Document ID: EPA-HQ-OPP-2006-0965-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-05-09T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES, AND

TOXIC SUBSTANCES

Date:  March 15, 2007

UMEMORANDUMU

SUBJECT:	Flufenacet:  HED Human Health Risk Assessment for Uses on
Wheat, Perennial Grasses Grown for Seed and Sweet Corn. (Petitions:
6F04631, 0F6095; PC: 121903, DP318555)

FROM:	Jack Arthur, Environmental Scientist (RAB3)

Kathleen Raffaele, Toxicologist (Toxicology Branch)

Amelia Acierto, Chemist (RAB3)

Susan Stanton, Environmental Scientist (RRB3)

Health Effects Division (7509P)

TO:		Tobi Colvin-Snyder/James Tompkins, Risk Manager 

Herbicide Branch

Registration Division (RD) (7505P)

THRU:	Paula Deschamp, Chief

Registration Action Branch 3

Health Effects Division (7509P)

Bayer CropScience has submitted a petition to replace the temporary
tolerances (Section 18) on livestock commodities and wheat commodities
with permanent tolerances and to expand the uses of the herbicide to
include pre-emergence and early season post-emergence applications to
sweet corn, wheat, and perennial grasses grown for seed.  The
Registration Division of the Office of Pesticide Programs (OPP) has
requested that HED evaluate hazard and exposure data and conduct
dietary, occupational, residential, and aggregate exposure assessments,
as needed, to estimate the risk to human health that will result from
the requested uses of flufenacet.

A summary of the findings and an assessment of human risk resulting from
the uses of flufenacet are provided in this document.  The residue
chemistry assessment was provided by Amelia Acierto (RAB3), the dietary
exposure assessment by Susan Stanton (RRB3), the hazard characterization
by Kathleen Raffaele (Toxicology Branch), the drinking water assessment
by Ron Parker of the Environmental Fate and Effects Division (EFED),
percent crop treated assessment by Arthur Grube of the Biological and
Economic Analysis Division (BEAD), and the risk assessment and
occupational/residential exposure assessment by Jack Arthur (RAB3).

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc164766744"  TU1.0 
EXECUTIVE SUMMARYUT	  PAGEREF _Toc164766744 \h  3  

  HYPERLINK \l "_Toc164766745"  TU2.0  PHYSICAL/CHEMICAL PROPERTIES
CHARACTERIZATIONUT	  PAGEREF _Toc164766745 \h  9  

  HYPERLINK \l "_Toc164766746"  TU2.1  Identification of Active
IngredientUT	  PAGEREF _Toc164766746 \h  9  

  HYPERLINK \l "_Toc164766747"  TU2.2Physical and Chemical Properties of
Active IngredientUT	  PAGEREF _Toc164766747 \h  10  

  HYPERLINK \l "_Toc164766748"  TU3.0  HAZARD CHARACTERIZATIONUT	 
PAGEREF _Toc164766748 \h  10  

  HYPERLINK \l "_Toc164766749"  TU3.1  Hazard ProfileUT	  PAGEREF
_Toc164766749 \h  10  

  HYPERLINK \l "_Toc164766750"  TU3.2  FQPA ConsiderationsUT	  PAGEREF
_Toc164766750 \h  14  

  HYPERLINK \l "_Toc164766751"  TU3.2.1  Determination of
SusceptibilityUT	  PAGEREF _Toc164766751 \h  15  

  HYPERLINK \l "_Toc164766752"  TU3.2.2  Degree of Concern Analysis and
Residual UncertaintyUT	  PAGEREF _Toc164766752 \h  15  

  HYPERLINK \l "_Toc164766753"  TU3.2.3  FQPA Safety Factor for Infants
and ChildrenUT	  PAGEREF _Toc164766753 \h  16  

  HYPERLINK \l "_Toc164766754"  TU3.3  Dose-Response AssessmentUT	 
PAGEREF _Toc164766754 \h  17  

  HYPERLINK \l "_Toc164766755"  TU3.4  Endocrine DisruptionUT	  PAGEREF
_Toc164766755 \h  20  

  HYPERLINK \l "_Toc164766756"  TU4.0  EXPOSURE ASSESSMENTUT	  PAGEREF
_Toc164766756 \h  20  

  HYPERLINK \l "_Toc164766757"  TU4.1  Summary of Established UsesUT	 
PAGEREF _Toc164766757 \h  20  

  HYPERLINK \l "_Toc164766758"  TU4.2  Dietary Exposure/Risk PathwayUT	 
PAGEREF _Toc164766758 \h  23  

  HYPERLINK \l "_Toc164766759"  TU4.2.1  Residue ProfileUT	  PAGEREF
_Toc164766759 \h  23  

  HYPERLINK \l "_Toc164766760"  TU4.2.2  Dietary (Food plus Drinking
Water) Exposure/Risk AnalysesUT	  PAGEREF _Toc164766760 \h  26  

  HYPERLINK \l "_Toc164766761"  TU4.2.3  Acute Dietary (Food plus
Drinking Water) AnalysisUT	  PAGEREF _Toc164766761 \h  29  

  HYPERLINK \l "_Toc164766762"  TU4.2.4  Chronic Dietary (Food plus
Drinking Water) AnalysisUT	  PAGEREF _Toc164766762 \h  31  

  HYPERLINK \l "_Toc164766763"  TU4.2.5  Anticipated Residue and Percent
Crop Treated (%CT) InformationUT	  PAGEREF _Toc164766763 \h  31  

  HYPERLINK \l "_Toc164766764"  TU4.3  Residential Exposure/Risk
PathwayUT	  PAGEREF _Toc164766764 \h  36  

  HYPERLINK \l "_Toc164766765"  TU4.3.1  Non-Occupational Off-Target
ExposureUT	  PAGEREF _Toc164766765 \h  36  

  HYPERLINK \l "_Toc164766766"  TU5.0  AGGREGATE RISK ASSESSMENTS AND
RISK CHARACTERIZATIONUT	  PAGEREF _Toc164766766 \h  36  

  HYPERLINK \l "_Toc164766767"  TU6.0  CUMULATIVE RISKUT	  PAGEREF
_Toc164766767 \h  36  

  HYPERLINK \l "_Toc164766768"  TU7.0  OCCUPATIONAL EXPOSUREUT	  PAGEREF
_Toc164766768 \h  37  

  HYPERLINK \l "_Toc164766769"  TU7.1  Occupational HandlerUT	  PAGEREF
_Toc164766769 \h  37  

  HYPERLINK \l "_Toc164766770"  TU7.2  Occupational Postapplication
ExposureUT	  PAGEREF _Toc164766770 \h  41  

  HYPERLINK \l "_Toc164766771"  TU7.3  IncidentsUT	  PAGEREF
_Toc164766771 \h  43  

  HYPERLINK \l "_Toc164766772"  TU8.0  DATA NEEDS/LABEL REQUIREMENTSUT	 
PAGEREF _Toc164766772 \h  43  

  HYPERLINK \l "_Toc164766773"  TU8.1 ChemistryUT	  PAGEREF
_Toc164766773 \h  43  

  HYPERLINK \l "_Toc164766774"  TU8.2  ToxicologyUT	  PAGEREF
_Toc164766774 \h  43  

  HYPERLINK \l "_Toc164766775"  TUATTACHMENT 1 – Optional Endpoint
Selection Table for CFRUT	  PAGEREF _Toc164766775 \h  45  

 

1.0  EXECUTIVE SUMMARY

Bayer CropScience has submitted a petition (PP#0F6095) to establish
permanent tolerances for the use of flufenacet on winter wheat,
perennial grasses grown for seed and sweet corn.  In addition, Bayer
CropScience requests that the temporary tolerances for flufenacet in
meat and meat byproducts currently associated with the Section 18 uses
of flufenacet (Axiom) in wheat be made permanent in support of the
proposed crop uses.  

Hazard Assessment

Since completion of the previous risk assessment for flufenacet (ref:
Flufenacet in/on Corn and Soybeans.  HED Human Health Risk Assessment. 
J. Arthur.  May 14, 2003.  DP#: 288185), no new toxicity data have been
submitted that would change the endpoint selection or FQPA findings upon
which the previous assessment was based.   

Flufenacet has low-moderate acute toxicity by the oral route and low
acute toxicity by the dermal route.  It is not irritating to the skin,
slightly irritating to the eyes, and is a dermal sensitizer according to
the guinea pig maximization test, but not the Buehler test.  Several
target tissues have been identified, including the liver and nervous
systems across several species; changes in thyroid hormones were also
reliably seen in several species.  No increase in susceptibility was
seen in rat and rabbit developmental studies, but qualitative and/or
quantitative increases in susceptibility were seen in the rat
reproduction study and in the rat developmental neurotoxicity studies. 
Review of acceptable carcinogenicity and mutagenicity studies provide no
indication that flufenacet is carcinogenic or mutagenic.

Dose Response Assessment and Food Quality Protection Act (FQPA) Decision

On April 23, 2003, the Health Effects Division (HED) Hazard
Identification Assessment Review Committee (HIARC) reviewed the
recommendations of the toxicology reviewer for flufenacet with regard to
the acute and chronic Reference Doses (RfDs) and the toxicological
endpoint selection for use as appropriate in occupational/residential
exposure risk assessments.  In addition, the HIARC evaluated the FQPA
Safety Factor in accordance with the 2002 OPP 10X guidance document. 
While the endpoints and uncertainty factors (UF) selected by the HIARC
in 2003 remain unchanged, this current flufenacet risk assessment
reflects HED’s new guidance on the categorization of the FQPA Safety
Factors.  Specifically, in this assessment the 10X FQPA Safety Factor
has been retained; attributable to the lack of a NOAEL in the DNT study
(UFBLB) and the lack of comparative susceptibility data for thyroid
hormone levels (UFBDBB).  The new policy guidance has been adopted to
help clarify the appropriate use of the FQPA Safety and Uncertainty
Factors by including all safety factors typically used in HED risk
assessments (except inter- and intra-species factors) under a single
value identified only as the “FQPA Safety Factor.”  This avoids the
confusion of parsing out the uncertainty factors under “FQPA” and
“Special FQPA,” as was done in the previous flufenacet risk
assessment.

