The 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) in
males/females. The initial half

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

### Page 16 of 81

Mass balance, tissue distribution and biliary excretion studies were performed in rats at doses of 150 mg/kg and 7.5 mg/kg. These studies indicated that radioactivity was widely distributed in
both s exes within 16 hours, with bioavailability estimated to be between 65

- 80%. A similar pattern of distribution was observed in males and females: the highest concentrations were found in the gut contents and stomach contents. However, lower concentrations were found in numerous other organs/tissues, including the liver, thyroid, adrenal glands, kidney, pancreas, testes/uterus, and brain. For both male and female rats, radioactivity declined in all tissues over
time. The time course of the amount of radioac tivity found in urine and feces indicated the excretion occurred predominantly within three days after dosing, indicating a low potential for bioaccumulation. For both dose groups, the majority of the radioactivity (84

- 94%) was excreted
via the feces wit hin 168 hours. The amount excreted via the urine during this time was 3

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

- 64% of radioactivity eliminated via this route. Negligible amounts were excreted a s 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 t he 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, includ ing M700F001 (from hydrolysis of the amide bond between the pyrazole and biphenyl rings) and M700F002 (from N

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

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

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. Pharmacoki netic 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 facto r of 8.4% at dose of 5.6 μg/cm 2 

### for potential use in future
risk assessments.

4.3 Toxicological Effects

In mammals, the primary target organ for fluxapyroxa d exposure is the liver, with toxic ity
observed in several species: rats, mice, and dogs . In rats, the most sensitive species, effects ranged from increased liver weights and changes in liver enzyme activities in subchronic studies

### Page 17 of 81

to hepatocellular necrosis and neoplast ic liver changes (foci, masses) in chronic studies . In
subchronic studies in mice, increased liver weights were observed along with fatty changes in the liver, with few observations of hepatocellular hypertrophy. At higher doses, liver necrosis was also observed. Liver effects in subchronic studies in dogs were limited to increas ed liver weights at high doses. However, in chronic studies, increased liver weights were observed in conjunction
with fibrosis and cirrhosis.

Fluxapyroxad administration via the oral route also resulted in toxic effects in the thyroid. These thyroid ef fects occurred secondary to the effects on the liver and were seen only in rats. Thyroid effects in rats were observed throughout the toxicity database and included changes in serum thyroid hormone levels, enlarged thyroid, increased thyroid weights, and /or microscopic effects of thyroid follicular hypertrophy and hyperplasia. These effects showed a clear threshold, were evident within weeks and were observed out to two years. Although these effects were observed in male and female rats, male s were usua lly more sensitive . Supplementary studies (including 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 histopathological alterations in the thyroid.

Chronic oral administration of fluxapyroxad resulted in treatment

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

- genotoxic and/or species

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

- genotoxic modes
of action for liver and t hyroid tumors also indicated clear thresholds protective for tumorgenic
effects.

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

- related effects of decreased rearing (in males only) and decreased motor activity (in both sexes) were observed after dosing via oral gavage in the acute neurotoxicity study . These effects were considered equivocal for neurotoxcity, since they may indicate transient and reversible neurotoxicity from a bolus exposure and/or general malaise. There were no neurotoxic effects observed in the subchronic dietary toxicity study. Fluxapyroxad did not cause reproductive toxicity in rats. Developmental toxicity in rats was limited to decreased body weight and body weight gain in offspring and was observed at the same dose levels that caused thyroid dysregulation in parental animals

. Developmental toxicity in rabbits was limited to paw hyperflexion, a malformation that usually reverses as the animal matures, and was observed at the same dose levels that caused reduced maternal body weight. There were clear NOAELs for these developme ntal effects.

An unusual effect of tooth whitening was observed in rats in several studies. This effect was

### Page 18 of 81

observed with increasing oral doses of fluxapyroxad. This was likely due to decreased deposition of a yellow iron

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

- related changes in iron storage, but there was no evidence of microscopic damage to these tissues or clinical evidence of compromised tissue function. The Agency considered the potential for 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 pa rental and F1 males of the rat 2

- generation reproduction and fertility effects study.

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

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

Acute toxicity studies show that fluxapyroxad e xhibits 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 per formed 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 t hree 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 dose s similar to those that caused developmental effects in rabbits with fluxapyroxad treatment. However, these effects (abortions and resorptions) were of a different nature than for fluxapyroxad (paw hyperflexion) and are likely secondary to maternal toxici ty. These data are sufficient for the Agency to conclude that these metabolites do not have hazards that exceed those of fluxapyroxad in nature, severity, or potency.

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

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

The FQPA Safety Factor is reduced to 1X. This reduction is based on the availability of a complete toxicity database with clear NOAELs for characterizing neurot oxicity and sensitivity during development, supplemental studies that characterize the effects fluxapyroxad on thyroid hormones, and no residual uncertainties in the exposure data base. The information used to reduce uncertainties in hazard and exposure of infants and children is described in detail below.

### Page 19 of 81

4.4.1 Completeness of the Toxicology Database

The Agency considers the toxicity database used to characterize the hazards of fluxapyroxad to infants and children as complete. A 2

- generation reproductiv e and developmental toxicity study in rats and developmental toxicity studies in rats and rabbits are available to assess the quantitative and qualitative susceptibility of the fetus, infants, and children to fluxapyroxad. In addition to these lifestage

- s pecific 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 neurotoxi city studies are available for fluxapyroxad. Treatment

- related effects of decreased rearing and motor activity were observed only in the acute neurotoxicity study and only on the day of dosing. These effects are equivocal, as they may indicate transient and reversible neurotoxicity and/or general malaise. No developmental neurotoxicity study is available for fluxapyroxad. However, the Agency has considered the potential for fluxapyroxad to cause developmental neurotoxicity as a result of thyroid hormon e disruption, which is more sensitive than the endpoints used in a developmental neurotoxicity study. The Agency has evaluated supplemental thyroid hormone data submitted by the registrant and considered the ontogeny of thyroid hormone metabolism to deter mine that adverse thyroid hormone disruptions in the young are unlikely to occur at dose levels similar to the points of departure chosen for risk assessment. The Agency has low concern for neurotoxic effects of fluxapyroxad at any life
stage.

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

No evidence of quantitative susceptibility was observed in a reproductive and developmental toxicity study in rats or in developmental toxicity studies in rats and rabbits. Develop mental toxicity in rats in a 2 generation study was limited to decreased body weight and body weight gain in offspring and was observed at the same dose levels that caused thyroid follicular hypertrophy/hyperplasia in parental animals. However, low birth weights, which can result from thyroid dysregulation in maternal animals, was observed in the first generation only, with no decreased body weights observed in the second generation until lactation day 7. Developmental toxicity in rabbits was limited to pa w 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 hig h dose at which reduced maternal body weight was also observed. Although these developmental effects differed from the maternal effects and so indicate qualitative susceptibility, these developmental effects are of low concern to the Agency. The Agency’s rationale for low concern for developmental toxicity is that these effects were of low severity, were likely secondary to maternal toxicity, and demonstrated clear NOAELs. Nonetheless, the risk assessment is protective of paw hyperflexion because this ef fect occurs at dose levels higher

### Page 20 of 81

than the points of departure selected for risk assessment for repeat

- exposure scenarios.

4.4.4 Residual Uncertainty in the Exposure Database

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

4.5 Toxicity Endpoint and Point of Departure

4.5.1 Dose

- Response Assessment

The endpoint of decreased motor activity and decreased rearing identified in the acute neurotoxicity study in rats was chosen for the acute dietary endpoint because it was considered adverse and results from a single exposure . No other endpoints in the to xicity database for fluxapyroxad were identified that were likely to result from a single exposure. The endpoint of liver foci and masses identified in the chronic toxicity/carcinogenicity study in rats was chosen for the chronic dietary endpoint. The du ration of exposure in this study is appropriate for a chronic dietary endpoint and the point of departure at this endpoint is protective for all adverse effects in rats and other species that occur at higher doses and/or for shorter durations of

exposure.

The endpoint of thyroid follicular hypertr ophy/hyperplasia from the 90

- day oral toxicity study in
rats was identified for the short

- term incidental oral endpoint . This is the most sensitive endpoint in the most sensitive sp ecies and is appropriate for t he population of concern. 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 assessed in the dermal toxicity study, the Agency has low concern for developmental toxicity because the only observed effect, paw hyperflexion, was likely secondary to maternal toxicity and is not considered severe, since this effect is usually reversible as the anim al matures. For the inhalation endpoint, no route

- specific studies were available, thus oral studies were evaluated. The endpoint of thyroid follicular hypertrophy/hyperplasia was identified from the
90

- day oral toxicity study in rats for short

- term and intermediate

- term inhalation. This endpoint
was ch osen because it was the most sensitive endpoint in the most sensitive species.

4.5.2 Recommendations for Combining Exposure Routes

Under FQPA, when there are potential residential exposures to a pesticide, HED must aggregate exposures from the three routes of exposure: oral, dermal and inhalation exposures . There is no dermal hazard posed by fluxapyroxad. Oral and inhalation endpoi nts, and points of departure for regulation were selected from the same 90

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

### Page 21 of 81

4.5.3 Classification of Carcinogenic Potential

Tumors related to fluxapyroxad treatment were observed in the liver of male and female rats and in the thyroid in male rats only. Males were more sensitive than females to the tumorgenic effects of fluxapyroxad in the liver. Dose and temporal concordance data supported a 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 f oci and then to adenoma and carcinoma formation. The endpoint of changes in liver enzyme regulation at 2.1/2.7 mg/kg bw/day in males/females provides a clear threshold for liver tumors.

The incidence of treatment

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

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

(i) No treatment

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

(ii) Treatment

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

(iii) Treatment

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

(iv) There are no mutagenicity 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 mode of action met the criteria established by the Agency.

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

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

### Page 22 of 81

4.5.4 Summary of Points of Departure Used in Risk Assessment

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

.

