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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

MEMORANDUM 

DATE: January 21, 2011

SUBJECT: Flufenacet: Human Health Assessment Scoping Document in Support of 

Registration Review. 

PC Code: 121903 DP Barcode: 382463

Decision No.: 440255 Registration No.: N/A

Petition No.: N/A Regulatory Action: Registration Review 

Risk Assessment Type: Single Chemical Case No.: 7245

TXR No.: N/A CAS No.: 142459-58-3

MRID No.: N/A 40 CFR: §180.527

FROM: Sheila Healy, Toxicologist

Amelia Acierto, Chemist

Kristin Rury, Biologist

Risk Assessment Branch III 

Health Effects Division (7509P)

THRU: Paula Deschamp, Chief

Risk Assessment Branch III 

Health Effects Division (7509P)

TO: Wilhelmena Livingston, Chemical Review Manager

Risk Management and Implementation Branch IV

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

Executive Summary 

The Health Effects Division (HED) Flufenacet Registration Review Team has evaluated the 

status of the human health assessments for the herbicide flufenacet to determine the scope of 

work necessary to support Registration Review. HED has considered recent risk assessments for 

flufenacet, updates to its toxicity, exposure and usage databases, and the latest Agency science 

policy and risk assessment methodologies. The most recent risk assessment for flufenacet was 

conducted in 2007: HED Human Health Risk Assessment for Uses on Wheat, Perennial Grasses 

Grown for Seed and Sweet Corn (DP# 318555, J. Arthur, 03/15/2007). Additional documents 

used in this scoping document are cited below. 
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Flufenacet (FOE 5043, formerly thiafluamide), [N-(4-fluorophenyl)-N-(1-methylethyl)-2-[[5-

(trifluoromethyl)-1,3,4-thiadiazol-2-yl]oxy]acetamide], is an anilide herbicide registered for use 

on wheat (including triticale), perennial grasses grown for seed, corn (field and sweet), soybeans 

and fir trees (FIFRA 24(c) in WA and OR only). 

Under the new rules for toxicity data requirements (40 CFR §158.500), an immunotoxicity study 

is required for flufenacet. Additionally, a comparative thyroid assay is required. Since the last 

risk assessment, an acceptable 28-day inhalation study has been submitted. A protocol for a 

special comparative study on thyroid hormone levels has been submitted and reviewed. Once all 

of the requisite data have been received and reviewed, the flufenacet HED Registration Review 

Team will re-evaluate the sensitivity determination, as well as the points of departure and safety 

factors, used for risk assessment purposes. 

The only outstanding residue chemistry data requirement is a side-by-side bridging study needed 

to compare the liquid soluble concentrate (SC) and dry flowable (DF) formulations.

There are no registered residential uses of flufenacet. There is a potential for short- and 

intermediate-term occupational handler exposure to flufenacet during mixing, loading, and 

applying activities. There are currently no risks of concern. Flufenacet is available in both DF

and soluble concentrate SC formulations but occupational exposure during mixing and loading 

activities has only been assessed for the DF formulation. New flufenacet mixer/loader 

exposure/risk assessments will be needed for Registration Review for some use sites and SC 

formulations. 

Occupational postapplication exposure can occur via the dermal and/or inhalation route. 

Postapplication exposure assessments were conducted for all requisite registered use sites of 

flufenacet and there are no risks of concern.

Introduction 

HED has evaluated the status of the human health risk assessments for flufenacet to determine 

whether sufficient data are available and whether any updates are needed to support Registration 

Review. HED has considered the most recent risk assessment for flufenacet (DP# 318555, J. 

Arthur, 03/15/2007), HED and OPPIN databases, and conducted an open literature search. 

Flufenacet is an herbicide currently registered for ground application to pre-plant, pre-emergent, 

and early post-emergent wheat (including triticale), perennial grasses grown for seed, corn (field 

and sweet), soybeans and dormant fir trees (under FIFRA 24(c) registrations in Oregon and 

Washington). Aerial application is also permitted for dormant fir trees in Oregon and 

Washington only. The end-use formulations of flufenacet include dry flowable (50% ai), soluble 

concentrate (4 lb ai/gal) and a dry flowable multiple active ingredient (MAI; 54.4% flufenacet 

and 13.6% metribuzin). There are currently seven (7) end-use products and one (1) technical 

product registered for flufenacet. 

Hazard Identification/Toxicology of Flufenacet
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The toxicological data base for flufenacet is adequate for risk assessment but incomplete. In 

accordance with the new 40 CFR Part 158 data requirements for conventional pesticide 

registration, an immunotoxicity study in rats and/or mice is now required. Additionally, a 

comparative thyroid assay in rats is required. 

870.7800 Immunotoxicity: The immune system is highly complex and studies not 

specifically conducted to assess immunotoxic endpoints are generally inadequate to 

characterize a pesticide’s potential immunotoxicity. While data from hematology, 

lymphoid organ weights, and histopathology in routine chronic or subchronic toxicity 

studies might offer useful information on potential immunotoxic effects, these endpoints 

alone are generally insufficient to predict immunotoxicity. 

Comparative Thyroid Assay: qualitative and quantitative susceptibility was identified 

in the rat reproduction and developmental neurotoxicity studies. Available data in adult 

animals support the possibility of a decrease in thyroid hormones at dose levels similar to

those used in the submitted DNT study. Because pups were not directly dosed in the 

DNT study, but were exposed only in utero and potentially via lactation during maternal 

dosing (from GD6 through PND10), effects on thyroid hormone levels in young animals

following direct exposure to flufenacet have not been evaluated. 