For dietary assessments, the acute RfD (aRfD) was calculated by dividing
the Lowest-Observed-Adverse-Effect-Level (LOAEL) by 1000 [i.e., the
standard 10X UF for interspecies extrapolation and 10X UF for
intraspecies variation; and a 10X FQPA Safety Factor attributable to the
lack of a No-Observed-Adverse-Effect-Level (NOAEL) in the developmental
neurotoxicity study (UFBLB) and the unfulfilled requirement for a
comparative thyroid study (UFBDBB)].  For the aRfD, the LOAEL of 1.7
mg/kg was based on decreased body weight/body weight gain, and missing
brain morphometric measurements in caudate/putamen, in pups in the DNT
study.  The chronic RfD (cRfD) was calculated in the same manner as the
aRfD.  For the cRfD, the LOAEL of 1.7 mg/kg/day is based on decreased
body weight/body weight gain in pups in the DNT study.  

For occupational assessments, the same developmental neurotoxicity
endpoint and LOAEL was used as above.  Since the endpoint from the DNT
oral study was selected for all durations of dermal and inhalation
exposure, a 4% dermal absorption factor and a 100 % inhalation
absorption factor are used in the route-to-route extrapolation.  The
level of concern for occupational dermal and inhalation exposures is for
MOEs <300 [10X for interspecies extrapolation, 10X for intraspecies
variation; and 3X uncertainty factor (UFBLB) due to the lack of a NOAEL
in the developmental neurotoxicity study].  For the occupational
exposure assessment, dermal and inhalation exposure estimates can be
combined because oral equivalent doses and the same endpoint were used
for these routes of exposure.

Residential Exposure Estimates

There are no currently existing or proposed uses for flufenacet in
residential or public sites and therefore no residential risk
assessments were performed.  

Dietary (Food plus Drinking Water) Exposure/Risk Estimates 

Refined, Tier 3 acute probabilistic and chronic dietary (food + drinking
water) exposure assessments were conducted for all existing and proposed
food uses of flufenacet.  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 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.

Acute and chronic exposure estimates for all commodities were further
refined using percent crop treated (%CT) data, following the guidance
provided in HED SOP 99.6 (Classification of Food Forms with Respect to
level of Blending; 8/20/99).  UProjectedU %CT data were used to refine
anticipated residues for the new food uses (sweet corn and wheat). 
Available processing data were used to refine anticipated residues for
cereal grains and corn.  For all other processed commodities, DEEM (ver.
7.81) default processing factors were assumed.

Estimated drinking water concentrations (EDWCs) were provided by EFED
(R. Parker; DP Num: 318616, 318629; 10/04/06) and incorporated directly
into the DEEM analyses.  For the acute assessment, the entire 30-year
distribution of estimated daily surface water concentrations for the
Ohio corn crop scenario was used in a probabilistic analysis.  For the
chronic assessment, the estimated 1-in-10 year annual mean residue in
surface water was used as a point estimate in a deterministic analysis.

Short- and intermediate-term aggregate risk assessments were not
performed because flufenacet is not registered or proposed for
residential uses.  A cancer aggregate risk assessment was not performed
because flufenacet is not carcinogenic.  Aggregate risk assessments for
acute and chronic exposure (food + drinking water) are summarized as
follows:  

UAcute Dietary (Food plus Drinking Water) Exposure/Risk 

Estimated acute dietary exposure is below HED’s level of concern for
the U.S. population and all population subgroups.  Combined dietary
exposure from food and drinking water at the 99.9PthP percentile of
exposure is estimated to be 0.000514 mg/kg/day for the general U.S.
population, equivalent to 30% of the acute Population Adjusted Dose
(aPAD).  The population subgroup with the highest estimated acute
dietary exposure is infants, less than 1 year old, with an estimated
exposure at the 99.9PthP percentile of 0.001514 mg/kg/day, equivalent to
89% of the aPAD.  The major contributor to dietary exposure for all
population subgroups is drinking water.  Estimated acute dietary
exposure from food alone is less than or equal to 13% of the aPAD for
the general U.S. population and all subgroups.

UChronic Dietary (Food plus Drinking Water) Exposure/Risk

Chronic dietary exposure estimates for food and drinking water combined
are well below HED’s level of concern.  Using the DEEM-FCID software,
chronic dietary exposure is estimated at 0.000049 mg/kg/day for the
general U.S. population (2.9% of the chronic Population Adjusted Dose
(cPAD)) and 0.000156 mg/kg/day (9.2% of the cPAD) for infants <1 year
old, the population subgroup with the highest estimated chronic dietary
exposure to flufenacet.  As with the acute assessment, the major
contributor to estimated chronic dietary exposure is drinking water. 
Estimated chronic dietary exposure from food alone represents less than
1% of the aPAD for the general U.S. population and all subgroups.

UCharacterization of Inputs/Outputs

Both the acute and chronic dietary analyses may be considered partially
refined.  A characterization of the inputs/outputs and uncertainties
regarding the assessment is provided below.

Food:

The assessment for food incorporates anticipated residue estimates for
most crops and livestock commodities that were derived using field trial
data.  Although field trial data provide more refined exposure estimates
than tolerances, the results may still be considered somewhat
conservative, since field trials are conducted under maximum use
conditions (maximum allowed application rate, minimum PHI, etc.).  In
actual practice, flufenacet is likely to be applied using a range of
rates and PHIs, and treated commodities may be stored for various time
periods (beyond the minimum PHI) prior to consumption by humans or
livestock.

Anticipated residues for food commodities were adjusted for %CT, using
screening level usage estimates for the existing crops (field corn and
soybeans) and projected %CT estimates for new uses (sweet corn and
wheat), both of which are intended to provide protective  exposure
estimates.

Drinking Water:

Drinking water is the risk “driver” in both the acute and chronic
dietary analyses.  PRZM-EXAMS surface water modeling data were used
probabilistically in the acute analysis and deterministically in the
chronic analysis.  The modeling estimates were partially refined in that
they took into consideration crop-specific percent cropped area (PCA). 
PRZM/EXAMS data represent the range of concentrations that are estimated
to result from the annual use of flufenacet over a 30 year period at the
maximum application rate.  Although the PRZM/EXAMS models provide more
refined estimates of surface water residues than the Tier 1 FIRST model,
the drinking water inputs may be considered conservative, since they
assume that applications will be made at maximum application rates to
the entire crop within the watershed every year for 30 years.

The PRZM/EXAMS results for the Ohio corn scenario were used in this
assessment and in the previous 2003 dietary assessment for flufenacet. 
Although the Illinois corn scenario returned a slightly higher 1-in-10
year peak concentration in EFED’s current analysis, the difference is
so small (10 ppb vs. 8.6 ppb) that it would not be expected to
significantly impact the risk assessment results.  The results for the
Ohio corn scenario are considered to provide a reasonable, high-end
estimate of drinking water exposure to residues of flufenacet.

Occupational Exposure Estimates

Based on the proposed use patterns, there is a potential for short- and
intermediate-term dermal and inhalation exposure to flufenacet during
mixing, loading, and application.  Handler’s exposure and risk were
estimated for: (1) mixer/loader: open mixing dry flowable for
groundboom, and (2) ground-boom application: open cab.  No
chemical-specific handler exposure data were submitted in support of
this Section 3 registration request.  In accordance with HED’s
Exposure Science Advisory Council (SAC) policy, exposure data from the
Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented in
PHED Surrogate Exposure Guide (8/98) were used.

For handlers, daily short- and intermediate-term dermal exposures were
compared to a LOAEL = 1.7 mg/kg/day from an oral rat developmental
neurotoxicity study, using a 4 % dermal absorption factor for
route-to-route extrapolation and a 60 kg standard female body weight. 
Daily inhalation exposures also were compared to the 1.7 mg/kg/day LOAEL
from the oral rat developmental neurotoxicity study, using a 100%
absorption factor (for an oral equivalent dose).  Dermal and inhalation
exposure estimates, as described above, were then combined to obtain a
total dose and compared to the 1.7 mg/kg/day LOAEL from the oral rat
developmental neurotoxicity study, because the same endpoint is
applicable to both routes of exposure.  The level of concern (LOC) for
both short- and intermediate-term dermal and inhalation exposure is for
an MOE of 300 or less.  The MOEs for the combined dermal and inhalation
exposures for most scenarios are not of concern when handlers are
wearing baseline clothing, plus gloves.  However, mixing/loading dry
flowable to support groundboom applications on corn requires gloves,
coveralls and a dust/mist respirator (combined MOE = 330), or packaging
of the product in water-soluble packets (combined MOE = 1000) in order
to not be of concern to HED.

Negligible postapplication dermal exposure is expected because most
flufenacet applications are made preplant and preemergence.  Because a
limited post-emergence use (i.e. on wheat, to the 3PrdP leaf stage, and
sweet corn, to the 5PthP leaf stage) is proposed, a postapplication
exposure assessment was performed for scouting and irrigation
activities, using the same dermal toxicity endpoint and dose described
for occupational handlers.  The resulting MOEs of 460 to 4000 on the day
of application (i.e., day zero) are not of concern.  Technical
flufenacet has a Toxicity Category III for Acute Oral and Acute Dermal
(all other acute categories are IV).  Per the Worker Protection Standard
(WPS), a 12-hr REI is required for chemicals classified under Toxicity
Category III, and therefore, an REI of 12 hours should appear on all
flufenacetP Plabels. 

Recommendation for Tolerances

This human health risk assessment supports conditional registration (see
Section 8. Data Needs/Label Requirements) and the establishment of
permanent tolerances for the 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 in or on the following
commodities at the indicated levels:



Recommended Tolerances for Flufenacet

Commodity	Recommended Tolerance (ppm)

40 CFR §180.527(a).   Tolerances for the combined residues of the
Herbicide,
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.

Corn, field, forage 	0.45

Corn, field, grain	0.05

Corn, field, stover	0.30

Corn, sweet, forage 	0.45

Corn, sweet, kernel plus cob with husks removed	0.05

Corn, sweet, stover	0.30

Soybean, seed	0.05

Wheat, bran	0.80

Wheat, forage	6.0

Wheat, grain	0.60

Wheat, hay	1.2

Wheat, straw	0.35

Cattle, kidney	0.05

Goat, kidney	0.05

Hog, kidney	0.05

Horse, kidney	0.05

Sheep, kidney	0.05

40CFR §180.527(c).
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.

