UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON , O.C. 20460 

MEMORANDUM 

Date: .June 10, 2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Flufcnacet: Human Health Draft Risk Assessment for Registration Review 

PC Code: 12 1903 

Decision No.: 485585 

Petition No.: NA 

DP Barcode: 04 16546 

Registration No.: NA 

Regulato ry Action: Registration Review 

Risk Assessment Type: Aggregate Risk Assessment Case No.: 7245 

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

MRID No.: NA 40 CFR: § 180.527 

FROM : Kri

Miner

stin 

va 

Rur

Mercado, 

y, Biologist 

Toxico

~~ logis . 1 

Mcheret Negussie, Chemist /\-'~Y:.... 

Cassi Walls, Senior Chemist ~~ z. Uc~ 

Risk Assessment Branch 3 (RAB 3) 

Health Effects Division (7509P) 

THROUGH: Christine Olinger, Branch Chief .// U / . Risk Assessment Branch 3 (RAB /p7--L ___ _ Hea lth Effects Division (7509P) 

And 

Christina Swartz, RARC Designated Reviewer ~ -----~ 2> 

Wade Britton, RARC Designated Reviewer ~ 17 v ...., itJ( \N 

Health Effects Division (7509P) 

TO: Margaret Hathaway, Risk Manager Reviewer 

Kevin Costello, Risk Manager 

Pesticide Re-evaluation Division (PRO) (7508P) 

As part of Registration Review, PRO of the Office of Pesticide Programs (OPP) has requested 

that HED evaluate the hazard and exposure data and conduct occupational and residential 

exposure assessments, as needed, to estimate the risk to human hea lth that will result from the 

currently registered uses of pesticides. This memorandum serves as HED's draft human health 

Page 1 of 57 
risk assessment of the dietary, occupational, and residential exposure; and aggregate risk from 

the registered uses of flufenacet. The most recent quantitative human health risk assessment was 

performed in 2007 (J Arthur, 0318555, 03/J 5/2007). The following risk assessment updates 

have been made: 

• A route-specific inhalation toxicity study has been used as the basis for the inhalation 

point of departure (POD), an incidental oral POD has been added to evaluate risks from 

spray drift, and a comparative thyroid study has been submitted and reviewed by the 

Agency. 

• A dietary exposure assessment was completed to include estimated drinking water 

concentrations (EDWCs) 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 aggregate exposure assessment was completed, including updated dietary (food and 

drinking water) exposure estimates; and 

• An occupational exposure assessment for the registered uses was completed reflecting 

recent updates to HEO's Standard Operating Procedures (SOPs) along with policy 

changes for body weight assumptions. 

A summary of the findings and an assessment of human risk resulting 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 Physical/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 Dose-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 Estimates 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

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

Flufenacet end-use products (EPs) are formulated as soluble concentrates (SC) and dry flowables

(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 dry 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-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 restricted use pesticides (RUPs). 

Exposure Profile 

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, applicators 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 flufenacet, there is a potential for spray drift that may result in

exposures 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 children 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, suppression 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. Although 

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 (microscopic cataracts in mice and rats; 

gross cataracts and a variety of microscopic eye lesions in dogs). Neurotoxic effects were 

observed in both 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 not 

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. Mutagenicity 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 classified as Toxicity Category III via the oral and dermal routes, and Toxicity 

Category IV for inhalation exposure. Flufenacet is not an eye or skin irritant (Toxicity Category 

IV) and is not a dermal sensitizer.

The acute and chronic dietary and the dermal PODs 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 dietary, 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-todermal 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 calculate 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 (UFA), 

10X intraspecies (UFH) and 10X for the lack of a NOAEL (UFL). 

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 data are available to support the registered uses. 

Adequate methods are available for enforcement of the currently established tolerances. 

Dietary Exposure Assessment

A partially refined acute dietary (food + drinking water) exposure assessment was conducted for 

all existing food uses of flufenacet. Anticipated residues for field corn, soybean, sweet corn, and 

wheat were developed using field trial data; tolerance-level residues were used for cereal grains 

and livestock commodities; and empirical processing 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 incorporated directly into the dietary exposure analysis. The 

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 

same, 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 concern (LOC) for 

the U.S. population and all population subgroups. Combined dietary exposure from food and 

drinking water at the 95th 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 95th percentile equivalent to 92% of the aPAD. Drinking water is the major contributor to the 

dietary exposure estimates.