Flufenacet has low acute toxicity, and is classified as toxicity category III for oral and dermal 

dosing, and toxicity category IV for inhalation exposure. Flufenacet is classified as toxicity 

category IV for primary eye and skin irritation. Flufenacet is dermal sensitizer under the 

experimental conditions of the Guinea Pig Maximization Test but not under the conditions of the 

Buehler Test.

The available toxicity data show the liver and nervous system to be targets for flufenacet-induced 

toxicity. Treatment-related changes in thyroid hormones were also observed in several species.

Clinical signs of neurotoxicity were observed in the neurotoxicity screening battery and 

subchronic and chronic feeding studies of mice, rats and dogs at doses greater than the respective 

LOAELs. Decreased absolute brain weights were observed in rats in both the subchronic and 

chronic toxicity studies at approximately 20 mg/kg/day and 100 mg/kg/day, respectively. 

Vacuolation of the cerebral cortex was noted in dogs treated sub-chronically at approximately 

100 mg/kg/day. When dogs were treated for longer durations, CNS axonal degeneration was 

observed at approximately 30 mg/kg/day. Neurotoxicity was accompanied by ocular lesions 

ranging from cataracts in mice to nystagmus (involuntary eye movement), vacuolation and optic 

nerve degeneration in dogs. 

Thyroid effects were seen throughout the toxicology database. Increased thyroid weights were 

observed in maternal rabbits during a prenatal developmental toxicity study of flufenacet. 

Relative thyroid weights were increased in male rats treated at 109.1 mg/kg/day for 13 weeks 

and 39 mg/kg/day for 104 weeks. Thyroid follicular cell hyperplasia was increased in a dosedependent manner in mice treated with 64.2 mg flufenacet/kg/day; thyroid colloid was observed 

in males treated with 275 mg/kg/day. Increased organ weight and hypertrophy of thyroid 

follicular cells were also observed in both the subchronic and chronic toxicity studies in the dog. 
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Levels of thyroxine (T4) and triiodothyronine (T3) were consistently depressed with treatment 

throughout the database.

There is no indication of increased susceptibility of young rats or rabbits following pre-natal 

exposure to flufenacet in the developmental toxicity studies. There was an indication of 

qualitative susceptibility in the two generation reproduction study. Effects seen in the offspring 

in the reproductive toxicity studies (including increased pup death in early lactation and 

cannibalism) were more severe than those seen in the parental animals (increased liver weight 

and hepatocytomegaly), although there was no difference in the NOAELs/LOAELS between 

parental animals and offspring in that study. Increased susceptibility (qualitative and 

quantitative) was seen in the developmental neurotoxicity study in rats. Decreased body weight 

was seen in pups at all dose levels, and additional effects, including decreased motor activity, 

delayed developmental landmarks, and decreases in morphometric measurements were seen at 

mid and high doses. The slight decrease in body weight in mid and high dose dams during early 

lactation may have been due to palatability of test substance and was not considered adverse. 

The selection of 1.7 mg/kg/day as a LOAEL in the DNT is conservative and protective of effects 

seen in the two-generation reproduction study.

Flufenacet is not mutagenic in bacteria or cultured mammalian cells. There is also no indication

of a clastogenic effect up to toxic doses in vivo. Flufenacet is characterized as “not likely” to be a 

human carcinogen in the RfD Peer Review Committee report dated 7/16/1997.

In 2007, HED selected toxicity endpoints based on the most sensitive effect, decreased body 

weight gain and decreased body weight gain in pups in the DNT study which is protective of 

thyroid and liver effects. The DNT study is classified as acceptable/non-guideline/upgradable 

because of missing data, including the following: morphometric histopathology, learning and 

memory evaluations and positive controls. HED is not requesting additional developmental 

neurotoxicity data because the concern for susceptibility is low: the only effect seen in the 

absence of maternal toxicity at the lowest dose in DNT offspring (LOAEL = 1.7 mg/kg/day) was 

a transient decrease in body weight which was not observed in offspring at the lowest dose (4.9 

mg/kg/day) in the multigeneration reproduction study. While morphometric data may elucidate 

the neurotoxic action of flufenacet, it will not change the offspring endpoint. The toxicity 

endpoints selected in 2007 have been reevaluated and are consistent with current policy; they are 

valid and presented in Attachment 4 Table 5.

The FQPA safety factor has been re-examined based on the current policy and guideline 

requirements. An additional 10X FQPA safety factor (UFL + UFDB) is has been retained to 

address the lack of NOAEL in the DNT study and the lack of comparative susceptibility data for 

thyroid hormones and neuropathological lesions in pups following direct exposure to flufenacet. 

Available data support the possibility of decreases in thyroid hormones at dose levels similar to 

those used in the submitted DNT study, as well as increases in neurobehavioral and 

neuropathological findings in multiple species. At the time of the registration review risk 

assessment, if risk methodologies for applying uncertainty factors have been revised, these inputs

will be incorporated into the risk assessment.
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Open literature and submitted mechanistic studies indicate that thyroid effects of flufenacet 

toxicity are secondary to increased liver metabolism, namely induction of the T4-glucuronidating 

enzyme, UDP-GT.; thyroid toxicity is mediated through a mechanism separate and distinct from 

direct action on synthesizing and secreting functions of the pituitary, thyroid or hypothalamus. 

