### UNITED STA TES EN VIRO NMENTAL PROTECTION AGENCY

WASHINGTON

, O.C. 20460

MEMORANDUM



### Dat e : .J une 10, 20 1 5 OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PRE VENTION

SUBJECT: 

### F luf cnacet: Human Health Draft Ri s k Assess ment for R egistration Review

P C Code: 1 2 1 903

Deci s ion No.: 485585

Petit i on No .: NA DP Barcode: 04 1 6546

Re gis tration No.: NA

R eg ulat o r y Action: Re g istration R e vi e w
Case No.: 7245 Ri s k A ss ess m en t T y pe: Aggre ga te Ri s k Asse ss m e nt

TXR No .: NA CAS No.: 142459-58-3

40 CF R : § 180.527 MRID No.: NA

FRO M : Kri st in Rur y, Bi o logist

# ~~ M iner va Mercado, Toxico l og i s

. 1 M c h e r e t Negussie

, Chemi s t**/\-'~Y:....** Cassi Wa ll s, Sen ior Chemi s t

### ~~ 

## z.**Uc~** Ri s k Assessmen t Branch 3 ( RAB 3)

H ea lth Effects Division (7509P)

THROUGH: C hri s tine Olin ge r , Branch Chief .// 

# U /

. Ri s k Assessmen t B r anc h 

## 3 ( RAB

### /p7--L 

## ___ _ H ea lth Effects Division (7509 P )

And

Ch ri s tina Swart z, RARC De s i g nated Reviewer**~ -----~**  

### 2>

Wade Britton

, RARC D esignated R eviewer

### ~ 

### 17 v

...., itJ( \N

H ea lth Eff ects Division (7509 P )

TO: Mar ga ret H athaway, Risk Manager R ev i ewer
Kevin Costello

, Ri s k Mana ge r
Pesticide Re- eva luation Di v i s i o n ( PRO ) ( 7508P)

As p a rt of Registration Revi ew, PRO of the Office of P es ti c id e Pro grams ( OPP ) h as r eq ue s t ed

that H E D eva lu a t e th e ha zard and e xposur e data and conduct occup a tional and r es id e nt i al

exposu r e assessme n ts, as ne ede d

, t o est i m a t e the ri s k t o human he a lth that will r es ult from the currently registered u ses of pesticides. Th i s memorandum se rve s as H E D ' s draft human he a lth

P age 1 of 57

### risk assessment of the dietary, occupationa l

, and residential exposure; and aggregate risk from

the regist e red uses of flu fenacet. The most recent quantitative human health risk assessment was perform e d in 2007 (J 

### Arthu r , 0318555

, 03/J 5 / 2007). Th e following ri sk assessment updates
ha ve been mad e :

• A route-specific inhalation toxicity study has been used as the basis for the inhalation point of departure (POD), an incid ental oral POD ha s been added to eval u ate risks from

s pray drift

, and a comparative thyroid study h as been subm itt ed and r eviewed by the Agency.

• A dietary expos ure assessment was completed to include es timated drinking water

concen tration s (E DWCs) and updated consumption data from the United States Department of Agriculture (USDA) National Health and Nutrition Examination Survey / What We Eat in America (NHANES / WWEIA; 2003-2008);

• A quantitative spray-drift exposure / risk assessment was completed;

• An agg re ga t e expos ure assessment was completed

, includin g updated dietary (food and drinking water) exposu re estimates; and

• An occupa ti onal exposu r e assessment for the r egistered uses was completed reflecting

rec e nt updates to H EO's Standard Operating Pro cedu r es (SOPs) along with policy changes for body weight assumptions.

A s umm a r y of th e findings and an assessme nt of human ri s k r es ultin g from the registered uses of
flufenacet arc provided in this document.

Page 2 

### of 57

### Page 3 of 57

1.0 Executive Summary

................................ ................................ ................................ ........... 5
2.0 HED Conclusions and Recommendations

................................ ................................ ....... 8
2.1 Data Deficiencies

................................ ................................ ................................ ......... 9
2.2 Tolerance Considerations

................................ ................................ .......................... 9
2.2.1 Enforcement Analytical Method

................................ ................................ ............... 9
2.2.2 Recommended Tolerances

................................ ................................ ......................... 9
2.2.3 International Harmonization

................................ ................................ ................... 10
3.0 Introduction

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

................................ ................................ ................................ ..... 11
3.2 Ph ysical/Chemical Characteristics

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

................................ ................................ ................................ 12
3.4 Anticipated Exposure Pathways

................................ ................................ .............. 13
3.5 Consideration of Environmental Justice

................................ ................................ 13
4.0 Hazard Characterization and Dose

- Response Assessment

................................ .......... 14
4.1 Summary of Available Toxicity Studies

................................ ................................ . 14
4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

......................... 14
4.2.1 Dermal Absorption

................................ ................................ ................................ ... 15
4.3 Toxicological Effects

................................ ................................ ................................ . 15
4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

............................ 17
4.4.1 Completeness of the Toxicology Database

................................ .............................. 17
4.4.2 Evidence of Neurotoxicity

................................ ................................ ........................ 18
4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

........ 18
4.4.4 Residual Uncertainty in the Exposure Database

................................ ................... 18
4.5 Toxicity Endpoint and Point of Departure Selections

................................ ........... 18
4.5.1 Do se
- Response Assessment

................................ ................................ ...................... 18
4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

..... 20
4.5.3 Cancer Classification and Risk Assessment Recommendation

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

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

................................ ................................ ................................ ............................... 20
4.6 Endocrine Disruptor Screening Program

................................ .............................. 22
5.0 Dietary Exposure and Risk Assessment

................................ ................................ ......... 23
5.1 Residues of Concern Summary

................................ ................................ ............... 23
5.2 Food Residue Profile

................................ ................................ ................................ 23
5.3 Water Residue Profile

................................ ................................ .............................. 24
5.4 Dietary Risk Assessment

................................ ................................ .......................... 24
5.4.1 Description of Residue Data Used in Dietary Assessment

................................ .... 25
5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .............. 25
5.4.3 Dietary Risk Assessment

................................ ................................ .......................... 25
5.4.4 Summary Table

................................ ................................ ................................ ......... 26
6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 26
6.1 Residential Bystander Post

- application Inhalation Exposure

.............................. 26
6.2 Spray Drift

................................ ................................ ................................ ................. 26
6.2.1 Risk E stimates From Lawn Deposition Adjacent to Agricultural Applications 28
7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .. 30
8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 30
9.0 Occupational Exposure/Risk Characterization

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

### Page 4 of 57

9.1 Short

- and Intermediate

- Term Handler Risk

................................ ........................ 31
9.2 Short

- /Intermediate

- Term Post

- Application Risk

................................ ................. 33
9.2.1 Dermal Post

- application Risk

................................ ................................ .................. 33
10.0 Public Health and Pesticide Epidemiology Data

................................ ........................... 35
11.0 References

................................ ................................ ................................ ......................... 35 Appendix A. Toxicology Profile and Executive Summaries

................................ .................. 37
A.1 Toxicology Data Requirements

................................ ................................ ............... 37
A.2 Toxicity Profiles

................................ ................................ ................................ ........ 38 Appendix B. Physical/Chemical Properties

................................ ................................ ............. 50 Appendix C. Review of Human Research

................................ ................................ ................ 51 Appendix D. Occupational Exposure/Risk Summary Tables

................................ ................ 52 Appendix E. Flufenacet IRL Sheet

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

### Page 5 of 57

1.0 Executive Summary

HED has conducted a human health draft risk assessment (DRA) to evaluate all existing registrations of the active ingredient (ai) flufenacet, an oxyacetamide herbicide used to control

weeds

. This assessment was conducted as part of Registration Review.

Use Profile

F lufenacet is registered for use on corn, grasses grown for seed, soybeans, triticale, and wheat.

Flufenacet end

- use products (EPs) are formul ated as soluble concentrate s (SC) and dry flowable s (DF) containing 24% to 60% ai. The registered labels permit direct application via ground equipment only; use of aerial and chemigation application equipment is prohibited. Flufenacet is

also added to d ry bulk fertilizers and then applied to the registered crops along with the fertilizer using tractor

- drawn spreaders

. All registered labels list a 12

- hour restricted entry interval (REI). Occupational handlers must wear the following personal protective equipment (PPE) when handling flufenacet: long sleeved shirt, long pants, chemical resistant gloves, shoes

, and socks. In addition to the PPE listed above, a respirator and coveralls are required when mixing/loading EPA Reg. No. 264

- 765. Chemical

- resista nt aprons are also required when mixing/loading and cleaning equipment for EPA Reg. Nos. 264

- 800 and 264

- 852 (co

- formulations with isoxaflutole), which are two products classified as restricted use pesticides (RUPs).

Exposure Profile Humans may be expo sed to flufenacet in food and drinking water since flufenacet may be applied directly to growing crops and application may result in flufenacet reaching surface and ground sources of drinking water. In an occupational setting, applicators may be exposed w hile handling the pesticide prior to application as well as during application. There is also potential for post

- application exposure for workers re

- entering treated fields. Although there are no registered residential uses of flufenacet , there is a potential for spray drift that may result in

exposure s in residential and non

- occupational settings

.

Based on the currently registered uses of flufenacet, the durations of exposure are expected to be

both short

- term (1 to 30 days) and intermediate

- term (1 to 6 months) for occupational handlers; long

- term exposures (greater than 6 months) are not anticipated. There are no registered residential uses of flufenacet; however, a post

- application exposure assessment was conducted for adults (dermal) and child ren 1 to <2 years old (dermal and incidental oral) to evaluate potential exposure from deposition of spray drift onto residential areas from nearby agricultural applications.

Hazard Characterization

Flufenacet ’ main target tissue is the liver, however the eye, blood, and nervous system are also

affected . Liver effects ranged from metabolic enzyme induction, mild organ weight changes and high incidence of hepatocytomegaly, to necrosis and vacuolation. In most studies

, the liver effects were adaptive at lower dose levels and progressed to be adverse at higher dose levels. Interestingly, s uppression of serum thyroid hormone levels was consistently seen in many studies and in most species tested, and in many studies was the most sensitive endpoint. A ltho ugh incomplete mechanistic data are available, the decreased thyroid levels appear to be associated

with metabolic enzyme induction in the liver , and not with a direct action on the thyroid gland

.

### Page 6 of 57

Adverse eye effects were observed in multiple studies (mic roscopic cataracts in mice and rats; gross cataracts and a variety of microscopic eye lesions in dogs). Neurotoxic effects were

observed in b oth rats and dogs but were more severe in dogs (brain vacuolation, clinical signs, and axonal degeneration). The flufenacet metabolite thiadone produced similar ocular and hematological effects in dogs. Hematological and spleen changes suggestive of mild anemia were observed in rat. Delayed ossification, especially in the skull, was seen after in utero
exposure to flufenacet. Offspring effects were observed in the developmental neurotoxicity study (reduced body weight, decreased motor activity and decreased caudate putamen measurements) and rat developmental toxicity study (delayed ossification) at doses that did n ot
induce adverse effects to the maternal animals . In the available inhalation study portal of entry effects ( goblet cell hyperplasia and eosinophilic globules in the nasal cavity, and inflammation and metaplasia in the larynx ) were observed in the extrathoracic region after exposure to

flufenacet. M utagenicity and carcinogenicity studies for flufenacet were negative ; therefore flufenacet is classified as “not likely to be carcinogenic to humans”

. Flufenacet has low acute toxicity, and is classifie d as T oxicity C ategory III via the oral and dermal routes , and T oxicity

C ategory IV for inhalation exposur e. Flufenacet is not an eye or skin irritant (Toxicity C ategory
IV ) and is not a dermal sensitizer.

The acute and chronic dietary and the dermal POD s remain unchanged since the previous risk assessment. However, an incidental oral POD has been selected to evaluate the potential exposure from spray drift, and the inhalation POD has been revised to incorporate a submitted

route

- specific study. For die tary, incidental oral

, and dermal exposure scenarios, the PODs are based on the DNT study lowest observed adverse effect level ( LOAEL ) of 1.7 mg/kg/day ( based

on decreased pup body weight, delayed eye opening and preputial separation, and decreased

caudate putamen size in offspring ) . Since a NOAEL was not determined in the study , a 10X Uncertainty Factor (UF) has been retained for LOAEL to no observed adverse effect level (NOAEL) extrapolation (LOC = 1000)

. In the absence of dermal absorption data, a 4% oral

- to

dermal extrapolation factor, calculated from the LOAELs of rat subchronic oral and dermal

studies was used for risk assessment

. For inhalation scenarios, a LOAEL of 0.02 mg/L from a

route

- specific 28

- day inhalation study in rats was used to calcul ate a human

- equivalent concentration (HEC) of 0.00252 mg/L and a human

- equivalent dose (HED) of 0.143 mg/kg/day.

The LOC for inhalation exposure assessment is 300 which includes a 3X interspecies (UF A 

### )

, 10X intraspecies (UF H 

### ) and 10X for the lack of a NOA EL (UF L 

### )

.

Residue Chemistry The residue chemistry database is adequate to support current Registration Review data requirements. Adequate metabolism (crops, livestock, and rotational crops), storage stability, magnitude of the residue, and processing d ata are available to support the registered uses. Adequate methods are available for enforcement of the currently established tolerances.

Dietary Exposure Assessment A p artially refined acute dietary (food + drinking water) exposure assessment w as conducted for all existing food uses of flufenacet. Anticipated residues for field corn , soybean, sweet corn, and

wheat were d eveloped using field trial data; tolerance

- level residues were used for cereal grains and livestock commodities; and empirical p rocessing data were used when available. The assessment also assumed that 100% of the registered crops were treated with flufenacet.

### Page 7 of 57

Estimated Drinking Water Concentrations ( EDWCs ) were provided by the Environmental Fate and Effects Division ( EFED ) and i ncorporated directly into the dietary exposure analys i s. T he

entire 30

- year distribution of estimated daily surface water concentrations for the Illinois corn crop scenario was used in a probabilistic analysis. Because the acute and chronic POD are the

s ame, the acute dietary exposure assessment is protective of the chronic dietary exposure assessment; therefore, only an acute dietary exposure assessment has been conducted.

Estimated acute dietary exposure and risk estimates are below HED’s level of co ncern (LOC) for the U.S. population and all population subgroups. Combined dietary exposure from food and drinking water at the 95 th 

### percentile of exposure is equivalent to 44% of the acute population adjusted dose (aPAD) for the general U.S. population. The population subgroup with the highest estimated acute dietary exposure is all infants less than 1 year old, with an estimated exposure at
the 95 th 

### percentile equivalent to 92% of the aPAD. Drinking water is the major contributor to the dietary exposur e estimates

.

Spray Drift Assessment There are no registered residential uses of flufenacet ; h owever, a quantitative non

- occupational spray drift assessment was conducted. Adult dermal and children’s (1 to < 2 year old) dermal and incidental oral risk estimates from indirect exposure to flufenacet related to spray drift

exceed the LOC at various distances from the edge of the field

, depending on spray type/nozzle configuration . Results indicate that groundbo om application to corn results in the worst

- case estimate of exposure from drift. However, when using a low boom, and fine to medium/coarse sprays, there were no risks of concern estimated at the field’s edge.

Aggregate Exposure Assessment
Since there are no residential uses of flufenacet, all aggregate exposure estimates are equivalent to the dietary exposure estimates (food and drinking water only) and there are no risk estimates

of concern

.

Occupational Handler and Post

- Application Exposure Assess ment There are some occupational handler risk estimates of concern for the registered uses of

flufenacet with label

- specified PPE and engineering controls . At baseline, occupational dermal margins of exposure (MOEs) ranged from 40 to 4,000 (LOC = 1000) ; a nd occupational inhalation MOEs ranged from 22 to 1, 400 (LOC = 300)

. For occupational handlers, since the

dermal and inhalation PODs are based on different effects, combining routes of exposure is not appropriate.

All occupational short

- and intermed iate

- term post

- application risk estimates resulted in dermal

MOEs of concern assuming re

- entry on the day of application ( day 0 ) with default dislodgeable foliar residue (DFR) inputs

. There are no chemical

- specific DFR studies available for flufenacet. The dermal post

- application MOEs for flufenacet range from 88 to 800 on the day of application. HED estimated MOEs for longer re

- entry intervals; t he number of days for the MOE to reach the LOC of 1,000 range from 3 to 23 days for the registered uses of flufenacet. Therefore, the REI

of 12 hours is not adequate to protect workers from exposure to flufenacet , and DFR studies are required

.