Grass, forage	7.0

Grass, hay	0.4

40CFR §180.527(d).
N-(4-fluorophenyl)-N-(1-methylethyl)-2-[[5-(trifluoromethyl)-1,3,4-thiad
iazol-2-yl]oxy]acetamide and its metabolites containing the
4-fluoro-N-methylethyl benzenamine moiety for indirect or inadvertent
residues (Rotational Crop Tolerances)

Alfalfa, forage	2.0

Alfalfa, hay	 2.0

Alfalfa, seed	0.10

Clover, forage 	2.0

Clover, hay	2.0

Cereal, grain, crop group 15, except rice	0.10

Cereal, grain, forage, fodder, and straw, crop group 16, except rice 	

2.0

Grass, forage, fodder and hay, crop group 17	2.0

2.0  PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

Flufenacet is currently marketed by Bayer CropScience under the trade
names Define( DF Herbicide, 60% flufenacet (EPA Reg. No. 264-765),
Define( SC Herbicide, 41% flufenacet (EPA Reg. No.264-819); and Axiom®
DF Herbicide, 54.4% flufenacet and 13.6% metribuzin (EPA Reg. No.
264-766).

2.1  Identification of Active Ingredient

The chemical structure and nomenclature for flufenacet are presented in
Table 1. 

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]ac
etanilide

CAS name
N-(4-fluorophenyl)-N-(1-methylethyl)-2-[[5-(trifluoromethyl)-1,3,4-thiad
iazol-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).

2.2Physical and Chemical Properties of Active Ingredient

The physicochemical properties of flufenacet are presented in Table 2.

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#:

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

3.0  HAZARD CHARACTERIZATION

Reference:  FLUFENACET - 2PndP Report of the Hazard Identification
Assessment Review Committee. (Memo, K. Raffaele, 04/30/03, TXR# 0051853.

The existing toxicological database for flufenacet supports the
establishment of permanent tolerances for residues of flufenacet in/on
the RACs resulting from the registered and proposed uses.

3.1  Hazard Profile

Flufenacet has low-moderate acute toxicity by the oral route and low
acute toxicity by the dermal route.  It is not irritating to the skin,
slightly irritating to the eyes, and is a dermal sensitizer according to
the guinea pig maximization test, but not the Buehler test.  Several
target tissues have been identified, including liver and nervous system
across several species; changes in thyroid hormones were also reliably
seen in several species.  No increase in susceptibility was seen in rat
and rabbit developmental studies, but qualitative and/or quantitative
increases in susceptibility were seen in the rat reproduction study and
in the rat developmental neurotoxicity studies.  Review of acceptable
oncogenicity and mutagenicity studies provide no indication that
flufenacet is carcinogenic or mutagenic.  Acute toxicity of flufenacet
is presented in Table 3.   The subchronic, chronic, and other toxicity
profile of flufenacet is presented in Table 4.

Table 3.  Acute Toxicity of Flufenacet

Guideline

 No.	

Study Type	

MRID #(s)	

Results	

Toxicity Category

870.1100	

Acute Oral - rat	

43441104	

LDB50B = 1617 mg/kg (M)

589 mg/kg (F)	

3

870.1200	

Acute Dermal - rat	

43441106	

LDB50B = >2000 mg/kg	

3

870.1300	

Acute Inhalation - rat	

43441108	

LCB50B = >3.74 m/L	

4

870.2400	

Primary Eye Irritation - rabbits	

43850017	

slight eye irritant	

4

870.2500	

Primary Skin Irritation - rabbits	

43850023	

non-irritant	

4

870.2600	

Dermal Sensitization - Guinea pigs 

(Buehler test)	

43850015	

Not a skin sensitizer	

N/A

870.2600	

Dermal Sensitization - Guinea pigs

(Maximization test)	

43877601	

Skin sensitizer	

N/A

Table 4.  Subchronic, Chronic and Other Toxicity Profile for Flufenacet

Guideline	MRID	Type of Study	Results	Core

Grade

870.3100	43743401	90-day feeding-Rat	NOAEL(mg/kg/day)= <6.0(M); 7.2(F).

LOAEL(mg/kg/day)=6.0(M) based on decreased T4; 28.8(F) based on
hematology and clinical chemistry findings.	Acceptable

870.3100	4373801	90-day feeding-Mouse	NOAEL(mg/kg/day)=18.2(M);24.5(F).

LOAEL(mg/kg/day)=64.2(M);91.3(F) based on systemic toxicity and
histopathology of the liver, spleen, and thyroid.	Acceptable

870.3150	43619401	90-day feeding -Dog	NOAEL (mg/kg/day)=1.67(M);1.70(F).

LOAEL (mg/kg/day)=7.20 (M); 6.90(F) based on increases in LDH, globulin,
and spleen pigment in females, decreased T4 and ALT values in both
sexes, decreased albumin in males, and decreased serum glucose in
females.	Acceptable

870.3200	43850027	21-day Dermal-Rat	Dermal irritation

 NOAEL(mg/kg/day)=1000 (M;F).

Systemic toxicity

 NOAEL= 20(M); 150(F).

 LOAEL(mg/kg/day)= 150(M);1000(F) based on decreased T4 and FT4 levels
in both sexes and histopathological findings in females.	Acceptable

870.4200	43823501	Combined Chronic Toxicity/Carcinogenicity

-Rat	Systemic toxicity

NOAEL (mg/kg/day)=1.2(M); <1.5(F).

LOAEL (mg/kg/day)=19.3(M); 24.4(F)

based on methemoglobinemia and multi-organ effects in blood, kidney,
spleen, heart, brain, eye, liver, and uterus.

Carcinogenicity: Negative.	Acceptable

870.4300	43820701	Carcinogenicity-Mouse	NOAEL(mg/kg/day)= <7.4(M);
9.4(F) 

LOAEL(mg/kg/day)= 7.4(M); 38.4(F), based on increased incidence and
severity of cataracts.

Carcinogenicity: Negative.	Acceptable

870.4100b	43850028	Chronic oral-Dog	NOAEL(mg/kg/day)=1.29(M); 1.14(F)

LOAEL(mg/kg/day)=27.75(M); 26.82(F)

based on increased alkaline phosphatase, kidney, and liver weight in
both sexes, increased cholesterol in males, decreased T3, T4, and ALT
values in both sexes, and increased incidences of microscopic lesions in
the brain, eye, kidney, spinal cord, sciatic nerve, and liver.
Acceptable

870.3700a	43850030	Developmental-Rat	Maternal

  NOAEL= 25 mg/kg/day.

  LOAEL= 125 mg/kg/day based on decreased BWG initially.

Developmental

  NOAEL= 25 mg/kg/day.

  LOAEL= 125 mg/kg/day based on decreased fetal body weight, delayed
ossification in skull, vertebrae, sternebrae, and appendages, and
increased extra ribs.	Acceptable

870.3700b	43850029

43850031	Developmental-Rabbit	Maternal 

  NOAEL= 5 mg/kg/day.

  LOAEL= 25 mg/kg/day based on histopathological findings in liver.

Developmental 

  NOAEL= 25 mg/kg/day.

  LOAEL= 125 mg/kg/day based on increased skeletal variations.
Acceptable

870.3800	43850032

43850033	Two-generation Reproduction- Rat	Maternal toxicity

 NOAEL (mg/kg/day)= 1.4(M);1.5(F).

 LOAEL (mg/kg/day)= 7.4(M);8.2(F) based on increased liver weight in F1
females and hepatocytomegaly in F1 males.

Reproductive

  NOAEL(mg/kg/day)= 1.3.

  LOAEL(mg/kg/day)= 6.9 based on increased pup death in early lactation
(including cannibalism) for F1 litters and the same effects in F1 and F2
pups at 36 mg/kg/day.	Acceptable

870.6300	45232501	Developmental Neurotoxicity Study - Rat	Maternal
Toxicity

NOAEL = 40.8 mg/kg/day

LOAEL = Not established (no adverse effects seen)

Offspring Toxicity

NOAEL = Not established

LOAEL = 1.7 mg/kg/day based on decreased preweaning body weight and body
weight gain.  Not established for morphometric evaluations in PND72-76
female offspring, due to the failure to evaluate the caudate putamen at
the low dose level.	Acceptable/

Non-guideline

84-2	43850035	Ames Assay (USU. UtyphimuriumU)	Not mutagenic	Acceptable

84-2	43850034	UIn vivoU mammalian cytogenetics

-micronucleus assay (mouse)	Not mutagenic	Acceptable

84-2	43850036	UIn vitroU mammalian cytogenetics

-Chinese hamster lung

   fibroblasts (V79) cells	Not mutagenic	Acceptable

84-2	43850037	UIn vitroU cytogenetics

-chromosomal analysis of 

  cultured CHO cells	Not mutagenic	Acceptable

84-2	43850038	Unscheduled DNA synthesis in

rat hepatocytes Uin vitroU	Not mutagenic	Acceptable

870.7485	43850039	Metabolism - rat	Rapidly absorbed and metabolized
following oral exposure to either single or multiple doses. The urine
was the major route of excretion with small amount excreted via feces.
Significant amounts of radiolabel were eliminated as COB2B and CHB4B. A
maximum of 7% of the total recovered radiolabel was found in the tissues
and residual carcass. Twenty-five metabolites arising from the
fluorophenyl portion of the molecule were detected in excreta, and 17 of
these were identified. The total amount of radiolabel identified ranged
from [Fluorophenyl-UL-P14PC] FOE 5043 67%-86%; [Thiadiazole-2-P14PC] FOE
5043 84%-92%; and [Thiadiazole-5-P14PC] FOE 5043 53%-69%. All
unidentified residues in excreta were characterized.	Acceptable

N/A	43850041	Metabolism/Mechanism	Hypothesis of an extra thyroidal
mechanism of action for FOE 5043.	Acceptable

(Non-guideline)

N/A	43850042	Metabolism/Mechanism	Hypothesis of an extrathyroidal
mechanism of action for FOE 5043; a supplement to MRID 43850041.
Acceptable

(Non-guideline)

N/A	43695301	Metabolism/Metabolite	Evaluated a hypothesis that the
neurotoxicity observed in dogs dosed with high levels of FOE 5043 was
caused by metabolic limitations.	Acceptable

(Non-guideline)

870.6200	43735301	Acute oral neurotoxicity-Rat	NOAEL (mg/kg)= <75 (M,F)

LOAEL (mg/kg)= 75 (M,F) based on clinical signs in females
(uncoordinated gait and decreased activity) and decreased motor activity
in males.	Acceptable

870.6200	43819801

43850049	Subchronic neurotoxicity-Rat	NOAEL (mg/kg/day)= 7.30(M);
8.40(F)

LOAEL (mg/kg/day)= 38.1(M); 42.6(F) based on microscopic lesions
(including axonal swelling in brain and spinal cord).	Acceptable

3.2  FQPA Considerations

On April 23, 2003, the Health Effects Division (HED) Hazard
Identification Assessment Review Committee (HIARC) reviewed the
recommendations of the toxicology reviewer for flufenacet with regard to
the acute and chronic Reference Doses (RfDs) and the toxicological
endpoint selection for use as appropriate in occupational/residential
exposure risk assessments.  In addition, the HIARC evaluated the FQPA
Safety Factor in accordance with the 2002 OPP 10X guidance document. 
While the endpoints and uncertainty factors (UF) selected by the HIARC
in 2003 remain unchanged, this current flufenacet risk assessment
reflects HED’s new guidance on the categorization of the FQPA Safety
Factors.  Specifically, in this assessment the 10X FQPA Safety Factor
has been retained; attributable to the lack of a NOAEL in the DNT study
(UFBLB) and the lack of comparative susceptibility data for thyroid
hormone levels (UFBDBB).  The new policy guidance has been adopted to
help clarify the appropriate use of the FQPA Safety and Uncertainty
Factors by including all safety factors typically used in HED risk
assessments (except inter- and intra-species factors) under a single
value identified only as the “FQPA Safety Factor.”  This avoids the
confusion of parsing out the uncertainty factors under “FQPA” and
“Special FQPA,” as was done in the previous flufenacet risk
assessment.