Although the registrant has proposed that brain lesions are attributable to treatment-related 

metabolic limitations (decreased GSH reductase), the mechanism of flufenacet neurotoxicity has 

not been clearly elucidated. The Point of Departure (POD) used for all risk assessment scenarios 

is protective of thyroid effects and neurotoxicity.

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (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, and 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 quantitative relationship between the dose and the E, A, or T effect.

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. 

This list of chemicals was selected based on the potential for human exposure through pathways 

such as food and water, residential activity, and certain post-application agricultural scenarios. 

This list should not be construed as a list of known or likely endocrine disruptors.

Flufenacet is not among the group of 58 pesticide active ingredients on the initial list to be

screened under the EDSP. For further information on the status of the EDSP, the policies and 

procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, please 

visit our website: http://www.epa.gov/endo/.

Conclusions:

The newly required immunotoxicity study and a comparative thyroid assay are required to 

support registration review of flufenacet. HED will consider the existing toxicity database as 

well as all additional toxicity studies received during registration review and will re-evaluate the 

sensitivity determination, as well as the points of departure and safety factors, used for risk 

assessment purposes.

Dietary Exposure 

Refined, acute probabilistic and chronic dietary exposure assessments were conducted for all 

existing food uses of flufenacet and drinking water. Anticipated residues for many crops (field 

corn, soybean, sweet corn and wheat) were developed using field trial data. Anticipated residues 

for livestock commodities were derived using available feeding and metabolism studies in 
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conjunction with the anticipated dietary burden to ruminants, swine and poultry. Tolerance level 

residues were used to assess flufenacet exposure from the remaining commodities (i.e., cereal 

grains). Pesticide Data Program (PDP) monitoring data are available for wheat flour (2003, 

2004), wheat grain (2005) and pork fat/muscle (2005). The PDP data were not used to develop 

anticipated residues for wheat commodities, since they reflect the historical, regional Section 18 

use of flufenacet on wheat in the Pacific Northwest, rather than the proposed Section 3 national 

use. Since wheat makes up 80% of the theoretical swine diet, the PDP data for pork 

commodities are also considered inappropriate for estimating anticipated residues in these 

commodities.

The most recent acute probabilistic and chronic aggregate dietary (food and drinking water) 

exposure and risk assessments were conducted using the Dietary Exposure Evaluation Model 

DEEM-FCIDTM, Version 2.03, which uses food consumption data from the U.S. Department of 

Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 

1998. Estimated drinking water concentrations (EDWCs) in surface water were generated using 

the PRZM-EXAMS model. Ground water EDWCs were generated using SCI-GROW model. 

The modeled peak surface water value of 8.64 ppb was used in the acute dietary assessment. 

The modeled annual mean surface water value of 2.23 ppb was used in the chronic dietary 

assessment. 

For the chronic dietary risk assessment, average field trial residues were calculated and 

multiplied by the average %CT or projected %CT (wheat) estimate to derive an anticipated 

residue value. For the acute dietary assessment, an average of the field trial data for blended 

commodities was used with the maximum %CT. For non-blended or partially-blended 

commodities, all values from the field trials were included in the residue distribution file (RDF) 

along with the use of maximum %CT. 

At the 99.9th percentile, the food and drinking water exposure to infants, less than 1 year old (the 

most highly exposed population subgroup), from the existing uses of flufenacet results in an 

estimated risk equivalent to 89% of the acute population adjusted dose (aPAD). Combined 

dietary exposure from food and drinking water at the 99.9th percentile of exposure is estimated to 

be 0.000514 mg/kg/day for the general U.S. population, equivalent to 30% aPAD.

For the U.S. Population, the existing uses of flufenacet resulted in an exposure which is 

equivalent to 2.9% of the chronic population adjusted dose (cPAD). The most highly exposed 

subpopulation was infants, less than 1 year old, with an exposure equivalent to 9.2% of the 

cPAD.

Conclusions:

Pending completion and submission of data from the third side-by-side bridging study (Iowa 

field trial) there are no Residue Chemistry data gaps. Provided that EFED water values are not 

revised according to new policies, a new dietary assessment for flufenacet may not be required 

for the purpose of registration review.

Residential Exposure 
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Residential Handlers

Flufenacet is not currently registered for use by homeowners or in residential settings; therefore, 

no residential handler exposure potential is expected. Flufenacet is applied only to pre-and postemergent agricultural sites. 

Residential Postapplication

Flufenacet is not currently registered for use by homeowners or in residential settings. 

Conclusion:

Because flufenacet is not registered for use in residential settings, there is currently no risk 

concern for residential exposure. If exposure data and methodologies for estimating exposure 

have changed for issues such as volatilization, spray drift and track-in from field applications to 

residential settings, then a residential exposure assessment may be required. 

Aggregate Risk Assessment 

In the most recent human health risk assessment (DP# 318555, J. Arthur, 03/15/2007), aggregate 

exposure/risk assessments were not conducted. There are no residential uses of flufenacet;

therefore, the aggregate risk assessment for flufenacet includes only the contribution of risk from 

dietary (food and water) sources. 