### Page 8 of 57

Based on the Agency's current practices, a quantitative non

- cancer occupational post

- application inhalation exposu re assessment was not performed for flufenacet at this time. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational
post

- application inhalation exposure assessment for flufenacet

.

Environmental J

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

human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations. 1 

### ”

Human Studies This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their exposure. Appendix C provides additional

information on the review of human research used to complete the risk assessment. There is no regulatory barrier to continued reliance on these studies, and all applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40CFR Part 26) have been

satisfied.

2.0 HED Conclusions and Recommendations

HED is not recommending any changes to the established tolerance value s. However, the tolerance expressions for flufenacet have been reviewed and should be updated in accordance

with HED’s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner) as noted in

section 2.2.2. below

.

Although there are non

- dietary risks of concern, the POD used to assess dermal and incidental oral exposures is based on the most sensitive effect in the database, and is protective of all effects

seen in the flufenacet database. Since a NOAEL was not determined in the study, a 10X UF was also retained, which is a conservative assumption, but is consistent with Agency policy. Risk

estimates exceeded the level of co ncern for the following non

- dietary exposure scenarios:

Occupational Handler Exposure Assessment

There are risk estimate s of concern at the label

- specified PPE for some occupational handler

scenarios . Estimated risks are of concern for some scenarios at the highest level of available PPE and/or engineering controls

.

Occupational Post

-

Application Exposure Assessment All occupational short

- and intermediate

- term post

- application risk estimates resulted in dermal

MOEs of concern on day 0

. HED estimated MOEs for longer re

- entry intervals; the number of days for the MOE to reach the LOC of 1,000 range from 3 to 23 days for the registered uses of

flufenacet.

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

### Page 9 of 57

Spray Drift Assessment For the registered uses of flufenacet, the dermal MO Es at the edge of the field ranged from 670 to 8,700 for adults; and combined dermal and incidental oral MOEs ranged from 260 to 3,400 for children 1 to < 2 years old. Some scenarios require differing boom heights, spray droplet sizes,

or distances from t he field edge to be not of concern (dermal and incidental oral LOC = 1000).

2.1 Data Deficiencies

Dislodgeable Foliar Residue (DFR) Data: Since the highest estimated occupational post

application exposure using default DFR values for flufenacet is mi nimal in comparison to the level of concern (i.e., the calculated MOE is not greater than 2 times higher than the level of

concern, MOE = 2,000 compared to the LOC of 1,000 ); EPA is requiring the 40 CFR DFR data requirement to facilitate any necessary exposure assessments refinements and to further EPA’s general understanding of the availability of dislodgeable foliar pesticide residues. EPA is requesting that DFR studies be submitted on corn or soybeans in separate geographic locations. Additionally, a protocol should be submitted prior to starting these studies. 2



### 2 .2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

An adequate gas chromatographic/single ion mode (GC/SIM) common moiety method for

enforcement of the tolerances for flufenacet and its metabolites containing the 4

- fluoro

- N

methylethyl benzenamine moiety on plant and commodities is ava ilable.

The analytical method determines flufenacet and its phenyl

- ring containing metabolites as the hydrolysis product 4

- fluoro

- N

- methylethyl benzenamine (fluoroaniline). It is a common moiety method to enforce the current tolerances for flufenacet and its metabolites containing the 4

- fluoro

- N

- methylethyl b enzenamin e moiety in plant s and livestock commodities. The residues

are ext racted in acidic water, oxidized with potassium permanganate, and acid hydrolyzed by refluxing with concentrated sulfuric acid to form fluoroaniline. Hydrolyzed residues are steam distilled, partitioned into methyl

- t

- butyl ether, derivatized with trifluor oacetic anhydride, and cleaned up using a solid phase extraction cartridge. Residues are then determined by GC with mass selective detector (GC/MSD) and expressed as parent equivalents.

2.2. 2 Recommended Tolerances

2 http://www.ecfr.gov/cgi

- bin/text

idx?SID=a5983c2e243fca24493fbe7a02254834&mc=true&node=se40.24.158_11070&rgn=div8

### Page 10 of 57

Permanent tolerances have been estab lished in 40 CFR §180.5 27 for residues of flufenacet as

listed i n the table below. The residue chemistry database supports the currently established

toleran ces, as listed in 40 CFR §180.527. Table 2.2. 2 lists the recommended toler ances for

residues of fl ufenacet for harmonization purposes

. Upon establishment of the recommended tolerances, HED recommends to remove tolerances as in Table 2.2.3

. T he tolerance expressions

for flufenacet have been reviewed and should be updated as follows:

According to HED’ s Interim Guidance on Tolerance Expressions (5/27/09, S. Knizner), the tolerance expressions for flufenacet should be revised as follow s :

Under 40 CFR §180.527(a): (a) General. Tolerances are established for residues of flufenacet

, N

- (4

- fluorophenyl)

- N

- (1

- methylethyl)

- 2

- [[5

- (trifluoromethyl)

- 1,3,4

- thiadiazol

- 2

- yl] oxy]acetamide including its metabolites and degradates

, in or on the commodities in the table

below. Compliance with the tolerance levels specified below is to be determine d by measuring flufenacet and its metabolites containing the 4

- fluoro

- N

- methylethyl benzenamine moiety

, expressed as the stoichiometric equivalent of flufenacet, in or on the commodity.

HED is recommending similar change s to 40 CFR §180.527 (c) and (d)

.

Table 2.2.2

. Recommended Tolerance s for Flufenacet (40 CFR §180.527).

Eggs 0.05

Meat of cattle 0.05
Meat of goats 0.05
Meat of hogs 0.05

Meat of horses 0.05
Meat of poultry 0.05
Meat of sheep 0.05

Meat byproducts of cattle 0.05
Meat byproducts of goats 0.05
Meat byproducts of hogs 0.05
Meat byproducts of horses 0.05
Meat byproducts of sheep 0.05

Milk 0.01

Table 2.2.3. Tolerance Recommended for Removal from (40 CFR §180.527).

Commodity Established Tolerance (ppm)

40 CFR §180.527(a):
Cattle, kidney 0.05
Goat, kidney 0.05
Hog, kidney 0.05
Horse, kidney 0.05
Sheep, kidney 0.05



### 2.2.3 International Harmonization

No maximum residue limits (MRLs) for flufenacet have been established by Codex.

### Page 11 of 57

The tolerance definitions are harmonized between the US and Canada. Canada has established

M RL s on soybeans (0.1 ppm) ; field corn (0.05 ppm) ; c orn, sweet, kernel plus cob with husks

removed (K+CWHR) (0.05 ppm) ; wheat grain (0.6 ppm) ; wheat bran (0.8 ppm) ; meat and meat byproducts of cattle, goats, ho gs, horses, poultry, and sheep; eggs (0.05 ppm); and milk (0.01 ppm). Canada does not establish tolerances on feed stuffs.

The US tolerances are harmonized with Canadian MRLs on all registered crops, except the

feedstuffs. For livestock, the U S tolerances were established on kidney of livestock

commodities ; whereas

, Canadian MRLs were established on meat byproducts of livestock

commodities. Canada has established MRLs on eggs , milk, meat byproducts of poultry , and meat of (cattle, goats, hogs, horses, poultry, and sheep)

, while the US has not. HED is recommending to harmonize the livestock tolerances with Canada as listed in Section 2 .2.2

.

3.0 In troduction

Flufenacet ( N

- (4

- fluorophenyl)

- N

- (1

- methylethyl)

- 2

- [[5

- (trifluoromethyl)

- 1,3,4

- thiadia zol

- 2

- yl] oxy]acetamide) is an herbicide registered to control grasses and broadleaf weeds in corn, grasses grown for seed, soybeans, triticale, and wheat. The agricultural products are generally

formulated as SCs and DFs. There are no flufenacet product s registered for residential use sites.

The most recent scoping document was performed as part of Registration Review (S Healy, D382463, 01/21/2011) and the most recent risk assessment was completed in 2007 (J Arthur

, D318555 , 0 3/15/2007 )

.

3.1 Chemical Identity

Table 3.1

. Nomenclature of Flufenacet

.

Compound

Common name Flufenacet

Company experimental name FOE 5043

IUPAC name 4'

- fluoro

- N

- isopropyl

- 2

- [5

- (trifluoromethyl)

- 1,3,4

- thiadiazol

- 2

- yloxy]acetanilide

CAS name N

- (4

- fluorophenyl)

- N

- (1

- methylethyl)

- 2

- [[5

- (trifluoromethyl)

- 1,3,4

- thiadiazol

2

- yl]oxy]acetamide

CAS # 142459

- 58

- 3

### Page 12 of 57 Table 3.1

. Nomenclature of Flufenacet

. End

- use products/EP Define  SC Herbicide, 41% (EPA Reg. No.264

- 819), Axiom® DF Herbicide, 54.4% + 13.6% metribuzin (EPA Reg No. 264

- 766), Define  DF Herbicide, 60% (EPA Reg . No.264

- 765

, originally registered as EPA Reg. No. 3125

- 487).



### 3.2 Physical/Chemical Characteristics

Flufenacet has a log octanol/water partition coefficient (log P ow 

### ) of 3.20 and is considered relatively insoluble in water. The molecular weight of flufenacet is 363 g/mol (G. Rothman, D423236, 03/16/2015), indicating that the ability to cross biological barriers is somewhat limited. The vapor pressure of flufenacet is 4 x 10

- 6 

### torr, indicat ing that flufenacet is not significantly volatile. The physicochemical properties of flufenacet are summarized in Appendix

B.

3.3 Pesticide Use Pattern

The uses a nd application rates are summarized in Table 3.3.

Table 3 .3 . Su mmary of Directions for Use of Flufenacet

.

Applic. Timing, Type, and

Equip. Max.

Applic.

Rate Max. No.

Applic. per
Season Max.

Seasonal Applic. Rate RTI 1

(days) Use Directions and Limitations 4,5

Corn (field, silage, seed, and sweet)

Groundboom, Dry Bulk

Fertilizer 0.78 lb

ai/A 1 0.78 lb ai/A N/A Preplant surface, preplant incorporated, or preemergent application only

. Do not apply within 49 days of harvest of

field corn forage/silage. A PHI of 75 days or more is specified for forage (silage)

. Apply by ground application

only.

Dry Bulk Fertilizer 3 7.88 lb

ai/ton 1 7.88 lb ai/ton NA Use a minimum of 200 pounds and a maximum of 450 pounds per acre
Soybeans

Groundboom 0.46 lb

ai/A 1 0.46 lb ai/A N/A Preplant surface, preplant incorporated, or preemergent application only

. Do not graze or feed forage, hay, or straw

to livestock.

Dry Bulk Fertilizer 3 4.56 lb

ai/ton 1 4.56 lb ai/ton NA Use a minimum of 200 pounds and a maximum of 450 pounds per acre

Triticale & Wheat

Groundboom 0.34 lb

ai/A N/A 2 0.34 lb ai/A 21 Preemergent to early postemergent applications only

. Do not graze 30 days after treatment

. Grass Grown for Seed 6

Groundboom 0.44 lb

ai/A 1 0.44 lb ai/A N/A Allow a minimum of 4 weeks between application of flufenacet and other photosynthetic inhibitor herbicides

. Allow at least 120 days between application and harvest of seed grass.

### Page 13 of 57 Table 3 .3 . Su mmary of Directions for Use of Flufenacet

.

Applic. Timing, Type, and

Equip. Max.

Applic.

Rate Max. No.

Applic. per
Season Max.

Seasonal Applic. Rate RTI 1

(days) Use Directions and Limitations 4,5

Do not allow livestock to graze treated fields for a minimum of 30 days following application.

1. RTI = Re

- Treatment Interval

. 2. Sequential applications are allowed to triticale and wheat on EPA Reg. No. 264

- 766. However, the maximum seasonal application rate is 0.34 lb ai/A. Reduced maximum single application rates must be used if multiple applications per season are required. 3. To calculate the dry bulk fertilizer rate: Application Rate (fl oz product/A) × (1 gallon product/128 fl oz product) × (lb ai/gallon product) × (1 A/200 lb fertilizer) × (2000 lb fertilizer/1 t on fertilizer) = lb ai/ton fertilizer.

4. Application through any type of irrigation system and aerial applications are prohibited

5. The labels include the following rotational crop restrictions: (i) corn and soybeans may be replanted immediately in the event of crop failure, but do not make a second application of flufenacet; (ii) a 1

- month plant

- back interval (PBI) is specified for potatoes; (iii) a 4

- month PBI is specified for barley, buckwheat, cabbage, carrots, cotton, lettuce, pearl and proso

mil let, oats, peppers, radish, rye, sorghum, teosinte, sugar beets, wheat, triticale, and all other leafy vegetables; and (iv) a 12

- month PBI is specified for all other crops.

6. 24 C or Regional Registration



### 3.4 Anticipated Exposure Pathways

Humans may be exposed to flufenacet in food and drinking water since flufenacet may be applied directly to growing crops and application may result in flufenacet reaching surface and ground sources of drinking water. In an occupational setting, applicator s may be exposed while handling the pesticide prior to application as well as during application. There is also potential for post

- application exposure for workers re

- entering treated fields. Although there are no registered residential uses of flufenace t , there is a potential for spray drift that may result in

exposure s in residential and non

- occupational settings

.

This risk assessment considers all of the aforementioned exposure pathways based on the existing uses of flufenacet

.

3.5 Consideration of E nvironmental 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 Minor ity Populations and Low

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

to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on pat terns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s National Healt h 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.

Additio nally, OPP is able to assess dietary exposure to smaller, specialized subgroups and

### Page 14 of 5 7

exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

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

- application are evaluated. Spray drift can also potentially result in post

- application exposure and it w as considered in this analysis. Furthe r considerations are also currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to other types of possible bystander exposure s and farm workers as well as lifestyl e and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

The hazard characterization for flufenacet is discussed in detail in a previous risk assessment ( J
Arthur

, D318555 , 0 3/15/2007 )

. Since then, a new subchronic inhalation study (MRID 47473101) and a series of comparative thyroid studies (MRIDs 48898902

, 48898903 and

48898904 ) have been submitted

.

4.1 Summary of Available Toxicity Studies

The existing flufenacet toxicology database is a dequate for hazard characterization and endpoint

selection. Toxicology studies available for risk assessment are summarized in Appendix A.2 and

include : (1) subchronic oral toxicity studies in rats, mice and dogs; (2) 21/28 day dermal and

inhalation toxicity studies in rats; (3) prenatal developmental toxicity studies in rats and rabbits; (4) a 2

- generation reproduction study in rats ; (5) chronic toxicity study in dogs; (6) a carcinogenicity study in mice and combined chronic/carcinogenicity study in rats; (7) a battery of the required genotoxicity studies; (8) a metabolism studies in rats; (9) acute, subchronic

, and

DNT studies ; and (10) comparative thyroid studies

. The guideline immunotoxicity study was waived by the Hazard and Science Policy Counci l ( HASPOC) based on weight of evidence analysis (J

. Leshin , TXR#0056951, 04/24/ 2014). The 2

- generation reproduction study Data Evaluation Record (DER) has been revised since the last risk assessment to be consistent with current policies (see Appendix A.2 .1 )

.

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

Single and repeat

- dose metabolism studies are available in the rat. T he majority of an oral dose

of flufenacet is absorbed (78

- 100% )

. Once absorbed, flufenacet was metabolically cleaved into 3 types of residues with different pharmacokinetic properties: fluoropheny l residues, thiadiazole

residues

, and polar small molecular weight residues. Plasma levels of fluorophenyls reached 2 peaks of concentratio n at 1 hour and 6 to 24 hours post

- administration . The second peak may be

indicative of re

- entry into the systemic circulation through reabsorption from the intestinal tract.