3.2.1  Determination of Susceptibility

There is no indication of additional 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 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.  A 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 for the developmental
neurotoxicity study is considered to be a conservative recommendation,
because the decrease in pup body weight at that dose is transient, and a
similar decrease was not seen in the two-generation reproduction study
(decreased pup body weight seen in the one generation range-finding
reproduction study occurred at higher doses than those evaluated in the
developmental neurotoxicity study).

3.2.2  Degree of Concern Analysis and Residual Uncertainty

A number of potential effects that raised susceptibility issues were
evaluated with regard to flufenacet.  With the exception of one effect,
it was determined that the susceptibility issues posed diminished to low
levels of concern.

It was determined that the concern is low for the qualitative
susceptibility seen in the two generation reproduction study because the
pup death may be attributable to maternal cannibalism, and there was a
clear NOAEL for the effect.

There is diminished concern for susceptibility seen in the DNT. 
Decreased offspring body weights were seen at the low dose and multiple
offspring effects (including brain morphometric changes) were seen at
the mid- and high doses, and no adverse maternal effects were seen at
any dose. The concern for the decrease in the offspring body weight was
reduced since 1) it was the only effect seen at the lowest dose; 2) the
effect was transient; and 3) no decrease in body weight was seen in the
offspring in the reproduction study.  With regard to the lack of brain
morphometric data at the low dose, there is diminished concern since no
treatment-related changes were seen in Day 12 male or female offspring
or in Day 72 male offspring at any dose level.  Morphometric findings at
the mid dose were limited to a single region (caudate putamen) of the
brain, in one sex (females), at one time period (Day 72), and there was
no dose-response in spite of a 5-fold increase between the mid dose (8.3
mg/kg/.day; 10% decrease) and the high dose (40.8 mg/kg/day; 9%
decrease). Therefore, it is highly unlikely that either biological
significance or dose response will be demonstrated for this effect at
the lowest dose tested (1.7 mg/kg/day).

Finally, there is diminished concern regarding the potential for greater
sensitivity of the young to neuropathologic lesions as a result of
direct exposure to flufenacet.  Neurobehavioral and neuropathological
changes were seen in adult animals in multiple studies following direct
exposure to flufenacet.  Because dosing in the submitted DNT study was
to dams only, via the diet, from GD6 through PND10, pups were not
directly exposed to flufenacet and thus relative susceptibility to
neuropathologic effects following direct exposure to young animals has
not been evaluated.  Although the lack of comparative data for this
effect results in some uncertainty, the lowest dose at which the adverse
neuropathological effects were seen in adult rats (39 mg/kg/day after
one year of exposure in the chronic rat study) is many times higher than
the doses used as endpoints in this risk assessment (less than 1.7
mg/kg/day).

There are, however, residual concerns, regarding the potential for
greater sensitivity in the young to flufenacet’s effect on thyroid
hormone levels.  Available data in adult animals support the possibility
of decreases 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
has not been evaluated.  A special comparative sensitivity study on
thyroid hormone levels in neonatal and adult rats has been requested. 
There is a lack of comparative susceptibility data for thyroid hormone
levels.

3.2.3  FQPA Safety Factor for Infants and Children

The flufenacet risk assessment team has recommended that the 10X FQPA
Safety Factor be retained in the form of a database uncertainty factor. 
The primary reasons for retaining the 10X safety factor are the
uncertainty raised by the data gap for a comparative sensitivity study
on thyroid hormone levels in neonatal and adult rats, as well as the
lack of a NOAEL in the Developmental Neurotoxicity Study.  Also
supporting this decision, but of much less significance in the weight of
evidence evaluation, are (1) the fact that brain morphometric data were
not evaluated at the low dose in offspring in the developmental
neurotoxicity study, which resulted in not establishing an offspring
NOAEL for that effect; and (2) the absence of available data to compare
the relative sensitivity of young animals to neuropathological lesions
following direct exposure to flufenacet.  There are no additional
residual uncertainties for pre- or post-natal toxicity.  There was no
evidence of increased susceptibility in the developmental toxicity
studies (rats and rabbits), but qualitative and/or quantitative
increases in susceptibility were seen in the rat reproduction study and
in the rat developmental neurotoxicity studies.  There are also no
additional residual uncertainties with respect to exposure data:

* 	The dietary drinking water assessment utilizes water concentration
values generated by models and associated modeling parameters which are
designed to provide conservative, health protective, high-end estimates
of water concentrations which will not likely be exceeded.

* 	The dietary food exposure assessment is based on current
registrations and % CT data verified by BEAD for several existing uses.
Although somewhat refined, the assessment is based on reliable data and
will not underestimate exposure/risk.

* 	There are no residential uses for flufenacet.

3.3  Dose-Response Assessment

Acute Dietary Endpoint:  A rat developmental neurotoxicity study was
used to select the dose and endpoint for establishing the aRfD of 0.0017
mg/kg/day for the general U.S. population.  The LOAEL of 1.7 mg/kg was
based on decreased body weight/body weight gain, and missing brain
morphometric measurements in caudate/putamen, in pups.  This RfD is
applicable to the general U.S. population, including infants and
children, and is also protective of developmental effects which may
occur in females of reproductive age.  Application of a 1000-fold
uncertainty factor has been determined to be appropriate (10X
interspecies, 10X intraspecies, 10X for the lack of a NOAEL in the DNT,
and the requirement of a comparative thyroid study).  Although a
decrease in body weight/body weight gain is not considered to be a
single dose effect, decreases in morphometric measurements in PND 72-76
female offspring, which were seen at higher doses but were not evaluated
at the low doses, could occur following a single dose.  This endpoint
would be applicable to females 13-50 years of age, as well as to infants
and children, and thus is appropriate for the general population. 

Chronic Dietary Endpoint:  Same as for acute dietary endpoint (see
above).  Use of the DNT study for chronic exposures is supported by
similar NOAELs in chronic rat and dog studies (1.2 and 1.1 mg/kg/day,
respectively).

Carcinogenicity:  Characterized as "not likely" to be a human
carcinogen.

Dermal Penetration:  UDermal Absorption Factor:U  No dermal absorption
data are available.  The HIARC reaffirmed the dermal absorption rate of
4% selected by the TES Committee (document dated 2/97) based on a
comparison between the LOAEL of 6 mg/kg/day in the 90-day feeding study
in rats (MRID 43743401) and a LOAEL of 150 mg/kg/day in the 21-day
dermal study in rats (MRID 43850027) (both endpoints based on decreased
thyroid hormone levels in plasma).

Short-Term (1-30 days) and Intermediate-Term (1-6 months) Dermal
Endpoints:  Same as for acute dietary endpoint (see above).  The
available 21-day dermal study cannot be used for these endpoints, since
there is concern for potential changes in pup weight and in brain
morphometric measures; endpoints not addressed in the dermal study. 
Duration of exposure in the developmental neurotoxicity study is
appropriate for short-term use.  Use for intermediate-term exposures is
supported by similar NOAELs in chronic rat and dog studies (1.2 and 1.1
mg/kg/day, respectively).  This endpoint should be corrected for 4%
absorption for dermal exposure relative to oral absorption. 

Long-term Dermal Endpoint:  Not required for expected use pattern.

Inhalation Endpoint (all durations):  Same as for acute dietary endpoint
(see above).  No toxicity studies conducted via inhalation are
available.  Duration of the developmental neurotoxicity study is
appropriate for short-term endpoints.  Use for intermediate-term and
long-term exposures is supported by similar NOAELs in chronic rat and
dog studies (1.2 and 1.1 mg/kg/day, respectively).  Absorption by
inhalation is assumed to be equivalent to oral.

The doses/toxicological endpoints selected for exposure scenarios are
summarized in Tables 4 and 4a. 

Table 4 Summary of Toxicological Doses and Endpoints for Flufenacet for
Use in Dietary and Non-Occupational Human Health Risk Assessments

Exposure

Scenario	Point of Departure 	Uncertainty/

FQPA Safety Factors	RfD, PAD and Level of Concern for Risk Assessment
Study and Toxicological Effects

Acute Dietary

(General population including infants and children)	LOAEL = 1.7
mg/kg/day	UFBAB = 10X

UFBHB = 10X

FQPA SF = 10X (UFBLB, UFBDBB)	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,
and missing morphometric measurements in caudate/putamen, in pups.

Chronic Dietary

(All populations)	LOAEL= 1.7 mg/kg/day	UFBAB = 10X

UFBHB = 10X

FQPA SF = 10X (UFBLB, UFBDBB)	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,
and missing morphometric measurements in caudate/putamen, in pups.

Short-Term (1-30 days) and Intermediate-Term (1-6 months)

Incidental Oral	There are no residential uses currently registered or
proposed for flufenacet.  Consequently no exposure from residential uses
is expected and no residential assessment was performed.

Short-Term (1-30 days) and Intermediate-Term (1-6 months) Dermal	There
are no residential uses currently registered or proposed for flufenacet.
 Consequently no exposure from residential uses is expected and no
residential assessment was performed.

Short-Term (1-30 days) and Intermediate-Term (1-6 months) Inhalation
There are no residential uses currently registered or proposed for
flufenacet.  Consequently no exposure from residential uses is expected
and no residential assessment was performed.

Long-Term Dermal and Inhalation (>6 months)	Long term dermal and
inhalation exposure is not expected and there are no residential uses at
the present time.  Therefore, no residential risk assessment was
performed.