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

- Occupational Human Health Risk Assessments

Exposure/ Scenario Point of

Departure Uncertainty/

FQPA Safety
Factors RfD, PAD,

Level of
Concern for
Risk Assessment Study and Toxicological Effects

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

- 49 years of age) NOAEL=

125 mg/kg/day 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

MIRD 47923605 LOAEL = 500 mg/kg/day based on
decreased motor activity (both sexes) and decreased rearing (males only)

Chronic Dietary (All Populations) NOAEL=

2.1 mg/kg/day 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

MIRD 47923591 LOAEL = 11 mg/kg/day based on

non

- neoplastic changes in the liver

(foci, masses)

Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans below a defined dose range.

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adver se effect level.
LOAEL = lowes t 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 = popul ation adjusted dose (a = acute, c = chronic). RfD = reference dose. MOA=mode of action.

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Fluxapyroxad for Use in Residential
and Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk
Assessment Study and Toxicological Effects

Dermal Short

and
Intermediate

Term No hazard identified 28

- day dermal toxicity study in rats

MIRD 47923571
LOAEL = Not observed

Inhalation
Short

- Term (1

- 30 days) and
Intermediate

term (1

- 6 months) NOAEL=

7.3 mg/kg/day UF A =10x

UF H =10x Occupational /Res

idential LOC for
MOE = 100 90

- day dietary study in rats

MIRD 47923567 LOAEL = 35.1 mg/kg/day based on thyroid follicular hypertrophy/hyperplasia

### Page 23 of 81

Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Fluxapyroxad for Use in Residential
and Occupational Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk
Assessment Study and Toxicological Effects

Incidental Oral
Short

- Term (1

- 30 days) NOAEL=

7.3 mg/kg/day UF A =10x

UF H =10x Residential LOC

for MOE = 100 90

- day dietary study in rats

MIRD 47923567 LOAEL = 35.1 mg/kg/day based on thyroid follicular hypertrophy/hyperplasia Cancer (oral, dermal, inhalation) Classification: Not likely to be carcinogenic to humans below a defined dose range.

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adver se effect level.
LOAEL = lowest observed adverse effect level. UF = u ncertainty 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 = le vel of concern. N/A = not applicable.



### 5.0 DI ETARY 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 f luxapyroxad parent. Metabolite residues to be included in the risk assessment are M700F008 ; for milk only
the metabolites of concern for risk assessment are M700F008 and M700F010

. The registrant requested a waiver from additional nature of the residue st udies in fish/shellfish. The waiver request was granted by HED since enough information was obtained from the crayfish metabolism study and the bluegill bioaccumulation study reviewed by EFED.

5.1.2 Comparison of Metabolic Pathways

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

- group), N

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

- groups in addition to these reactions led to the observed large number of metabolites. The metabolic pathway of fluxapyroxad is similar in primary and rotational crop s but with some variation in metabolite levels. In general, the parent compound is the main residue followed by the metabolites M700F008, M700F002 and M700F048. For livestock, the parent, M700F008, M700F005, M700F004, M700F010 and dimer of the parent wer e observed as major residues in

### Page 24 of 81

fat, muscle, milk, liver, kidney and/or egg commodities. In the rat, the parent was the main residue followed by M700F008, and their corresponding metabolites hydroxylated in the biphenyl moiety (M700F009, M700F005, and M7 00F006). Other reactions led to the formation of a large number of minor metabolites. Metabolite structures are provided in Appendix B.

5.1.3 Environmental Fate and Transport

Fluxapyroxad degrades slowly under aerobic or anaerobic conditions in soil, with single 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. Fluxapyrox ad 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 rainfall/irrigation occurs, and where sandy soils with low organic matter exist. Fluxapyroxad will not likely bioaccumulate.

5.1.4 Residues of Concern Summary and Rationale

HED has concluded that the residue of concern for tolerance expression for all commodities is parent only based on the recommendation of the Residues of Concern Knowledgebase
Subcommittee (ROCKS , D 390225, 7/4/11 ). Although there was concern expressed abo ut 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 r espect to the parent at longer PHIs. The M700F008 metabolite is demethylated parent and is expected to have comparable toxicity to the parent. The major residues observed in the confined rotational studies are parent fluxapyroxad and M700F008, M700F002 and M700F048. The metabolite M700F002 was observed as a major residue in rotational spinach only and was not detected at all in the field studies of accumulation in rotational crops. The metabolite M700F048 was observed as a major residue in radish tops in the confined study, but was seen at much lower levels than the parent and M700F008 in the field studies. Toxicity studies with M700F002 and M700F048 show that these two metabolites are not likely to be more toxic than the parent. For livestock commodi ties, except milk, the ROCKS recommended that fluxapyroxad and M700F008 be included for risk assessment purposes based on results from metabolism and feeding studies which show that parent fluxapyroxad and M700F008 are the major residues in ruminant and p oultry commodities. For milk only, the ROCKS recommended that fluxapyroxad, M700F008 and M700F010 be included for risk assessment purposes based on the metabolism study in goat showed the presence of M700F010 at 12

- 15% TRR in milk which is highly consumed commodity by children. M700F010 is hydroxylated parent and likely to

### Page 25 of 81

have comparable toxicity to the parent. For water, the ROCKS committee recommended including parent fluxapyroxad only in the risk assessment. Parent fluxapyroxad and M700F001
were the only two major residues identified in the environmental fate studies. Although M700F001 was identified as a major degradate, available evidence suggests that this degradate has lower toxicity than the parent and will be present in low concentrations rela tive 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

.



### 5.2 Food Residue Profile

5.2.1 Residues in Crops

An adequate number and crop field trials conducted in appropriately representative locations are available for fluxapyroxad for the following crops: orange, lemon, grapefruit, alfalfa, clover, and grass (4 cultivars)

. Decline studies were submitted for ea ch commodity, as required. Detailed information on residue data from crop field trials on fluxapyroxad and its metabolites is provided in the Residue Chemistry Chapter. (D 425590 )

Table 5.2.1.1 Summary of Fluxapyroxad Residues

Crop Total

Application

Rate
lb ai/A (g ai/ha) PHI

(days) No of

Field
Trials Matrix Residues (ppm) 1

Fluxapyroxad M700F008

Orange 0.431

- 0.450

(483

- 505) 0 12 Whole fruit 0.093

- 0.583

HAFT= 0.558 <0.01

Lemon 0.435

- 0.448

(488

- 502) 0 8 Whole fruit 0.090

- 0.426
HAFT=0.380 <0.01

Grapefruit 0.436

- 0.450

(489

- 504) 0 6 Whole fruit <0.01

- 0.269
HAFT=0.203 <0.01

Alfalfa 2 0.218

- 0.231

(0.245

- 0.258) 12

- 17 10 Forage <0.01

- 8.641
HAFT=8.127 <0.01

- 0.503

HAFT=0.434 Hay 0.176

- 8.606 <0.01

- 1.367

### Page 26 of 81

Table 5.2.1.1 Summary of Fluxapyroxad Residues

Crop Total

Application

Rate

lb ai/A (g ai/ha) PHI

(days) No of

Field
Trials Matrix Residues (ppm) 1

Fluxapyroxad M700F008

HAFT=8.569 HAFT=1.284

Clover 2 0.218

- 0.231

(0.245

- 0.258) 12

- 15 9 Forage <0.01

- 5.007
HAFT=4.205 <0.01

- 0.139

HAFT=0.135

Hay 0.562

- 15.13

HAFT=14.98 <0.01

- 0.294

HAFT=0.274

Grass 0.221

- 0.229

( 247

- 257) 0

13 Forage 1.549

- 11.481
HAFT=10.992 <0.01

- 0.031

HAFT=0.030

Hay 3.282

- 29.226

HAFT=27.650 <0.01

- 0.503

HAFT=0.444

14 Forage 0.183

- 6.806
HAFT=5.985 0.011

- 0.062

HAFT=0.055

Hay 0.666

- 16.863

HAFT=13.842 0.019

- 0.133

HAFT=0.133

1 Range of residues refer to individual samples (two samples per trial collected); HAFT = Highest Average Field Trial ; Residues of metabolite
M700F008 is in parent equivalents.

2 For alfalfa and clover, three applications were made, two before first cutting and one after first cutting (after regrowth) . The PHIs refer to either first cutting or second cuttings ; around 14 days before each cutting . Highest residues reported in this table were either from the first or the second cuttings depending on the matrix (fo rage or hay) or crop (alfalfa or clover).



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

Table 5.2.1.2 Summary of Fluxapyroxad Processing Fac tors for
Citrus

. Commodity Average Processing factor

Wet Pomace 1.2x

Dried Pulp 4.8x

Peel 1.9x

Juice 0.02x

Marmalade 0.04x

Oil 59x



### Fluxapyroxad residues concentrate (on average) in wet pomace (1.2x), dried pulp (4.8x), peel (1.9x), and oil (59x) and do not concentrate in juice and marmalade. The metabolites M700F002, M700F008, and M700F048 generally do not concentrate in any orange p rocessing
commodities.

5.3 Water Residue Profile

5.3. 1 Estimated Drinking Water Concentrations

### Page 27 of 81

Monitoring data for fluxapyroxad is not available. Estimated Drinking Water Concentrations (EDWCs) for fluxapyroxad were provided by the Environmental Fate and Effects Division (EFED) (C. Peck, D425591, 9/10/2015) which basically confirms that the highest EDWC still
are from rice and turf uses for which EF ED conducted the assessment previously (C. Peck, D403944, 3/15/13 and D426700, 4/10/15). EFED generated the surface water estimates using
the Tier I Rice model. Ground water estimates were calculated using the Pesticide Root Zone

Mo del 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 provided in Table 5.3.1.1 . The estimated drinking water residue level for p eak concentration of 0.203 mg/L (ppm) was used in the acute assessment

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

- in10 year chronic drinking
water concentration of 0.188 mg/L (ppm) was used the chronic assessment.