Plasma levels of thiadiazoles reached only one concentration peak within 2 hour s of dosing, indicating that the two rings of flufenacet were probably separated prior to entering the systemic

circulation. B y 48 hours some thiadiazole s seem to remain in the body (13

- 25% of dose) while fluorophenyls had been mostly excreted. By 96 hou rs, t issue fluorophenyl residues were ≤3% of

the administered dose , mostly found in the GI tract but also in liver and blood , and t issue
thiadiazole residues were 1% of the administered dose

, mostly found in the liver, skin

, and kidney. Most of the dose was metabolized and excreted in urine. 21

- 41% of the fluorophenyls

### Page 15 of 57

were excreted in feces. 22

- 32% of the t hiadiazoles were exhaled into air, and 2

- 6% were found

in feces. Glutathione conjugation appeared to be the major metabolic pathway for fluoropheny l residues, however different sexes and treatment conditions yielded different primary metabolites

. The major urinary thiadiazole was thiadone (5

- trifluoromethyl

- thiadiazol

- 2

- one).

4.2.1 Dermal Absorption

No dermal absorption data ar e available. However

, for route

- to

- route extrapolation a factor of 4% has been established based on a comparison between the LOAEL of 6 mg/kg/day in the 90

- day feeding study in rats (MRID 43743401) and a LOAEL of 150 mg/kg/day in the 21

- day dermal study i n rats (MRID 43850027); endpoints in both studies are based on decreased thyroid hormone levels in plasma (K Raffaele , TXR 0051853, 4/23/2003; TXR 0013638, 0 2/19/1997). The 4% factor is appropriate for use in the absence of dermal absorption data because it accounts

for the different ial effect s between the dermal and oral routes of exposure, and it characterizes the differences between dermal and oral absorption together with differences in other processes that occur after flufenacet enters the body through either route, such as metabolism and transport to the target organs.

4.3 Toxicological Effects

Flufenacet is an oxyacetamide herbicide that inhibits plant cell divis ion and seedling shoot growth by inhibiting long chain fatty acid synthesis by very

- long

- chain fatty acid elongase (VLCFAE ), which occurs only in plants ( Lechelt

- Kunze et

. al.

, 2003)

. The mode of action of

flufenacet in mammals has not been elucidated.

The mammalian toxicological database identifies the liver as the main flufenacet target tissues

. Other tissues affected by flufenacet are the eye, blood, and nervous system

. However changes in thyroid hormones associated with non

- adverse liver effects, in cluding metabolic enzyme

induction , was the most sensitive endpoint in many studies . In developmental studies, delay ed ossification, especially in the skull, was seen after in utero exposure to flufenacet. In an inhalation study, portal of entry effects were observed in the extrathoracic region after flufenacet

exposure.

All species tested had liver effects that ranged from mild organ weight changes and high incidence of hepatocytomegaly, to necrosis and vacuolation. Metabolic liver enzyme induction

wa s observed in the only two studies where the parameter was measured (the 28

- day inhalation guideline study and a mechanistic feed study). However

, in most studies the liver effects were adaptive ( i.e. liver hypertrophy) at lower dose levels and progressed to be adverse at higher dose

levels

.

Suppression of serum thyroid hormone levels was consistently seen in many studies and in most species tested (dog, rat, and mouse). S pecial mechanistic studies in male rats asses sed liver metabolic enzyme induction, T4 clearance , pituitary function and thyroid iodine uptake after 3

- 13 week dietary exposure to flufenacet. Results of the special studies indicate that thyroid hormone depression is associated with liver enzyme inducti on and not with direct action on the functions of the pituitary, thyroid

, or hypothalamus. I ncreased levels of liver metabolic enzymes

### Page 16 of 57

occurred at lower or the same doses that depressed T4 serum levels and increase T4 excretion in

bile in the special stud ies, and metabolic enzyme induction also occurred at a lower dose than T4 decreases in the inhalation study

. Other special stud ies did not show an effect of flufenacet on the thyroid capacity to take up iodine (a key step in the production of thyroid horm ones) or the pituitary capacity to produce TSH (which regulates hormone production by the thyroid gland)

. Throughout the flufenacet database, some adult animals studies showed thyroid follicular cell hypertrophy

, a common indicator of increased hormone production to compensa te for low serum

hormone levels , and always at dose levels about 10

- fold higher than doses which elicited serum hormone suppression. While additional data would be needed to fully describe how the liver effects impact thyroid hormone levels, the flufenacet database seem to indicate that flufenacet does not directly act on thyroid gland function, but rather increases the levels of liver enzymes that are capable of deactivating T4.

.

Adverse eye effects were observed in the rat, dog, and mouse after chronic oral exposure via feed; these effects ranged from microscopic cataracts in mice and rats to gross cataracts and a variety of microscopic eye lesions in dogs ( i.e.

, optic nerve vacuolation, cil iary body epithelial vacuolation, eye/retina cysts).

Hematological and spleen changes suggestive of mild anemia were observed in rat oral and inhalation studies. Methemoglobinemia was observed in rats and mice after chronic oral

exposure. The flufenac et metabolite thiadone produced similar ocular and hematological effects in dogs as seen in subchronic and chronic dog studies.

Neurotoxic effects were observed in dogs and rats. These effects were more severe in the dog, and ranged from brain vacuolat ion in the subchronic study to clinical signs and axonal degeneration in the chronic study. While neurotoxic effects were not observed in the rat general toxicity studies, the subchronic neurotoxicity study (SCN) and the DNT studies demonstrated

neurotoxi city in the rat. In the SCN, increased number of lesion s per affected animal and lesion severity (but not number of animals affected ) were noted for axonal swelling in the cerebellum/medulla and spinal cord, as well as decreased fore limb strength, increa sed foot splay

and decreased motor activity. In the DNT, females exposed to flufenacet throughout development had de creased motor activity and a significant decrease in caudate putamen

measurements as adults. Although the registrant has proposed that bra in lesions in dogs are attributable to a specific metabolite ( thiadone ) and treatment

- related metabolic limitations ( i.e.

, decreased GSH reductase), such assessment is based on very limited data that does not provide enough information to elucidate the mechanism of flufenacet neurotoxicity.

In addition to the offspring central nervous system ( CNS ) effects, decreased body weight, delayed eye opening and delayed male puberty were also observed in the DNT. Prenatal developmental effects were also observed in rats and rabbits, namely increased incidence of delayed ossification in the skull in both species, and delayed vertebrae and sternebrae

ossification in the rat. According to the scientific literature (Forhead and Fowden 2014;

Christian and Trenton 200 3), mammalian plasma T4 concentrations correlate positively with fetal and neonatal body weight, and maternal/fetal hypothyroidism can lead to abnormal neuromotor development, reduced gonadotropin levels and delayed puberty, and delays in bone development including delayed development of the skull. Offspring effects observed in the

### Page 17 of 57

flufenacet DNT and rat prenatal developmental stud ies occurred at similar or higher doses as thyroid hormone (T4) depression in adult rat studies of similar duration

. In additio n, in a recently submitted series of non

- guideline comparative thyroid studies maternal T4 levels were decreased during gestation, and TSH levels were decreased in the fetus (fetal T4 levels could not be evaluated due to technological limitations)

. Therefo re, it is possible that effects observed in

the developmental studies after flufenacet treatment ( i.e.

, reduced body weight, decreased motor activity

, decreased caudate putamen measurements , and delayed ossification ) are influenced by the depressed circula ting thyroid hormone levels, especially while in utero

. As described above, flufenacet effects on liver enzyme induction, T4 clearance, and thyroid iodine uptake suggest that the reduction in T4 is secondary to liver effects.

As described above, q ualitative and/or quantitative offspring susceptibility were seen in the rat developmental study and rat DNT studies. No increase in susceptibility was seen in the rabbit developmental study or rat 2

- generation reproductive study

.

While oral toxicity stu dy elicited a variety of effects, the most sensitive endpoints after inhalation exposure are portal of entry effects manifested as : goblet cell hyperplasia and eosinophilic globules in the nasal cavity ; and inflammation and metaplasia in the larynx

. S perm a tic debris in the testis and epididymis and oligospermia (low number of sperm) were also observed at the same dose as portal of entry effects, however these effects did not have a

consistent dose

- response

. At higher exposure concentrations, a variety of sy stemic effects similar to those seen with oral exposure (i.e. decreased serum thyroid hormone, hypertrophy

, metabolic enzyme induction in the liver, retinal atrophy/degeneration, mild anemia) were reported showing a consistency in the systemic toxicity pro file for flufenacet regardless of exposure route

. In
addit i on , moderate oligospermia (low sperm count ) and debris in the epididymides were also

found , but no dose

- response was observed

. The sperm effects were only observed in the inhalation study

, and no t in the oral studies.

No treatment

- related tumors were seen in the rat or mouse carcinogenicity studies for flufenacet and mutagenicity studies were negative ; therefore, flufenacet is classified as “not likely to be a carcinogenic in humans ”

. Flufenacet has low acute toxicity, and is classified as T oxicity

C ategory III via the oral and dermal routes , and T oxicity C ategory IV for inhalation exposur e. Flufenacet is not an eye or skin irritant ( Toxicity C ategory IV ) and is not a dermal sensitizer

.

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

Based on the currently available toxicity and exposure data, the FQPA Safety Factor has been

retained at 10X for oral and dermal risk assessment scenarios

, as a LOAEL to NOAEL extrapolatio n factor (UF L 

### ) due to the of lack of a NOAEL in the DNT study used as the basis for

the POD

. Furthermore, there are indications of quantitative and qualitative susceptibility of offspring in rat developmental studies

. The selected POD s address and are pr otective of the effects of concern, which are indicative of neurotoxicity and susceptibility in young rats by the

oral route . There is no uncertainty in the exposure database. The details for determining the FQPA safety factor are elaborated below.

4.4.1 Completeness o f the Toxicology Database

### Page 18 of 57

The flufenacet database is adequate for risk assessment. A guideline inhalation study was submitted by the registrant since the last risk assessment and was evaluated by the Agency and

considered in the selec tion of PODs for risk assessment

. N on

- guideline comparative thyroid studies submitted by the registrant since the last risk assessment ha ve been evaluated by the Agency and additional information on those studies have been requested from the registrant

. The requirement for the immunotoxicity study has been waived for flufenacet ( J. Leshin, TXR#0056951, 04/24/2014 )

.

4.4.2 Evidence of N eurotoxicity

The flufenacet database demonstrated neurological effects in acute and subchronic neurotoxicity

studies in rats, DNT study in rats , and 1

- year dog study as described in S ection 4.3 above.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

There was indication of quantitative and qualitative susceptibility in the rat pre

- natal developmental study, where delayed ossification was observed in fetuses in the absence of any maternal toxicity. There is no indication of increased susceptibility of rabbits following pre

- natal exposure to flufenacet. There is no indication of increased susceptibility of young rats in a 2

- generation reproductive study.

Increased susceptibility (qualitative and quantitative) was seen in the DNT in rats. While a

LOA EL was not observed for dams in this study ( i.e.

, no adverse effects were observed up to 40.8 mg/kg/day), decreased body weight was seen in pups at all dose levels (≥ 1.7 mg/kg/day), and additional effects, including decreased motor activity, delayed devel opmental landmarks and decreases in morphometric measurements, were seen at mid

- and high

- doses. It should be noted that a similar decrease in pup weight was not seen in the 2

- generation reproduction study (both studies used Sprague Dawley rats, but from different suppliers, and the studies were conducted 5 years apart and with different dosing schedules).

4.4.4 Residual Uncertainty in the Exposure Datab ase

There are no residual uncertainties in the flufenacet exposure database. Although partially refined, the dietary (food and drinking water) assessment is based on reliable data and will not underestimate exposure/risk. The drinking water assessment utilized water concentration values generated by models and associated modeling parameters which ar e designed to produce conservative, high

- end estimates of water concentrations which are not likely to be exceeded.

There are no registered residential uses for flufenacet ; however a spray drift assessment was conducted to assess exposures resulting from drift onto residential areas from agricultural applications of flufenacet.

4.5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- Response Assessment

### Page 19 of 57

The do ses/toxicological endpoints selected for exposure scenarios are summarized in Table

4.5. 4

.

A rat DNT study was used to select endpoint s for dietary (acute and chronic), incidental oral and

dermal assessments . The LOAEL of 1.7 mg/kg was based on decrease pup body weight and decreased caudate putamen size in offspring. The effect on pup body weight cannot be attributed to a single exposure, therefore it is not appropriate for acute endpoints

. The se effects in the DNT study are the most sensitive oral endp oints in the flufenacet database. Although these effects are considered acute, in the case of flufenacet, they are also appropriate for chronic risk exposures as an acute exposure would

– by definition

– precede a chronic exposure. The effect on the caud ate putamen size was seen at higher doses than the selected POD; however, the effect was not evaluated at the low doses, therefore, a NOAEL was not observed for decreased caudate putamen

size . As described above, a total uncertainty factor (UF) of 1000X h as been determined appropriate , which includes 10X interspecies (UF A 

### ) , 10X intraspecies (UF H 

### ) and 10X for the

lack of a NOAEL (UF L 

### )

. T he 10X applied as an UF L 

### is also appropriate as a FQPA UF in dietary and incidental oral assessment, and is protective of possible neurotoxicity and offspring susceptibility

.

Acute Dietary Endpoint ( all populations ) : A n a cute reference dose (a RfD ) of 0.0017 mg/kg/day

was established for all population subgroups , based on the DNT study LOAEL and a 1000X UF

. This a RfD is protective of developmental effects which may occur in females of reproductive

age , infants

, and children because s everal of the effects observed in the DNT study could be due to disruption of fetal development and/ or postnatal development, and may occur f ollowing a single dose. As explained above

, the 1000X UF includes a 10X FQPA UF and is protective of potential effects in the young.

Chronic Dietary Endpoint : A chronic reference dose ( c RfD ) of 0.0017 mg/kg/day was established for the general U.S. pop ulation , based on the DNT study LOAEL and a 1000X UF

. This cRfD is protective of post

- natal offspring effects, as well as neurotoxic effects in adults. For instance, u se of the DNT study for chronic exposures in adults and children is supported by similar NOAELs in the chronic rat and dog studies (1.2 and 1.1 mg/kg/day, respectively) , and is protective of neurotoxicity observed in adults in the subchronic neurotoxicity study (NOAEL = 75 mg/kg/day)

. As explained above the 1000X UF includes a 10X FQP A UF and is protective of potential effects in the young.

Short

- Term (1

- 30 days) and Intermediate

- Term (1

- 6 months) Incidental Oral Endpoints : Duration of exposure in the DNT study is appropriate for short

- and intermediate

- term use

, therefore t he LOAEL of 1.7 mg/kg was select ed as incidental oral endpoint. As explained above, a 1000X UF applies to this scenario, which includes a 10X FQPA UF and is protective of potential effects in the young.

Short

- Term (1

- 30 days) and Intermediate

- Term (1

- 6 months) D ermal Endpoints : A dermal toxicity study is available for flufenacet , which showed suppression of thyroid hormone (T4) at higher doses than oral studies. However, the DNT study LOAEL of 1.7 mg/kg /day is more appropriate for endpoint selection because it is based on developmental toxicity endpoints, which were not measured in the dermal study. Duration of exposure in the DNT study is also

### Page 20 of 57

appropriate for short

- and intermediate

- term use

. As explained above, a 1000 X UF applies to this scenario, which includ es a 10X UF L 

### for the lack of a NOAEL in the DNT study. This endpoint

should be adjust ed for 4% oral

- to

- dermal route extrapolation factor as explained in section 4.2.1

above

.

Short

- Term (1

- 30 days) and Intermediate

- Term (1

- 6 months) Inhalation Endpoint s : A LOAEL of 0.02 mg/L from a route

- specific 28

- day inhalation study in rats was used to calculate h uman

equivalent concentration s (HEC s ) and human

- equivalent doses ( HED s) using the reference concentration (RfC) methodology described in the 1994 EPA guidan ce document. An HEC of 0.00252 mg/L was derived based on the portal of entry effects in the extrathoracic (ET) region (i.e., goblet cell hyperplasia and eosinophilic globules in the nasal cavity, and inflammation and metaplasia in the larynx) which is als o protective of systemic effects (increased incidence of

sperm

- related lesions of the testis and epididymis) observed in the inhalation study

. The HED s of 0.143

- 0.501 mg/kg/day for females and 0.206

- 0.719 for males are protective of developmental

effects observed in the DNT that would be of concern for female workers. Since residential uses are not registered at this time, residential HECs or HEDs were not calculated. S ee Appendix A .3

f or details regarding the calculation of the HECs and HEDs. The LOC i s 300 which includes a 3 X UF A 

### , a 10 X UF H 

### , and a 10 X UF L 

### (for lack of a NOAEL in the inhalation study ) . The UF A 

### was reduced from default 10 X to 3 X because the HEC calculation accounts for pharmacokinetic interspecies differences. The default intraspecies factor is retained at 10 X because the HEC calculation does not account for pharmacodynamic intraspecies differences.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

Human health r isk assessment must consider exposures from thr ee major sourc es: oral, dermal,

and inhalation exposures. In the case of flufenacet, there are no registered residential uses; however, incidental oral exposure is combined with dermal exposure for children 1

- 2 years old in the spray drift exposure assess ment because incidental oral and dermal PODs are based on the

same study . For occupational handlers, since the dermal and inhalation PODs are based on different effects, combining routes of exposure is not appropriate

.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Flufenacet is classified as “not likely to be a human carcinogen ”. This classification is b ased on

the lack of treatment

- related tumors in the combined rat chronic/ carcinogenicity study or in the

mouse carcinogenicity mouse , and the lack of genotoxicity in an acceptable battery of mutagenicity studies.