Occupational Exposure 

Flufenacet is registered for use on wheat (including triticale), perennial grasses grown for seed, 

corn (field and sweet) and soybeans. Flufenacet is also registered under FIFRA 24(c)

registrations for use on dormant fir trees (Douglas fir (forest/shelterbelt), fir (forest, shelterbelt), 

Fraser fir (forest, shelterbelt), Grand fir (forest) and noble fir (forest)) in Washington and 

Oregon. There is a potential for short- and intermediate-term exposure to flufenacet during 

mixing, loading, and applying activities. Occupational risk assessments have been conducted for 

only DF formulations of flufenacet; however, flufenacet is also registered as a SC. New 

flufenacet liquid mixer/loader exposure assessments will be needed for corn (field and sweet), 

soybeans and wheat under Registration Review. Mixer/loader, applicator and flagger 

assessments will also be needed for fir trees. 

Occupational Handlers

Tables 6 and 7 summarize the occupational scenarios that exist for flufenacet and whether or not 

each scenario has been adequately assessed. Table 8 summarizes representative margins of 

exposure (MOEs). In all cases, flufenacet labels require mixer/loader and applicators to wear 

long sleeved shirts, long pants, shoes and socks. In some cases, waterproof or chemical resistant 

gloves, a chemical resistant apron and/or a dust mist respirator are also required for 

mixer/loaders. 

Previous occupational assessments used The Pesticide Handlers Exposure Database (PHED) 

Surrogate Exposure Guide (Version 1.1), August 1998 for unit exposure values. Risks of 

concern were identified for mixing and loading of DF flufenacet to support groundboom 

application to corn at baseline personal protective equipment. Mixing and loading of flufenacet 
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for ground application to corn requires additional protection in order to not be of concern to HED 

(MOE) > 300). MOEs for other registered use sites ranged from 440 to 2,700 for dermal 

exposure and 850 to 2,000 for inhalation exposure at baseline. New exposure assessments are 

needed for mixer/loaders to support flufenacet application to corn, soybeans, and wheat 

(including triticale) to incorporate liquid formulations of flufenacet. New exposure assessments 

are also needed for mixing, loading, flagging and aerial application of flufenacet (DF 

formulation only) to dormant fir trees.

Postapplication Exposure

Occupational post-application exposure to flufenacet can occur via the dermal and/or inhalation 

routes. Table 9 summarizes the occupational post-application scenarios that exist for flufenacet 

and whether or not each scenario has been previously assessed. Post-application exposure 

assessments were conducted for all requisite registered use sites of flufenacet. The dermal 

MOEs ranged from 460 to 1,000 (LOC = 300). 

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for flufenacet at this time. However, volatilization of pesticides 

may be a potential source of post-application inhalation exposure to individuals nearby to 

pesticide applications. The Agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report 

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

Agency is currently evaluating the SAP report and may, as appropriate, develop policies and 

procedures to identify whether to incorporate post-application inhalation exposure into the 

Agency’s risk assessments, and methods to assess post-application inhalation exposure. If new 

policies or procedures are implemented, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment for flufenacet.

Conclusions:

The following occupational exposure scenarios listed below have not been assessed using current 

ORE policies. A revised occupational assessment is needed. All other occupational exposure 

scenarios were assessed adequately and do not present risks of concern. At the time of the 

registration review risk assessment, if exposure data and methodologies for estimating exposure 

have changed, these inputs will be incorporated into the assessment. 

ORE Assessment deficiencies include: 

New mixer/loader occupational risk assessments will be needed to incorporate the liquid 

formulations of flufenacet for corn, soybeans, wheat (and triticale). 

New mixer, loader, applicator and flagger risk assessments will be needed for aerial 

application of flufenacet on dormant fir trees.

Labels for flufenacet application to corn should be revised to require coveralls for 

mixer/loaders (risks of concern result with only baseline PPE and gloves).

Public Health and Pesticide Epidemiology Data
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For this evaluation, both of the OPP Incident Data Systems (IDS) were consulted for pesticide 

incident data on the active ingredient flufenacet. For IDS aggregate summaries, from January 1, 

2002 to May 27, 2010, there are eight cases reported for flufenacet. Because it falls within the 

categories reported as counts (which includes minor, unknown or no effects), there is no unique 

report that provides details about the incident and single chemical incidents are not distinguished 

from multiple chemical incidents. For the main IDS, from January 1, 2002 to October 7, 2010,

there are no cases reported for single chemical, flufenacet only in the database. 

Therefore, 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 included in the risk assessment

Tolerance Assessment and International Harmonization 

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

or Canada for any agricultural commodity. In Mexico, an MRL of 0.05 mg/kg was established 

in corn (communication with S. Funk, 8/17/2006). 

U.S. tolerances are currently expressed in terms of flufenacet and its metabolites containing the

4-fluoro-N-methylethyl benzenamine moiety in or on the following commodities at the indicated 

levels (Table 3): 

Environmental Justice 

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

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

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

(http://www.eh.doe.gov/nepa/tools/guidance/Volume1/2-6-EO_12898envjustice.pdf). The 

Office of Pesticide Programs (OPP) typically considers highest potential exposures from the 

legal use of a pesticide when conducting human health risk assessments, including, but not 

limited to, people who obtain drinking water from sources near agricultural areas, the variability 

of diets within the U.S., and people who may be exposed when harvesting crops. Should these 

highest exposures indicate potential risks of concern, OPP further refines the risk assessments to 

ensure that the risk estimates are based on the best available information. 

Cumulative

The Agency has not determined whether flufenacet shares a common mechanism of toxicity with 

other chemical substances. For information on 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 

mechanistic 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. 