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

- in

- 10 year acute (μg/L) 1

- in

- 10 year chronic (μg/L)

Surface Water (Rice Model) 127 127

Ground Water (PRZM

- GW) 203 18 8



### 5

. 4 Dietary and Drinking Water Exposure and Risk

HED conducted screening

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

- FCIDTM). Dietary risk assessment incorporates both exposure and toxicity of a given pesticide. For 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 1

- 2 years old, the subgroup with the highest risk estimate, is
12 %. The 95 th 

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

### Page 28 of 81

Table 5.4.1.1 Summary of Acute Dietary Exposure and Risk for Fluxapyroxad

Population Subgroup aPAD (mg/kg/day) Acute (95th Percentile) Exposure (mg/kg/day) % aPAD General U.S. Population

1.25 0.09 6292 7.7 All Infants (< 1 year old) 0.099 800 8.0
Children 1

- 2 years old 0. 151501 12
Children 3

- 5 years old 0.151 447 12
Children 6

- 12 years old 0.0 86744 6.9
Youth 13

- 19 years old 0.074 856 6.0
Adults 20

- 49 years old 0.0 94594 7.6
Adults 50

- 99 years old 0.09 3364 7.5
Females 13

- 49 years old 0.099 615 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 u sed. 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 pro cessing 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 ot her population subgroups. The population subgroup with the highest risk estimate is all infants <1 year old with a % chronic PAD (cPAD) of 66 %. The % cPAD for the general U.S. population is 32 %.

Table 5.4.2

. 1 Summary of Chronic Dietary Exposure and Risk for Fluxapyroxad

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

0.021 0.00 6701 32 All Infants (< 1 year old) 0.0138 59 66
Children 1

- 2 years old 0.0 13446 6 4
Children 3

- 5 years old 0.010599 51
Children 6

- 12 years old 0.006 756 32
Youth 13

- 19 years old 0.004 805 23
Adults 20

- 49 years old 0.006 305 30
Adults 50

- 99 years old 0.00 6365 30
Females 13

- 49 years old 0.00 6292 30

### Page 29 of 81

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

Fluxapyroxad has been classified as “not likely to be carcinogenic to humans below a defined dose range ”. 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. As shown in Section 5.4.2, there are no chronic risks of concern for fluxapyroxad.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no resident ial exposure associated with the proposed uses in this action; however, t here are existing turf uses that were previously assessed for fluxapyroxad. An updated turf assessment was completed in this document due to a correction in the single maximum applic ation rate from 2.47 lb ai/gallon to 0.005 lb ai/gallon. The previous turf assessment conducted the residential handler and post

- application exposure assessment at a rate of 2.47 lb ai/gallon. The corrected residential handler and residential post

- applic ation scenarios are
included in Section 6.1.2 and 6.2

. below ; see Appendix E for rates. The corrected turf assessment will impact the human health aggregate risk assessment for fluxapyroxad.

6.1 Residential Handler Exposure

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

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

 Mixing/loading/applying liquids with a manually

- pressurized handwand,

 Mixing/loading/applying liquids with a hose

- end sprayer,

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

 Mixing/loading/applyi ng liquids with a sprinkler can.

6.1.1 Handler Exposure Data

No chemical

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

- exposure

- sop.html ).

### Page 30 of 81

6

. 1

. 2 Residential Handler Exposure Assumptions

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

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

Unit Exposures and Area Treated or Amount Handled: Unit exposure values and esti mates for area treated or amount 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 Esti mate Equations The algorithms used to estimate exposure and dose for residential handlers can be found in the
2012 Residential SOPs.

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

- term risk
estimates for residential handlers are included in Table 6.1.2.1

.

Summaries of the short

- t erm risk estimates for residential post

- application activities are included
in Table 6.1.2.1

.

Table 6.1.2.1. Short

- Term Residential Handler Exposure and Risk Estimates for Fluxapyroxad

Exposure Scenario Inhalation
Unit Exposure Maximum

Application
Rate 1 Area

Treated or
Amount
Handled Daily 2 Inhalation

Dose 3 MOE 4
mg/lb ai mg/kg/day
Mixer/Loader/Applicator for Reassessed Turf Uses M/L/A Liquids for Hose

- End

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

M/L/A Liquids for Manually

Pressurized Handwand 0.018 0.005 lb ai/gallon 5 gallons 0.0000056 1,300,000

M/L/A Liquids for Sprinkler Can 0.022 0. 000005 lb
ai/ft2 1,000 ft 2 0.00000 14 5,3 00,000

M/L/A Liquids for Backpack 0.14 0.005 lb ai/gallon 5 gallons 0.000044 170,000

### Page 31 of 81

1. Based on EPA Reg. No. 7960

- 350 label (D403943, J. Miller, 7/23/13); 2. Based on HED’s 2012 Residential SOPs ( http://www.epa.gov/pesticides/science/residential

- expos ure

- sop.html ). 3. Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Hand led (A/day or gallons/day) ÷ BW (80 kg). 4. Inhalation MOE = Inhalation NOAEL (7.3 mg/kg/day) ÷ Inhalation Dose (mg/kg/day)



### 6.2 Post

- Application Exposure

Residential post

- application dermal risk for adults was not quantitatively assessed for fluxapyroxad because there is no identified systemic dermal hazard. Incidental oral exposure for
children for turf use s is anticipated. Post

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

exposure.

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

- to

- mouth, object

- to

- mouth and inc idental soil ingestion) for the turf use . This combination should be considered a protective estimate of children’s exposure to pesticides used indoors.

As a standard practice, post

- application non

- dietary ingestion exposure (i.e., hand

- to

- mouth, object

- t o

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

– it is assumed that an adult would not place pesticide

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

The quantitative oral exposure/risk assessment for residential post

- application exposures is based
on the incidental oral scenario for children 1<2.

Residential Post

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

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

. Available at : htt p://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 )

.

A summary of the residential post

- application exposures and risks are provided below in Table
6.2.2.1 and reflects hand

- to

- mouth exposures of children 1<2 years old from playing on turf.

Table 6.2.2.1

. Residential Post

- application Non

- Cancer Exposure and Risk Estimates for Fluxapyroxad Turf Uses

Lifestage Post

- application Exposure Scenario Application Rate 1 (lb ai/A) Dose 2 (mg/kg/day) MOE 3

Liquids

Child 1 < 2 year old Oral Hand

- to

- Mouth

0.23 0.0035 2,100 Object

- to

- Mouth 0.00011 69,000 Soil Ingestion 0.0000078 940,000

### Page 32 of 81

1 Based on EPA Reg. No. 7960

- 350 label (D403943, J. Miller, 7/23/13).
2 Dose (mg/kg/day) algorithms provided in 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential

- exposure

- sop.html).
3 MOE = POD (mg/kg/day) ÷ Dose (mg/kg/day).

### Page 33 of 81

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

- application residential exposure of children.

6.3 Residential Risk Estimates for Use in Aggregate Assessment

The recommended residential exposure for use in the adult aggregate assessment reflects handler inhalation exposure from applications to turf via backpack and in children 1<2 years old reflects hand

- to

- mouth exposures from post

- application exposures from children playing on turf

. The residential doses to be used for the aggregate risk assessment and the source of those exposures a re shown in Table 6.3.1 , below.

Table 6.3

. 1 Recommendations for the Short

- and Intermediate

- Term Residential Exposures for the Fluxapyroxad Aggregate Assessment 1

Lifestage Handler Exposure

(mg/kg/day) 2 Residential

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

Handler
Total MOE 4 Post

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

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

application MOE 6 Dermal Inhalation Dermal Inhalation Oral

Short

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

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

Intermediate

- Term
Adult Male

N/A N/A Adult Female

Child

1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment.
2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed from Table 6.1.2.1.

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

. 4 Residential Post

- application Dose = the highest post

- application dose for each applicable lifestage of all scenarios assessed from Table
5 Residential Post

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

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

### Page 34 of 81

6.4 Non

- Occupational Bystander Post

- A pplication Inhalation Exposure and Risk
Estimates

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pes ticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency has e valuated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

- OPP

- 2014

- 0219). During Registration Review, the Agency will utilize this analy sis to determine if data (i.e., flux studies, route

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

6. 5 Non

- Occupational Spray Drift Exposure and Risk Estimates

Spray drift is a potential source of exposure to those nearby pesticide applications. This is particularly the case with aerial application, but, to a lesser extent, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for f

luxapyroxad

. The Agency has been working with the Spray Drift Task Force (a task force composed of various registrants which was developed as a result of a Data
Call

- In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information). 2 The Agency has also developed a policy on how to appropriately consider spray drift as a potential source of exposure in risk assessments for pesticides.

The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

- Residential Exposure Assessment Standard Operatin g Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification
of indirect non

- occupational exposure to drift.

7 .0 AGGREGATE EXPOSURE AND RISK ASSESSMENT

In accordance with the FQPA, when there are potential resident ial exposures to a pesticide, aggregate risk assessment must consider exposures from three major routes: oral, dermal, and
inhalation. Additionally, aggregate exposure should consider exp os ure across both the dietary and residential pathways. In an aggre gate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various

2 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm

### Page 35 of 81

sources, HED consider s both the route and duration of exposure. The proposed/registered fluxapyroxad uses are expected to result in residential exposure via inhalation for residential handlers and incidental oral exposure for toddlers

.

7.1 Acute Aggregate Risk

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

7.2 Short

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

- term aggregate risks for fluxapyroxad are no t of concern and are shown in Table 7.2.1 below.

Table 7.2 .1 Short

- Term and/or Intermediate Term Aggregate Risk Calculations

Population Short

- or Intermediate

- Term Scenario

NOAEL mg/kg/day LOC 1 Max
Allowable Exposure 2 mg/kg/day 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 7.3 100 0.073 0.0063 65 

### 0.000044 0.006 4 09 1 13 9

Child 7.3 100 0.073 0.01 34 46 0.0035 0.0169 46 4 3 1

1 The LOC of 100 is based on the standard inter

- and intra

- species extrapolation factors.

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

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

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

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



### 7. 3 Intermediate

- Term Aggregate Risk

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

- term exposure to fluxapyroxad ; therefore, an intermediate

- term aggregate risk assessment is not required.

7.4 Chronic, Non

- Cancer, Aggregate Risk

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

- term (chronic)

expos ure; therefore, the chronic aggregate risk is equivalent to the chronic dietary (food and water) risk, and as shown in Section 5.4.2, there are no risks of concern.