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk
Assessment

The toxicological doses and endpoints selected for various exposure scenarios are summarized in

Table 4.5.4.

### Page 21 of 57

Table 4 .5. 4. Summary of Toxicol ogical Doses and Endpoints for Flufenacet for Use in Dietary
, Occupational 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 (All Populations) L OAEL= 1.7

mg/kg/day UF A = 10 x

UF H = 10 x

FQPA SF=

10 x ( UF L ) Acute RfD =

0.0017 mg/kg/day

aPAD = 0.0017 mg/kg/day Developmental neurotoxicity

study in rats. LOAEL = 1.7 mg/kg/day based on delayed eye opening

, delayed preputial separation, and decreased caudate putamen size.

Chronic Dietary (All Populations) L OAEL= 1.7

mg/kg/day UF A = 10 x

UF H = 10 x

FQPA SF=

10 x ( UF L ) Chronic RfD =

0.0017 mg/kg day

aPAD = 0.0017mg/kg/day
Developmental n eurotoxicity

study in rats. LOAEL = 1.7 mg/kg/day based on decreased pup body weight, delayed eye opening

, delayed preputial separation, and decreased caudate putamen size

. Incidental Oral

Short

- Term (1

- 30 days) and

Intermediate

- Term (1

- 6 months) L OAEL= 1.7

mg/kg/day UF A = 10 x

UF H = 10 x

FQPA SF=

10 x ( UF L ) Residential LOC

for MOE = 1000

Dermal Short

- Term (1

- 30 days) and

Intermediate

- Term (1

- 6 months) L OAEL= 1.7

mg/kg/day

4% oral

- to

- dermal route extrapolation

factor UF A = 10x

UF H = 10x

UF L = 10x Occupational

LOC for MOE =

1000

Residential =

1000

Inhalation Short

Term (1

- 30 days)

and Intermediate

Term (1

- 6 months) L OAEL = 0.0 2 mg/L

HEC = 0.00252 mg/L

f = 8.3 L/min

HED =

0. 143 mg/kg/day

f Handlers = 16.7 L/min

HED
s = 0. 289 mg/kg/day

f Handheld Spray = 29 L/min

HED =

0. 501 mg/kg/day UF A = 3 x

UF H = 10x

UF L = 10x Occupational

LOC for MOE =

300

Residential =

N/A (no exposure with current uses) 28

- day inha lation toxicity study

in rats. LOAEL = 0. 0 2 mg/ L based on portal of entry effects ( nasal cavity goblet cell hyperplasia in males and larynx inflammatory infiltrate in

females ) and increased incidence of sperm

- related

lesions of the testis and epididymis

.

Cancer (oral, dermal, inhalation) Classification: Not likely to be a human carcinogen (RfD Peer Revi ew Committee report,

7/16/1997)

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

- response data and

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolatio n from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to account for the absence of key data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c

### Page 22 of 57

= chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. HEC = human equivalent concentration (see Appendix A.3). HED = human equivalent dose (see Appendix A.3). f =

ventilation rate (see Appendix A.3)

.



### 4. 6 Endocrine Disruptor Screening Program

As required by the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA ) and the Federal Food, Drug, and Cosmetic Act ( FFDCA ) , EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, includin g assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, org an weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in

differen t taxonomic groups. As part of its most recent registration decision for flufenacet , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p),

flufenacet is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredie nts) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required

d eterminations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

- response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between
October 2009 and Februar y 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 3 

### and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our

website. 4

3 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

4 http://www.epa.gov/endo/

### Page 23 of 57

5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary

The residues of concern for dietary risk assessment and th e tolerance expression are summarized in Table 5.1. For tolerance expression and risk assessment in plants

, parent and the metabolites containing the 4

- fluoro

- N

- methylethyl benzenamine moiety are adequate indicators of misuse, and are the only residues in cluded in the tolerance expression. The residues of concern in drinking water include flufenacet and its degradate thiadone. Available livestock metabolism studies should be used to account for conjugate conversion to species of toxicological concern (fr ee thiadone and thiadone glucuronide). However, the tolerance for livestock (kidney) commodities is set at an adequate level to account for residues resulting from the conjugate

conversion. A more detailed discussion of the rationale for the residues of concern decision may

be found in N. Dodd, D241928, 12/18/1997

.

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression

.

Matrix Residues included in Risk
Assessment Residues included in

Tolerance Expression

Plants Primary Crop Parent and metabolites containing the 4

- fluoro

- N

methylethyl benzenamine moiety Parent and metabolites containing the 4

- fluoro

- N

methylethyl benzenamine moiety Rotational Crop

Livestock Ruminant Parent and metabolites containing the 4

- fluoro

- N

methylethyl benzenamine moiety including the glycoside (THNG) and malonylalanine conjugates of

thiadone Parent and metabolites containing the 4

- fluoro

- N

methylethyl benzenamine moiety Poultry

Drinking Water Parent flufenacet and thiadone Not Applicable



### 5 .2 Food Residue Profile

Adequate field trial data are available to support the registered uses. Residues of f lufenacet are generally very low on most human foods

, ranging from non

- quantifiable in corn (field and sweet) grain and quantifiable , but still low

, on wheat grain and soybean s . Residues were higher on livestock feedstuffs (forage, hay, and stover). Adequate analytical methods and storage stability data a re available to support the registered u ses.

Adequate processing studies are available for corn, soybeans, wheat

, and sorghum (rotated crop).

The data generally indicate that residues do not concentrate upon processing for most grains with the exception of processing to wheat bran

.

Based on the available cattle feeding stud y and the registered uses

, tolerance s of 0.05 ppm for

residues in kidney of cattle, goat, sheep, horse, and hog were established

. There is no reasonable

### Page 24 of 57

expectation of finite resides in any other livestock commodities , so the Agency has not established tolerances, and there is no change to this conclusion during R egistration R eview

.

Adequate limited

, as well as extensive

, rotational field trial data are also available. The data indicate that there is potential for residues to persist and carry over to the succeeding crop

. Therefore, rotational crop tolerances were established. In addition, plant

- back intervals of 1

- 18 months are specified on the label.

5.3 Water Res idue Profile

Flufenacet is moderately persistent i n soil and water with primary decline occurring due to biodegradation in aerobic environments over time. Flufenacet half

- lives range from 23.1 days

– 63.6 days in aerobic soil environments and 18

– 77 days in aerobic aquatic environments.

Flufenacet is st able in anaerobic soil environments and persistent in anaerobic aquatic systems

with a half

- life of 492 days.

The drinking water residues used in the dietary risk assessment were provided by EFED ( G. Rothman, D423236, 0 3 /16/ 20 15). The EDWCs of flufenac et and thiadone in surface water were modeled using t he Surface Water Concentration Calculator interface (SWCC version 1.092, dated March 6, 2014) and the Tier II Pesticide Root Zone Model/ Exposure Analysis Modeling System (PRZM/ EXAMS )

.

Ground water estimated concentrations resulting from the existing uses of flufenacet are estimated using the PRZM

- Groundwater ( GW ) (version 1.0 7

, March 6, 2014 ) and will be used to evaluate ground water exposure. PRZM

- GW is publically available on

- line at http://www.epa.gov/oppefed1/models/water/#przm_gw

.

For the acute assessment, the entire 30

- year distribution of estimated daily concentrations from

the Illinois corn scenario incorpora ted into PRZM/EXAMS was used in a probabilistic analysis. This distribution is a refinement from a screening

- level estimate. As a result, the individual EWDCs given in Table 5.3 were not used in the acute assessment.

Table 5.3 . Summary of Estimated S urface Water and Groundwater Concentrations for
Flufenacet

. Surface Water

Acute Chronic Cancer

29.87 ppb 1 9.07 ppb 1 5.21 ppb 1

Ground Water

Acute Chronic and Cancer

12.47 2 11.02 ppb 2

1. Based on SWCC IL Corn crop scenario

2. Based on PRZM

- GW WI Sands scenario.



### 5.4 Dietary Risk Assessment

In support of Registration Review, an updated acute dietary (food and drinking water) exposure and risk assessment was conducted using DEEM

- FCID (ver. 3.16) which incorporates

### Page 25 of 57

consumption data from the USDA NHANES/WWEIA; 2003

- 2008. The entire 30

- year distribution of EDWCs w as incorporated directly into the acute dietary analyses as “water, direct, all sources” and “water, indirect, all sources.”

Since the POD is the same for acute and chronic dietary exposure durations, the acute dietary exposure assessment is protective of chronic dietary exposures. Acute dietary assessments incorporate more conservative inputs and use the entire distribution of consumers, including individuals who consume a greater amount of a specific commodity per day, while chronic assessments rely on average per capita exposures for each subpopulation over a longer period. In addition, the acute dietary risk estimates repor ted for flufenacet represent the 95 th 

### percentile of exposure, whereas chronic risk estimates would reflect average exposure and risk for the relevant subpopulations. Therefore, a separate chronic dietary exposure assessment was not conducted.

5.4.1 De scription of Residue Data Used in Dietary Assessment

Partially refined acute dietary exposure assessments were conducted for all registered food uses of flufenacet and drinking water. Since field corn, soybean, and wheat are extensively blended prior to distribution, average field trial residues were used in the dietary exposure assessment

. A ll residues in the sweet corn field trial data were non

- detect able

, so 1⁄2 of the limit of quantification ( LOQ ) was used . Tolerance level residues were used for all o ther cereal grains

and livestock commodities (kidney)

. The tolerance for livestock (kidney) is set at a level that covers the conjugates so no further adjustment was needed

.

5.4.2 Percent Crop Treated Used in Dietary Assessment

One hundred percent crop t reated was assumed in the assessment

.

5.4.3 Dietary Risk Assessment

A cute dietary risk estimates are below HED’s level of concern for the U.S. population and all population subgroups. Combined dietary exposure from food and drinking water at the 9 5 th 

### percentile of exposure is estimated to be 0.000750 mg/kg/day for the general U.S. population, equivalent to 44% of the aPAD. The population subgroup with the highest estimated acute dietary exposure is infants ( less than 1 year old ) with an estimated exposure at the 95 th 

### percentile of 0.001561 mg/kg/day, equivalent to 92% of the aPAD.

Dietary exposure from drinking water alone at the 95 th 

### percentile of exposure is estimated to be 0.000405 mg/kg/day for the general U.S. population, equivalent to 24% of the aPAD. The population subgroup with the highest estimated acute dietary exposure from drinking water alone

is infants ( less than 1 year old ) with an estimated exposure at the 95 th 

### percentile of 0.001230 mg/kg/day, equivalent to 72% of the aPAD. Drinkin g water is the major contributor to the dietary assessment.

The results of the acute dietary exposure and risk analyses at the 95 th 

### percentile of e xposure are reported in Table 5.4. 4

.

### Page 26 of 57

5.4. 4 Summary Table

Table 5.4.4. Summary of Dietary (Food and Drinking Water) Exposure and Risk f or Flufenacet.

Population Subgroup Acute Dietary (95th Percentile)

Dietary Exposure (mg/kg/day) % aPAD*

General U.S. Population 0.000750 44

All Infants (<1 year old) 0.001561 92

Children 1

- 2 years old 0.001375 81

Children 3

- 5 years old 0.001170 69

Children 6

- 12 years old 0.000889 52

Youth 13

- 19 years old 0.000622 37

Adults 20

- 49 years old 0.000620 37

Adults 50

- 99 years old 0.000561 33

Females 13

- 49 years old 0.000610 36
*The subpopulation(s) with the highest risk estimates



### 6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no registered non

- occupational uses for flufenacet ; therefore

, a residential handler and residential post

- application exposure and risk assessment is not required ; however, exposures from spray drift were assessed to account for flufenacet agricultural applications drifting onto

residential areas.

6. 1 Residential Bystander Post

- application Inhalation Exposure

Volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fu ngicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has develope d 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

st udies, route

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

flufenacet.

6. 2 Spray Drift

Off

- target movement of pesticides can occur via many types of pathways and it is governed by a variety of factors. Sprays that are re leased and do not deposit in the application area end up off

target and can lead to exposures to those it may directly contact. They can also deposit on surfaces where contact with residues can eventually lead to exposures ( e.g. , children playing on

### Page 27 of 57

lawns where residues have deposited next to treated fields). The potential risk estimates from these residues can be calculated using drift modeling coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment is based on a premise of compliant applications which, by definition, should not result in direct exposures to individuals because of existing label language and other regulatory requirements in tended to prevent them. 5 

### Direct exposures would include inhalation of the spray plume or being sprayed directly. Rather, the exposures addressed here are thought to occur indirectly through contact with impacted areas, such as residential lawns, when com pliant applications are conducted. Given this premise, exposures for children (1 to < 2 years old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus resulting in an indirect exposure are the focus of t his analysis analogous to how exposures to turf products are

considered in risk assessment.

In order to evaluate the drift potential and associated risks, an approach based on drift modeling coupled with techniques used to evaluate residential uses of p esticides was utilized. Essentially, a residential turf assessment based on exposure to deposited residues has been completed to address drift from the agricultural applications of flufenacet

. In the spray drift scenario, the deposited residue value was determined based on the amount of spray drift that may occur at varying distances from the edge of the treated field using the AgDrift ( v2.1.1) model and the Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Dr ift Policy

. Once the deposited residue values were determined, the remainder of the spray drift assessment was based on the algorithms and input values specified in the recently revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

.

A screening approach was developed based on the use of the AgDrift model in situations where specific label guidance that defines application parameters is not available. 6 

### AgDrift is appropriate for use only when applications are made by aircraf t, airblast orchard sprayers, and groundboom sprayers. When AgDrift was developed, a series of screening values (i.e., the Tier 1 option) were incorporated into the model and represent each equipment type and use under varied conditions. The screening op tions specifically recommended in this methodology were selected because they are plausible and represent a reasonable upper bound level of drift for common application methods in agriculture. These screening options are consistent with how spray drift is considered in a number of ecological risk assessments and in the process used to develop drinking water concentrations used for risk assessment. In all cases, each scenario is to be evaluated unless it is not plausible based on the anticipated use patter n (e.g., herbicides are not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are not allowed).

In many cases, risks are of concern when the screening level estimates for spray drift are used as

the basis for the analysis. In order to account for this issue and to provide additional risk management options additional spray drift deposition fractions were also considered. These drift estimates represent plausible options for pesticide labels

5 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.

6 http://www.epa.gov/pesticides/science/models_pg.htm

### Page 28 of 57

6.2.1 Risk Estimates From Lawn Deposition Adjacent to Agricultural Applications

Flufenacet is used on numerous agricultural crops and can only be applied via groundboom equipment. The spray drift risk estimates are based on an estimated deposited residue

concentrat ion as a result of the screening level agricultural application scenarios. The recommended drift scenario screening level options are listed below:

 Groundboom applications are based on the AgDrift option for high boom height and using very fine to fine spray type using the 90 th 

### percentile results.

The highest exposure resulted from drift following flufenacet applications to corn using groundboom equipment . T here were dermal risk estimates of concern at the field edge for adults following application t o corn, and dermal and incidental oral combined risk estimates of concern

for children 1 to <2 years old following application to corn, soybeans, and grasses grown for

seed

. However, if a low boom or medium/ coarse sprays are used or the distance from the field edge is increased , these MOEs are not of concern

. See Table s 6.2

. 1 and 6.2.2 for detailed results.