Human Studies 
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Flufenacet occupational risk assessments rely in part on data from studies in which adult human 

subjects were intentionally exposed to a pesticide or other chemical. These studies have been 

determined to require a review of their ethical conduct, and have received that review. The 

Agency has reviewed these studies, which comprise PHED and the ARTF, and has determined 

that they have been conducted ethically. 

Data Requirements

Toxicology

Under the 40 CFR 158.500 data requirements an immunotoxicity study is required. 

Additionally a special comparative sensitivity study on thyroid hormone levels in neonatal and 

adult rats is required based on the changes seen in thyroid hormones in multiple species in adult 

toxicity studies. 

Residue Chemistry 

Data from a third side-by-side bridging study for the SC and DF formulations are required

Occupational Exposure

No additional occupational exposure data for flufenacet is needed for risk assessment purposes. 
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References 

Memoranda Relevant to Registration Review of Flufenacet

Author Barcode (DP#) Date Title

J. Arthur D318555 03/15/2007

Flufenacet: HED Human Health Risk Assessment for 

Uses on Wheat, Perennial Grasses Grown for Seed and 

Sweet Corn. (Petitions: 6F04631, 0F6095; PC: 121903, 

DP318555)

S. Stanton D334695 12/05/2006

Flufenacet: Acute and Chronic Aggregate Dietary 

Exposure and Risk Assessments for the Proposed 

Section 3 Registration on Wheat, Sweet Corn and 

Grass Grown for Seed. 

A. Acierto D288564

D288565 11/29/2006

Flufenacet. Registration for Use on Field Corn, Sweet 

Corn, Soybeans, Wheat, and Grass Grown for Seed. 

Summary of Analytical Chemistry and Residue Data. 

Petition Number: 6F04631

A. Acierto D372545 10/26/2010

Flufenacet. Bridging Studies Supporting Foliar 

Application Uses of SC Formulation. Summary of 

Analytical Chemistry and Residue Data.

S. Recore D383691 11/30/2010 Flufenacet: Review of Human Incidents

R. Prieto N/A 06/21/2010 Usage/Use Report Package in Support of Registration 

Review of Flufenacet (121903)

K. Raffaele TXR 0051853 04/30/2003 FLUFENACET - 2

nd Report of the Hazard 

Identification Assessment Review Committee.

A. Grube D320497

D321194 10/25/2006

Projected Crop Treated for Herbicide Flufenacet (PC 

121903) on Sweet Corn, Wheat and Grasses Grown for 

Seed.
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Attachments 

1. Chemical Identity Table

2. Tolerance Summary Table

3. Percent Crop Treated Data Comparison Table

4. Endpoint Selection Table 

5. Occupational Exposure Tables 

7. Data Call-In Tables
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Attachment 1

Chemical Identity Table

Table 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

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).

Table 2. Physicochemical Properties of Technical Grade Flufenacet

Parameter Value Reference

Melting point/range ( C) 75.5-77.0

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

MRID#:

43441101

Vapor pressure at 25 C 2 X 10-6

h Pa (N-isomer) (equivalent to 4 X 10-6torr)

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

S

N N

N

CH3 H C3

O

O

CF3

F
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Attachment 2 

Tolerance Summary Table 

Flufenacet (PC Code 121903; 11/23/10)

Summary of US and International Tolerances and Maximum Residue Limits 

US Canada Mexico1Codex2

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-fluoroN-methylethyl benzenamine moiety

N-(4-fluorophenyl)-N-(1-

methylethyl)-2-[[5-

(trifluoromethyl)-1,3,4-

thiadiazol-2-yl]oxy]acetamide

None

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

Commodity US Canada Mexico 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

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

Wheat, forage 6.0

Wheat, grain 0.60

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

Completed: M. Negussie; 11/29/2010
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1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

(c) Tolerances with regional registrations . Tolerances are established for combined residues of 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, with regional registration.

Commodity Parts per million

Grass, forage 7.0

Grass, hay 0.4

(d) Indirect or inadvertent residues. Tolerances are established for indirect or inadvertent residues of the herbicide 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 in or on the following raw agricultural commodities when present therein as a 

result of application of flufenacet to the growing crops in paragraph (a) of this section.

Commodity Parts per million

Alfalfa, forage 0.1

Alfalfa, hay 0.1

Alfalfa, seed 0.1

Clover, forage 0.1

Clover, hay 0.1

Grain, cereal, group 15, except rice 0.1

Grain, cereal, forage, fodder, and straw, group 16, except rice 0.1

Grass, forage, fodder, and hay, group 17 0.1
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Attachment 3

Percent Crop Treated Data Comparison Table

Table 4. Percent Crop Treated Data Comparison for Flufenacet

Average %CT Data Maximum %CT Data

Crop 2006 2010 2006 2010

Corn1

3 <2.5 10 5

Pasture <1 <1 100 <2.5

Soybeans N/A <1 N/A <2.5

Sweet Corn 3 <1 10 <2.5

Wheat 1 <1 3 <2.5

1

Since the flufenacet usage on field corn is at a low and stable level, it is expected that usage on 

sweet corn will be similar to usage on field corn. (A. Grube, D320497, 10/25/2006)

All numbers rounded

<500 Less than 500 pounds of active ingredient

<2.5 Less than 2.5% of crop treated

<1 Less than 1% of crop treated

SLUA data sources include: 

USDA-NASS (United States Department of Agriculture’s National Agricultural Statistics Service

Private Pesticide Market Research 

California DPR (Department of Pesticide Regulation
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Attachment 4

Endpoint Selection Table

Table 5. Flufenacet Endpoint Selection Table

EXPOSURE

SCENARIO

Point of 

Departure 

(mg/kg/day)

Uncertainty

Factors

(FQPA SF = 

1x)

RfD

Level of 

Concern

STUDY & Toxicological Effects

Acute Dietary 

(General 

population

including infants 

and children)

LOAEL = 

1.7 

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 

10X (UFL, 

UFDB)

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

decreased body weight/body weight gain.

Chronic Dietary LOAEL= 1.7

mg/kg/day

UFA = 10X

UFH = 10X

FQPA SF = 

10X (UFL, 

UFDB)

Chronic RfD = 

0.0017 

mg/kg/day

cPAD = 0.0017

mg/kg/day

Developmental Neurotoxicity study in 

rats.

LOAEL = 1.7 mg/kg/day based on

decreased body weight/body weight gain.

Short- and 

Intermediate-Term

Dermal 

LOAEL= 1.7 

mg/kg/day

(dermal 

absorption 

rate = 4%)

UFA = 10X

UFH = 10X

FQPA SF = 

3X (UFL)

Occupational 

LOC for MOE 

= 300

Developmental Neurotoxicity study in 

rats.

LOAEL = 1.7 mg/kg/day based on

decreased body weight/body weight gain 

in pups.

Short- and 

Intermediate-Term

Inhalation

LOAEL=1.7

mg/kg/day

(inhalation 

absorption 

rate = 100%)

UFA = 10X

UFH = 10X

FQPA SF = 

3X (UFL)

Occupational

LOC for MOE 

= 300

Developmental Neurotoxicity study in 

rats.

LOAEL = 1.7 mg/kg/day based on

decreased body weight/body weight gain 

in pups.

Cancer 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). RfD = reference dose. MOE = margin of exposure. LOC = 

level of concern. 
18 of 24

Attachment 5

Occupational Exposure Tables

Table 6 provides a comparison of mixer/loader scenario inputs previously assessed and current standard HED inputs. The current 

maximum use rate listed on flufenacet labels. 

Table 6. Occupational Mixer/Loader Scenarios for Registered Uses of Flufenacet

Crop/Use 

Site

Application 

Equipment 

Assessed

Possible 

Application 

Types

Formulation 

Types

Formulation 

Assessed

Label 

Application 

Rate

Application 

Rate 

Assessed

Max 

Acres 

treated 

Assessed

Max 

Acres 

Treated 

Needed

Risk 

Assessment 

Needed

Notes

Corn Groundboom Groundboom DF, SC DF 0.78 0.78 200 200 Yes 

Liquid 

assessment 

needed

Soybeans Groundboom Groundboom DF, SC DF 0.44 0.44 200 200 Yes

Liquid 

assessment 

needed

Triticale NA Groundboom DF, SC NA 0.34 NA NA 200 No 

Will be 

covered by 

wheat

Wheat Groundboom Groundboom DF, SC DF 0.34 0.34 200 200 Yes

Liquid 

assessment 

needed

Fir 

(Douglas 

fir, Fraser 

fir, Grand 

fir, and 

Noble fir)

NA Aerial, 

Groundboom DF NA 0.68 NA NA 1200, 80 Yes 

Aerial 

assessment 

needed

Grass 

Grown 

for Seed

Groundboom Groundboom DF, SC DF 0.44 0.44 200 80 No 

Will be 

covered by 

Soybean 

assessment
19 of 24

Table 7 provides a comparison of applicator scenario inputs previously assessed and current standard HED inputs by use site. 

Table 7. Occupational Applicator & Flagger Scenarios for Registered Uses of Flufenacet

Crop/Use 

Site

Application 

Equipment 

Assessed

Possible 

Application 

Types

Formulation 

Types

Formulation 

Assessed

Label 

Application 

Rate

Application 

Rate 

Assessed

Max 

Acres 

treated 

Assessed

Max 

Acres 

Treated 

Needed

Risk 

Assessment 

Needed

Corn Groundboom Groundboom DF, SC DF 0.78 0.78 200 200 No

Soybeans Groundboom Groundboom DF, SC DF 0.44 0.44 200 200 No

Triticale NA Groundboom DF, SC NA 0.34 NA NA 200 No

Wheat Groundboom Groundboom DF, SC DF 0.34 0.34 200 200 No

Fir 

(Douglas 

fir, Fraser 

fir, Grand 

fir, and 

Noble fir)

NA Aerial, 

Groundboom DF NA 0.68 NA NA 1200, 80 Yes

Grass 

Grown for 

Seed

Groundboom Groundboom DF, SC DF 0.44 0.44 200 80 No

Flagger

Fir 

(Douglas 

fir, Fraser 

fir, Grand 

fir, and 

Noble fir)

NA Aerial, 

Groundboom DF NA 0.68 NA NA 1200, 80 Yes
20 of 24

Table 8 summarizes representative margins of exposure (MOEs). In all cases, flufenacet labels require mixer/loader and applicators to 

wear long sleeved shirts, long pants, shoes and socks. In some cases, waterproof or chemical resistant gloves, a chemical resistant 

apron and/or a dust mist respirator are also required for mixer/loaders.

Table 8. Summary of Representative Occupational Handler Exposure Scenarios and Risks for Flufenacet (all using DF Formulation)

Exposure Scenario Assessed

Maximum 

Application Rate 

Assessed

Acres 

Treated 

(acres/day)

Unit Exposure (mg/lb ai)1 Dose2 Short/Intermediate 

Term Risk (MOE)3

Dermal Inhalation Dermal Inhalation Dermal Inhalation

Mixer/Loader

Groundboom (Corn) with coveralls 0.78 200 0.047 0.00077 0.0048 0.002 350 850

Groundboom (Soybeans) baseline 0.44 200 0.066 0.00077 0.0039 0.0012 440 1,400

Groundboom (Wheat) baseline 0.34 200 0.006 0.00077 0.003 0.00087 570 2,000

Groundboom (Grass Grown For Seed) 

baseline 0.44 200 0.0066 0.00077 0.0039 0.0012 440 1,400

Applicator 

Groundboom (Corn) open cab 0.78 200 0.014 0.00074 0.0015 0.0019 1,100 900

Groundboom (Soybeans) open cab 0.44 200 0.014 0.00074 0.00082 0.0011 2,100 1,500

Groundboom (Wheat) open cab 0.34 200 0.014 0.00074 0.00063 0.00084 2,700 2,000

Groundboom (Grass Grown For Seed) 

open cab 0.44 200 0.014 0.00074 0.00082 0.0011 2,100 1,500

1 Unless otherwise specified, unit exposure values are for workers wearing baseline clothing, (i.e., long-sleeved shirt, long pants, shoes and socks)

2 Daily Dose = [Application Rate (lb ai/A) x Acres Treated (A/day) x Unit Exposure (mg/lb ai handled)*DAF]/Body Weight (Dermal Absorption Factor: 4%)

3 MOE = NOAEL/ Daily Dose. Short- and Intermediate-term Dermal & Inhalation 

NOAEL=1.7 mg/kg/day. 
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Table 9 summarizes the occupational post-application scenarios that exist for flufenacet and whether or not each scenario has been 

previously assessed. Post-application exposure assessments were conducted for all the registered use sites of flufenacet except fir 

trees

Table 9. Summary of Occupational Post-application Risk of Flufenacet by Use Site

Crop/Use Site DP#

Maximum 

Transfer 

Coefficient

DFR1 MOE2

Post-application 

Assessment 

Needed? 

Corn D334694 & 

D289839 400 1.75 460 No

Grasses grown for Seed D334694 400 0.987 800 No

Soybeans D289839 400 0.987 800 No

Wheat & Triticale D334694 & 

D289839 400 0.763 1,000 No

1. Dislodgeable foliar residue = Application rate (lb ai/A) x CF (4.54E+8 μg/lb) x CF (2.47 E-8 A/cm2) x 0.2

2. Daily dose = (DFR x TC x Exposure Time (8 hours) x Dermal Absorption Factor (4%))/((CF 1000 μg/mg) x Body Weight)
22 of 24

Attachment 7

Data Call-In Tables

Guideline Number: 870.7800

Study Title: Immunotoxicity 

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a 

pesticide (food and non-food uses). 

The Immunotoxicity Test Guidance (OPPTS 870.7800) prescribes functional immunotoxicity testing and is 

designed to evaluate the potential of a repeated chemical exposure to produce adverse effects (i.e., suppression) 

on the immune system. Immunosuppression is a deficit in the ability of the immune system to respond to a 

challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory Syndrome 

(SARS), or neoplasia. Because the immune system is highly complex, studies not specifically conducted to 

assess immunotoxic endpoints are inadequate to characterize a pesticide’s potential immunotoxicity. While data 

from hematology, lymphoid organ weights, and histopathology in route chronic or subchronic toxicology studies 

may offer useful information on potential immunotoxic effects, these endpoints alone are insufficient to predict 

immunotoxicity. 

Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provide critical scientific information needed to characterize potential hazard to the 

human population on the immune system from pesticide exposure. Since epidemiologic data on the effect of 

chemical exposures on immune parameters are limited and are inadequate to characterize a pesticide’s potential 

immunotoxicity in humans, animal studies are used as the most sensitive endpoint for risk assessment. These 

animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and 

are considered a primary data source for reliable reference dose calculation. For example, animal studies have 

demonstrated that immunotoxicity in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8-

tetrachlorodibenzo-p-dioxin) among developmental, reproductive, and endocrinologic toxicities. Additionally, 

the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on the observed 

immunotoxicity in animal studies (IRIS, 1997). 

How could the data impact the Agency's future decision-making?

If the immunotoxicity study shows that the test material poses either a greater or diminished risk than that given 

in the interim decision’s conclusion, the risk assessments for the test material may need to be revised to reflect 

the magnitude of potential risk derived from the new data. 

If the Agency does not have this data, a 10X database uncertainty factor may be applied for conducting a risk 

assessment from the available studies. 

Guideline Number: Special Study

Study Title: Comparative Thyroid Assay (CTA)

Rationale for Requiring the Data

The Office of Pesticide Programs’ Guidance for Thyroid Assays in Pregnant Animals, Fetuses and Postnatal 

Animals and Adult Animals addresses the issue of disruption of thyroid hormone homeostasis during 

development. Chemicals that perturb thyroid homeostasis and result in hypothyroidism are known to be 

associated with neurological disorders and alterations in neurological development, both in animals and humans.

Qualitative and quantitative susceptibility was identified in the rat reproduction and developmental neurotoxicity 

studies of flufenacet. Available data in adult animals support the possibility of a decrease in thyroid hormones at 

dose levels similar to those used in the submitted DNT study. Because pups were not directly dosed in the DNT 
23 of 24

study (which included thyroid hormone satellite groups), but were exposed only in utero and potentially via 

lactation during maternal dosing (from GD6 through PND10), effects on thyroid hormone levels in young 

animals following direct exposure to flufenacet has not been evaluated. There is insufficient data to adequately 

characterize flufenacet’s potential to disrupt thyroid hormone homeostasis and consequent neurodevelopment.

Practical Utility of the Data

How did the Agency make its re-registration decision without these data? 

The Agency used the developmental neurotoxicity study for dietary and non-dietary risk assessments. The 

LOAEL established in this study (DNT) was used along with the 10X Safety Factor for the use of the LOAEL 

(i.e., the lack of a NOAEL) and the data gap for a comparative thyroid assay (CTA) which could provide data on 

the thyroid effects in the offspring. 

How will the data be used? 

The data generated from the CTA may provide a dose and endpoints of concern for use in risk assessment and/or 

enable the Agency to confirm or revise the FQPA safety factor used in the risk assessments for flufenacet. For 

example, if the CTA identifies a clear NOAEL that would be protective of the effects seen in the DNT, then this 

study may be appropriate for selection of a point of departure and thereby eliminate uncertainty in extrapolating 

risk from a LOAEL.

How could the data impact the Agency’s future decision-making?

The newly generated CTA data could potentially impact the dose and/or FQPA safety factor currently used in the 

overall risk assessment of flufenacet. If the FQPA safety factor changes, then this impacts the calculation of the 

acute and chronic Population Adjusted Doses, and therefore may either reduce or increase risk estimates in the 

dietary assessments for the flufenacet risk assessment. If the dietary risk is increased based on information in the 

new CTA study, then additional mitigation may be needed to address potential risks of concern. If the dietary 

risk is decreased, then the registrant may be able to expand uses.

Guideline Number: 830.1500 

Study Title: Bridging Studies Supporting Postemergence Application Uses of SC Formulation

Rationale for Requiring the Data

Sweet corn (corn-on-the-cob) is a human food, and field corn is both a livestock feed item and a source of human 

food items (e.g., corn oil, corn syrup). The forage and fodder of both are livestock feed items.

Data to determine the level of residues on the foods and on the feeds (which could be transferred to meat and milk 

and eggs used for human consumption) are necessary to determine human exposure to flufenacet from this pathway 

and to set appropriate tolerances. Field trials are required for each commodity/commodity group according to 

guidelines that take into account where the crop is grown and how much of the crop is grown. Field trials are 

required for each type of formulation because the formulation can have significant effect on the magnitude of the 

pesticide residue left on the corp. Residue trials need to represent the maximum application rate on the label and 

have a geographic distribution representative of the commodity/commodity group. Some of the best ways to gather 

such information is to compare residues derived from different types of formulations in side-by-side trials. 

In this case, adequate data from field trials conducted with a DF (dry flowable) formulation were used to establish 

tolerances and evaluate human exposure. Bridging trials, or side-by-side trials, of the DF and a proposed formulation 

(SC, suspension concentrate) are needed to demonstrate the equivalency (or difference) in residues from identical 

uses of the two formulations. 

It should be noted that three side-by-side trials for bridging purposes is a minor requirement compared to the number 

of trials required without consideration of a bridging approach, 20 for corn and 12 for sweet corn (32 total). Three 

trials is regarded as the minimum needed to make an accurate comparison of the residue levels from the two different 

formulations.

Practical Utility of the Data
24 of 24

How did the Agency make a re-registration decision without this data? Crop field trials are required for each 

type of formulation and must be conducted in areas reflecting the geographic distribution. For flufenacet, the Agency 

used the available and adequate crop field trial data for the DF formulation to make the registration decision for corn 

and sweet corn commodities. The registrant subsequently requested addition of an SC formulation for use on corn 

and sweet corn. There is no way to predict residue levels from the SC formulation, even though the use pattern 

(method of application, rate of application, interval from application to harvest) is identical to the DF formulation. 

The Agency used field trial data for the DF formulation and has made conservative assumptions within the risk 

assessment to account for the lack of magnitude of the residue data for the SC formulation. 

How will the data be used? 

A bridging study with two side-by-side trials has been received and evaluated. Three trials were requested. The 

results indicate no residues at the limit of quantitation on field corn grain and sweet corn from either formulation and 

slightly higher residues from the DF formulation on forage and fodder. 

These results indicate that the tolerance set based on the DF formulation may be extended to the SC formulation and 

that human dietary risk assessment conducted with DF formulation results will also cover the SC formulation. The 

results of the required third side-by-side trial will be confirmatory.

Farmers rely on the Agency to set adequate and appropriate tolerances in conjunction with label directions. Farmers 

understand that if they rely on label directions and follow those directions, their crop will be under-tolerance and can 

therefore be sold in interstate commerce thereby preventing legal uses from producing over-tolerance residues 

resulting in crop seizure. 

How could the data impact the Agency’s future decision-making?

These data could result in the need to increase the tolerances for corn and sweet corn commodities, although partial 

results indicate that this is not the situation. Dietary risk assessments might also require revision.