Cancer (oral, dermal, inhalation)	Because the cancer classification is
‘Not Likely’ these risk assessments are not required.

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL =
no-observed-adverse-effect-level, LOAEL =
lowest-observed-adverse-effect-level, PAD = population-adjusted dose (a
= acute, c = chronic), RfD = reference dose (a = acute, c = chronic),
MOE = margin of exposure, LOC = level of concern, NA = Not
Applicable/Not Required.

Table 4a Summary of Toxicological Doses and Endpoints for Flufenacet for
Use in Occupational Human Health Risk Assessments

Exposure

Scenario	Point of Departure 	Uncertainty/

FQPA Safety Factors	RfD, PAD and Level of Concern for Risk Assessment
Study and Toxicological Effects

Short-Term Dermal (1 to 30 days)	LOAEL= 1.7 mg/kg/day

(dermal absorption rate = 4%)	UFBAB = 10X

UFBHB = 10X

FQPA SF = 3X (UFBLB)	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.

Intermediate-Term

Dermal (1 to 6 months)	LOAEL= 1.7 mg/kg/day

(dermal absorption rate = 4%)	UFBAB = 10X

UFBHB = 10X

FQPA SF = 3X (UFBLB)	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.

Long-Term Dermal (>6 months)	Long term dermal exposure is not expected;
therefore, quantification of risk was not performed.

Short-Term Inhalation (1 to 30 days)	LOAEL= 1.7 mg/kg/day

(inhalation absorption rate = 100%)	UFBAB = 10X

UFBHB = 10X

FQPA SF = 3X (UFBLB)	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.

Intermediate-Term Inhalation (1 to 6 months)

	LOAEL=1.7 mg/kg/day

(inhalation absorption rate = 100%)	UFBAB = 10X

UFBHB = 10X

FQPA SF = 3X (UFBLB)	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.

Long-Term Inhalation (>6 months)	Long term inhalation exposure is not
expected; therefore, quantification of risk was not performed.

Cancer (dermal, inhalation)	Because the cancer classification is ‘Not
Likely’ these risk assessments are not required.

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL =
no-observed-adverse-effect-level, LOAEL =
lowest-observed-adverse-effect-level, PAD = population-adjusted dose (a
= acute, c = chronic), RfD = reference dose (a = acute, c = chronic),
MOE = margin of exposure, LOC = level of concern, NA = Not
Applicable/Not Required.

For occupational exposures, use of the 3X UFBLB is sufficient to
extrapolate from LOAEL to NOAEL since decreased offspring body weight
gain in the DNT study was transient and was not reproduced in the
reproductive toxicity study at similar doses.

3.4  Endocrine Disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following recommendations of its Endocrine Disruptor and Testing
Advisory Committee (EDSTAC), EPA determined that there was a scientific
basis for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

4.0  EXPOSURE ASSESSMENT

Reference:  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. (Memo, A. Acierto,
11/29/06, DP#’s: 288564 and 288565)

4.1  Summary of Established Uses

Flufenacet is a herbicide which, based on its chemical structure, is in
a class of chemicals called the oxyacetamides.  Like other acetamide
herbicides, flufenacet inhibits root and shoot growth of germinating
seeds and very small emerged seedlings.  The herbicidal mechanism of
action is not well-defined, but may be via disruption of fatty acid
incorporation into lipid membranes.

Flufenacet is currently marketed by Bayer CropScience as a dry flowable
formulation under the trade names Define( DF Herbicide, 60% flufenacet
(EPA Reg. No. 264-765), Define( SC Herbicide, 41% flufenacet (EPA Reg.
No.264-819); and Axiom® DF Herbicide, 54.4% flufenacet and 13.6%
metribuzin (EPA Reg. No. 264-766).  The 0.78 lb ai/acre rate for sweet
corn was used in this current assessment as the maximum seasonal/single
application rate for the occupational and drinking water exposure
assessments. 

A summary of the use profile proposed for this Section 3 registration is
presented in Table 5.  A more detailed description of use is presented
in the residue chemistry support document (Acierto, 11/29/06, DP#:
288564) referenced above.  

Table 5 Summary of Proposed Use Profile for Flufenacet.

For Control of Grasses and Broadleaf Weeds in the Following Crops	

Max. Single (and Seasonal) Application Rate  (lb ai/A)

	

Application Methods and Timing

Sweet Corn 	

0.78

	

* Preplant surface: single or sequential application(s) made up to 45
days before planting in corn.

* Preplant incorporated: upper 1-2 inches of soil, up to 14 days before
planting.

* Preemergence: surface broadcast or banded spray after planting, but
before weed or crop emergence.

* Early postemergence through the 5PthP leaf collar growth stage.

* Groundboom (Not to be applied aerially or by chemigation)

Perennial Grasses Grown for Seed	

0.44	* Only one application per use season.

* Allow 120 days between application and harvest of seed grass.

* Works best when applied preemergence to very early postemergence (1 to
2-leaf stage).

* Groundboom (Not to be applied aerially or by chemigation)

Wheat	

0.34	

* Most effective application from spike to 3 leaf growth stage (early
postemergence).  Do not use beyond the 3PrdP leaf growth stage.

* Groundboom (Not to be applied aerially or by chemigation)

4.2  Dietary Exposure/Risk Pathway

4.2.1  Residue Profile

Nature of the Residue – Plants

The nature of flufenacet residues in plants is understood based on
adequate studies using a preplant application to corn and soybeans and a
postemergence application to corn and wheat.  The metabolism of
flufenacet was similar for the three crops and the two types of
applications.  Flufenacet is metabolized in plants beginning with
cleavage of the trifluoromethyl thiadiazole moiety.  The remaining
acetamide portion of the molecule is conjugated with glutathione, and
subsequent oxidation of the glutathione moiety yields a variety of
metabolites containing the 4-fluoro-N-methylethyl benzenamine moiety,
several of which are conjugated with glucose.  The thiadiazole moiety
from the initial cleavage reaction was either converted to conjugated
compounds containing thiadone (TH) or degraded and incorporated into
naturally occurring compounds.  The Metabolism Assessment Review
Committee concluded in a meeting on 7/16/97 that the residues of concern
in plants for both tolerance expression and risk assessment are parent
and the metabolites containing the 4-fluoro-N-methylethyl benzenamine
moiety.

Nature of the Residue- Livestock

The nature of the residue in livestock is also understood, based on
adequate goat and poultry metabolism studies using P14PC-labeled parent
and plant metabolites.  The metabolism of flufenacet and its plant
metabolites are similar in ruminants and poultry.  The main plant
metabolite arising from the thiadiazole portion of flufenacet is
thiadone-N-glycoside (THNG;
3-glycosyl-5-trifluoromethyl-1,3,4-thiadiazole-2(3H)-one).  Flufenacet,
which is not found in livestock feed items, is initially cleaved at the
ether bond releasing thiadone which is then conjugated to glucuronic
acid.  The remaining portion of the molecule, containing the
4-fluoro-N-methylethyl benzenamine moiety, is then conjugated with
glutathione.  Further metabolism involves the mercapturic acid pathway,
with additional metabolism of the cysteine or mercapturic acid
conjugates of flufenacet to methylsulfonyl-containing metabolites.  

In both ruminants and poultry, accumulation and metabolism of FOE
oxalate, a major plant metabolite containing the 4-fluoro-N-methylethyl
benzenamine moiety, was limited with FOE oxalate being the principal
residue in eggs, milk, and tissues.

Based on these studies, the MARC (DP Barcode 241928, N. Dodd, 12/18/97)
concluded that the residues of concern in ruminants and poultry for the
tolerance expression are parent and the metabolites containing the
4-fluoro-N-methylethyl benzenamine moiety.  The dietary risk assessment
for livestock commodities should include the glycoside (THNG) and
malonylalanine conjugates of thiadone, which may be found in some
livestock feed items.  Available livestock metabolism studies should be
used to account for conjugate conversion to species of toxicological
concern (free thiadone and thiadone glucuronide).

Residue Analytical Methods

An adequate gas chromatographic/single ion mode (GC/SIM) common moiety
method (Bayer Report #106406-1) for enforcement of the tolerances for
flufenacet and its metabolites containing the 4-fluoro-N-methylethyl
benzenamine moiety on plant commodities is available following its
revision in compliance with the recommendations by EPA’s Analytical
Chemistry Laboratory (ACL) (Memorandum, 4/8/2004, Charles J. Stafford,
DP Barcode 290377).   The method determines flufenacet and its
phenyl-ring containing metabolites as the hydrolysis product
4-fluoro-N-methylethyl benzenamine (fluoroaniline).  A closely related
method (Bayer Report #106773) for determining residues of flufenacet in
livestock commodities has been adequately radiovalidated in an
independent laboratory.   HED has requested ACB to conduct a petition
method validation (PMV) of Bayer’s proposed tolerance enforcement
methods for determining flufenacet and its metabolites in livestock (A.
Acierto, 4/13/2006).

Multiresidue Method (MRM)

Flufenacet and selected metabolites (FOE oxalate, FOE sulfonic acid, and
FOE thioglycolate sulfoxide) have also undergone Multiresidue Method
Testing.  Reference standards for flufenacet, FOE oxalate, and FOE
sulfonic acid (sodium salt) are currently available at the EPA National
Pesticide Standards Repository.  However, a standard for the FOE
thioglycolate sulfoxide metabolite is not available and should be
submitted.

Magnitude of Residues in Plants

Based on the proposed and recommended tolerances, the maximum
theoretical dietary burdens (MTDB) are 0.60 ppm for beef cattle, 0.49
ppm for dairy cattle, and 0.49 ppm for poultry and swine.  An adequate
cattle feeding study is available in which dairy cattle were dosed for
29 days at levels equivalent to 13.0x, 41.2x, and 137x the MTDB of beef
cattle.  The available residue data support a tolerance level of 0.05
ppm for kidney of cattle, goat, sheep, horse, and hog.  No other
tolerances for livestock commodities are needed. 

Since the field trials were conducted with a DF formulation, bridging
studies (side-by-side field trials) are needed to compare the SC
formulation (Define™ SC, EPA Reg. No. 264-819) and the DF formulation
(Define™ DF Herbicide, EPA Reg, No. 264-765) on field corn for the
midseason use (i.e., broadcast early postemergence application at the
5th leaf  collar stage).  Three side-by-side field trials should be
conducted for field corn.  (Note: Bridging studies are not needed for
the preplant, preemergence or crop stubble applications since data for
the DF formulation can be translated to the SC formulation for these
applications.)