Table 6.2.1 . Adult Dermal Risk Estimates (MOEs) Related to Spray Drift Exposure to Flufenacet from the Registered Agricultural Uses. Application

T ype Spray Type/Nozzle

Configuration Appl. Rate

(lb ai/A) TTR ( μg/cm 2 ) 2 At Edge (LOC = 1000) 10 Feet (LOC =

1000)

Corn

Groundboom High Boom Very

fine to Fine

0.78 0.086697 670 1,300

Low Boom Very

fine to Fine 1,500

N/A High Boom Fine to

Medium/Coarse 2,600

Low Boom Fine to

Medium/Coarse 3,800

Soybeans

Groundboom High Boom Very

fine to Fine

0.46 0.051129 1,100

N/A Low Boom Very

fine to Fine 2,500

High Boom Fine to

Medium/Coarse 4,300

Low Boom Fine to

Medium/Coarse 6,400

Grass Grown for Seed

Groundboom High Boom Very

fine to Fine

0.44 0.048906 1,200

N/A Low Boom Very

fine to Fine 2,600

High Boom Fine to

Medium/Coarse 4,500

Low Boom Fine to

Medium/Coarse 6,700

Wheat/Triticale

Groundboom High Boom Very

fine to Fine 0.34 0.037791 1,500 N/A

### Page 29 of 57

Table 6.2.1 . Adult Dermal Risk Estimates (MOEs) Related to Spray Drift Exposure to Flufenacet from the Registered Agricultural Uses. Application

T ype Spray Type/Nozzle

Configuration Appl. Rate

(lb ai/A) TTR ( μg/cm 2 ) 2 At Edge (LOC = 1000) 10 Feet (LOC =

1000) Low Boom Very

fine to Fine 3,400

High Boom Fine to

Medium/Coarse 5,900

Low Boom Fine to

Medium/Coarse 8,700

1 HED’s default assumption that 10 % of the application is available for transfer on day 0 following the application and the residues dissipate at a rate of 10% each following day.

Table 6.2.2

. Children 1 to < 2 Years Old Combined Dermal and Hand

- to

- Mouth Risk Estimates (MOEs) Related to Spray Drift Exposure to Flufenacet from the Registered Agricultural Uses.

Application Type Spray

Type/Nozzle Configuration Appl.

Rate (lb ai/A) TTR ( μg/cm 2 ) 1 At Edge (LOC = 1000) 10 Feet

(LOC = 1000) 25 Feet

(LOC = 1000) 50 Feet

(LOC = 1000)

Corn

Groundboom High Boom Very

fine to Fine

0.78 0.086697 260 520 870 1,400

Low Boom Very

fine to Fine 570 1,500

N/A N/A High Boom Fine

to
Medium/Coarse 990 2,600

Low Boom Fine

to
Medium/Coarse 1,500 N/A

Soybeans

Groundboom High Boom Very

fine to Fine

0.46 0.051129 440 880 1,500

N/A Low Boom Very

fine to Fine 970 2,600

N/A High Boom Fine

to
Medium/Coarse 1,700

N/A Low Boom Fine

to
Medium/Coarse 2,500

Grass Grown for Seed

Groundboom High Boom Very

fine to Fine

0.44 0.048906 460 920 1,500

N/A Low Boom Very

fine to Fine 1,000

N/A N/A High Boom Fine

to
Medium/Coarse 1,800

Low Boom Fine

to
Medium/Coarse 2,600

Wheat/Triticale

Groundboom High Boom Very

fine to Fine 0.34 0.037791 600 1,200 N/A N/A

### Page 30 of 57

Table 6.2.2

. Children 1 to < 2 Years Old Combined Dermal and Hand

- to

- Mouth Risk Estimates (MOEs) Related to Spray Drift Exposure to Flufenacet from the Registered Agricultural Uses.

Application Type Spray

Type/Nozzle Configuration Appl.

Rate (lb ai/A) TTR ( μg/cm 2 ) 1 At Edge (LOC = 1000) 10 Feet

(LOC = 1000) 25 Feet

(LOC = 1000) 50 Feet

(LOC = 1000)

Low Boom Very

fine to Fine 1,300

N/A High Boom Fine

to
Medium/Coarse 2,300

Low Boom Fine

to
Medium/Coarse 3,400

1 HED’s default assumption that 10 % of the application is available for transfer on day 0 following the application and the residues dissipate at a rate of 10% each following day.



### 7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposur es and risks from various sources, HED considers both the route and duration of exposure.

The acute aggregate risk assessment includes food and water exposure only. The acute food plus drinking water risk estimates are not of concern to HED for the gener al population and all population subgroups. Refer to section 5.4.3 fo r a detailed discussion of the acute dietary risk

assessment.

Since there are no residential uses for flufenacet that would result in contributions to the
aggregate assessment , short

- a nd intermediate

- term aggregate risk assessments are not required. Residential exposures resulting from spray drift are not included in the aggregate assessment

because the likelihood of co

- occurrence with dietary (food + drinking water) exposures is very low and that the inputs for the spray drift assessment are considered highly conservative. Additionally, the chronic aggregate risk assessment would only include food and drinking water exposures; however the acute dietary (food and drinking water) exposur e assessment is protective of chronic dietary exposures since the POD is the same for both durations.

Since flufenacet has been classified as not likely to be carcinogenic, quantification of aggregate cancer risk is not required.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as

to flufenacet and any other sub stances and flufenacet does not appear to produce a toxic metabolite produced by other substances. For the purposes of Registration Review , EPA has not

### Page 31 of 57

assumed that flufenacet has a common mechanism of toxicity with other substances. For information rega rding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinatio ns and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

An occupational exposure and risk assessment was complete d to include all registered uses of

flufenacet (K. Rury, D427119, 06/03/2015)

.

9.1 Short

- and Intermediate

- Term Handler Risk

HED uses the term “ handlers ” to describe those individuals who are involved in the pesticide application process. HED has determ ined that there are potential exposures to handlers during application of f

lufenacet . Scenarios assessed include mixing/loading wettable powders and

soluble concentrate formulations for ground equipment application, including tractor

- drawn spreaders for im pregnated dry bulk fertilizers. Use of aerial and chemigation application equipment is prohibited.

No chemical

- specific data for assessing human exposures during pesticide handling activities were submitted to the Agency for flufenacet. It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the

absence of chemical

- specific data, include the Pesticide Handlers Exposure Database ( PHED ) 1.1, the Agricultural Handlers Exposure Task Force ( AHETF ) database, or other registrant

submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA.

Occupational handle rs must wear the following PPE when handling flufenacet: long sleeved shirt, long pants, chemical resistant gloves, shoes and socks. In addition to the PPE listed above, a respirator and coveralls are required when mixing/loading EPA Reg. No. 264

- 765. Ch emical resistant aprons are also required when mixing/loading and cleaning equipment for EPA Reg.

Nos. 264

- 800 and 264

- 852 (co

- formulations with isoxaflutole), which are two products classified as RUPs. The occupational handler assessment was completed as suming the labeled maximum single application rate for each crop or use site. Based on the currently registered uses of flufenacet, the durations of exposure are expected to be both short

- term (1 to 30 days) and

intermediate

- term (1 to 6 months) for occup ational handlers. Long

- term exposures (greater than 6 months) are not anticipated based on the curr ently registered use pattern.

There are some occupational handler risk estimates of concern for the registered uses of flufenacet at baseline, PPE, and engineering control mitigation. The level of concern (LOC) for occupational handler dermal risk estimates is a MOE of 1,000. The LOC for occupational handler inhalation risk estimates is a MOE of 300. At baseline, occupational dermal MOEs ranged from 40 to 4,000; and occupational inhalation MOEs ranged from 22 to 1, 4 00.

### Page 32 of 57

The following scenarios are not of concern at baseline PPE :

 Applying sprays via groundboom equipment to sod; and

 Applying flufenacet in on

- farm impregnated dry bulk fertilizers to so ybeans

.

The following scenario requires gloves to be not of concern :

 Mixing/loading liquid flufenacet to produce impregnated dry bulk fertilizers on

- farm to treat soybeans.

The following scenarios require the use of a PF5 respirator to be not of concer n :

 Mixing/loading dry flowable flufenacet for groundboom application to sod; and

 Applying flufenacet sprays via groundboom equipment to corn.

The following scenario requires gloves and double layer clothing to be not of concern :

 Mixing/loading dry flowa ble flufenacet for groundboom application to wheat.

The following scenario requires gloves, double layer clothing, and a PF10 respirator to be not of

concern :

 Mixing/loading liquid flufenacet for groundboom application to soybeans.

The following scenarios require the use of engineering controls to be not of concern :

 Mixing/loading dry flowable flufenacet to produce impregnated dry bulk fertilizers on

farm to treat corn and soybeans;

 Mixing/loading dry flowable flufenacet for groundboom application to corn and soybeans;

 Mixing/loading liquid flufenacet to produce impregnated dry bulk fertilizers on

- farm to treat corn; and

 Mixing/loading liquid flufenacet for groundboom application to corn.

The following scenarios are of concern at all levels of PPE and engineering controls :

 Mixing/loading dry flowable flufenacet to produce impregnated dry bulk fertilizers

commercial ly to treat corn and soybeans; and

 Mixing/loading liquid flufenacet to produce impregnated dry bulk fertilizers

commercial ly to treat corn and soybeans.

The use of gloves when handling flufenacet is already required on the flufenacet labels. In addition to gloves, a respirator and coveralls are already required when mixi ng/loading EPA Reg. No. 264

- 765. Chemical resistant aprons are also required when mixing/loading and cleaning equipment for EPA Reg. Nos. 264

- 800 and 264

- 852. Therefore, HED recommends that

P RD require the appropriate PPE and EC on all relevant labels so that the scenarios above are not of concern.

A summary of the occupational handler scenarios and the PPE required to be not of concern for each scenario is provided in Table 9.1 . Detailed scenarios and exposure estimates are provided in Appendix D.

### Page 33 of 57

Table 9. 1. Summary of PPE or Engineering Controls Required (if any) for MOEs to be Not of Concern for Occupational

Handler s of Flufenacet

.

Exposure Scenario and Formulation Crop or Target PPE Required to be not of concern (Dermal LOC = 1000) (Inhalation LOC = 300)

Mixer/Loader

Mixing/Loading Dry Flowables for Commercial Treatment To

Produce Impregnated Fertilizers Corn

X 1 Soybeans

Mixing/Loading Dry Flowables for On

- Farm Treatment To

Produce Impregnated Fertilizers Corn Engineering Controls Soybeans

Mixing/Loading Dry Flowables for Groundboom Application Sod Gloves + PF5 Respirator

Corn Engineering Controls Soybeans Engineering Controls

Wheat Double Layer Clothing + Gloves +

PF10

Mixing/Loading Liquids for Commercial Treatment To Produce

Impregnated Fertilizers Corn

X 1 Soybeans

Mixing/Loading Liquids for On

- Farm Treatment To Produce

Impregnated Fertilizers Corn Engineering Controls

Soybeans Gloves

Mixing/Loading Liquids for Groundboom Application Corn EC Soybeans Applicator

Applying Sprays via Groundboom Equipment Sod None (Baseline)

Corn Gloves + PF5 Respirator Soybeans Gloves

Wheat Gloves Applying Impregnated Dry Bulk Fertilizer

- Commercial

Treatment Corn PF5 Respirator Soybeans

Applying Impregnated Dry Bulk Fertilizer

- On

- Farm Treatment Corn Soybeans None (Baseline)

1 Scenarios of concern with maximum PPE and engineering controls. PRD should evaluate other options that would allow the risks to be not of concern with the Registrant (e.g., reduced application rates, etc.).



### 9.2 Short

- /Intermediate

- Term Post

- Application Risk

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applica tions, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

9.2.1 Dermal Post

- application Risk

HED uses the term post

- application to describe exposures that occur when individuals are present in an environment t hat has been previously treated with a pesticide (also referred to as re

entry exposure). HED has determined that there are potential exposures to persons entering treated sites (e.g., harvesters) after application of flufenacet is complete. D ermal expos ures

### Page 34 of 57

during post

- application activities were estimated using (1) dermal transfer coefficients from the Science Advisory Council for Exposure Standard Operating Procedure (SOP) Number 3: Agricultural Transfer Coefficients, March 2013 ; (2) the standard assum ption that 25 percent of the application rate is initially available to dislodge from foliar surfaces ; and (3) the standard assumption that residues dissipate at a rate of 10 percent per day. The LOC for occupational
post

- application risk is a MOE of 1,000. All occupational short

- and intermediate

- term risk estimates resulted in dermal MOEs of concern on day 0. The dermal post

- application MOEs for flufenacet range from 88 to 800 on the day of application. The days to reach an MOE of 1,000 for each activity are listed in Table 9.2.1

. Therefore, HED recommends that P RD require the appropriate REIs on all relevant labels to address these concerns

.

Table 9.2.1

. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Flufenacet

.

Crop/Site Activities Transfer Coefficient (cm 2 /hr) DFR/TTR 1 Dermal Dose (mg/kg/day) 2 MOE 3 Days for MOE to
Reach LOC of 1,000

Corn Scouting 210 2.19 0.0021 800 3

Hand

- Set Irrigation 1,900 0.019 88 23

Grasses
Grown for

Seed* Hand

- Set Irrigation 1,900 1.23 0.011 160 18

Scouting 1,100 1.23 0.0063 270 13

Soybean Scouting 1,100 1.29 0.0066 260 13

Wheat Scouting 1,100 0.95 0.0049 350 10

1 DFR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; wher e F = 0.25 and D = 0.10 per day (used for corn, soybeans,

wheat); TTR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.1 and D = 0.10 per day (used for sod).

2 Daily Dermal Dose = [DFR /TTR (μg/cm 2 ) × Tr ansfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption ( 4.0 %)]  BW ( 69 kg).

3 MOE = POD ( 1.7 mg/kg/day) / Daily Dermal Dose.

* The post

- application exposure inputs for “forage crops” was used as a surrogate.



### Dislodgeable Foliar Residue (DFR) Data: Since the highest estimated occupational post

application exposure using default DFR values for flufenacet is minimal in comparison to the level of concern (i.e., the calculated MOE is not greater than 2 times higher than the level of

concern, MOE = 2,000 compared to the LOC of 1,000 ); EPA is requiring the 40 CFR DFR data requirement to facilitate any necessary exposure assessments refinements and to further EPA’s general understanding of the availability of dislodgeable foliar pesticide residu es. EPA is requesting that DFR studies be submitted on corn or soybeans in separate geographic locations. Additionally, a protocol should be submitted prior to starting these studies. 7



### Restricted Entry Interval The REI specified on the proposed label is based on the acute toxicity of flufenacet , which is classified as Toxicity Category III via the dermal route and Toxicity Category IV for skin irritation potential. It is not a skin sensitizer. Short

- and intermediate

- term post

- application risk

estima tes were not a concern on day 0 (12 hours following application) for activities related to sod production. However, there were risk estimates of concern related to scouting and hand

- set irrigation in corn, and scouting for soybeans and wheat. Therefore, HED recommends that P RD require the appropriate REIs on all relevant labels to address these concerns

.

7 http://www.ecfr.gov/cgi

- bin/text

idx?SID=a5983c2e243fca24493fbe7a02254834&mc=true&node=se40.24.158_11070&rgn=div8

### Page 35 of 57

9.2.2 Inhalation Post

- application Risk

There are multiple potential sources of post

- application inhalation exposure to individuals performing post

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

- HQ

OPP

- 2014

- 0219 ). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies) or further analysis is required for flufenacet

.

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

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

- application inhalation expo sure into the agency's risk assessments.

10.0 Public Health and Pesticide Epidemiology Data

B oth the OPP Incident Data System (IDS) and the Centers for Disease Control and Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Senti nel Event Notification System for Occupational Risk

- Pesticides (SENSOR) databases were consulted for pesticide incident data on the active ingredient flufenacet

. In addition, findings from the Agricultural Health Study (AHS) were reviewed. Flufenacet is not included in the AHS, and therefore this study does not provide information for this report. No incidents were identified for

flufenacet the IDS. A query of SENSOR

- Pesticides from 1998

- 2011 identifies five cases involving flufenacet. These incidents involve multiple active ingredients and are classified as low severity. There does not appear to be a concern at this time that would warrant further investigation. The Agency will continue to monitor the incident information and if a concern is triggere d, additional analysis will be conducted.

11.0 References

S. Healy; January 21, 2011; D382463. Flufenacet: Human Health Assessment Scoping Document in Support of Registration Review.

C. Lechelt

- Kunze, R. C . Meissner, M. Drewes, K. Tietjen (2003) Flufen acet herbicide treatment phenocopies the fiddlehead mutant in Arabidopsis thaliana

. Pest Manag

. Sci

. 59:847

– 856

J. Leshin; June 10, 2014; TXR#0056951. Flufenacet

- Report of the Hazard and Science Policy Council (HASPOC) Meeting of April 24, 2014: Waiver for the Immunotoxicity Study.

### Page 36 of 57

Gabe Rothman ; February 16, 2015 ; D423236 . Tier 1 Drinking Water Assessment for the flufenacet and its thiadone degradate for Registration Review of exi sting uses on corn for silage, sweet corn, field corn, Douglas Fir, Frasier Fir, Grand Fir, Noble Fir, grass seed, soybeans, triticale, and wheat.

S. Recore ; April 29, 2015 ; D42701 3. Flufenacet: Tier 1 Update of Human Incidents/Epidemiology for Draft Risk Assessment.

K. Rury. June 3

, 2015, D427119

, FLUFENACET. Occupational and Residential Exposure Assessment for Registration Review

.

C. Walls. May 01, 2015; D427118. Flufena cet: Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments for the Registration Review Preliminary

Risk Assessment.

### Page 37 of 57

A ppendix A

. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158. 500 ) for food uses for flufenacet are i n Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

................................ ....................... 870.1200 Acute Dermal Toxicity

................................ .................. 870.1300 Acute Inhalation Toxicity

................................ .............. 870.2400 Primary Eye Irritation

................................ .................... 870.2500 Primary Dermal Irritation

................................ .............. 870.2600 Dermal Sensitization

................................ ..................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

................................ ............... 870.3150 Oral Subchronic (nonrodent)

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 28

- Day Inhalation

................................ .......................... yes

yes

no

no

no yes

yes

yes

- yes

870.3700a Developmental Toxicity (rodent)

................................ .. 870.3700b Developmental Toxicity (nonrodent)

............................ 870.3800 Reproduction

................................ ................................ . yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

................................ .............. 870.4100b Chronic Toxicity (nonrodent)

................................ ........ 870.4200a Oncogenicity (rat)

................................ .......................... 870.4200b Oncogenicity (mouse)

................................ ................... 870.4300 Chronic/Oncogenicity

................................ ................... yes

yes

yes

yes

no yes 1

yes

yes 1

yes

yes 870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

... 870.5550/395 Mutagenicity

— Other Genotoxic Effects

................ yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotoxicity (hen)

............................... 870.6100b 90

- Day Neurotoxicity (hen)

................................ .......... 870.6200a Acute Neurotoxicity Screening Battery (rat)

................. 870.6200b 90

- Day Neurotoxicity Screening Battery (rat)

.............. 870.6300 Develop. Neurotoxicity

................................ ................. no

no

yes

yes

yes -

- yes

yes

yes

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

no

yes yes

- waived 2

1 = A chronic/onco genicity study is available for the rat, thus separate chronic and oncogenicity are not necessary.

2 = Based on a weight of evidence approach a n immuno toxicity study is not required for the current uses (TXR

0056951 ).

### Page 38 of 57

A.2 Toxicity Profile s

Table A.2.1 Acute Toxicity Profile

- Flufenacet

.

Guideline

No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral rat 43441104 LD 50 = 1617 mg/kg (M) 589 mg/kg (F) III

870.1100 Acute oral rat

– thiadone (metabolite)

Note: Study is unacceptable because

an LD50 was not determined. 43850009 All animals died 10 min after dose of 600 mg/kg

females males or 1650 mg/kg males NA

870.1200 Acute dermal rat 43441106 LD 50 ≥ 2000 mg/kg III

870.1300 Acute inhalation rat 43441108 LC 50 > 3.74 mg/L IV

870.2400 Acute eye irritation rabbit 43850017 slight eye irritant IV

870.2500 Acute dermal irritation r abbit 43850023 not a dermal irritant IV

870.2600 Skin sensitization guinea pigs

–

Buehler method 438500 2 5 not a dermal sensitizer N/A

870.2600 Skin sensitization guinea pigs

–

Maximization method 43877601 dermal sensitizer N/A



### Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Flufenacet

.

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3100 90

- Day oral

toxicity (rat) 43743401 ( 1995 )

Acceptable/guideline

0 , 100, 400, 1600, 3000 ppm

M: 0, 6

, 24 , 109, 191 mg/kg/d

F: 0, 7

, 29 , 127 , 225 mg/kg/d NOAEL could not be determined.
LOAEL = 6mg/kg/d based on s uppression of

T4 and T3 in male s ; female s had similar effects at next higher dose

. M ale hemoglobin was decreased and female cholesterol was decreased

at 6/7 mg/kg/day (M/F)

.

870.3100 90

- Day oral

toxicity (mouse) 43738 1 01 ( 1995 )

Acceptable/guideline

0, 100, 400, 1600, 4000 ppm

M: 0

, 18, 64, 275, 824 mg/kg/d F: 0, 25, 91, 432, 1134 mg/kg/d NOAEL = 18 mg/kg/day

LOAEL = 64 mg/kg/day based on suppression

of T4 in both sexes

. At the next highest dose, increased incidence of clinical signs and hepatocytomegaly were observed in both sexes.

870.3150 90

- Day oral

toxicity (dog) 43619401 ( 1990 )

Acceptable/guideline

0, 50, 200, 800, 2400 ppm
M: 0, 1.67, 7.2, 27, 97 mg/kg/d F: 0, 1.70, 6.9, 28, 93 mg/kg/d NOAEL could not be determined.
LOAEL = 1.67 mg/kg/d based on suppression

of T4 and T3 in males; females had simi lar effects at next higher dose

. F emale serum lactate dehydrogenase (LDH) levels were also

increased at 1.70 mg/kg/day

.

### Page 39 of 57

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Flufenacet

.

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.3200 21/28

- Day

dermal toxicity (rat) 43850027 ( 1995 )

Acceptable/guideline

0, 20, 150, 1000 mg/kg/d Dermal irritation NOAEL ≥ 1000 mg/kg/d

LOAEL was not observed

. Systemic NOAEL = 20 mg/kg/day
LOAEL = 150 mg/kg/d based on suppression of

T4 and free T4 in males; females had similar

effects at the 1000 mg/kg/day

.

870.3465 28

- Day

inhalation toxicity (rat) 47473101 (2008)

Acceptable/guideline

0, 0.02, 0.22, or 0.41 mg/L
(Equivalent to 0, 0.14, 0.29, or 0.50 mg/kg/day) NOAEL could not be established
LOAEL = 0.02 mg/L based on increased incidence nasal cavity goblet cell hyperplasia and sperm

- related lesions of testis/epididymis in males, and larynx inflammatory infiltrate in females; additional nasal and laryngeal lesions including laryngeal epithelial metaplasia, and changes and in hematology, spleen, liver and retinal lesions at the next highest dose.

S uppression of T4 and T3 in both sexes at the high est dose.

870.3700a Prenatal

developmental

in rat 43850030 ( 1993 )

Acceptable/guideline

0 , 5, 25, 125 mg/kg/d Maternal NOAEL = 125 mg/kg/day.

LOAEL was not observed.

Developmental NOAEL = 25 mg/kg/day
LOAEL = 125 mg/kg/day based on decreased fetal body weight and delays in ossification in the skull, vertebrae and sternebrae.

870.3700b Prenatal

developmental

in rabbit 43850029 ( 1995 )

438500 31 ( 1991 )
Acceptable/guideline

0 , 5, 25, 125 mg/kg/d Materna l NOAEL = 25 mg/kg/day
LOAEL = 125 mg/kg/day based increased incidence of hepatocyte vacuolation

. Developmenta l NOAEL = 25 mg/kg/day
LOAEL = 125 mg/kg/day based on incidence of supernumerary ribs and additional presacral

vertebrae ; d elayed ossification of the skull and enlarged fontanelles at next highest dose

.

870.3800 Reproduction

and fertility

effects

(rat) 4385003 3, 4385003 2 ( 1995 )

Acceptable/guideline

0, 0, 20, 100, 500 ppm
M: 0, 1.4, 7.4, 38 mg/kg/d F: 0, 1.5, 8.2, 41 mg/kg/d Parental NOAEL = 8.2 mg/kg/day
LOAEL = 41 mg/kg/day (M/F) based on

increased incidence of liver congestion in P

females and liver necrosis in F1 females

. No
adverse effects were noted in males.
Reproductive NOAEL ≥ 38/41 mg/kg/day

LOAEL was not observed.
Offspring NOAEL ≥ 38/41 mg/kg/day

LOAEL was not observed

.

### Page 40 of 57

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Flufenacet

.

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.4100b Chronic toxicity

(dog) 43850028 ( 1995 )

Acceptable/guideline

0, 40, 800, 1600 ppm
M: 0, 1.3, 28, 62 mg/kg/d F: 0, 1.1, 27, 59 mg/kg/d NOAEL = 1.1 mg/kg/day
LOAEL = 27 mg/kg/day based on increased incidence and severity of ocular effects (optic nerve vacuolation, ciliary body epithelial vacuolation, eye/retina cysts) ; a t next higher

dose : suppression of T4 and T3

, adverse and/or adaptive effects in the liver, kidney, heart and
nervous system

.

870.4200 Carcinogenicity

(mouse) 43820701 ( 1995 )

Acceptable/guideline

0, 50, 200, 400 ppm
M: 0, 7.4, 30, 62 mg/kg/d F: 0, 9.4, 38, 77 mg/kg/d NOAEL was not observed

. LOAEL = 7.4 mg/kg/day based on increased

incidence of microscopic cataracts in males; at next highest dose, increased incidence of microscopic cataracts in females, and gross cataracts and increase methemoglobin levels in

both sexes

. No evidence of carcinogenicity

870.4300 Combined

chronic /carcinogenicity (rat) 43823501 (1995 )

Acceptable/guideline

0, 25, 400, 800 ppm
M: 0, 1.2, 19, 39 mg/kg/d F: 0, 1.5, 24, 50 mg/kg/d NOAEL = 1.2mg/kg/day

LOAEL = 19 mg/kg/day based on methemoglobinemia ( increased level of methemoglobin) and increased incidence and/or severity of microscopic lesions in the kidney, eye, liver, spleen, heart, lung, skull, and ut erus; thyroid weights increased at the next highest

dose.

No evidence of carcinogenicity

870.5100 Bacterial

Reverse

Mutation Test 43850035

Acceptable/guideline

16

- 5000 μg/plate Negative in Salmonella typhimurium strains TA1535, TA1537, TA98 or TA100

, with or

without metabolic activation.

870.5550 Unscheduled

DNA synthesis

in vitro 4385003 8

Acceptable/guideline

0, 2.5, 5.o, 10, 20 or 40 μg/mL Negative in rat (Sprague

- Dawley) hepatocytes

.

870.5300 In vitro

mammalian gene mutation 43850036

Acceptable/guideline

7.8

- 500 μg/mL Negative in Chinese hamster lung fibroblasts (V79) cells , with or without metabolic

activation.

870.5375 In vitro

mammalian

chromosomal analysis 4 3850037

Acceptable/guideline

0, 8, 40 or 200 μg/mL Negative in Chinese hamster ovary (CHO)

cells , with or without metabolic activation.

870.5395 Mammalian

Erythrocyte

Micronucleus

Test 43850034

Acceptable/guideline

0 or 250 mg/kg Negative male and female NMRI mice

.

### Page 41 of 57

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Flufenacet

.

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.6200a Acute

neurotoxicity screening battery 43735301 ( 1995 )

Acceptable/guideline

M: 0, 75, 200, or 450 mg/kg F: 0, 75, 150, or 300 mg/kg Systemic NOAEL = 75 mg/kg/day.
LOAEL = 150 mg/kg/day based on clinical signs (ataxia, decreased activity) in females; increased mortality and clinical signs were observed i n both sexes at the next higher dose

. Neurotoxicity NOAEL ≥ 450/300 mg/kg

LOAEL was not observed

870.6200b Subchronic

neurotoxicity screening battery 43819801

, 43850049 ( 1995 )

Acceptable/guideline

0, 120, 600, or 3000 ppm
M: 0, 7.3, 38, or 219 mg/kg/d F: 0, 8.4 , 43 , or 247 mg/kg/d Systemic NOAEL = 38 mg/kg/day.

LOAEL = 219 mg/kg/day based on decreased body weights.
Neurotoxicity NOAEL = 38mg/kg/day
LOAEL = 219 mg/kg/day based on increased lesion severity/ frequency of axonal swelling in cerebellum/medulla and spinal cord, decreased

fore limb strength, increased foot splay and increase motor activity.

870.6300 Developmental

neurotoxicity 45232501 ( 2000 )

Acceptable/guideline

0, 20, 100, 500 ppm

Gestation: 0, 1.7, 8.3, 40.8 mg/kg/d

Lactation : 0, 3.0, 15.4, 76.7 mg/kg/d Maternal NOAEL = 40.8 mg/kg/day

LOAEL could not be determined (no adverse effects observed).
Offspring NOAEL could not be determined (decreased weight at all doses AND caudate putamen was not measured at the lowest dose).
LOAEL = 1.7 mg/kg/day based on decreased

pre

- weaning body weight in both sexes and decreased caudate putamen measurements in adult females (which was observed at the next highest dose but not measured at 1.7 mg/kg/day); delayed eye opening, delayed preputial separation, and decreased motor activity for PND 14 females were observed at the next higher dose.

### Page 42 of 57

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Flufenacet

.

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

870.7485 Metabolism and

pharmacokine

tics

(rat) 43850039 ( 1992 )

Acceptable/guideline

S ingle dose: 1 and 150 mg/kg

M ultiple dose: 1 mg/kg/day for 14 days Rapidly absorbed and metabolized following

oral exposure to either single or multiple doses.

The urine was the major route of excretion with

small amount excreted vi a feces. Significant

amounts of radiolabel were eliminated as CO2

and CH4. A maximum of 7% of the total

recovered radiolabel was found in the tissues

and residual carcass. Major metabolites included glutathione

- derived fluorophenyl residues ( N

- acetylcy stei ne fluorophenyl

acetanilide in females

, des

- isopropyl fluorophenylacetanalide methylsulfone and fluorophenylacetanalide sulfoxide in males), thiadone (5

- trifluoromethylthiadiazol

- 2

- one) and its oxalyacetic and glucuronic acid conjugates, and a very polar ( unidentified) compound

. Special study Mechanistic

study (feed)

– iodine uptake and comparative responses (rat) 43850041 (1995)

Acceptable/non

- guideline

0, 25, 400 , 1000, 1600 or 3000

ppm
0, 1.6, 22, 71, 84, or 145 mg/kg/day

3 , 6, 13, or 17 weeks duration Based on the similarity of the changes in circulating thyroid hormone levels in intact and thyroidectomized+T4/T3 rats and the lack of functional changes in the thyroid (measured as capacity to take up 125 I), an extra

- thyroidal site

of action i s suggested. Increased liver weights and hypertrophy were observed at all dosing

interval and dose levels.

Special study Mechanistic

study (feed)

– T4 clearance

and liver effects (rat) 43850042 (1995)

Acceptable/non

- guideline

0, 25, 1000 or 3000 ppm

0, 1.7, 70.5 or 224 mg/kg/d

3 weeks duration Treated rats had decreased circulating total and

free T4 levels, increase 125 I

- T4 clearance from

blood

, increased hepatocellular binding and biliary excretion of 125 I

- T4 , compared to the controls; T3 and TSH concentrations were comparable to the control values. Thyroid and pituitary function ( measured I discharge from thyroid and pituitary TSH secretion in response to exogenous challenge ) was unaffected by

treatment. H epatic UDP

- GT was induced whil e 5'DI was decreased

, in a dose

- related manner

. Special study Mechanistic

study (subcutaneous pump)

– N eurotoxicity of metabolite (dog) 43695301

Acceptable/non

- guideline

0 or 14 mg thiadone /kg/d Both dogs ( 1/sex/group ) treated with the

flufenacet metabolite thiadone had responses

similar to those seen in chronic and subchronic dog studies (c orneal opacity

, slight precipitate in both eye s, hematology, clinical chemistry, clinical signs, electroencephalography

, electrocardiogram). N eurotoxicity signs

included wide stance, hyperactivity, postural

abnormalities

, proprioceptive placing deficits, head tilt, hypermetria, and stumbling gait. B rain

stem and cerebellar levels of glutathione

reductase , and ventricular levels of glutathione peroxidase were decreased.

### Page 43 of 57

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile

- Flufenacet

.

Guideline

No. Study Type MRID No. (year)/
Classification /Doses Results

Special study Comparative

thyroid assay battery 48898902

, 48898903

,

48898904
Acceptable/non

- guideline

0, 1.3, 6.8 or 34.8 mg/kg/day Maternal NOAEL = 1.3 mg/kg/day

LOAEL = 6.6 mg/kg/day, based on dose

dependent decreases in mean T4 and T3 levels on lactating dams (LD 21)
Offspring NOAEL = 1.3 mg/kg/day

LOAEL = 6.8 mg/kg/day, based on a dose

dependent decreases in mean fetal TSH . Fetal

T4 levels could not be measured due to technological limitations.



### A.2.1 Update d executive summary for MRID

In a 2

- generation reproduction stud y ( MRID # 43850033 ), FOE 5043 technical (95.2

- 99.0% a.i.)

was administered starting 10/12 weeks (P/F1 generation) before mating to 30 Sprague

- Dawley

rats/sex/dose via the diet at nominal dos e levels of 0, 20, 1 00, and 500 ppm (equivalent to p re

mating doses of 0, 1.4, 7.4, or 37.5 for the P generation; and 0, 1.5, 8

. 2, or 41.5 mg/kg/day for

the F1 generation)

. There was one litter per generation. The dose levels during gestation were: P gen eration: 0, 1.3, 7.0, and 36.1

, F1 generation: 0, 1.2, 6.8, and 36.2 mg/kg/day; during

lactation: P generation: 0, 2.4, 13.3, and 70.7, F1 generation: 0, 2.4, 13.3, and 66.6 mg/kg/day.

There was a slight decrease in body weight ( 93

- 94% of control ) in the P generation fema les during the pre

- mating phase and during gestation

. T here was no effect on survival, food consumption, or clinical signs except cannibalism (see below) , at any dose level. Liver w eight was increased in the high dose females in both ge nerations an d in the F1 females at the mid dose

. P generation dams had decreased ovarian weight. Statistically increased incidence of

h epatocytomegaly was obs erved at the high dose in males of both generations and in F1 females,

and at the mid dose in F1 males

. Increased incidence of liver congestion was observed in P generation females. Increased incidence of liver necrosis was observed in high dose F1 females.

Other necropsy findings were comparable among the groups in both generations

The parental sy stemic LOAEL is 41.2 mg/kg bw/day, based on increased incidence of liver congestion in P females and liver necrosis in F1 females

. No adverse effects were noted in

males. The parental systemic NOAEL is 8.2 mg/kg bw/day.

The number of estrous cycles and their length were comparable among the groups in both generations, and insemination and gestation lengths were comparable among the groups in both generations. There were no treatment

- related effects on the mating index, fertility index, or gestation inde x in either generation, and the birth index was comparable among the groups in both generations, although it is to be noted that the percentage of dams displaying a birth index of ≤ 80% was increased at the high

- dose level in both generations. No data on sp erm parameters

or s exual maturation (F1) were provided.

### Page 44 of 57

The reproductive LOAEL was not observed . The reproductive NOAEL is equal or larger

than 41.2 mg/kg bw/day

.

The number of cannibalized pups from P dams was increased at the mid

- and high

- dose lev els,

and the number of P dams with cannibalized pups was increased at these two dose levels also

. While this effect may be treatment

- related , it did not affect the number of live pups born in each group, therefore is not considered biologically significant

. There was no adverse effect observed on pup body weight in either generation

.

The offspring LOAEL was not observed . The offspring NOAEL is equal or larger than 41.2 mg/kg bw/day

.

This study is acceptable (guideline) and satisfies the guideline requirement for a 2

- generation reproductive study (OPPTS 870.3800); OECD 416 in rats.

COMMENTS : This is a revised Executive Summary only and does not alter the conclusions of the previous review. However, the root DER esta blished a No Observed Effect Level (NOEL). The current supplemental DER establishes a No Observed Adverse Effect Level (NOAEL) that is in concordance with the previously established NOEL and/or current Agency policy

.

COMPLIANCE : Signed and dated GLP, Qua lity Assurance, and Data Confidentiality statements were provided.

### Page 45 of 57

Appendix A.3 . Flufenacet Inhalation Human

- Equivalent Dose (HED ) Calculations

A.3.1 Methodology

Based on the EPA’s reference concentration (RfC) guidance document ( Methods for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry , 1994), the methodology for RfCs derivations is an estimate of the quantitative dose

- response assessment of

non

- cancer toxicity for individual inhaled chemicals. Thi s method includes dosimetric adjustments to account for (1) species

- specific relationship between exposure concentration and deposited/delivered dose, (2) pharmacokinetic differences between laboratory animals and humans, (3) differences in exposure durati on between animal studies and expected human exposure, and (4) physicochemical properties of the chemical. While the RfC methodology was developed to estimate toxicity of inhaled chemicals over a lifetime, it can also be used for shorter inhalation exposu res because the dosimetric adjustment incorporates mechanistic determinants of disposition that can be applied to shorter durations of exposure s . The method does not account for pharmacodynamic differences between laboratory animals and humans. Different sets of equations are used if the chemical behaves as a gas or as an aerosol/particle. To provide greater accuracy, the RfC also takes into account the effect of aerosols or gases on the extrathoracic, tracheobronchial, and/or pulmonary respiratory region s as described in the figure below.

Figure A.3. 1 : Regions of the human respiratory tract used for HEC calculations

( Figure 3

- 1 of the 1994 RfC methodology document)

Flufenacet is an aerosol/particle. Aerosols/particles are assumed to be spherical, re latively insoluble, and non

- hygroscopic particles and thus physically distinct from gases. For such chemicals, key parameters used in the RfC method include: the inhalation study NOAEL (or LOAEL if a NOAEL is not available), minute ventilation rates (V E 

### ) for animals and humans; the chemical’s particle size as described by the mass median aerodynamic diameter ( MMAD ) and

### Page 46 of 57

geometric standard deviation (GSD ), and duration (hours/day and days/week) of the expected human exposure scenarios. The NOAEL/LOAEL, MMAD and GSD were determined experimentally under the conditions of the inhalation toxicity study for flufenacet (MRID 47473101) as described in section A.3 .2 below. All other parameters use default assumptions described in EPA’s RfC guidance (1994).

Deriv ation of a Human Equivalent Concentration (HEC) for inhaled aerosols/particles is described by the following equation:

HEC r 

### = E × (D A 

### ÷ D H 

### ) × (W A 

### ÷ W H 

### ) × RDDR r 

### Equation 1

HEC: Human equivalent concentration (mg/L)

E : Experimental exposure level (mg/L) or P oint of Departure (POD) , i.e. NOAEL or LOAEL

D: Number of hours exposed per 24 hours

W: Number of days exposed per 7 days

RDDR : R egional deposited dose ratio

r: R espiratory region (extrathoracic, tracheobronchial or pulmonary )

A: Test animals

H: Human s



### The regional deposited dose ratio (RDDR) used in the above equation is the ratio between the estimated regional deposited doses (RDD) in test animals and humans. The RDDR is determined by characterizing the particulate exposure, which is in turn define d by the MMAD
and the σ g 

### . The RDDR is generally described by the following equation:

RDDR r 

### = (RDD r,A 

### ÷ RDD r,H 

### ) × (NF H 

### ÷ NF A 

### ) Equation 2 = ((10

- 6 

### × C i,A 

### × V E,A 

### × F r,A 

### ) ÷ (10

- 6 

### × C i,H 

### × V E,H 

### × F r,H 

### )) × (NF H 

### ÷ NF A 

### ) = (C i,A 

### ÷ C i,H 

### ) × (V E,A 

### ÷ V E,H 

### ) × (F r,A 

### ÷ F r,H 

### ) × (SA r,H 

### ÷ SA r,A 

### )

C i : Inhaled c oncentration (mg/ c m 3 = 10

- 6 mg/m 3 )

V E : Minute volume (mL/min)

F
r : Fractional deposition in the specific respiratory region

SA
r : Surface area of the specific respiratory region



### In the above equation, the fractional deposition (F) is determined in part by the MMAD and σ g 

### , which describe the particle size distribution. The calculations to derive F are beyond the scope of this document and available in Appendix G of the EPA’s RfC g uidance document (1994).

Using EPA’s route

- to

- route extrapolation guidance ( Memo, “Route

- to

- Route Extrapolations” J. Whalen and H. Pettigrew, 10/10/ 19 98 ), HEC inhalation units of mg/L can be converted into human equivalent dose (HED) units of mg/kg/day. HEDs can be calculated for different inhalation exposure scenarios. The route

- to

- route extrapolation is described by the following equation:

HED r 

### = HEC r 

### × A × CF × D H 

### × AF ) Equation 3

HED: Human equivalent dose (mg/kg/day)

HEC: Human equivalent concen tration (mg/L)

A: Absorption ratio through the respiratory tract as compared to the oral route; assumed to be unity

### Page 47 of 57

CF: Human

- specific value (L/hr/kg)

D H : Number of hours exposed per 24 hours for humans

AF: Activity factor



### The equation above uses a single conversion factor (CF) to account for default body weights and respiratory volumes per unit time

. CF equals 11.8 L/hr/kg based on the EPA’s RfC guidance

document default breathing rate assumed for a typical human (i.e., CF = 13.8 L/min ÷ 70 kg)

. An activity factor (AF) is used to account for increased exposure , compared to the default 13.8 L/min, resulting from increased respiration rates for different occupational scenarios, as
indicated in EPA’s route

- to

- route extrapolation guidance ( AF is the ratio of the exposure specific

scenario V E 

### and the default value of 13.8 L/min )

.

A

. 3. 2 Calculations for Flufenacet Occupational and Inhalation Exposure Scenarios

Table A.3. 2.1 contains HECs for potential occupational scenarios, generated using the E quations

1 and 2 described in section A.3. 1 above. Since flufenacet behaves as an aerosol/particulate and produced portal of entry toxicity in the extrathoracic region (ET), HECs were calculated using an

RDDR ET 

### that should be protective of both the respira tory toxicity (i.e., goblet cell hyperplasia of nasal cavity and inflammatory infiltrate of the larynx ) and systemic toxicity (i.e., sperm

- related findings in the testis and epididymis ) observed in the 28

- day inhalation study. Occupational handler exposur e was assumed to be 8 hours/day and 5 days/week.

Table A .3. 2 .1 Calculated HE Cs and Parameters Used for Derivation

– Occupational Short

and Intermediate Risk Assessment
Study / POD / r D A D H W A W H RDDR HEC (mg/L) UF Inhalation Toxicity

MRID 47473101

LOAEL = 0.02 mg/L

r = ET 6 8 5 5 0. 168 female

0.241 male 0.00252 female

0.00362 male UF A = 3x

UF H = 10x

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level (mg/L). LOAEL = lowest observed adverse effect level (mg/L). r = target respiratory region. D A = Number of hours exposed per 24 hours for animals. D H = Number of hours exposed per 24 hours for humans. W A = Number of days exposed per 7 days for animals. W H = Number of days exposed per 7 days for humans. RDDR = Regional deposited dose

ratio. HEC = Human Equivalent Concentration (mg/L). UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). N/A = not applicable. ET = Extrathoracic. TB = Tracheobronchial. PU = Pulmonary.



### Table A .3.2 contains HEDs for potential occupational scenarios generated using the Equation 3

described in section A.3 .1 above. Occupational exposure scenarios for were assigned breathing rates (i.e. V E 

### ) of 8 .3, 16.7 a nd 29 L/min. The relative activity factor (AF) is the ratio of the exposure scenario

- specific V E 

### and the default V E 

### of 13.8 L/min.

Table A .3.2 Calculated HED s and Parameters Used for Derivation

– Occupational Short and Intermediate

Risk Assessment

Specific Breathing Rate HEC (mg/L) A CF D H AF HED (mg/kg/day) UF

8.3 L/min 0.00252 female

0.00362 male 1.0 11.8 8 0.6 0.143 females

0.206 males UF A = 3x

UF H = 10x

### Page 48 of 57

Table A .3.2 Calculated HED s and Parameters Used for Derivation

– Occupational Short and Intermediate

Risk Assessment

Specific Breathing Rate HEC (mg/L) A CF D H AF HED (mg/kg/day) UF

16.7 L/min 1.2 0.289 females

0.414 males

29 L/min 2.1 0.501 females

0.719 males
HEC = Human Equivalent Concentration (mg/L). HED = Human Equivalent Dose (mg/kg/day). A = Absorption ratio through the respiratory tract as compared to the oral route. CF = Human

- specific value that accounts for volume respired per unit

time

. D H = Number of hours exposed per 24 hours for humans. AF = ratio of the specific breathing rate and the

default value of 13.8 L/min. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity amon g members of the human population (intraspecies). N/A = not applicable.



### A .3 .3 28

- day Inhalation Toxicity Study in Rats (MRID 47473101 )

In a subchronic inhalation toxicity study (MRID 47473101), flufenacet (97% a.i., Batch No. EDHB001715) was administered as an aerosol to 10 Wistar rats/sex/concentration by dynamic

directed

- flow, nose

- only exposure at target concentrations of 0, 19.1, 219.8, or 409.0 mg/m 3 

### (analytical concentrations of 0, 0.02, 0.22, or 0.41 mg/L) for 6 hours per day, 5 days/week for 4

wee ks. In all exposure groups the mass median aerodynamic diameter (MMAD) was 2.3 μm with a geometric standard deviation (GSD) of about 2, as determined by critical orifice cascade impactor analysis.

No adverse, treatment

- related effects were observed on mo rtality, clinical signs, reflexes, rectal temperatures, ocular lesions, urinalysis, or organ weights. A variety of organs seem to be affected by flufenacet treatment in the mid and high dose groups, and in most cases males seem

to be more sensitive than f emales. Body weights were decreased throughout treatment in all exposed male groups, however magnitude of the decrease was larger in the mid dose groups (10

- 11, p≤0.01) than in the high dose groups (7

- 9%, p≤0.5). Significant changes in hematological

para meters indicative of anemia as well as increased incidence and/or severity of spleen changes (weight, congestion, pigmentation and increased hematopoiesis) were observed at the high dose and mostly in males. In the liver, relative weights (but not absolut e) were mildly increased (7

- 12%) in both sexes, and 3 types of metabolic activity (cytochrome P450, N

- demethylase and O

demethylase) were significantly increased at the mid and high doses in both sexes; cytochrome P450 activity was also increased at the lo w dose in both sexes. Liver hypertrophy was observed

in most males treated with flufenacet at all doses but not in controls or in treated females. Thyroid hormones (T3 and T4) were decreased at the high dose, without an accompanying significant change in thyroid stimulating hormone; males had an apparent dose dependent increased incidence of thyroid follicular hypertrophy (SNI, statistical significance not indicated). The incidence and/or severity of retinal atrophy/degeneration (minimal to slight) also s eem to
increase in a dose

- dependent manner (SNI). The following testicular and/or epididymis lesions were observed in most treated males at all doses: spermatic debris in testis and/or epididymides (minimal to marked) and epididymides oligospermia (slight to moderate). Epididymides sperm granuloma (slight to marked) was also observed in all treated male groups but not in the controls,

however the incidence was not dose

- dependent.

### Page 49 of 57

The systemic LOAEL for rats was 0.02 mg/L based on increased incidence of sperm
- related lesions of the testis (spermatic debris) and epididymis (spermatic debris, oligospermia); changes in hematology, spleen and liver parameters and/or lesions as well as and retinal lesions occurred at the next highest dose. A NOAEL was not obse rved.