Spray Drift Assessment 

There are no registered residential uses of flufenacet; however, 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 groundboom 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 Assessment

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); and 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 intermediate-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; 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. 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 exposure 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 Justice

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

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

to Address Environmental Justice in Minority Populations and Low-Income Populations.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 values. 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 concern for the following non-dietary exposure scenarios:

Occupational Handler Exposure Assessment

There are risk estimates 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 MOEs 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 the 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 postapplication 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 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-Nmethylethyl benzenamine moiety on plant and commodities is available.

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 benzenamine moiety in plants and livestock commodities. The residues 

are extracted 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 trifluoroacetic 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/textidx?SID=a5983c2e243fca24493fbe7a02254834&mc=true&node=se40.24.158_11070&rgn=div8
Page 10 of 57

Permanent tolerances have been established in 40 CFR §180.527 for residues of flufenacet as 

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

tolerances, as listed in 40 CFR §180.527. Table 2.2.2 lists the recommended tolerances for 

residues of flufenacet for harmonization purposes. Upon establishment of the recommended 

tolerances, HED recommends to remove tolerances as in Table 2.2.3. The 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 follows:

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 determined 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 changes to 40 CFR §180.527 (c) and (d).

Table 2.2.2. Recommended Tolerances 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 

MRLs on soybeans (0.1 ppm); field corn (0.05 ppm); corn, 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, hogs, 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 US 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 Introduction

Flufenacet (N-(4-fluorophenyl)-N-(1-methylethyl)-2-[[5-(trifluoromethyl)-1,3,4-thiadiazol-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 products 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, 03/15/2007). 

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-thiadiazol2-yl]oxy]acetamide

CAS # 142459-58-3

S

N N

N

CH3 H C3

O

O

CF3

F
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 Pow) 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 10-6torr, indicating that flufenacet is not 

significantly volatile. The physicochemical properties of flufenacet are summarized in Appendix 

B. 

3.3 Pesticide Use Pattern

The uses and application rates are summarized in Table 3.3. 

Table 3.3. Summary of Directions for Use of Flufenacet.

Applic. Timing, Type, and 

Equip.

Max. 

Applic. 

Rate

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. Rate 

RTI1

(days) Use Directions and Limitations4,5

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 Fertilizer3 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 Fertilizer3 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/A2 0.34 lb ai/A 21

Preemergent to early postemergent 

applications only. Do not graze 30 

days after treatment.

Grass Grown for Seed6

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. Summary of Directions for Use of Flufenacet.

Applic. Timing, Type, and 

Equip.

Max. 

Applic. 

Rate

Max. No. 

Applic. per 

Season

Max. 

Seasonal 

Applic. Rate 

RTI1

(days) Use Directions and Limitations4,5

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 ton 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 

millet, 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. 24C 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, applicators 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 flufenacet, there is a potential for spray drift that may result in

exposures 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 Environmental Justice

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

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

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

(http://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 patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns are compiled by the U.S. Department of 

Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, 

(NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a 

pesticide. These data are analyzed and categorized by subgroups based on age and ethnic group. 

Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and 
Page 14 of 57

exposure assessments are performed when conditions or circumstances warrant. Whenever 

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

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

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

exposure and it was considered in this analysis. Further 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 exposures and 

farm workers as well as lifestyle 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, 03/15/2007). 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 adequate 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 Council (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. The 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: fluorophenyl residues, thiadiazole

residues, and polar small molecular weight residues. Plasma levels of fluorophenyls reached 2 

peaks of concentration 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 hours of dosing,

indicating that the two rings of flufenacet were probably separated prior to entering the systemic 

circulation. By 48 hours some thiadiazoles seem to remain in the body (13-25% of dose) while 

fluorophenyls had been mostly excreted. By 96 hours, tissue fluorophenyl residues were ≤3% of 

the administered dose, mostly found in the GI tract but also in liver and blood, and tissue

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 thiadiazoles were exhaled into air, and 2-6% were found 

in feces. Glutathione conjugation appeared to be the major metabolic pathway for fluorophenyl

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 are 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 in 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, 02/19/1997). 