Adequate field trail data are available to support the current and
proposed uses on soybean, corn, wheat, and grass grown for seed.  An
adequate number of field trials were conducted at approximately the
maximum proposed use rates, and the appropriate commodities were
collected at the proposed preharvest intervals (PHIs).  Samples were
analyzed using an adequate analytical method, and the sample storage
intervals are supported by the available storage stability data.

The available soybean field trial data support the existing use pattern
on soybeans and the established 0.1 ppm tolerance for soybean seeds. 
Although the new or amended products (Define SC Herbicide, 41% ai and
Axiom DF Herbicide, 54.4% ai) are proposed for use at a lower rate of
0.59 and 0.84 lb ai/A/season, respectively, the available field trial
data for corn field and sweet corn support the application of flufenacet
at up to 0.9 lb ai/A as either preplant, preemergence, or early
postemergence applications.  These data support the established 0.05 ppm
tolerance for field corn grain but indicate that the current tolerance
for field corn forage should be increased to 0.45 ppm and the tolerance
for field corn stover should be decreased 0.30 ppm   These tolerance
levels were obtained from use of the Tolerance/MRL Harmonization
Spreadsheet.  The Maximum Likelihood Estimation (MLE) method was also
used to supplement the data set for corn forage and stover.

The submitted field trial data for wheat support a single, early season
postemergence application of flufenacet to wheat at up to 0.36 lb ai/A. 
The residue data indicate that the proposed tolerances on wheat forage
(10 ppm), hay (2.0 ppm), straw (0.5 ppm) and grain (1.0 ppm) are too
high; a revised tolerance of 6.0 ppm for wheat forage, 1.2 ppm for hay,
0.35 ppm for straw and 0.60 ppm for grain should be proposed.  These are
also the tolerance levels obtained from use of the Tolerance/MRL
Harmonization Spreadsheet.  The Maximum Likelihood Estimation (MLE)
method was also used to supplement the data set for wheat grain.

The available grass field trial data support a single, early season
postemergence application of flufenacet to grass at up to 0.44 lb ai/A.
This use would be restricted to grass grown for seed in the Pacific NW. 
The available grass field trial data support tolerances (with regional
restriction) of 7.0 ppm for grass forage and 0.40 ppm for grass hay.

Adequate storage stability data are available to support the field
trials, processing studies, rotational crop field trials, and the
livestock feeding study.  The available data indicate that flufenacet
and its metabolites are stable in frozen wheat, corn, soybean and turnip
matrices for at least 20-28 months and that FOE oxalate is stable in
livestock tissues and milk for up to 13 months. 

Processed Food and Feed

Adequate processing studies are available for corn, soybeans, wheat and
sorghum (rotated crop).  The data indicate that separate tolerances are
not required on soybean, corn, sorghum, and wheat processed commodities.
 Based on HAFT residues of 0.35 ppm in wheat grain and a processing
factor of 2.1x in wheat bran, the maximum expected residues in bran
would be 0.74 ppm.  A separate tolerance for wheat bran of 0.80 ppm is
needed since the recommended tolerance for wheat grain is 0.60 ppm.

Rotational Crops

Adequate confined rotational crop studies using both
[fluorophenyl-P14PC] and [thiadiazole-2-P14PC] flufenacet are available
and indicate that limited field rotational crop trials are required. 
Residues of concern were identified in rotational crops from a 12-month
plant-back interval (PBI) at levels in excess of 0.01 ppm.  The
metabolism of flufenacet in rotational crops is similar to that in the
primary crops.

The available limited rotational field trial data are adequate and
support the label-specified  1-month PBI for potatoes and the 4-month
PBI for all other root vegetables, leafy vegetables, and cotton. 
Rotational crop tolerances are not required for these crops.  

Adequate extensive rotational field trial data are also available for
cereal grain crops.  The extensive field trial data on barley and
sorghum (reflecting a 1-month PBI), along with limited field trial data
on wheat (reflecting 1 and 4 month PBIs) will support either a 1-month
PBI for cereal grain crops or the currently specified 4-month PBI. 
Based on the residue data on barley (hay, straw, and grain), sorghum
(forage, stover, and grain), and wheat (forage, hay, grain and straw)
from the 1-month PBI, the following rotational crop tolerances are
appropriate: 2.0 ppm for cereal grain forage, stover, and straw (crop
group 16, except rice), and 0.10 ppm for cereal grain (crop group 15,
except rice); 2.0 ppm for alfalfa, forage; 2.0 ppm for alfalfa, hay;
0.10 ppm for alfalfa, seed; 2.0 ppm for clover, forage; 2.0 ppm for
clover, hay; and 2.0 ppm for grass, forage, fodder, and hay group.

International Tolerance 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).  However, the petitioner indicated in Section G of the
petition that MRLs are established or proposed for countries of the
European Communities on the following commodities: cereals at 0.5 mg/kg,
corn at 0.5 mg/kg, potato at 0.1 mg/kg, sunflower at 0.05 mg/kg, soybean
at 0.05 mg/kg, livestock meat at 0.05 mg/kg, livestock edible offals at
0.05 mg/kg, livestock fat at 0.05 mg/kg, milk at 0.01 mg/kg and eggs at
0.05 mg/kg.

4.2.2  Dietary (Food plus Drinking Water) Exposure/Risk Analyses

Reference:  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.  (Memo, S. Stanton, 12/05/06, DP#:
334695)

Refined, Tier 3 acute probabilistic and chronic dietary exposure
assessments were conducted for all existing and proposed new 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 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.

Acute and chronic exposure estimates for all commodities were further
refined using %CT data, following the guidance provided in HED SOP 99.6
(Classification of Food Forms with Respect to level of Blending;
8/20/99).  UProjectedU %CT data were used to refine anticipated residues
for the new food uses (sweet corn and wheat).  Available processing data
were used to refine anticipated residues for cereal grains and corn. 
For all other processed commodities, DEEM (ver. 7.81) default processing
factors were assumed.

Food

-FCID™, Version 2.03), which incorporates consumption data from
USDA’s Continuing Surveys of Food Intakes by Individuals (CSFII),
1994-1996 and 1998.  The 1994-96, 98 data are based on the reported
consumption of more than 20,000 individuals over two non-consecutive
survey days. Foods “as consumed” (e.g., apple pie) are linked to
EPA-defined food commodities (e.g. apples, peeled fruit - cooked; fresh
or N/S; baked; or wheat flour - cooked; fresh or N/S, baked) using
publicly available recipe translation files developed jointly by
USDA/ARS and EPA.  For chronic exposure assessment, consumption data are
averaged for the entire U.S. population and within population subgroups,
but for acute exposure assessment are retained as individual consumption
events.  Based on analysis of the 1994-96, 98 CSFII consumption data,
which took into account dietary patterns and survey respondents, HED
concluded that it is most appropriate to report risk for the following
population subgroups: the general U.S. population, all infants (<1 year
old), children 1-2, children 3-5, children 6-12, youth 13-19, adults
20-49, females 13-49, and adults 50+ years old.

For chronic dietary exposure assessments, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form to produce a residue intake
estimate.  The resulting residue intake estimate for each food/food form
is summed with the residue intake estimates for all other food/food
forms on the commodity residue list to arrive at the total average
estimated exposure.  Exposure is expressed in mg/kg body weight/day and
as a percent of the cPAD.  This procedure is performed for each
population subgroup.

For acute exposure assessments, individual one-day food consumption data
are used on an individual-by-individual basis.  The reported consumption
amounts of each food item can be multiplied by a residue point estimate
and summed to obtain a total daily pesticide exposure for a
deterministic exposure assessment, or “matched” in multiple random
pairings with residue values and then summed in a probabilistic
assessment.  The resulting distribution of exposures is expressed as a
percentage of the aPAD on both a user (i.e., only those who reported
eating relevant commodities/food forms) and a per-capita (i.e., those
who reported eating the relevant commodities as well as those who did
not) basis.  In accordance with HED policy, per capita exposure and risk
are reported for all tiers of analysis.  However, for Tiers 1 and 2, any
significant differences in user vs. per capita exposure and risk are
specifically identified and noted in the risk assessment.

The residues of concern in plants for both tolerance expression and risk
assessment are parent and the metabolites containing the
4-fluoro-N-methylethyl benzenamine moiety.  The residues of concern in
ruminants and poultry for the tolerance expression are parent and the
metabolites containing the 4-fluoro-N-methylethyl benzenamine moiety. 
The dietary risk assessment for livestock commodities should also
include thiadone related residues, glycoside conjugate (THNG) and the
malonylalanine conjugate of thiadone. 

Drinking Water 

The residues of concern in drinking water include flufenacet and its
degradate, thiadone.  The Environmental Fate and Effects Division (EFED)
provided estimated drinking water concentrations (EDWCs) of flufenacet
and thiadone in surface water using the Tier II PRZM/EXAMS models. 
Groundwater EDWCs were provided for parent flufenacet only using the
Tier I SCIGROW model. (Reference: Revised Estimated Drinking Water
Concentrations of Flufenacet and Degradate Thiadone for the Use in Human
Health Risk Assessment; Ronald Parker; DP Num: 318616, 318629; 10/04/06)
 

Ground Water:  For ground water, the acute and chronic flufenacet EDWC
from the SCIGROW model is 0.10 ppb.  Ground-water monitoring information
provided by the registrant supports the SCIGROW model result as a
reasonable estimate of groundwater concentrations.  Acute and chronic
concentrations of 0.18 ppb and 0.03 ppb, respectively, were seen in a
small-scale prospective groundwater study conducted by the registrant in
a Nebraska aquifer that could reasonably be expected to be used for
drinking water. (FOE 5043; Reregistration Eligibility Document;
October,1997). The Agency has been unable to locate any other field
monitoring data for flufenacet in groundwater.

Surface Water:  For surface water, the combined one-in-ten-year peak
(acute) and one-in-ten-year mean (chronic) estimated concentrations of
flufenacet and thiadone are presented in Table 6 for two Midwest corn
belt cropping scenarios (Ohio corn and Illinois corn).  Thiadone
concentrations are expected to average 11 percent of parent flufenacet
concentrations at the time of year when combined concentrations are the
highest.  Therefore, combined concentrations of flufenacet and thiadone
were derived by multiplying parent flufenacet concentrations by a factor
of 1.11.

Table 6. Combined Acute and Chronic Surface Water Concentrations for
Parent Chemical Flufenacet Plus Degradate Thiadone.