7.5 Cancer Aggregate Risk

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

- linear

### Page 36 of 81

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

8.0 CUMULATIVE RISK

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider “available information” concerning the cumulative effects of a particular pesticide's residues and “other substances that have a common mechanism of toxicity.”

EPA does not have, at this time, available data to determine whether fluxapyroxad has a common mechanism of toxicity with other substances. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxici ty, 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 thi s 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 eva luate the cumulative effects of such chemicals, see the policy statements released by EPA’s OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on
EPA’s website at http://www.epa.gov/fedrgstr/EPA_PEST/2002/January/Day_16/

.

9 .0 OCCUPATIONAL EXPOSURE / RISK CHARACTERIZATION

9

. 1 Occupational Handler Exposure/Risk Estimates

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each 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.

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 ional handlers is based on the following scenarios:

 Mixing/Loading liquids for aerial application

,

 Mixing/Loading liquids for airblast application

,

 Mixing/Loading liquids for chemigation (including overhead track sprayer) application

,

### Page 37 of 81

 Mixing/Loading liq uids for groundboom application,

 Applying sprays for aerial application

,

 Applying sprays for airblast application,

 Applying sp rays for groundboom application,

 Flagging for liquid aerial app lication,

 Mixing/Loading/Applying liquids for backpack applicatio n,

 Mixing/Loading/Applying liquids using a manually

- pressurized handwand, and

 Mixing/Loading/Applying liquids using a mechanically

- pressurized handgun.

Occupational Handler Exposure Data and Assumptions

A series of assumptions and exposure factors serve d as the basis for completing the occupational handler risk assessments. Each assumption and factor is detailed below on an individual basis.

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

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

- specific data, include PHED 1.1, the AHETF database, the ORETF database, and the Residential SOPs. Some
of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occup ational Pesticide Handler Unit Exposure Surrogate Reference Table 3 ”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 4

.

Area Treated or Amou nt Handled: The area treated or amount handled is based on HED ExpoSAC Policy No. 9.1. Refer to Table 9. 1 .1 for these assumptions for each scenario.

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

- term and exposures 30 days to six months as intermediate

- term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site. For most agricul tural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for
more than a one

- month time frame; however, there may be a large agribusiness and/or commercial applicators who may apply a product over a peri od of weeks (e.g., completing multiple applications for multiple clients within a region). For fluxapyroxad, based on the proposed uses, short

- and intermediate

- term exposures are expected. Long

- term exposures are not expected.

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

3 Available: http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf

4 Available: http://www.epa.gov/pesticides/science/handler

- exposure

- data.html

### Page 38 of 81

calculated for various levels of personal protective equipment (PPE). Results are presented for “baseline,” defined as a single layer of clothing consisting of a l ong sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator. For the proposed use label (EPA Reg.
No. 7969

- 306), the label requires applicators and handlers to wear baseline attire with the addition of protective eyewear. For the proposed use labels (EPA Reg. No. 7969

- 309) and (EPA Reg. No. 7969

- 311), the label requires applicators and other handlers to wear baseline attire.

Occupational Handler Non

- Cancer Exposure and Risk Estimate Equations

The algorithms used to estimate non

- cancer exposure and dose for occupational handlers can be found in Appendix A.

Summary of Occupational Handler Non

- Cancer Exposure and Risk Estimates

The occupational handler exposure and risk estimates indicate that the short

- and intermediate

term inhalation MOEs are not of concern to HED (i.e., MOEs > 100) with baseline attire. The summary of the occupational handler exposure and risk estimates are provided in Table 9. 1 .1.

Table 9.1.1

. Short

- and Intermediate

- term Occupational Handler Exposure and Risk Estimates f or Fluxapyroxad

.

Exposure Scenario Crop or Target 1 Baseline
Inhalation
Unit Exposure 2 μg/lb ai Maximum

Application

Rate 3

lb ai/A (unless
otherwise noted) Area

Treated

or Amount
Handled Daily 4

Acres (unless
otherwise noted) Dose 5

mg/kg/day Short

- and

Intermediate

- term Inhalation

MOE 6

LOC = 10 0

Mixer/Loader M/L Liquids for Aerial Application 7 Orchard/Vineyard 0.219 0.12 350 0.000115 63,000

M/L Liquids for Aerial Application7 Typical Field Crop 0.219 0.089 350 0.0000853 86,000

High

- Acreage Field Crop 0.089 1,200 0.000293 25,000 M/L Liquids for Airblast Application Orchard/Vineyard 0.219 0.12 40 0.0000131 560,000

M/L Liquids for Chemigation Application Orchard/Vineyard

0.219 0.12 350 0.000115 63,000 Typical Field Crop 0.089 350 0.0000853 86,000

High

- Acreage Field Crop 0.089 350 0.0000853 86,000

M/L Liquids for Groundboom Application Typical Field Crop 0.219 0.089 80 0.0000195 370,000

M/L Liquids for Groundboom Application High

- Acreage Field Crop 0.219 0.089 200 0.0000488 150,000

Applicator Applying Sprays for Orchard/Vineyard 0.0049 0.12 350 0.00000258 2,800,000

### Page 39 of 81

Table 9.1.1

. Short

- and Intermediate

- term Occupational Handler Exposure and Risk Estimates f or Fluxapyroxad

.

Exposure Scenario Crop or Target 1 Baseline
Inhalation
Unit Exposure 2 μg/lb ai Maximum

Application

Rate 3

lb ai/A (unless
otherwise noted) Area

Treated

or Amount
Handled Daily 4

Acres (unless
otherwise noted) Dose 5

mg/kg/day Short

- and

Intermediate

- term Inhalation

MOE 6

LOC = 10 0

Aerial Application 7 (EC)

Applying Sprays for Aerial Application 7 Typical Field Crop 0.0049 (EC) 0.089 350 0.00000191 3,800,000

High

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

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

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

Applying Sprays for Groundboom Application High

- Acreage Field Crop 0.34 0.089 200 0.0000756 97,000

Flagger for Aerial Application for Liquids Orchard/Vineyard

0.35 0.12 350 0.000184 40,000 Typical Field Crop 0.089 350 0.000136 54,000

High

- Acreage Field Crop 0.089 350 0.000136 54,000

1 “Typical field crops” include grass grown for seed; “High

- acreage field crops” include grass forage, fodder, straw, and hay, alfalfa, and clover; “Orchard/Vineyard” include citrus fruit.

2 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline, Eng.
Controls.
3 Based on proposed label (See Appendix E ).
4 Exposure Science Advisory Council Policy #9.1.
5 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) x Application Rate (lb ai/A or gallon) x Area treated or Amount Handled (A/day or gallons/day) / Body Weight (80 kg).

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



### 9.3 Post

- Application Exposure

HED uses the term “post

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

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

9.3.1 Dermal PostApplication Risk

Occupational post

- application dermal risk was not assessed for fluxapyroxad because there is no identified systemic dermal hazard.

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

### Page 40 of 81

(2007), one or more DFR stud ies are required when a pesticide has residential or occupational uses that could result in post

- application dermal exposure. Since there is no hazard via the dermal route of exposure, a non

- cancer dermal post

- application risk assessment was not performed for fluxapyroxad. Therefore, DFR studies are not needed for fluxapyroxad at this time. If the PODs change, the need for DFR studies may be reevaluated in the future to refine the post

- application assessment.

9.3.2 Inhalation Post Application Risk

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or p articulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received th e SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.gov/#!docketDetail;D=EPA

- HQ

OPP

- 2014

- 0219 ). During Registration Review, the Agency will utilize this analysis to determine if data (i.e., flux studies, ro ute

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

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force. G iven these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

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

Although a quantitative occupational post

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

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

- application inhalation exposure scenarios.

The Worker Protection Standard for Agricultural Pesticides contains re quirements for protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements.[40 CFR 170.110, (3) (Restrictions associated with pesticide applications)]

9.3. 3 Restricted Entry Interval

The REI specified on the proposed label is based on the acute toxicity of fluxapyroxad. Fluxapyroxad is classified as Toxicity Category III via the dermal route and Toxicity Category

### Page 41 of 81

IV for skin irritation potential. It is not a skin sensitizer. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irritation are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to pro tect agricultural workers from post

- application exposures to fluxapyroxad.

10. REFERENCES

Fluxapyroxad. Occupational and Residential Exposure Assessment for Proposed Uses On Ornamentals , Citrus Fruit, Grasses, Alfalfa, and Clover. M. Hawkins, D424427

, 2/18/2016

Fluxapyroxad (BAS 700F) Section 3 Registration And Establishment of Permanent Tolerances For Citrus Crop Group 10

- 10, Grass Crop Group 17, Non

- Grass Crop Group 18, And Poultry Fat; Tolerance Amendment for Egg. Summary of Analytical Chemistry and Residue Data. M. Sahafeyan

, D425590, D425592, D425597, D425600,
D425601

, 4/20/16

Fluxapyroxad

– Revised Acute and Chronic Dietary Exposure and Risk Assessments for Proposed New Uses of Fluxapyroxad on Citrus, Grass, Nongrass

. M. Sahafeyan

, D425592

, 4/20/16

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

Fluxapyrox ad (BAS 700F) Waiver Request for Requirement of Additional Fish/Shellfish Nature of the Residue
Studies. T. Morton, D 416489

, 12 /5/13

### Page 42 of 81

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 A. 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1. Guideline Data Requirements for Fluxapyroxad

Guideline
No. Study Type Technical MRID
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 1 47923567

47923568
47923569
47923571

---

--- 870.3700a
870.3700b
870.3800 Prenatal Developmental Toxicity

- Rodent

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

Prenatal Developmental Toxicity

- Non

- Rodent

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

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

Y

Y Y

Y

Y 47923603

47923604
47923602

870.4100a

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

- Rodent

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

Chronic (Oral) Toxicity

- Non

- Rodent (Dog)

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

- Rat Carcinogenicity

- Mouse Combined Chronic Toxicity /Carcinogenicity

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

Y

Y

Y

Y Y

Y

Y

Y

Y 47923591

47923592
47923570
47923591
47923592
47923591
47923592

870.6100a
870.6100b
870.6200a
870.6200b
870.6300
870.7800 Neurotoxicity

- Acute Delayed Neurotox.

- Hen

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

Neurotoxicity

- Subchronic

- Hen

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

- Acute

- Rat

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

- Subchronic

- Rat

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

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

N

Y

Y

N

Y N

N

Y

Y

N

Y ---

--- 47923605
47923606

--- 47923633

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



### A.2 Toxicity Profiles

Table A.2.1.1 Acute Toxicity Profile

– Fluxapyroxad

Guideline

No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral

– rat (females) 47923607 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

### Page 43 of 81

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 chemistry changes

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

Non

- Guideline Thyroid hormone
levels

- 28 days

- rat 47923594 (2009) Acceptable, non

guideline

0, 50, 250, 1500, 3000

ppm (0/0, 3.5/4.4, 19/20, 105/117, 214/237 mkd) Increased TSH, decreased T4 in males only at 3000 ppm only days 14 through 28. Accompanied by increased absolute and relative liver and thyroid weights. Supports hypothesis that an increased conjugation and elimination of circulating thyroxine (T 4 ) leads to compensatory release of thy roid 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

guideline

50 ppm Mechanistic investigations of enzyme induction (thyroid and liver).

Non

- Guideline Enzyme induction 47923593 (2010) Acceptable, non

guideline

0, 250, 1500, 3000

ppm 0/0, 16/19, 96/126,
192/234 mkd Mechanistic investigations of enzyme induction (thyroid and liver).

Non

- Guideline
S

- phase induction

1

- 3

- 7

- 14 days 47923598 (2010) Acceptable, non

guideline

0, 50, 250, 1500, 3000 Mechanistic tnvestigations of hepatocellular proliferation.

### Page 44 of 81

Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)
Guideline No Study Type MRID/Classification
Doses Results

ppm Non

- Guideline
S

- phase induction

7

- 28

- 91 days 47923597 (2010) Acceptable, 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 necr osis in the
liver

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

870.3100
90

- Day dietary in rats 47923567 (2009) Acceptable, guideline

0, 100, 500, 2000, 6000 ppm

0/0, 6.1/7.3, 31.2/35.1, 126/144, and 407/424 mkd (M/F) NOAEL = 500 ppm (31.2 mkd) males; 100 ppm (7.3 mkd)
females

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

870.3150
90

- Day Oral Toxicity Feeding

- dog 47923569 (2009) Acceptable/guideline

0, 300, 1500, 10000/7500 (M/F) NOAEL=1500 ppm (45/51 mkd M/F)

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

### Page 45 of 81

Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)
Guideline No Study Type MRID/Classification
Doses Results

0/0, 9/10, 45/51,
295/238 mkd M/F

870.3200
28

- Day Dermal Toxicity

- rat 47923571 (2009) Acceptable, guideline

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

LOAEL=not observed

870.3465
90

- Day Inhalation Waived by HASPOC (TXR# 0056561)

870.3700a
Prenatal Developmental

- rat 47923603 (2009) Acceptable, guideline

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

Offspring
NOAEL=1000 mkd
LOAEL =Not observed

870.3700b
Prenatal 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

870.4100
Chronic Toxicity

- dog 47923570 (2009) Acceptable/guideline

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

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

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

NOAEL=50 ppm (2.1/2.7 mkd in males/females)

### Page 46 of 81

Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)
Guideline No Study Type MRID/Classification
Doses Results

in rats 0, 50, 250, 1500, 3000

ppm

0/0, 2.1/2.7, 11/14, 68/82, 145/182 mkd (M/F) LOAEL =250 ppm (11/1 mkd) based on neoplastic changes in the liver (foci, masses).

Carcinogenicity

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

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

0, 150, 750, 3000, 6000 ppm

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

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

Gene Mutation
870.5100

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

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

Gene Mutation
870.5300

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

0

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

Cytogenetics
870.5375

In vitro Mammalian Cytogenetics
Chromosomal Aberration 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

- Erythrocyte
Micronucleus

- mouse 47923584 (2006) Acceptable, guideline

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

870.6200a Acute Neurotoxicity

- rat 47923605 (2009) Acceptable, guideline

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

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

870.6200b
Subchronic Neurotoxicity

- rat 47923606 (2009) Acceptable, guideline

0, 200, 100, and 5000 NOAEL (neurotoxicity)=5000 ppm (302/338 mkd M/F)

LOAEL (neurotoxicity) =Not observed

### Page 47 of 81

Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)
Guideline No Study Type MRID/Classification
Doses Results

ppm

0, 11.5/13.4, 57.7/67.2,
302.2/337.7 mkd M/F

870.7485
Metabolism and
Pharmacokinetics

- rat 47923555 (2009)

47923556 (2009) The times to maximum plasma levels (T MAX ) were 24 hours (500 mg/kg bw), 8 hours (50 mg/kg bw), and 1 hour (5 mg/kg bw) in both sexes. No sex differences in the rate or extent of absorption was observed. AUCs scaled with dose, indicating that absorption was not saturated.

Radioactivity was widely distributed in both sexes with a similar pattern: the highest concentrations were found in the gut contents and stomach contents. However, lower concentrations were found in numerous other organs/tissues, including the liver, thyroid, adrenal glan ds, kidney, pancreas, testes/uterus, and brain. For males and females, radioactivity declined in all tissues over time. The time course of the amount of radioactivity found in urine and feces indicated the excretion occurred predominantly within three day s after dosing. Bile duct cannulation experiments showed that the bile was a major route of excretion.

The main biotransformation steps of BAS 700 F in rats are hydroxylation at the biphenyl ring system, N

- demethylation at the pyrazole ring system, loss of a fluorine atom at the biphenyl ring system, and conjugation with glucuronic acid or with glutathione derivatives. A further, but negligible transformation route is cleavage at the amide bond between the pyrazole ring system and the biphenyl ring system.

870.7600 Dermal penetration 47923632 (2010) Acceptable, guideline

5.6, 33,4, 1670 μg/cm 2

for 8 h e xposure and
24 and 120 h
termination

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

870.7800 Immunotoxicity

- mice (male) 47923633 (2009) Acceptable, guideline

0, 500, 2000 and 6000

ppm

0, 106, 450 and 1323 mg/kg/d Not immunotoxic.

### Page 48 of 81

Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Fluxapyroxad (BAS 700F)
Guideline No Study Type MRID/Classification
Doses Results

Non

- guideline
S

- phase Response Liver 1, 3, 7, 14 days

- rat 47923598 (2009)

0, 50, 250, 1500 and 3000 ppm Cell proliferation in both sexes was dose

- dependent at maximal at Day 7 (males) and Days 7& 14 (females).

Non

- guideline
S

- phase Response Liver 7, 28, 91 days

- rat 47923596 (2009) 0, 50 ppm (nominal)

- Acceptable, 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
dose

- dependent.

Reversib ility investigated at 28 days treat/28 days recovery.

Non

- guideline Enzyme induction (Phase I and Phase II) with Thyroid Hormone
Levels

- 14 days 47923593 (2009) Acceptable, non

guideline

0, 250, 1500, 3000

ppm

1/1, 16/19, 96/126,
192/234 mkd Dose

- dependent increase in Phase I and Phase II enzymes in both sexes and increased liver and thyroid weights with correlating histopathology. Effects partially (thyroid histopathology) to totally (all other effects) reversible in 4 week recovery group.

Non

- OPPTS guideline,
OECD 486 47923589 (2009) Acceptable, non

guideline

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

Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for
Metabolite M700F001
Guideline No Study Type MRID
Classification
Doses Results

870.3100
90

- Day dietary in rats 47923608 (2009) Acceptable,

- guideline

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

870.3700b
Prenatal 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

### Page 49 of 81 Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for
Metabolite M700F001
Guideline No Study Type MRID
Classification
Doses Results

Gene Mutation
870.5100

In vitro Bacterial Gene
Mutation 47923609 (2009) Acceptable, guideline Not mutagenic.

Gene Mutation
870.5300

In vitro Mammalian
Cells Gene Mutation (Chinese Hamster Ovary Cells) 47923611 (2009) Acceptable, guideline Not mutagenic.

Cytogenetics
870.5375

In vitro Mammalian Cytogenetics
Chromosomal Aberration 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

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

### Page 5 0 of 81 Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for
Metabolite M700F002
Guideline No Study Type MRID
Classification
Doses Results

958.4/928.7 mkd M/F

870.3700b
Prenatal 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 51 of 81 Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for
Metabolite M700F048
Guideline No Study Type MRID
Classification
Doses Results

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

0, 50, 200, 1000 mkd (nominal)

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

870.3700b
Prenatal 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)
Acc eptable, guideline

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

870.7485
Metabolism and
Pharmacokinetics

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

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

### Page 52 of 81 Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for
Metabolite M700F048
Guideline No Study Type MRID
Classification
Doses Results

Non

- OPPTS guidel ine,
OECD 417 47923630 (2009) Acceptable, non

guideline

1000 mkd, oral (gavage) M700F048 is 5077265 is systemically bio a vailable and its 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 53 of 81 Table A. 3 Subchronic, Chronic and Other Toxicity Profile Toxicity Profile for Impurity B
Guideline No Study Type MRID
Classification
Doses Results

Gene Mutation
870.5100

In vitro Bacterial Gene
Mutation 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 54 of 81

A.3 Toxicological Endpoints

A.3.1 Acute Reference Dose (aRfD)

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

- 49)



### Study Selected: Acute Neurotoxicity Study in Rats

MRID No.: 47923606

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

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

A cute RfD= acute PAD = 125 mg/kg/day = 1.25 mg/kg/day
100

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

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

- generation reproduction study were 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 a ll populations (i.e. the general population, including infants and children and females ages 13 to 49 years old).