The 4% factor is appropriate for use in the absence of dermal absorption data because it accounts 

for the differential effects 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 division 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, including metabolic enzyme 

induction, was the most sensitive endpoint in many studies. In developmental studies, delayed

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 

was 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). Special mechanistic studies in male rats assessed 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 induction and not with direct action on the

functions of the pituitary, thyroid, or hypothalamus. Increased 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 studies, and metabolic enzyme induction also occurred at a lower dose than T4 

decreases in the inhalation study. Other special studies did not show an effect of flufenacet on 

the thyroid capacity to take up iodine (a key step in the production of thyroid hormones) 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 compensate 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, ciliary 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 flufenacet 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 vacuolation 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 

neurotoxicity in the rat. In the SCN, increased number of lesions 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, increased foot splay 

and decreased motor activity. In the DNT, females exposed to flufenacet throughout 

development had decreased motor activity and a significant decrease in caudate putamen 

measurements as adults. Although the registrant has proposed that brain 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 2003), 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 studies occurred at similar or higher doses as 

thyroid hormone (T4) depression in adult rat studies of similar duration. In addition, 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). Therefore, 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 circulating 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, qualitative 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 study 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.

Spermatic 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 systemic 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 profile for flufenacet regardless of exposure route. In 

addition, 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 not 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 Toxicity 

Category III via the oral and dermal routes, and Toxicity Category IV for inhalation exposure. 

Flufenacet is not an eye or skin irritant (Toxicity Category IV) and is not a dermal sensitizer.

4.4 Safety Factor 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 

extrapolation factor (UFL) 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 PODs address and are protective 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 of 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 selection of PODs for risk assessment. Non-guideline comparative thyroid 

studies submitted by the registrant since the last risk assessment have 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 Neurotoxicity

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 Section 4.3 above.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or 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 

LOAEL 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 developmental 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 Database

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 are 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 Departure Selections

4.5.1 Dose-Response Assessment
Page 19 of 57

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

4.5.4.

A rat DNT study was used to select endpoints 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. These effects in the DNT 

study are the most sensitive oral endpoints 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 caudate 

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 has been determined 

appropriate, which includes 10X interspecies (UFA), 10X intraspecies (UFH) and 10X for the 

lack of a NOAEL (UFL). The 10X applied as an UFL 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): An acute reference dose (aRfD) of 0.0017 mg/kg/day

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

This aRfD is protective of developmental effects which may occur in females of reproductive 

age, infants, and children because several of the effects observed in the DNT study could be due 

to disruption of fetal development and/or postnatal development, and may occur following 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 (cRfD) of 0.0017 mg/kg/day was 

established for the general U.S. population, 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, use 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 FQPA 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 the LOAEL of 1.7 mg/kg was selected 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) Dermal 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 1000X UF applies to this 

scenario, which includes a 10X UFL for the lack of a NOAEL in the DNT study. This endpoint 

should be adjusted 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 Endpoints: A LOAEL of 

0.02 mg/L from a route-specific 28-day inhalation study in rats was used to calculate humanequivalent concentrations (HECs) and human-equivalent doses (HEDs) using the reference 

concentration (RfC) methodology described in the 1994 EPA guidance 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 also protective of systemic effects (increased incidence of 

sperm-related lesions of the testis and epididymis) observed in the inhalation study. The HEDs

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. See Appendix A.3 

for details regarding the calculation of the HECs and HEDs. The LOC is 300 which includes a 

3X UFA, a 10X UFH, and a 10X UFL (for lack of a NOAEL in the inhalation study). The UFA

was reduced from default 10X to 3X because the HEC calculation accounts for pharmacokinetic 

interspecies differences. The default intraspecies factor is retained at 10X 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 risk assessment must consider exposures from three major sources: 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 assessment 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 based 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.
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Table 4.5.4. Summary of Toxicological 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)

LOAEL= 1.7

mg/kg/day

UFA= 10x

UFH= 10x

FQPA SF= 

10x (UFL)

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)

LOAEL= 1.7

mg/kg/day

UFA= 10x

UFH= 10x

FQPA SF= 

10x (UFL)

Chronic RfD = 

0.0017 mg/kg day

aPAD = 

0.0017mg/kg/day

Developmental neurotoxicity 

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)

LOAEL= 1.7

mg/kg/day

UFA= 10x

UFH= 10x

FQPA SF= 

10x (UFL)

Residential LOC 

for MOE = 1000

Dermal Short-Term 

(1-30 days) and 

Intermediate-Term 

(1-6 months)

LOAEL= 1.7

mg/kg/day

4% oral-to-dermal 

route extrapolation 

factor

UFA= 10x

UFH= 10x

UFL = 10x

Occupational

LOC for MOE = 

1000

Residential = 

1000

Inhalation ShortTerm (1-30 days)

and IntermediateTerm (1-6 months)