PRZM Scenario	 Acute Parent Flufenacet (ppb)	 Chronic Parent Flufenacet
(ppb)	Acute Degradate Thiadone (ppb)	Chronic Degradate Thiadone (ppb)
Sum: Acute Parent Plus Degradate (ppb)	Sum: Chronic Parent Plus
Degradate (ppb)

Ohio Corn	7.78	2.01	0.86	0.22	8.64	2.23

Illinois Corn	9.07	2.55	1.00	0.28	10.07	2.83

Of all the labeled crops, the highest surface water concentrations would
be expected for corn and soybeans, because the application rate is
higher and there is more area planted to these crops; and surface water
EDWCs for these two crops should not be different. The Ohio and Illinois
corn scenarios were chosen as the most appropriate national-level
scenarios based on their location in the Midwestern corn belt.  The
modeling results for these two scenarios are similar, with the Illinois
scenario returning only slightly higher values.  This slight difference
is not due to differences in soil vulnerability in Ohio and Illinois;
rather, it is an artifact of planting date selection relative to
rainfall events at these two locations.  EFED selected application dates
14 days before recommended planting dates without regard to rainfall
dates for the two scenarios.  Since growers seek to maximize the benefit
of pesticide applications, they would be expected to apply flufenacet
when dry weather is forecast.  Therefore, the model results for the Ohio
corn scenario were selected as appropriate for use in the dietary
assessment.  The selection of the Ohio scenario also provides
consistency with the previous 2003 dietary assessment which used
drinking water estimates based on the Ohio corn scenario.

The estimated surface water concentrations of flufenacet are nearly 2
orders of magnitude higher than estimated ground water concentrations. 
Therefore, the PRZM/EXAMS surface water modeling results were used in
the dietary assessment.   For the acute assessment, the entire 30-year
distribution of estimated daily concentrations from the Ohio corn
scenario was used in a probabilistic analysis.  For the chronic
assessment, the estimated 1-in-10 year annual mean residue was used as a
point estimate in a deterministic analysis.

4.2.3  Acute Dietary (Food plus Drinking Water) Analysis

Estimated acute dietary exposure is below HED’s level of concern for
the U.S. population and all population subgroups.  Combined dietary
exposure from food and drinking water at the 99.9PthP percentile of
exposure is estimated to be 0.000514 mg/kg/day for the general U.S.
population, equivalent to 30% of the acute Population Adjusted Dose
(aPAD).  The population subgroup with the highest estimated acute
dietary exposure is infants, less than 1 year old, with an estimated
exposure at the 99.9PthP percentile of 0.001514 mg/kg/day, equivalent to
89% of the aPAD.  The acute dietary exposure results at the 99.9PthP
percentile are compared to the results at the 95PthP and 99PthP
percentiles in Table 7.

Table 7.  Results of Acute Dietary (Food plus Drinking Water) Exposure
Analysis Using DEEM FCID 

Population Subgroup	aPAD (mg/kg/day)	95PthP Percentile	99th Percentile
99.9th Percentile

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

General U.S. Population	0.0017	0.000115	6.8	0.000230	14	0.000514	30

All Infants (< 1 year old)

0.000396	23	0.000790	46	0.001514	89

Children 1-2 years old

0.000185	11	0.000361	21	0.000720	42

Children 3-5 years old

0.000171	10	0.000325	19	0.000635	37

Children 6-12 years old

0.000118	7.0	0.000227	13	0.000444	26

Youth 13-19 years old

0.000088	5.2	0.000178	10	0.000389	23

Adults 20-49 years old

0.000105	6.2	0.000206	12	0.000424	25

Adults 50+ years old

0.000104	6.1	0.000190	11	0.000344	20

Females 13-49 years old

0.000106	6.2	0.000207	12	0.000418	25

The major contributor to dietary exposure for all population subgroups
is drinking water.  Estimated acute dietary exposure from food alone is
less than or equal to 13% of the aPAD for the general U.S. population
and all subgroups.  

4.2.4  Chronic Dietary (Food plus Drinking Water) Analysis

Chronic dietary exposure estimates for food and drinking water combined
are well below HED’s level of concern.  Using the DEEM-FCID software,
chronic dietary exposure is estimated at 0.000049 mg/kg/day for the
general U.S. population (2.9% of the chronic Population Adjusted Dose
(cPAD)) and 0.000156 mg/kg/day (9.2% of the cPAD) for infants <1 year
old, the population subgroup with the highest estimated chronic dietary
exposure to flufenacet.  As with the acute assessment, the major
contributor to estimated chronic dietary exposure is drinking water. 
Estimated chronic dietary exposure from food alone represents less than
1% of the aPAD for the general U.S. population and all subgroups. 
Estimated chronic exposures from food alone and drinking water alone are
compared to exposures for food and water combined in Table 8, below.

Table 8.  Summary of Chronic Dietary (Food plus Drinking Water) Exposure
and Risk for FlufenacetP1P

Population Subgroup	Food Only	Drinking Water Only	Total

	 Exposure

(mg/kg/day)	% cPAD	 Exposure

(mg/kg/day)	% cPAD	 Exposure

(mg/kg/day)	% cPAD

	cPAD = 0.0017 mg/kg/day

General U.S. Population	0.000002	<1	0.000047	2.8	0.000049	2.9

All Infants (< 1 year old)	0.000002	<1	0.000154	9.1	0.000156	9.2

Children 1-2 years old	0.000005	<1	0.000070	4.1	0.000075	4.4

Children 3-5 years old	0.000005	<1	0.000065	3.8	0.000070	4.1

Children 6-12 years old	0.000003	<1	0.000045	2.7	0.000048	2.9

Youth 13-19 years old	0.000002	<1	0.000034	2.0	0.000036	2.1

Adults 20-49 years old	0.000002	<1	0.000044	2.6	0.000046	2.7

Adults 50+ years old	0.000001	<1	0.000046	2.7	0.000048	2.8

Females 13-49 years old	0.000002	<1	0.000044	2.6	0.000045	2.7

P1PThe population subgroup with the highest estimated chronic dietary
(food + drinking water) exposure and risk is indicated by bold text.

4.2.5  Anticipated Residue and Percent Crop Treated (%CT) Information

	BEAD recommended that a projected percent crop treated (PPCT) of 3% be
used for flufenacet on  sweet corn and 1% on wheat for chronic dietary
risk assessment, and a PPCT of 10% be used for flufenacet on sweet corn
and 3% on wheat for acute dietary risk assessment.  BEAD has considered
all information currently available and believes it is unlikely that the
above estimates for PPCT will be exceeded during the next five years. 
(ref: BEAD memo from A. Grube and N. Zinn, Projected Percent Crop
Treated for Herbicide Flufenacet on Sweet Corn, Wheat and Grasses Grown
for Seed, DP#’s 320497 and 321194, 10/25/06)

Residue Data used for the Acute and Chronic Assessments  

Food:  Refined, Tier 3 acute probabilistic and chronic dietary exposure
assessments were conducted for all existing and proposed new 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 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.

Acute and chronic exposure estimates for all commodities were further
refined using %CT data, following the guidance provided in HED SOP 99.6
(Classification of Food Forms with Respect to level of Blending;
8/20/99).  UProjectedU %CT data were used to refine anticipated residues
for the new food uses (sweet corn and wheat).  Available processing data
were used to refine anticipated residues for cereal grains and corn. 
For all other processed commodities, DEEM (ver. 7.81) default processing
factors were assumed.  Anticipated residues for plant commodities were
calculated in accordance with HED guidance for Tier 3 assessments as
follows:

UAcute AssessmentU:

Field corn, soybean and wheat (blended commodities):  Average field
trial residues were calculated and multiplied by the maximum %CT or
projected %CT (wheat) estimates in the acute DEEM analysis.  A residue
value equal to ½ the Limit of Quantitation (LOQ) was assumed for all
field trial samples with non-detectable (ND) residues.

Other cereal grains (blended commodities):  Flufenacet is not registered
for direct application to these crops; however, inadvertent residues may
occur in these crops from flufenacet’s use on other crops.  In the
DEEM analysis, the tolerance level of 0.1 ppm for inadvertent residues
was multiplied by the maximum projected %CT estimate for wheat (the
field crop with the highest estimated or projected maximum %CT).

Sweet corn (not blended or partially blended):  All sweet corn field
trial samples contained ND residues of flufenacet.  For the acute
assessment, a residue distribution file was constructed using ½ the LOQ
for non-detectable residues and incorporating zeros to account for the
percent of the crop not likely to be treated with flufenacet.

UChronic AssessmentU:

Field corn, soybean, wheat (blended commodities) and sweet corn (not
blended or partially blended):  Average field trial residues were
calculated and multiplied by the average %CT or projected %CT (wheat)
estimates in the chronic DEEM analysis.  A residue value equal to ½ the
Limit of Quantitation (LOQ) was assumed for all field trial samples with
non-detectable residues.

Other cereal grains (blended commodities):  Flufenacet is not registered
for direct application to these crops; however, inadvertent residues may
occur in these crops from flufenacet’s use on other crops.  In the
DEEM analysis, the tolerance level of 0.1 ppm for inadvertent residues
was multiplied by the average projected %CT estimate for wheat (the
field crop with the highest estimated or projected average %CT).

The residue data for plant commodities used in the chronic and acute
dietary assessments are summarized in the table below.  

Data and Residue Estimates Used in Dietary Analyses

RAC	Food

Forms	ClassificationP1P	Data

Source	No. of

Samples	No. of

Detectable

Residues	LOQ

(ppm)	%CT	Processing

Factors	Anticipated Residue Estimates/Tolerance

	Ave.	Max.