A.3.2 Chronic Reference Dose (cRfD)

- All Populations

Study Selected: Chr onic Toxicity/Carcinogenicity Study in Rats

MRID No: 47923591

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

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

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

### Page 55 of 81 Chronic RfD = chronic PAD = 2.1 mg/kg/day = 0.021 mg/kg/day
100

Comments abo ut 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 see n in the 28

- and 90

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

A.3.3 Incidental Oral Exposure (Short

- Term (1

- 30 days))

Study Selected: 28

- Day Dietary Toxicity Study in the Rat

MRID No: 47923564

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

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

- species, 10X
intra

- species factor) (proposed)

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

A.3.4 Incidental Oral Exposure (Intermediate

- Term (1

- 6 months))

Study Selected: 90

- Day Dietary Toxicity Study in the Rat

MRID No: 47923567

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

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

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

A.3.5 Occupational and Residential Dermal Exposure (Short

- and
Intermediate

- Term)

In a 28

- day dermal toxicity study in rats, no d ermal irritation or systemic effects were observed

### Page 56 of 81

up to the limit dose of 1000 mg/kg/day. This is a route

- specific study that also assessed all of the endpoints used in the other exposure scenarios and durations of exposure (e.g. neurological endpoints, thyroid and liver histopathology). In addition, no increased susceptibility was seen between offspring and adult animals in the developmental toxicity studies in rats and rabbits and
in the 2

- generation reproduction study in rats. Therefore, the quantific ation of dermal risk is not required since no hazard was identified.

A.3.6 Occupational and Residential Inhalation Exposure (Short

- Term)

Study Selected: 28

- Day Dietary Toxicity Study in the Rat

MRID No: 47923564

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

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

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

- day oral toxicity study in rats was used for inhalation risk assessment. The

se lected endpoint is the most sensitive endpoint and most sensitive species for this duration of

exposure.

A.3.7 Occupational and Residential Inhalation Exposure (Intermediate

Term)

Study Selected: 90

- Day Dietary Toxicity Study in the Rat

MRID No: 47923567

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

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

Comments about Study/Endpoint/UF: No inhalation studies are available for fluxapyroxad; therefore, a 90

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

Based on the proposed use pattern for fluxapyroxad, occupational long

- term inhalation exposure is not anticipated.

### Page 57 of 81

A.4 EXECUTIVE 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/female s) for at least 90 days. Significant decreases in body weight and body weight gain were observed in 6000 ppm males and females and were
considered adverse.

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

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

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

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

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

The LOAEL is 2000 ppm (126 mg/kg bw/day) in males and 500 ppm (35.1 mg/kg bw/day) in females, based on thyroid follicular hypertrophy and hyperplasia. The NOAEL is 500 ppm (31.2 mg/kg bw/day) in males and 100 ppm (7.3 mg/kg bw/day) in females.

This stu dy is classified as totally reliable ( acceptable/guideline) and satisfies the guideline requirement for a 90

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

### Page 58 of 81

870.3100 90

- Day Oral Toxicity

– Mice MRID 47923568

BAS 700 F (Batch: COD

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

- 12.6%) and body weight gain (

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

The liver was identified as a target organ as indicated by changes of a number of clinical chemistry parameters down to a dietary dose level of 400 ppm in males as well as statistically significant increases of absolute and relative liver weights at 2000 ppm or higher in both sexes. The clinical chemistry changes consisted of increased alkaline phosphatase, 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 p pm (390 mg/kg bw/day) in males and 6000 ppm (1657 mg/kg bw/day) in females.

This 90

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

- day oral toxicity study (OPP TS 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 mal es 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 th ere were not histopathological correlates.

### Page 59 of 81

The LOAEL is 10000 ppm (295 mg/kg bw/day) in males and 7500 ppm (238 mg/kg bw/day) in females, based on vomiting and clinical chemistry changes. The NOAEL is 1500 ppm in both sexes (45 mg/kg bw/day in males an d 51 mg/kg bw/day in females).

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

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

- rodents.

870.3200 21/28

- Day Dermal Toxicity

– Rat MRID 47923571

Dermal Administration of BAS 700 F (Batch: COD

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

occlusive dressing) for 4 weeks at dose levels of 0, 100, 300 and 1000 mg/kg bw/d caused no
substance

- related adverse findings.

An increase in absolute and relative liver weights in both sexes was possibly treatment related, Since there was neither a histopathological correlate nor any accompanying treatment

- related changes of clinical chemistry parameters, this effect was not considered adverse.

The LOAEL in males and females was not identified. The NOAEL in males and females was 1000 mg/kg bw/day.

This study is classified as totally reliable ( acceptable/guideline) and satisfies the guideline requirement for a dermal toxicity study (OPPTS 870.3200; OECD 410) in rats.

870.3465 90

- Day Inhalation

– Rat

- NA

-

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study

– Rat 4792 3603

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 h igh 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 signif icantly, but slightly (9

- 13%) at this dose and occurred in the absence of corroborating effects on serum liver enzymes (liver histopathology was not examined). This effect was considered as most likely due to hepatocellular hypertrophy (due to extensive e vidence of hepatocellular hypertrophy in conjunction with increased liver weights throughout the database for this chemical) and so was
not considered adverse.

### Page 60 of 81

The LOAEL for maternal toxicity in females is 1000 mg/kg bw/day, based on increased
absolute and relative thyroid weights and thyroid hypertrophy/hyperplasia. The NOAEL is 200 mg/kg bw/day.

No treatment

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

treatment

- related external, visceral or skeletal malformations we re 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 s igns of maternal toxicity as indicated by one abortion, decreased food consumption (

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

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

No treatment

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

treatment

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

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 may reverse since tendons stretch postnatally as limbs grow and are being used. Although this variation occurred in presence of substantial maternal toxicity and so may be secondary to maternal toxicity, it was an effect of
treatment and so is consid ered potentially adverse.

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

This st udy is classified as totally reliable (acceptable/guideline) and satisfies guideline

### Page 61 of 81

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

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Eff ects

– Rat MRID 47923602

BAS 700 F (Batch COD

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

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

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

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

No treatment

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

treatment

- related external, visceral or skeletal malformations were noted. The only 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 may reverse since tendons stretch postnatally as limbs grow and are being used. Although this variation occurred in presence of substantial maternal toxicity and so may be secondary to maternal toxicity, it was an effect of treatment and so is considered potentially adverse.

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

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

A.4.4 Chronic Toxicity

870.4100b Chronic Toxicity

– Dog MRID 47923570

BAS 700 F (Batch: COD

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

### Page 62 of 81

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

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

aminotransferase levels as well as decreased total protein, albumin, cholesterol, total bilirubin, creatinine, urea and calcium levels in either or both sexes. Histopathlogical analysis of the or gan 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 f rom 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 w ere considered potentially adverse.

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

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

The LOAEL is 1500 ppm in females (43 mg/kg bw/day) based on hepatic fibrosis and clinical chemistry changes. The NOAEL in females in 9 mg/kd bw/day. The LOAEL in males is 12000 ppm ( 335 mg/kg bw/day) based on vomiting, clinical chemistry changes, and hepatic fibrosis and cirrhosis. The NOAEL in males is 1500 ppm (39 mg/kg bw/day).

This study is classified as totally reliable ( acceptable/guideline) and satisfies guideline requirem ents for a chronic toxicity study (OPPTS 870.4100; OECD 452) in non

- rodents.

A.4.5 Carcinogenicity

870.4300 Carcinogenicity/Chronic Study

– Rat 47923591

BAS 700 F (Batches COD

– 000899 up to study day 454 and COD

- 001049 from study day 455

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

In the carcinogenicity group (50/sex/dose), body weight decreases after two years of 8% were

### Page 63 of 81

noted in males at 3000 ppm. In females, body weights were decreased 11.9% or mo re at ≥ 250 ppm. This indicated that dosing was adequate. Treatment with BAS 700 F did not affect the survival of rats in the carcinogenicity group. Tumors considered a result of treatment were observed in the liver and thyroid only. Hepatocellular tumors were in the form of adenomas and carcinomas in both sexes, with a significant increase in the combined incidence of these tumor types in males at ≥ 1500 ppm and in females at 3000 ppm. Significant increases in hepatocellar
carcinomas were observed only in males and only at 3000 ppm. Adenomas were observed in both sexes at a higher incidence than carcinomas and at lower doses. Significant increases in adenomas were observed in males at ≥ 1500 ppm and in females at 3000, ppm. However,
adenoma inci dence was greater than the upper limit of historical controls in males at ≥ 250 ppm and in females at ≥1500 ppm, and so was determined to be an effect of treatment. Non

neoplastic changes in the livers of these animals included increases in the absolute a nd 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 li ver discoloration at  1500

ppm.

Thyroid tumors resulting from treatment were in the form of follicular cell adenomas and carcinomas. The combined incidence of adenomas and carcinomas was significantly increased for males only at 3000 ppm compared to conc urrent controls. The incidence was within the historical control range, but was still considered an effect of treatment. The individual incidence of thyroid follicular adenomas or carcinomas did not reach statistical significance for males or
females. F or 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 incid ence of adenomas did not reach statistical significance at any dose compared to concurrent controls and was within the historical control range. These results were consistent with thyroid histopathology, which showed significant thyroid follicular hyperpl asia in males at  1500 ppm. Colloid was also altered in both sexes at 1500 ppm and above.

In addition, the bones of animals in the carcinogenicity group were examined by gross and histopathology. In the femora and other bones of affected animals (nasal turbinates, sternae, vertebrae) deposition of Perl's Prussian Blue stain positive material, most probably iron, was

observed at  250 ppm in both sexes. No changes of the bone structure were identified by light microscopy. Gross pathological evaluation identified white discoloration of skull bones (frontal bone, dorsal skull, tympanic cavity) t hat 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 wei ght 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 conjunct ion with centrilobular hepatocellular hypertrophy at  1500 ppm in males

### Page 64 of 81

and females, pigment storage (likely lipofucsin) in males and females at  1500 ppm, and liver discoloration at 3000 ppm in both sexes. None of these changes were considered clearl y 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 femal es at  1500 ppm, (not considered adverse), increased cholesterol and triglycerides in females at 3000 ppm (considered potentially adverse) decreased glucose in males at  250 ppm (not to a magnitude considered adverse), and decreased total biliribun in m ales 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 w ere 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

### Page 65 of 81

and 33, 158, 652 and 1307 mg/kg bw in females). There were no treatment

- related neoplasms.

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

≥ 3000 ppm and females at 6000 ppm. The liver was 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 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 were exposed to BAS 700 F (Batch COD

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

In the plate incorporation assay as well as in the preincubation test, BAS 700 F was tested up to the limit concentration of 5000 μg/plate. Concentrations of 20, 100, 500, 2500 and 5000 μg/p late were used with and without metabolic activation. In both the plate incorporation assay and the preincubation assay a weak bacteriotoxic effect was occasionally observed depending on the
strain and test conditions at concentrations of 500 μg/plate (str ain 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 re sponse 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 t he experimental conditions of the study.

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

### Page 66 of 81

requirement for a bacterial reverse mutation test (OPPTS 870.5100, OECD 471).

MRID 47923579
BAS 700 F (Batch COD

- 00 0899; 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 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, addition of Colcemid arrested cells in the metaphase. After slide preparation and staining of the cells, at least 200 well spread metaphases per dose and treatment condition

### Page 67 of 81

were analyzed for chromosomal aberrations.

At concentratio ns 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 concentr ations with or without metabolic activation. A confirmatory experiment was performed using a prolonged treatment and preparation interval (4 hours treatment and 24 hours recovery with S9

- mix, 18 hours treatment and 0 hours or 10 hours recovery without S9

- m ix). In this experiment a slight increase above the historical control range was observed for the lowest evaluated concentration with metabolic activation only. This increase was not confirmed at higher concentrations and is, therefore, considered not rele vant.

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/guidel ine) 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 indu ce spindle poison effects (aneugenic activity) in NMRI mice using the micronucleus test method. For this purpose, the test substance suspended in corn oil was administered twice orally within a 24

- hour period to groups of 5 male mice at dose levels of 500, 1000, and 2000 mg/kg body weight in a volume of 10 mL/kg body weight. The vehicle served as negative and cyclophosphamide and vincristine sulfate as positive controls. The vehicle was administered twice at a 24 h interval and the positive controls once. T he animals
were sacrificed 24 hours after the last administration and the bone marrow of the two femora was prepared. After staining of the preparations, 2000 polychromatic erythrocytes were evaluated per animal and investigated for micronuclei. The normoc ytes 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 smal l 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 erythroc ytes, did not occur. Signs of systemic toxicity were not observed up to the highest tested dose of 2000 mg/kg bw.

Both of the positive control chemicals, i.e. cyclophosphamide for clastogenic effects and vincristine for induction of spindle poison effects , led to the expected increase in the rate of polychromatic erythrocytes containing small (cyclophosphamide) or small and large (vincristine sulphate) micronuclei, thus demonstrating the sensitivity of the test system.

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

### Page 68 of 81

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

A.4.7 Neurotoxicity

870.6100 Delayed Neurotoxicity Study

- Hen

- NA

870.6200a Acute Neurotoxicity MRID 47923605 The acute neurotoxicity of BAS 700 F (Batch COD

- 001026; Purity: 99.4%) was investigated in groups of 10 male and female Wistar rats ( Crl:WI(Han) after a s ingle administration by gavage at dose levels of 0, 125, 500, and 2000 mg/kg bw/d.

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

### Page 69 of 81

bw/d in males and 338 mg/kg bw/d in females.

The NOAEL for neurotoxicity is 5000 ppm (302 mg/kg bw/day in males and 338 mg/kg bw/day in females). The LOAEL was not observed.

This study is classified as totally reliable ( acceptable/guideline) and satisfies the guideline requirement for a chronic neurotoxicity study (OPPTS 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 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
difference in tissue distribution between males and females and would explain the slightly higher AUCs in females at doses of 150 and 500 mg/kg bw and the difference in bile excretion pattern.

Doses of 150 and 7.5 mg/kg bw 14 

### C

– BAS 700 F were chosen for mass balance, tissue distribution, and biliary excretion studies, based on the results of the plasma kinetic studies and repeated

- 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 sacrificed at 16, 56 , 80, and 104 hours. The highest tissue concentrations of radioactivity in males and females were found at 16 hours. Radioactivity was widely distributed in both sexes with a similar pattern: the highest concentrations were found in the gut contents
and stomach contents. However, lower concentrations were found in numerous other organs/tissues, including the liver, thyroid, adrenal glands, kidney, pancreas, testes/uterus, and brain. For males and females, radioactivity declined in all tissues over time . In the single, low dose study, 7.5 mg/kg bw 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

### Page 70 of 81

the administration of the test substance. A similar pattern of distribution of the radiolabel was observed as in the high dose group. Radioactivity declined in all tissues over time for the males and females except for the gut contents, which increased in 3

- fold males from 1 hour to 8 hours prior to decreasing. A similar effect occurred in gut content in females, which increased from 1 to 20 hours about 1.5 fold up to 1.7

- fold at 28 hours prior to decreasing at 48 h.

Mass balance and excretion were investigated in males and females in single do se studies with 150 or 7.5 mg/kg 14 

### C

– BAS 700 F in animals with or without bile catheterization in 4 animals/sex/dose. Excreta and bile were collected in cannulated animals out to 72 hours, while
excreta were collected in uncannulated animals out to 168 h. A subset of uncannulated animals (2 /sex/dose) were monitored in metabolic cages equipped to measure 14 

### C in expired air. A repeated

- dose study was also performed in which males and females (4/sex) were administered
14 doses of unlabeled BAS 700 F one per day on 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

were > 89% in males and females for all dose groups. For all dose groups, the majority of the
administered rad ioactivity was excreted via feces (84.43

– 94.30% after 168 hours). The total amount of radioactivity excreted in urine after 168 hours was in the range of 3.47

– 16.7%. Non

relevant portions of the administered radioactivity were excreted as CO 2 

### in exhaled ai r. The time course of the amount of radioactivity found in urine and feces indicated the excretion occurred predominantly within three days after dosing, indicating low potential for bioaccumulation. Bile duct cannulation experiments showed that the bile w as 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. Within 72 hou rs 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

– independent excretio n pattern for 14 

### C

– BAS 700 F.

Based on the amounts of radioactivity excreted via bile and urine, as well as the radioactive residue found in cage wash and carcass, the bioavailability of 14 

### C

– BAS 700 F in rats was
calculated to be about 65% and 67% of the applied dose for males and females at a dose of
150 mg/kg bw and about 68% and 80% of the applied dose for males and female rats at a dose level of 7.5 mg/kg bw.

This study is classified as totally reliable ( acceptable/guideline) and, together with the metabolism study, satisfies the guideline requirement for a metabolism and pharmacokinetics study (OPPTS 870.7485; OECD 417) in rats.

The metabolic fate of 14 

### C

– BAS 700 F was investigated in a follow

- up study (BASF Reg. Doc. # 2009/1019789). Material fr om 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 specifically for the metabolism study. Urine, plasma, and bile, as well as extracts of feces, liver, fat, and kidney tissue were analyzed by HPLC. Individual metabolites were detected down to a level of about

### Page 71 of 81

0.1% of the dose administered or less. Metabolites were identifi ed by LC

– MS and LC

– MS/MS.

In urine , 23 metabolites were identified. The main metabolites were in the range of 0.2% to 8.6% of the applied dose and identified to be M700F004, M700F005/M700F024 (detected only in male rats), M700F009/M700F028, M700F014, M70 0F015, and M700F061 (detected only in female rats). For all dose groups and both genders, no amounts of the unchanged parent compound were detectable at any of the time intervals investigated.

In feces , the unchanged parent compound was found to be the main constituent of the extracts at high dose levels, i.e. , dose group D, C, and DX (for both labels (19

– 44% of the dose applied), and represented only a minor part of the extractable radioactivity (3% of the dose applied) at the low dose level (dose group B). The main metabolites were identified as M700F009 (8

– 53% of the dose applied), M700F005 (ranging from 3

– 9% of the dose applied), and its isomer M700F006 (3

– 13% of the dose applied), and M700F016 (2

– 12 % of the dose applied).

In bile , the main metabolites were in the range of 3.4 to 22.0% of the applied dose and identified to be M700F004 and its isomer M700F125, M700F009, M700F014 and its isomer M700F123, M700F005, M700F024, and M700F122.

In liver , the main metabolites were in the range of 0.1 to 0.9% of the applied dose and identified as M700F005, M700F006, M700F008, and M700F009. The parent compound was identified at levels up to 3.7 and 0.4% of the dose applied for the low and the high dose grou p, respectively.

In kidney, the main metabolite was identified to be M700F008 (0.02 to 0.11% of the applied dose). The active substance was present at levels up to 0.50 and 0.05% of the dose applied for the low and the high dose group, respectively.

In fat , two components were detected: the metabolite M700F008 (0.05 to 0.29% of the applied dose) and unchanged BAS 700 F (0.35 to 2.72% of the applied dose).

In plasma , the main metabolite was identified to be M700F006 (0.03 to 0.11% of the applied dose). The parent compound was present at levels up to 0.13 and 0.01% of the dose applied for the low and the high dose group, respectively.

The main biotransformation steps of BAS 700 F in rats are hydroxylation at the biphenyl ring system, N

- demethylation at the pyrazole ring system, loss of a fluorine atom at the biphenyl ring system, and conjugation with glucuronic acid or with glutathione derivatives. A further, but negligible transformation route is cleavage at the amide bond between the pyrazole ring syst em 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 rat s.

### Page 72 of 81

870.7600 Dermal 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, 3 3.4, 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

gro up, animals were sacrificed and surface radioactivity removed with 2 tape strips prior to isolation of application site and surrounding skin and quantification of radioactivity in the carcass. For two post

- observation groups, clean dressing was applied an d the experiment
continued out to 24 hours or 120 hours with continued collection of excreta. At the end of the
post

- observational period, dressings were removed and skin was washed and surface radioactivity removed with 2 tape strips prior to isolation o f application site and surrounding skin and quantification of radioactivity in the carcass.