LOAEL = 0.02 mg/L

HEC = 0.00252 mg/L 

f = 8.3 L/min

HED = 

0.143 mg/kg/day

f Handlers = 16.7 L/min

HEDs = 

0.289 mg/kg/day

fHandheld Spray = 

29 L/min

HED = 

0.501 mg/kg/day

UFA= 3x

UFH= 10x

UFL = 10x

Occupational

LOC for MOE = 

300

Residential = 

N/A (no exposure 

with current uses)

28-day inhalation toxicity study 

in rats. LOAEL = 0.02 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 Review 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. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = 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, including 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, organ 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 

different 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 ingredients) 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 

determinations. 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 February 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, 20133and 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 the 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 included 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 

(free 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-Nmethylethyl benzenamine 

moiety

Parent and metabolites 

containing the 4-fluoro-Nmethylethyl benzenamine 

moiety Rotational Crop

Livestock

Ruminant

Parent and metabolites 

containing the 4-fluoro-Nmethylethyl benzenamine 

moiety including the 

glycoside (THNG) and 

malonylalanine conjugates of 

thiadone

Parent and metabolites 

containing the 4-fluoro-Nmethylethyl 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 flufenacet 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 soybeans. Residues were higher 

on livestock feedstuffs (forage, hay, and stover). Adequate analytical methods and storage 

stability data are available to support the registered uses.

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 study and the registered uses, tolerances 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 Registration Review.

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 Residue Profile

Flufenacet is moderately persistent in 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 stable 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, 03/16/2015). The EDWCs of flufenacet and thiadone in surface water were 

modeled using the 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 1.07, 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 incorporated 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 Surface Water and Groundwater Concentrations for 

Flufenacet.

Surface Water

Acute Chronic Cancer

29.87 ppb1 9.07 ppb1 5.21 ppb1

Ground Water

Acute Chronic and Cancer

12.472 11.02 ppb2

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 was 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 reported for flufenacet represent the 95th 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 Description 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. 

All residues in the sweet corn field trial data were non-detectable, so 1⁄2 of the limit of 

quantification (LOQ) was used. Tolerance level residues were used for all other 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 treated was assumed in the assessment.

5.4.3 Dietary Risk Assessment

Acute 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 95

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 95th percentile 

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

Dietary exposure from drinking water alone at the 95th 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 95th percentile of 0.001230 

mg/kg/day, equivalent to 72% of the aPAD. Drinking water is the major contributor to the 

dietary assessment.

The results of the acute dietary exposure and risk analyses at the 95th percentile of exposure 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 for 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, Fungicide, and Rodenticide Act 

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

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

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

subsequent Volatilization Screening Analysis 

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

During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux 

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

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 released and do not deposit in the application area end up offtarget 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 intended 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 compliant 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 this 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 pesticides 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 Drift 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 aircraft, 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 options 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 pattern (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.

6http://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 

concentration 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 90th percentile results. 

The highest exposure resulted from drift following flufenacet applications to corn using 

groundboom equipment. There were dermal risk estimates of concern at the field edge for adults 

following application to 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 Tables 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 

Type

Spray Type/Nozzle 

Configuration

Appl. Rate 

(lb ai/A) TTR (μg/cm2

)

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 

Type

Spray Type/Nozzle 

Configuration

Appl. Rate 

(lb ai/A) TTR (μg/cm2

)

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/cm2)

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/cm2)

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 exposures 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 general population and all 

population subgroups. Refer to section 5.4.3 for 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- and 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) exposure 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 substances 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 regarding EPA’s efforts to determine which chemicals have a common mechanism 

of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements 

released by EPA’s Office of Pesticide Programs concerning common mechanism determinations 

and procedures for cumulating effects from substances found to have a common mechanism on 

EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

An occupational exposure and risk assessment was completed 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 determined that there are potential exposures to handlers during 

application of flufenacet. Scenarios assessed include mixing/loading wettable powders and 

soluble concentrate formulations for ground equipment application, including tractor-drawn 

spreaders for impregnated 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 registrantsubmitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), 

and subject to the data protection provisions of FIFRA. 

Occupational handlers 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. Chemical 

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 assuming 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 occupational handlers. Long-term exposures (greater than 

6 months) are not anticipated based on the currently 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 1,400. 
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 soybeans.