Acute (Tol., AR, RDF)P5P	Chronic (Tol., AR)

Cereal Grains (Barley, Buckwheat, Millet, Oat, Popcorn, Rye, Sorghum)
All	B	Tolerance	N/A	N/A	N/A	1P2P	3P2P	Flour: 0.44xP3

Bran: 2.1xP3

	0.1 ppm adjusted by 3%CT	0.1 ppm adjusted by  1%CT

Corn, field	All	B	Ave. Field Trial; MRID: 45012405 & 45012407	62	0	0.05
<1P4P	<2.5P4P	All: 1xP5P	0.025 ppm adjusted by 2.5%CT	0.025 ppm adjusted
by 1%CT

Corn, sweet	All	NB/PB	Field Trial; MRID: 45012405 & 45012407	18	0	0.05
3P6P	10P6P	N/A	RDF:

'Sweet Corn, using maximum projected 10%CT

TOTALZ=90

TOTALLOD=10

LODRES=0.025	0.025 ppm adjusted by 3%CT

Soybean	All	B	Ave. Field Trial: MRID: 43850093	22	2	0.05	<1P4P	<2.5P4P
1xP5P	0.03 ppm adjusted by 2.5%CT	0.03 ppm adjusted by 1%CT

Wheat/Triticale	All	B	Ave. Field Trial: MRID: 45012401	38	38 (29 above
LOQ)	0.05	1P6P	3P6P	Flour: 0.44xP3

Bran: 2.1xP3

	0.13 ppm adjusted by 3%CT	0.13 ppm adjusted by 1%CT

1.	Classification of blended (B), partially blended (PB), not blended
(NB).

2.	Based on projected %CT for wheat, the field crop with the highest
estimated ave. and max. %CT.

3.	Based on processing data for wheat: MRID#45012408; A. Acierto; DP
Num: 288564; 07/27/06.

4.	Screening Level Usage Analysis; BEAD; 08/18/2005

5.	N. Dodd; DP Num: 224142: 12/12/96

6.	Projected Percent Crop Treated for Herbicide Flufenacet (PC 121903)
on Sweet Corn, Wheat and Grasses Grown for Seed; N. Zinn & A Grube; DP
Nums: 320497, 321194; 10/25/2006

4.3  Residential Exposure/Risk Pathway

There are no residential uses currently registered or proposed for
flufenacet.  Consequently no exposure from residential uses is expected
and no residential assessment was performed.

4.3.1  Non-Occupational Off-Target Exposure

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from groundboom application methods.  The Agency has been
working with the Spray Drift Task Force, EPA Regional Offices and State
Lead Agencies for pesticide regulation and other parties to develop the
best spray drift management practices.  The Agency is now requiring
interim mitigation measures for aerial applications that must be placed
on product labels/labeling.  The Agency has completed its evaluation of
the new database submitted by the Spray Drift Task Force, a membership
of U.S. pesticide registrants, and is developing a policy on how to
appropriately apply the data and the AgDRIFT computer model to its risk
assessments for pesticides applied by air, orchard airblast and ground
hydraulic methods.  After the policy is in place, the Agency may impose
further refinements in spray drift management practices to reduce
off-target drift and risks associated with aerial as well as other
application types where appropriate.

5.0  AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

Short- and intermediate-term aggregate risk assessments were not
performed because flufenacet is not registered or proposed for
residential uses.  A cancer aggregate risk assessment was not performed
because flufenacet is not carcinogenic.   Aggregate risk assessments for
acute exposure (food + drinking water) and chronic exposure (food +
drinking water) are presented in Sections 4.2.2.1 and 4.2.2.2 above.  

6.0  CUMULATIVE RISK

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

EPA does not have, at this time, available data to determine whether
flufenacet has a common mechanism of toxicity with other substances.
Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to flufenacet and any other
substances and flufenacet does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance action,
therefore, EPA has not assumed that flufenacet has a common mechanism of
toxicity with other substances. For information regarding EPA’s
efforts to determine which chemicals have a common mechanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA’s Office of Pesticide Programs concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA’s website at
http://www.epa.gov/pesticides/cumulative/.

7.0  OCCUPATIONAL EXPOSURE

Reference:  Occupational and Residential Risk Assessment for Request to
Establish Permanent Tolerances for the Use of Flufenacet (Thiafluamide)
on Winter Wheat, Perennial Grasses Grown for Seed and Sweet Corn. (Memo,
J. Arthur, 12/22/06, D334694)

7.1  Occupational Handler

There is a potential for occupational exposure to flufenacet during
mixing, loading and  applying. The Hazard Identification Assessment
Review Committee (HIARC) selected dermal (short-term and
intermediate-term) and inhalation (for any time period) endpoints for
flufenacet. Chronic exposures are not expected for handlers or
postapplication workers.  Occupational exposure assessments for
short-term and intermediate-term dermal and inhalation exposures were
conducted.  No chemical-specific handler exposure data were submitted in
support of this Section 3 registration request.  Therefore, data from
the Pesticide Handlers Exposure Database (PHED) Version 1.1 as presented
in PHED Surrogate Exposure Guide (8/98) were used.

For handlers, daily short- and intermediate-term dermal exposures were
compared to a LOAEL = 1.7 mg/kg/day from an oral rat developmental
neurotoxicity study, using a 4% dermal absorption factor for
route-to-route extrapolation and a 60 kg standard female body weight. 
Daily inhalation exposures also were compared to the 1.7 mg/kg/day LOAEL
from the oral rat developmental neurotoxicity study, using an absorption
factor of 100% (for an oral equivalent dose).  Dermal and inhalation
exposure estimates, as described above, were then combined to obtain a
total dose and compared to the 1.7 mg/kg/day LOAEL from the oral rat
developmental neurotoxicity study, because the same endpoint is
applicable to both routes of exposure.  The level of concern (LOC) for
both short- and intermediate-term dermal and inhalation exposure is for
an MOE of 300 or less.  The MOEs for the combined dermal and inhalation
exposures for most scenarios are not of concern when handlers are
wearing baseline clothing, plus gloves.  However, mixing/loading dry
flowable to support groundboom applications on sweet corn requires
gloves, coveralls and a dust/mist respirator (combined MOE = 330), or
packaging of the product in water-soluble packets (combined MOE = 1000)
in order to not be of concern to HED.  It should be noted that the use
of water-soluble packets may not be practical since formulation as a dry
flowable is already considered as an engineering control.

The minimum level of PPE for handlers is based on acute toxicity for the
end-use product.  The Registration Division (RD) is responsible for
ensuring that PPE listed on the label is in compliance with the Worker
Protection Standard (WPS).

Assumptions and estimates for occupational handler exposure are
summarized below in Tables 9 and 9a.     



Table 9.  Exposure and Risk Estimates for Occupational Mixer/Loader and
Applicators at Baseline Clothing

PHED Scenario

Selected from PSEG  

Version 1.1	

Personal Protective Equipment 	

Exposure Route	

Application Rate

(lb ai/acre)	

Acres Treated

(acres/

day)	

PHED Unit Exposure

(mg/lb ai) 	

PHED

Data

Confidence	

Absorption Factor	

Body

Weight (kg)	

Daily Dose P1P

(mg/kg/day)	

Short- and 

Intermediate-

Term NOAEL

(mg/kg/day)	

Short- and Intermediate Term

 MOE P2P

1. Mixer/loader 

Dry Flowable (Open Mixing) for Groundboom on Sweet Corn 	

Long Sleeves,

Long Pants, 

Gloves P4P	

Dermal	

0.78	

200	

0.066	

High	

0.04	

60	

0.0069	

1.7	

250 P3P

Inhalation	

0.78	

200	

0.00077	

High	

1.0	

60	

0.0020	

1.7	

850

		Total:	

0.0089	

1.7	

190 P3P

2. Applicator Groundboom (Open Cab) for Sweet Corn P	P	

Long Sleeves,

Long Pants

	

Dermal	

0.78	

200	

0.014	

High	

0.04	

60	

0.0015	

1.7	

1100

Inhalation	

0.78	

200	

0.00074	

High	

1.0	

60	

0.0019	

1.7	

900

                                                                        
                                                                        
                                                                        
                                                          Total:	

0.0034	

1.7	

500

3. Mixer/loader 

Dry Flowable (Open Mixing) for Groundboom on Grass Grown for Seed	

Long Sleeves,

Long Pants,

Gloves P4P	

Dermal	

0.44	

200	

0.066	

High	

0.04	

60	

0.0039	

1.7	

440

Inhalation	

0.44	

200	

0.00077	

High	

1.0	

60	

0.0012	

1.7	

1400

		Total:	

0.0051	

1.7	

330

4. Applicator Groundboom (Open Cab) for Grass Grown for Seed	

Long Sleeves,

Long Pants

	

Dermal	

0.44	

200	

0.014	

High	

0.04	

60	

0.00082	

1.7	

2100

Inhalation	

0.44	

200	

0.00074	

High	

1.0	

60	

0.0011	

1.7	

1500

		Total:	

0.0019	

1.7	

890

3. Mixer/loader 

Dry Flowable (Open Mixing) for Groundboom on Wheat	

Long Sleeves,

Long Pants,

Gloves P4P	

Dermal	

0.34	

200	

0.066	

High	

0.04	

60	

0.003	

1.7	

570

Inhalation	

0.34	

200	

0.00077	

High	

1.0	

60	

0.00087	

1.7	

2000

                                                                        
                                                                        
                                                                        
                                                           Total:	

0.0039	

1.7	

440

4. Applicator Groundboom (Open Cab) for Wheat	

Long Sleeves,

Long Pants	

Dermal	

0.34	

200	

0.014	

High	

0.04	

60	

0.00063	

1.7	

2700

Inhalation	

0.34	

200	

0.00074	

High	

1.0	

60	

0.00084	

1.7	

2000

                                                                        
                                                                        
                                                                        
                                                           Total:	

0.0015	

1.7	

1100

P1 PDaily Dose =[Application Rate (lb ai/A) x Acres Treated (A/day) x
Unit Exposure(mg/lb ai handled) x Absorption Factor]/Body Weight

P2P Short- and Intermediate Term MOE = Short- and Intermediate Term
NOAEL (1.7 mg/kg/day)/Daily Dose.  

P3 PDoes not reach MOE of 300, and therefore is of concern to HED.

P4P PHED value is the same for gloved and ungloved hand.  Confidence in
gloved hand data is high, and use of gloves is recommended.



Table 9a.  Exposure and Risk Estimates for Occupational Mixer/Loader and
Applicators with Additional Mitigation Measures

PHED Scenario

Selected from PSEG  

Version 1.1	

Personal Protective Equipment 	

Exposure Route	

Application Rate

(lb ai/acre)	

Acres Treated

(acres/

day)	

PHED Unit Exposure

(mg/lb ai) 	

PHED

Data

Confidence	

Absorption Factor	

Body

Weight (kg)	

Daily DoseP 1P

(mg/kg/day)	

Short- and 

Intermediate-

Term NOAEL

(mg/kg/day)	

Short- and Intermediate Term

 MOE P2P

1. Mixer/loader 

Dry Flowable (Open Mixing) for Groundboom on Sweet Corn 	

Long Sleeves,

Long Pants, 

Gloves, plus Coveralls	

Dermal	

0.78	

200	

0.047	

High	

0.04	

60	

0.0048	

1.7	

350

Inhalation	

0.78	

200	

0.00077	

High	

1.0	

60	

0.0020	

1.7	

850

		Total:	

0.0068	

1.7	

250 P3P

2. