### 1 of 24 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY
AND POLLUTION PREVENTION



### MEMORANDUM

DATE: January 21 , 201 1

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

T XR 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 Ass essment 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.

### 2 of 24

Flufenacet (FOE 5043, formerly thiafluamide), [ N

- (4

- fluorophenyl)

- N

- (1

- m ethylethyl)

- 2

- [[5

- (trifluoromethyl)

- 1,3,4

- thiadiazol

- 2

- yl]oxy]acetamide ]

, is an anilide herbicide registered for use

on whea t (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 stu dy 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 concentrat e ( 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 t here are no risks of concern

.

Introduction

HED has evaluated the status of the huma n health risk assessments for flufenacet to determine whether sufficient data are available and whether any updates ar e needed to support Registration

Review. HED has considered the most re cent risk assessment for flufenacet ( DP# 318555, J. Arthur, 03/15/2007 ), HED and OPPIN databases, and conducted an ope n literature search.

Flufenacet is an herbicide currently registe red 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

### 3 of 24

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 immunotoxic ity study in rats and/or mice is now required . Additionally, a comparative thyroid assay i n rats is required

.

870.7800 Immunotoxicity : T he 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 hem atology, 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 fl ufenacet 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 classif ied as to xicity
category IV for p rimary eye and skin irritation. Flufenacet is dermal se nsitizer under the experimental conditions of the Guinea Pig Maximization Test but not under the conditions of the

Buehler Test.

The available toxici ty data show the liver and nervous system to be target s for flufenacet

- induced toxicity. Treatment

- related changes in thyroid hormones were also observed in several species

. Clinical signs of neuro toxicity were observed in the neurotoxicity screening battery and

subchronic and ch ronic 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, respectiv ely. 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 wei ghts 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 hype rplasia was increased in a dose

dependent manner in mice treated with 64.2 mg flufenacet/kg/day; thyroid colloid was observed in males treated with 275 mg/kg/da y. Increased organ weight and hypertrophy of thyroid

follicular cells were also observed in bot h the subchronic and chronic toxicity studies in the dog.

### 4 of 24

Levels of thyroxine (T4) and triiodothyronine (T3) were consistently depressed with treatment

thr oughout the database

.

There is no indication of increased susceptibility of young rats or rabbits f ollowing 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 hepato cytomegaly), 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 consi dered 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 i s no t mutagenic in bacteria or cultured mammalian cells. There i s 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 200 7 , 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: morph ometric 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 th e lowest do se in DNT offspring (LOA E L = 1.7 mg/kg/day) was

a transient decrease in bod y 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 neur otoxic action of flufenacet, it will not change the offspring endpoint. The toxicity endpoints selected in 200 7 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 r e

- examined based on the current policy and guideline requirements. An additional 10X FQPA safety factor (UF L 

### + UF DB 

### ) is has been retained to address the lack of NOAEL in the DNT study and the lack of comparative susceptibility data for thyroid horm ones 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 neurobehav ioral 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

.

### 5 of 24

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 sep arate 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 red uctase), 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 dev eloped 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 substa nce 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 EDS P 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 n ewly 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 s tudies 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

R efined, acute probabilistic and chronic dietary ex posure assessments were conducted fo r 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 commod ities were derived using available feeding and metabolism studies in

### 6 of 24

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., ce real 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 S ection 18 use of flufenacet on wheat in the Pacific Northwest, rather than the proposed S ection 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 a cute 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 Agric ulture’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 tria l 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 99.9 th 

### 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 99.9 th 

### 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 p opulation adjusted dose (cPAD) . The most h ighly exposed subpopulation was infants , less than 1 year old, with an exposure equivalent to 9. 2% of the

cPAD

.

Conclusion s : Pending completion and submission of data from the third side

- by

- side bridging study (I owa field trial) there are no Residue Chemistry data gaps

. Provided that EFED water value s are not revised according to new policies , a new dietary a ssessment for flufenacet may not be required

for the purpose of registration review

.

Residential Exposure

### 7 of 24

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 post

emergent agri cultural sites.

Residential Post a pplication 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 h uman health risk assessment ( DP# 3 1 85 55

, J

. Arthur

, 0 3 / 1 5 /200 7 ), aggregate exposure/risk assessments were not conducted. There are no residential uses of flufenacet ; therefore

, the aggregate risk assessment for flufenacet include s only the contribution of risk from dietary (food and water) sources

.

Occupational Exposure

Flufenacet is registered for use on wh eat (including triticale), perennial grasses grown for seed, corn (field and sweet) and soybeans . Flufenacet is also registered under FIFRA 24(c) registration s for use on dormant fir trees ( Douglas fir (forest/shelterbelt), fir (forest, shelterbelt),

Fras er 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, a pplicator 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. I n 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 Exposur e 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

### 8 of 24

fo r 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 expo sure 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

- applic ation 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 inhal ation 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 Dec ember 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 ident ify 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 quantitati ve post

application inhalation exposure assessment for flufenacet

.

Conclusion s: T he 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 metho dologies 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 flufenace t 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

### 9 of 24

For this evaluation, both of the OPP Incident Data System s (IDS) w ere consulted for pesticide incident data on the active ingredient flufenacet

. For IDS aggregate summaries, from January 1,

200 2 to May 27, 2010, there are eight case s 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, 200 2 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 i f 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 agric ultural 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 c urrently expressed in terms of flufenacet and its metabolites containing the

4

- fluoro

- N

- methylethyl benzenamine moi ety 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. Exe cutive 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, includin g, 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 re leased 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

### 10 of 24

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

determin ed 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 a n 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

D ata 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.

### 11 of 24

References

Memoranda Relevant to Registration Review of Flufenacet

Author Barcode (DP#) Date Title

J. Arthur D 318555 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 D 334695 12 / 05 /200 6 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 D 288564

D 288565 11 / 29 /200 6 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 D 3 72545 10/26 /20 10 Flufenacet. Bridging Studies Supporting Foliar Application Uses of SC Formulation. Summary of Analytical Chemistry and Residue Data.

S. Recore D 383691 11 / 30 /20 10 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.

### 12 of 24

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

### 13 of 24

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

- thiadiazol

2

- 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 Techn ical 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 - 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

### 14 of 24

Attachment 2 Tolerance Summary Table



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

Summary of US and International Tolerances and Maximum Residue Limits

US Canada Mexico 1 Codex 2

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 

### 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

### 15 of 24 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 regis trations . 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

### 16 of 24

Attachment 3 Percent Crop Treated Data Comparison Table

Table 4

. Percent Crop Treated Data Comparison for Flufenacet

Average %CT Data Maximum %CT Data Crop 200 6 20 10 200 6 20 10

Corn 1 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 cr op 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

### 17 of 24

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 UF A = 10X

UF H = 10X FQPA SF =

1 0 X (UF L , UF DB ) Acute RfD =

0.0017

m g/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 UF A = 10X

UF H = 10X FQPA SF =

1 0 X (UF L , UF DB ) Chronic RfD =

0.0017

m g/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 %) UF A = 10X

UF H = 10X FQPA SF =

3 X (UF L ) Occupational

L OC 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%) UF A = 10X

UF H = 10X FQPA SF =

3 X (UF L ) Occupation al

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 environment ally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). RfD = reference dose. MOE = margin of exposure. LOC =

level of concern.

### 18 of 24

Attachment 5 Occupational Exposure Tables

Table 6 provides a compari son 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 (Doug las 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

Ass essed 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 applic ators 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 Dose 2 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 Interm ediate

- term Dermal & Inhalation NOAEL=1.7 mg/kg/day.

### 21 of 24

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 Pos t

- application Risk of Flufenacet by Use Site

Crop/Use Site DP# Maximum

Transfer

Coefficient DFR 1 MOE 2 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 = Applicatio n rate (lb ai/A) x CF (4.54E+8 μ g/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 Abs orption Factor (4%))/((CF 1000 μ g/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 bacteri al 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 p esticide’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 insuffic ient 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 an d 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

- tetrachlorodibe nzo

- 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 cou ld 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 developmen t, 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 g roups), 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 thy roid 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 ris k 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 r isk 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 toleran ces. 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 th e 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

toleran ces 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 regi stration 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 (met hod 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 qua ntitation 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 formulati on 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 tole rances 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 produ cing 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.