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 concern: 

 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 flowable 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 onfarm 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 

commercially to treat corn and soybeans; and

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

commercially 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 mixing/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 

PRD 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 

Handlers 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

X1

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

X1

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

Soybeans PF5 Respirator

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 reentry 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 applications, 

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 that has been previously treated with a pesticide (also referred to as reentry exposure). HED has determined that there are potential exposures to persons entering 

treated sites (e.g., harvesters) after application of flufenacet is complete. Dermal exposures 
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 assumption 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 PRD 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 (cm2/hr) DFR/TTR1 Dermal Dose (mg/kg/day)2 MOE3

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/cm2; where 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/cm2; where F = 0.1 and D = 0.10 per day (used for sod). 

2 Daily Dermal Dose = [DFR/TTR (μg/cm2) × Transfer 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 postapplication 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 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.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 

estimates 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 PRD 

require the appropriate REIs on all relevant labels to address these concerns. 

 

7 http://www.ecfr.gov/cgi-bin/textidx?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-application activities in previously treated fields. These potential sources 

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

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

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

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

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

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

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

if data (i.e., flux studies) 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 exposure into the agency's risk assessments.

10.0 Public Health and Pesticide Epidemiology Data

Both the OPP Incident Data System (IDS) and the Centers for Disease Control and 

Prevention/National Institute for Occupational Safety and Health (CDC/NIOSH) Sentinel 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 

triggered, 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) Flufenacet 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 existing 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; D427013. 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. Flufenacet: Acute and Chronic Aggregate Dietary (Food 

and Drinking Water) Exposure and Risk Assessments for the Registration Review Preliminary 

Risk Assessment. 
Page 37 of 57

Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for food uses for flufenacet are in 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

yes1

yes

yes1

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

-

waived2

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

2 = Based on a weight of evidence approach an immunotoxicity study is not required for the current uses (TXR 

0056951).
Page 38 of 57

A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Flufenacet.

Guideline 

No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral rat 43441104 LD50 = 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 LD50 ≥ 2000 mg/kg III

870.1300 Acute inhalation rat 43441108 LC50 > 3.74 mg/L IV

870.2400 Acute eye irritation rabbit 43850017 slight eye irritant IV

870.2500 Acute dermal irritation rabbit 43850023 not a dermal irritant IV

870.2600 Skin sensitization guinea pigs –

Buehler method

43850025 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 suppression of 

T4 and T3 in males; females had similar effects 

at next higher dose. Male hemoglobin was 

decreased and female cholesterol was decreased

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

870.3100 90-Day oral 

toxicity (mouse)

43738101 (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 similar 

effects at next higher dose. Female 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.

Suppression of T4 and T3 in both sexes at the 

highest 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)

43850031 (1991)

Acceptable/guideline

0, 5, 25, 125 mg/kg/d

Maternal NOAEL = 25 mg/kg/day

LOAEL = 125 mg/kg/day based increased 

incidence of hepatocyte vacuolation.

Developmental NOAEL = 25 mg/kg/day

LOAEL = 125 mg/kg/day based on incidence of 

supernumerary ribs and additional presacral 

vertebrae; delayed ossification of the skull and 

enlarged fontanelles at next highest dose.

870.3800 Reproduction 

and fertility 

effects

(rat)

43850033, 43850032 (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); at 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 uterus; 

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 

43850038

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 

43850037

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 in 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 

pharmacokinetics

(rat)

43850039 (1992)

Acceptable/guideline

Single dose: 1 and 150 mg/kg

Multiple 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 via 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-acetylcysteine fluorophenylacetanilide 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 125I), an extra-thyroidal site 

of action is 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 125I-T4 clearance from 

blood, increased hepatocellular binding and 

biliary excretion of 125I-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. Hepatic UDP-GT was induced while 

5'DI was decreased, in a dose-related manner.

Special 

study

Mechanistic 

study 

(subcutaneous 

pump) – 

Neurotoxicity 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 (corneal opacity, slight precipitate

in both eyes, hematology, clinical chemistry, 

clinical signs, electroencephalography, 

electrocardiogram). Neurotoxicity signs

included wide stance, hyperactivity, postural

abnormalities, proprioceptive placing deficits, 

head tilt, hypermetria, and stumbling gait. Brain 

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 dosedependent 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 dosedependent decreases in mean fetal TSH. Fetal 

T4 levels could not be measured due to 

technological limitations.

A.2.1 Updated executive summary for MRID 

In a 2-generation reproduction study (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 dose levels of 0, 20, 100, and 500 ppm (equivalent to premating 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 generation: 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 females 

during the pre-mating phase and during gestation. There was no effect on survival, food 

consumption, or clinical signs except cannibalism (see below), at any dose level. Liver weight 

was increased in the high dose females in both generations and in the F1 females at the mid dose. 

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

hepatocytomegaly was observed 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 systemic 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 index 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 sperm parameters 

or sexual 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 levels, 

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 established 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, Quality 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. This 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 duration 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 exposures because the dosimetric adjustment incorporates mechanistic determinants of 

disposition that can be applied to shorter durations of exposures. 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 regions 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, relatively 

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 (VE) 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). 

Derivation of a Human Equivalent Concentration (HEC) for inhaled aerosols/particles is 

described by the following equation:

HECr = E × (DA ÷ DH) × (WA ÷ WH) × RDDR r Equation 1

HEC: Human equivalent concentration (mg/L)

E: Experimental exposure level (mg/L) or Point 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: Regional deposited dose ratio 

r: Respiratory region (extrathoracic, tracheobronchial or pulmonary)

A: Test animals

H: Humans

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 defined by the MMAD

and the σg. The RDDR is generally described by the following equation:

RDDRr = (RDDr,A ÷ RDDr,H) × (NFH ÷ NFA) Equation 2

 = ((10-6 × Ci,A × VE,A × Fr,A) ÷ (10-6 × Ci,H × VE,H × Fr,H)) × (NFH ÷ NFA)

= (Ci,A ÷ Ci,H) × (VE,A ÷ VE,H) × (Fr,A ÷ Fr,H) × (SAr,H ÷ SAr,A)

Ci: Inhaled concentration (mg/cm3 = 10-6 mg/m3)

VE: Minute volume (mL/min)

Fr: Fractional deposition in the specific respiratory region

SAr: Surface area of the specific respiratory region

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

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 guidance document (1994). 

Using EPA’s route-to-route extrapolation guidance (Memo, “Route-to-Route Extrapolations” J. 

Whalen and H. Pettigrew, 10/10/1998), 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:

HEDr = HECr × A × CF × DH × AF) Equation 3

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

HEC: Human equivalent concentration (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)

DH: 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 VE 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 Equations 

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 

RDDRET that should be protective of both the respiratory 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 exposure was assumed to be 8 hours/day and 5 days/week. 

Table A.3.2.1 Calculated HECs and Parameters Used for Derivation – Occupational Short 

and Intermediate Risk Assessment

Study / POD / r DA DH WA WH 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

UFA = 3x

UFH = 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. DA = 

Number of hours exposed per 24 hours for animals. DH = Number of hours exposed per 24 hours for humans. WA = Number of 

days exposed per 7 days for animals. WH = Number of days exposed per 7 days for humans. RDDR = Regional deposited dose 

ratio. HEC = Human Equivalent Concentration (mg/L). UF = uncertainty factor. UFA = extrapolation from animal to human 

(interspecies). UFH = 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. VE) of 8.3, 16.7 and 29 L/min. The relative activity factor (AF) is the ratio of the 

exposure scenario-specific VE and the default VE of 13.8 L/min.

Table A.3.2 Calculated HEDs and Parameters Used for Derivation – Occupational Short and Intermediate 

Risk Assessment

Specific 

Breathing Rate

HEC (mg/L) A CF DH 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 females0.206 males

UFA = 3x

UFH = 10x
Page 48 of 57

Table A.3.2 Calculated HEDs and Parameters Used for Derivation – Occupational Short and Intermediate 

Risk Assessment

Specific 

Breathing Rate

HEC (mg/L) A CF DH 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. DH = 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. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among 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/m3

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

weeks. 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 mortality, 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 females. 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 

parameters 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 absolute) were mildly increased (7-

12%) in both sexes, and 3 types of metabolic activity (cytochrome P450, N-demethylase and Odemethylase) were significantly increased at the mid and high doses in both sexes; cytochrome 

P450 activity was also increased at the low 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 seem 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 observed.

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). Larynx epithelial metaplasia was observed in all animals exposed to 

the mid and high doses, and severity (minimal to moderate) seemed to increase in a dosedependent manner. 

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

incidence 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 website8. 

 

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 

Rate2 (lb 

ai/A)

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation

Baseline* Baseline*

Dose 

(mg/kg/day)4

MOE5 

(LOC = 1000)

Dose 

(mg/kg/day)6

MOE7 

(LOC = 

300)

Mixer/Loader

Mixing/Loading Dry Flowables for 

Commercial Treatment with 

Impregnated Fertilizers

Corn

9.8 0.24

7.88 lb 

ai/ton 960 tons

0.043 40 0.02228 22

Soybeans 4.56 lb 

ai/ton 0.0249 68 0.0131 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 0.00394 73

Corn 0.78

200 acres

0.0205 83 0.0175 17

Soybeans 0.46 0.0121 140 0.0103 28

Wheat 0.34 0.00893 190 0.00761 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 OnFarm Treatment with Impregnated 

Fertilizers

Corn

220 0.219

0.78

160 acres

0.0159 110 0.000341 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 680

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 0.00150 950

Corn 0.78

200 acres

0.00713 240 0.000662 220

Soybeans 0.46 0.00419 410 0.000391 370

Wheat 0.34 0.0031 550 0.000289 490

Applying Impregnated Dry Bulk 

Fertilizer - Commercial Treatment

Corn 9.9 1.2 0.78 320 acres 0.00143 1,200 0.00375 130

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 (80 

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. 

Exposure Scenario Crop or 

Target

Dermal Unit 

Exposure (μg/lb 

ai)1

Inhalation Unit 

Exposure 

(μg/lb ai)1

Maximum 

Application 

Rate2

(lb ai/A)

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation

Gloves Baseline Dose 

(mg/kg/day)4

MOE5 

(LOC = 1000)

Dose 

(mg/kg/day)6

MOE7 

(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 0.000201 1,400

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, 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 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 (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 

Rate2

(lb ai/A)

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation

Gloves PF5 Respirator Dose 

(mg/kg/day)4

MOE5 

(LOC = 1000)

Dose 

(mg/kg/day)6

MOE7 

(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 0.000133 1,100

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) × 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 (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 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 

Rate2

(lb ai/A)

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation

Baseline PF5 Respirator Dose 

(mg/kg/day)4

MOE5 

(LOC = 1000)

Dose 

(mg/kg/day)6

MOE7 

(LOC = 300)

Applicator

Applying Impregnated Dry 

Bulk Fertilizer - Commercial 

Treatment

Corn

9.9 0.24

0.78

320 acres

0.00143 1,200 0.000749 670

Soybeans 0.46 0.000846 2,000 0.000441 1.100

Applying Impregnated Dry 

Bulk Fertilizer - On-Farm 

Treatment

Corn 0.78 160 acres 0.000719 2,400 0.000375 1,300

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 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 (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 

Rate2

(lb ai/A)

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation

DL + G Baseline Dose 

(mg/kg/day)4

MOE5 

(LOC = 1000)

Dose 

(mg/kg/day)6

MOE7 

(LOC = 300)

Mixer/Loader

Mixing/Loading Liquids for 

Groundboom Application Soybeans 29.1 0.219 0.46 200 acres 0.00155 1,100 0.000251 1,200

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 LOAEL (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, Gloves, 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 

Rate2

(lb ai/A)

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation

DL + G PF10 Dose 

(mg/kg/day)4

MOE5 

(LOC = 1000)

Dose 

(mg/kg/day)6

MOE7 

(LOC = 300)

Mixer/Loader

Mixing/Loading Dry 

Flowables for Groundboom 

Application

Wheat 41.2 0.896 0.34 200 acres 0.00162 1,000 0.000761 380

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 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 (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 

Rate2

(lb ai/A)

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation

EC EC Dose 

(mg/kg/day)4

MOE5 

(LOC = 1000)

Dose 

(mg/kg/day)6

MOE7 

(LOC = 300)

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 1,300

Soybeans 0.46 0.00042 4,100 0.000221 2,300

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 

Rate2

(lb ai/A)

Area 

Treated or 

Amount 

Handled 

Daily3

Dermal Inhalation

EC EC Dose 

(mg/kg/day)4

MOE5 

(LOC = 1000)

Dose 

(mg/kg/day)6

MOE7 

(LOC = 300)

Mixing/Loading Liquids for 

Groundboom Application Corn 8.6 0.083 0.78 200 acres 0.00078 2,200 0.000161 3,100

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 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 (80 

kg).

7 Inhalation MOE = Inhalation NOAEL (0.143, 0.289, or 0.501 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 Mexico1 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 Mexico1 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.