Effects were noted in the nose and larynx, however it was not established if these effects were due to a localized irritant effect. At the low dose, goblet cell hyperplasia of the nasal cavity was observed in most males and inflammatory infiltrate of the larynx was observed in most females; these same lesions were observed in most mid and high dose animals of both sexes. The incidence of eosinophilic globules in the nasal cavities was also increased at the mid and high dose in both sexes (SNI). La rynx epithelial metaplasia was observed in all animals exposed to the mid and high doses, and severity (minimal to moderate) seemed to increase in a dose

dependent manner.

The inhalation (portal of entry) LOAEL for rats was 0.02 mg/L based on increased

i ncidence of goblet cell hyperplasia of the nasal cavity in males and inflammatory infiltrate of the larynx in both sexes ; additional nasal lesions (eosinophilic globules) and laryngeal epithelial metaplasia, occurred in both sexes at the next highest dose. A NOAEL was not

observed.

### Page 50 of 57

Appendix B

. Physical/Chemical Properties

Table B .1. Physicochemical Properties of Technical Grade Flufenacet

.

Parameter Value Reference

Melting point/range (  C) 75.5

- 77.0

43441101 pH 4.49 (approx. 1% aqueous slurry)

Density 1.312 g/mL (at 20  C)

Water solubility (20  C) 56 mg/L (0.0056 g/100 ml)

Solvent solubility (g/l at

20  C) n

- hexane: 8.7

2

- propanol: 170

acetonitrile: >200

1

- octanol: 88 dimethylformamide: >200 polyethylene glycol + ethanol:

160 toluene: >200
dichloromethane: >200

acetone: >200 dimethylsulfoxide: >200 polyethylene glycol: 74

Vapor pressure at 25  C 2 X 10

- 6 h Pa (N

- isomer) (equivalent to 4 X 10

- 6 torr)

Dissociation constant (pKa) Does not dissociate in water.

Octanol/water partition coefficient Log(KOW) Pow = 1600 at 24  C; log Pow = 3.20

UV/visible absorption spectrum (λmax, nm) Not available

### Page 51 of 57

Appendix C

. Review of Human Research

Human Studies Review This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These data, which include studies from PHED 1.1; the AHETF database; and the ARTF database are (1) subject to ethics review pursuant to 40 CFR 26 , (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 8



### .

8 http://www.epa.gov/pesticides/science/handler

- exposure

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

- app

- exposure

- data.html

### Page 52 of 57

Appendix D. Occupational Exposure/Risk Summary Tables

Table D.1. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flufenacet at Baseline PPE.

Exposure Scenario Crop or Target Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application

Rate 2 (lb ai/A) Area

Treated or
Amount

Handled Daily 3 Dermal Inhalation

Baseline * Baseline * Dose (mg/kg/day) 4 MOE 5

(LOC = 1000) Dose

(mg/kg/day) 6 MOE 7

(LOC = 300)

Mixer/Loader

Mixing/Loading Dry Flowables for

Commercial Treatment with Impregnated Fertilizers Corn

9.8 0.24 7.8 8 lb

ai/ton 960 tons 0.04 3 40 0.02 228 22

Soybeans 4. 56 lb

ai/ton 0.02 49 68 0. 01 31 38

Mixing/Loading Dry Flowables for

On

- Farm Treatment with Impregnated Fertilizers Corn

227 8.96 0.78

160 acres 0.0164 100 0. 0140 21

Soybeans 0.46 0.00968 180 0. 00824 35

Mixing/Loading Dry Flowables for Groundboom Application Sod

227 8.96 0.44 80 acres 0.00463 370 0.00 394 73

Corn 0.78

200 acres 0.0205 83 0.0 175 17 Soybeans 0.46 0.0121 140 0. 01 03 28

Wheat 0.34 0.00893 190 0. 00 761 38

Mixing/Loading Liquids for

Commercial Treatment with Impregnated Fertilizers Corn

8.6 0.083 7.88 lb

ai/ton 960 tons 0.0377 45 0. 00785 64

Soybeans 4.56 lb

ai/ton 0.0218 48 0. 00454 110

Mixing/Loading Liquids for On

Farm Treatment with Impregnated

Fertilizers Corn

220 0.219 0.78

160 acres 0.0159 110 0.0003 41 850

Soybeans 0.46 0.00939 180 0. 000201 1, 400

Mixing/Loading Liquids for Groundboom Application Corn 220 0.219 0.78 200 acres 0.0199 85 0. 000428 6 80 Soybeans 0.46 0.0117 150 0. 000251 1,200 Applicator

Applying Sprays via Groundboom

Equipment Sod

78.6 0.34 0.44 80 acres 0.00161 1,100 0. 001 50 950

Corn 0.78

200 acres 0.00713 240 0. 000 662 220 Soybeans 0.46 0.00419 410 0. 000 391 370

Wheat 0. 3 4 0.0031 550 0. 000 289 490 Applying Impregnated Dry Bulk

Fertilizer

- Commercial Treatment Corn 9.9 1.2 0.78 320 acres 0.00143 1,200 0. 00375 1 3 0 Soybeans 0.46 0.000846 2,000 0. 00221 230 Applying Impregnated Dry Bulk

Fertilizer

- On

- Farm Treatment Corn 9.9 1.2 0.78 160 acres 0.000719 2,400 0. 00188 270 Soybeans 0.46 0.000423 4,000 0. 00110 460

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”; Level of mitigation: Baseline, PPE, Eng. Controls. *Baseline for mixing/loading for commercial treatment of impregnated fertilizers is engineering controls in a closed system.

2 Based on registered labels. See Appendix B.

3 Exposure Science Advisory Council Policy #9.1.

### Page 53 of 57 4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or tons /day) × DAF (4 %) ÷ BW (69 kg).

5 Dermal MOE = Dermal LOAEL (1.7 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal ) × Area Treated or Amount Handled (A or gal/day) ÷ BW ( 8 0 kg).

7 Inhalation MOE = Inhalation NOAEL (0.143, 0.289, or 0.501 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

Table D.2 . Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flufenacet

- Scenario requiring Gloves to Be Not of Concern.

Exposu re Scenario Crop or Target Dermal Unit Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application

Rate 2 (lb ai/A) Area

Treated or
Amount

Handled Daily 3 Dermal Inhalation

Gloves Baseline Dose (mg/kg/day) 4 MOE 5

(LOC = 1000 ) Dose

(mg/kg/day) 6 MOE 7

(LOC = 300)

Mixer/Loader Mixing/Loading Liquids for

On

- Farm Treatment with Impregnated Fertilizers Soybeans 37.6 0.219 0.46 160 acres 0.00161 1,100 0. 0002 01 1, 4 00

Applicator Applying Sprays via Groundboom Equipment Soybeans 16.1 0.34 0.46 200 acres 0.000858 2,000 0. 000391 370

Wheat 0.34 0.000632 2,700 0. 000289 490

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”; Level of mitigation: Baseline, PPE, En g. Controls.

2 Based on registered labels. See Appendix B

. 3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF ( 4 %) ÷ BW ( 69 kg).

5 Dermal MOE = Dermal L OAEL ( 1.7 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal ) × Area Treated or Amount Handled (A or gal /day) ÷ BW ( 80 kg).

7 Inhalation MOE = Inhalation NOAEL ( 0.143, 0.289, or 0.501 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

Table D.3 . Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flufenacet

- Scenarios Requiring Gloves and a PF5 Respirator to be Not of
Concern.

Exposure Scenario Crop or Target Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application

Rate 2 (lb ai/A) Area

Treated or
Amount

Handled Daily 3 Dermal Inhalation

Gloves PF5 Respirator Dose (mg/kg/day) 4 MOE 5

(LOC = 1000 ) Dose

(mg/kg/day) 6 MOE 7

(LOC = 300)

Mixer/Loader Mixing/Loading Dry

Flowables for Groundboom Application Sod 51.6 1.792 0.44 80 acres 0.00106 1,600 0. 000789 370

Applicator Applying Sprays via Groundboom Equipment Corn 16.1 0.068 0.78 200 acres 0.00146 1,200 0. 0001 33 1,10 0

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”; Level of mitigation: Baseline, PPE, Eng. Controls.

2 Based on registered labels. See Appendix B

.

### Page 54 of 57 3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DA F ( 4 %) ÷ BW ( 69 kg).

5 Dermal MOE = Dermal L OAEL ( 1.7 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Ex posure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled ( A or gal/day) ÷ BW ( 80 kg).

7 Inhalation MOE = Inhalation NOAEL ( 0.143, 0.289, or 0.501 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

Table D.4 . Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flufenacet

- Scenarios Requiring a PF 5 Respirator to be Not of Concern.

Exposure Scenario Crop or Target Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application

Rate 2 (lb ai/A) Area

Treated or
Amount

Handled Daily 3 Dermal Inhalation

Baseline P F5 Respirator Dose (mg/kg/day) 4 MOE 5

(LOC = 1000 ) Dose

(mg/kg/day) 6 MOE 7

(LOC = 300 ) Applicator Applying Impregnated Dry

Bulk Fertilizer

- Commercial

Treatment Corn

9.9 0.24 0.78

320 acres 0.00143 1,200 0. 000 749 670

Soybeans 0.46 0.000846 2,000 0. 000 441 1.100

Applying Impregnated Dry

Bulk Fertilizer

- On

- Farm

Treatment Corn 0.78 160 acres 0.000719 2,400 0. 000 375 1, 3 00

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”; Level of mitigation: Baseline, PPE, Eng. Controls.

2 Based on registered labels. See Appendix B

. 3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposur e (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF ( 4 %) ÷ BW ( 69 kg).

5 Dermal MOE = Dermal L OAEL ( 1.7 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhal ation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amo unt Handled (A or gal/day) ÷ BW ( 80 kg).

7 Inhalation MOE = Inhalation NOAEL ( 0.143, 0.289, or 0.501 mg/kg/day) ÷ Inhalation Dose ( mg/kg/day).

Table D.5 . Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flufenacet

- Scenarios requiring Double Layer and Gloves Not of
Concern.

Exposure Scenario Crop or Target Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application

Rate 2 (lb ai/A) Area

Treated or
Amount

Handled Daily 3 Dermal Inhalation

DL + G Baseline Dose (mg/kg/day) 4 MOE 5

(LOC = 1000) Dose

(mg/kg/day) 6 MOE 7

(LOC = 3 0 0)

Mixer/Loader Mixing/Loading Liquids for

Groundboom Application Soybeans 29.1 0.219 0.46 200 acres 0.00155 1,100 0. 000 251 1,200

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”; Level of mitigation: Baseline, PPE, En g. Controls.

2 Based on registered labels. See Appendix B

. 3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF ( 4 %) ÷ BW ( 69 kg).

5 Dermal MOE = Dermal L OAEL ( 1.7 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

### Page 55 of 57 6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal ) × Area Treated or Amount Handled (A or gal /day) ÷ BW ( 80 kg).

7 Inhalation MOE = Inhalation NOAEL ( 0.143, 0.289, or 0.501 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

Table D.6 . Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flufenacet

- Scenarios requiring Double Layer, Glove s , and a PF10 Respirator to be Not of Concern.

Exposure Scenario Crop or Target Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application

Rate 2 (lb ai/A) Area

Treated or
Amount

Handled Daily 3 Dermal Inhalation

DL + G PF10 Dose (mg/kg/day) 4 MOE 5

(LOC = 1000) Dose

(mg/kg/day) 6 MOE 7

(LOC = 3 0 0)

Mixer/Loader Mixing/Loading Dry
Flowables for Groundboom Application Wheat 41.2 0.896 0.34 200 acres 0.00162 1,000 0. 000761 3 8 0

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”; Level of mitigation: Baseline, PPE, Eng. Controls.

2 Based on registered labels. See Appendix B

. 3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF ( 4 %) ÷ BW ( 69 kg).

5 Dermal MOE = Dermal L OAEL ( 1.7 mg/kg/day) ÷ Dermal Dose (mg/kg/day).

6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW ( 80 kg).

7 Inhalation MOE = Inhalation NOAEL ( 0.143, 0.289, or 0.501 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

Table D.7 . Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flufenacet

- Scenarios requiring Engineering Controls to be Not of
Concern.

Exposure Scenario Crop or Target Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application

Rate 2 (lb ai/A) Area

Treated or
Amount

Handled Daily 3 Dermal Inhalation

EC EC Dose (mg/kg/day) 4 MOE 5

(LOC = 1000) Dose

(mg/kg/day) 6 MOE 7

(LOC = 3 0 0)

Mixer/Loader Mixing/Loading Dry
Flowables for On

- Farm

Treatment with Impregnated

Fertilizers Corn

9.8 0.24 0.78

160 acres 0.00071 2,400 0. 000375 1, 3 00

Soybeans 0.46 0.00042 4,100 0. 000221 2,3 00

Mixing/Loading Dry

Flowables for Groundboom Application Corn 0.78

200 acres 0.00089 1,900 0. 000468 1,100

Soybeans 0.46 0.00052 3,300 0. 000276 1, 800

Mixing/Loading Liquids for

On

- Farm Treatment with Impregnated Fertilizers Corn 0.78 160 acres 0.00062 2,700 0. 000130 3, 900

### Page 56 of 57 Table D.7 . Occupational Handler Non

- Cancer Exposure and Risk Estimates for Flufenacet

- Scenarios requiring Engineering Controls to be Not of
Concern.

Exposure Scenario Crop or Target Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

Exposure (μg/lb ai) 1 Maximum

Application

Rate 2 (lb ai/A) Area

Treated or
Amount

Handled Daily 3 Dermal Inhalation

EC EC Dose (mg/kg/day) 4 MOE 5

(LOC = 1000) Dose

(mg/kg/day) 6 MOE 7

(LOC = 3 0 0) Mixing/Loading Liquids for Groundboom Application Corn 8.6 0.083 0.78 200 acres 0.00078 2,200 0. 000161 3

, 1 00

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table”; Level of mitigation: Baseline, PPE, En g. Controls.

2 Based on registered labels. See Appendix B

. 3 Exposure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF ( 4 %) ÷ BW ( 69 kg).

5 Dermal MOE = Dermal L OAEL ( 1.7 mg/kg/day) ÷ Dermal Dose (mg/k g/day).

6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal ) × Area Treated or Amount Handled (A or gal/day) ÷ BW ( 80 kg).

7 Inhalation MOE = Inhalation NOAEL ( 0.143, 0.289, or 0.5 01 mg/kg/day) ÷ Inhalation Dose (mg/kg/day)

.

### Page 57 of 57

Appendix E . Flufenacet IRL Sheet



## Flufenacet ( PC Code 121903)

Table E .1. Summary of US and International Tolerances and Maximum Residue
Limits

. US Canada Mexico 1 Codex

Residue Definition:

40CFR180.527 Plants/Livestock: Flufenacet, N

- (4

- fluorophenyl)

- N

- (1

- methylethyl)

- 2

- [[5

- (trifluoromethyl)

- 1, 3, 4

- thiadiazol

- 2

- yl] oxy]acetamide and its metabolites containing the

4

- fluoro

- N

- methylethyl benzenamine moiety N

- (4

- fluorophenyl)

- N

- (1

- methylethyl)

- 2

- [[5

- (trifluoromethyl)

- 1,3,4

- thiadiazol

- 2

- yl]oxy]acetamide, including metabolites containing the 4

- fluoro

- N

- methylethyl benzenamine moiety None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg) Commodity US Canada Mexico 1 Codex Cattle, kidney 0.05 0.05 Meat byproducts of cattle Corn, field, forage 0.4 Corn, field, grain 0.05 0.05 Field corn Corn, field, stover 0.4 Corn, sweet, forage 0.45 Corn, sweet, kernel plus

cob with husks removed 0.05 0.05

Corn, sweet, stover 0.30 Goat, kidney 0.05 0.05 Meat byproducts of goats Hog, kidney 0.05 0.05 Meat byproducts of hogs Horse, kidney 0.05 0.05 Meat byproducts of horses Sheep, kidney 0.05 0.05 Meat byproducts of sheep Soybean, seed 0.1 0.1 Dry soybeans Wheat, bran 0.80 0.8 Wheat, forage 6.0 Wheat, grain 0.60 0.6 Wheat, hay 1.2 Wheat, straw 0.35 MRLs with no US equivalent
Eggs 0.05 Meat byproducts of poultry 0.05

Meat of cattle 0.05 Meat of goats 0.05 Meat of hogs 0.05

Meat of horses 0.05 Meat of poultry 0.05 Meat of sheep 0.05

Milk 0.01

1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.