Average recoveries in all groups were acceptable and ranged from 88

- 105%. The majority of the radioactivity in all treatment groups was removed in the first ski n 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 amoun t 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
f irst 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 ab sorbed at the end of the 120 hours post

observation period increased with decreasing dose, ranging 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 a mount 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 ski n (tape) strips does not changes this value.

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

A.4.9 Immunotoxicity

870.7800 Immunotoxicity

– Mouse MRID 47923633 The immunotoxic potential of BAS 700 F (Batch: COD

- 001049; Purity: 99.2%) in male C57BL/6J Rj mice (8/dose) was analyzed using dietary dose levels of 0, 500, 2000 and 6000 ppm (corresponding to approximate mean intake levels of 106, 450 and 1323 mg/kg/d,

### Page 73 of 81

respectively) for 28 days.

Treatment with BAS 700 F did not result in systemic toxicity as assessed by clinical signs, food consumption and body weight development. The parameters used for detection of potentia l test substance related alterations in the morphology of the immune system included a) the determination of lymphoid organ weights (spleen and thymus) and b) the total lymphocyte count as well as lymphocyte subpopulation distribution including natural kil ler cells. Furthermore, functional parameters comprising of the analysis of the primary humoral (IgM response) immune response to sheep red blood cells (SRBC) and natural killer cell activity were integrated in this study. None of the parameters mentioned above was affected by treatment with BAS 700 F up to the highest dose level.

Concurrent treatment with positive control substance, cyclophosphamide (12 mg/kg bw/d by oral gavage) induced clear signs of immunotoxicity, demonstrating the reliability of the test system under the study conditions employed.

Based on the obtained results it can be concluded that BAS 700 F did not have an immunomodulatory/immunotoxic potential under the conditions of this study.

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

### Page 74 of 81

APPENDIX B. Chemical Names And Structures Of Metabolites

B. 1 Chemical Names and Structures

Metabolite Designation (Code)
Chemical Name Molecular Mass Structure

BAS 700 F
=M700F000
3

- (difluoromethyl)

- 1

- methyl

- N

- (3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1Hpyrazole

- 4

- carboxamide M = 381

M700F001
3

- (difluoromethyl)

- 1

- methyl

- 1H

- pyrazole

- 4

- carboxylic acid M = 176

M700F002
3

- (difluoromethyl)

- 1H

- pyrazole

- 4

- carboxylic acid M = 162

M700F004
3

- (difluoromethyl)

- 1

- methyl

- N

- ((1

- glucuronyl)oxy

- 3',4',5'

- trifluoro

- [1,1'

- biphenyl]

- 2

- yl

- 1H

- pyrazole

- 4

- carboxamide M = 573

M700F005
3

- (difluoromethyl)

- 1

- methyl

- N

- (4

- hydroxy

- 3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 397

M700F006
3

- (difluoromethyl)

- 1

- methyl

- N

- (hydroxy

- 3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 397

M700F008
3

- (difluoromethyl)

- N

- (3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

4

- carboxamide M = 367

### Page 75 of 81 M700F009
3

- (difluoromethyl)

- N

- (hydroxy

- 3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1Hpyrazole

- 4

- carboxamide M = 383

M700F010
3

- (difluoromethyl)

- N

- (hydroxy

- 3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1Hpyrazole

- 4

- carboxamide M = 383

M700F011
3

- (difluoromethyl)

- 1

- methyl

- N

- (hydroxy

- (1

- glucuronyl)oxy

- 3',[4' or 5']

- difluoro

- [1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 571

M700F012
3

- (difluoromethyl)

- N

- ((1

- glucuronyl)oxy

- 3',4',5'

- trifluoro

- [1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 559

M700F013
3

- (difluoromethyl)

- 1

- methyl

- N

- ((1

- glucuronyl)oxy

- 3',4',5'

- trifluoro

- [1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 573

M700F014
3

- (difluoromethyl)

- N

- ((1

- glucuronyl)oxy

- 3',4',5'

- trifluoro

- [1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 559

M700F015
3

- (difluoromethyl)

- 1

- methyl

- N

- ((1

- glucuronyl)oxy

- 3',[4' or 5']

- difluoro

- [1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 555

### Page 76 of 81 M700F016
3

- (difluoromethyl)

- 1

- methyl

- N

- (methylthio

- hydroxy

- 3',4',5'

- trifluoro

- [1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 443

M700F019

3

- (difluoromethyl)

- 1

- methyl

- N

- ((1

- glucuronyl)oxy

- 3',4',5'

- trifluoro

- [1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 573

M700F020

3

- (difluoromethyl)

- 1

- methyl

- N

- (hydroxy

- (1

- glucuronyl)oxy

- 3',4',5'

- trifluoro

- [1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 589

M700F021

3

- (difluoromethyl)

- N

- ((1

- glucuronyl)oxy

- 3',[4' or 5']

- difluoro

- [1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 541

M700F022

3

- (difluoromethyl)

- N

- ((1

- glucuronyl)oxy

- 3',4',5'

- trifluoro

- [1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 559

M700F023

3

- (difluoromethyl)

- N

- ((1

- glucuronyl)oxy

- 3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 559

M700F024

3

- (difluoromethyl)

- 1

- methyl

- N

- (hydroxy

- 3',[4' or 5’]

- difluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 379

### Page 77 of 81 M700F025

3

- (difluoromethyl)

- N

- ((hydroxysulfonyl)oxy

- 3',4',5’

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 463

M700F026

3

- (difluoromethyl)

- 1

- methyl

- N

- ((hydroxysulfonyl)oxy

- 3',4',5’

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 477

M700F027

3

- (difluoromethyl)

- 1

- methyl

- N

- ((hydroxysulfonyl)oxy

- 3',[4' or 5’]

- difluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 459

M700F028

3

- (difluoromethyl)

- 1

- methyl

- N

- (methylthio

- (1

- glucuronyloxy)

- 3',4',5'

- trifluoro

- [1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 619

M700F029

3

- (difluoromethyl)

- N

- (methylthio

- (1

- glucuronyl)oxy

- 3',4',5'

- trifluoro

- [1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 605

M700F032

3

- (hydroxycarbonyl)

- N

- (hydroxy

- 3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide or tautomer M = 361

M700F042

3

- (difluoromethyl)

- 1

- methyl

- N

- (hydroxy

- 3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 397

### Page 78 of 81 M700F048

3

- (difluoromethyl)

- 1

- (

- D

- glucopyranosyl)

- N

- (3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide

M700F050

3

- (difluoromethyl)

- N

- ((1

- glucuronyl)oxy

- 3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 559

M700F061

3

- (difluoromethyl)

- 5

- (1

- glucuronyl)oxy

- N

- (3',4',5'

- trifluoro[1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 559

M700F063

3

- (difluoromethyl)

- 1

- methyl

- N

- ((S

- cysteinyl)

- hydroxy

- 3',[4' or 5']

- difluoro

- [1,1'

- biphenyl]

- 2

- yl)

- 1H

- pyrazole

- 4

- carboxamide M = 498

### Page 79 of 81

APPENDIX C. Physical/Chemical Properties

TABLE C 1 . 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 ]

### Page 80 of 81

APPENDIX D. Studies Reviewed for Ethical Conduct

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.

Agricultural Re

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

### Page 81 of 81

APPENDIX E. Proposed Use Directions for Fluxapyroxad

Table E1. Summary of Proposed Use Directions for Fluxapyroxad.

Use Site Application Equipment Formulation Application Rate Use Directions and
Limitations

Grass grown for seed

Ground, Aerial, Chemigation Imbrex Xemium

Brand Fungicide

EPA Reg. No. 7969

- 306

Emulsifiable
Concentrate (5.96 % a.i.)

(0.52 lb ai/gallon) 0.089 lb ai/A For optimal disease control, begin applications of Imbrex prior to disease development
and continue on a 14 to 21 day interval. Grass forage, fodder, straw, and hay, alfalfa, and clover 0.075 lb ai/A Do not use on rangeland.

Citrus fruit Aerial, Chemigation,
Airblast 0.12 lb ai/A (0.0012 lb ai/gallon) 3 For aerial application to citrus orchards, Do Not use less than 10 gallons of spray solution

per acre. Grass grown for seed

Ground, Aerial, Chemigation, Sercadis Xemium Brand Fungicide

EPA Reg. No. 7969

- 309

Suspension
Concentrate (26.55 % a.i.)

(2.47 lb ai/gallon) 0.089 lb ai/A For aerial application to citrus orchards, Do Not use less than 10 gallons of spray solution

per acre. Grass forage, fodder, straw, and hay, alfalfa, and clover Do not use on rangeland.

Citrus fruit Aerial, Chemigation,
Airblast 0.12 lb ai/A (0.0012 lb ai/gallon) 3 For optimal disease control, begin applications of Imbrex prior to disease development
and continue on a 14 to 21 day interval. Grass grown for seed

Ground, Aerial, Chemigation Priaxor Xemium

Brand Fungicide

EPA Reg. No. 7969

- 311

Suspension
Concentrate

(14.33% a.i.)

(1.39 lb ai/gallon) 0.075 lb ai/A For optimal disease control, begin applications of Imbrex prior to disease development
and continue on a 14 to 21 day interval.

Alfalfa Do not use on rangeland.

Citrus fruit

Aerial, Chemigation,
Airblast 0.12 lb ai/A (0.0012 lb ai/gallon) 3 For aerial application to citrus orchards, Do Not use less than 10 gallons of spray solution

per acre.

1 HED received written information from the registrant to clarify that 50

- 700 gallons of solution/A are used for outdoor ornamentals. Therefore: 0.00002 lb ai/gallon in 700 gallons/acre = 0.014 lb ai/A

2 HED received written information from the registran t to clarify that 50

- 400 gallons of solution/A are used for indoor ornamentals. Therefore: 0.00002 lb ai/gallon in 400 gallons/acre = 0.008 lb ai/A

3 HED received written information from the registrant to clarify that 100

- 400 gallons of solution/A are u sed for citrus fruit. Therefore: 0.12 lb ai/A in 100 gallons of solution/A = 0.0012 lb ai/gallon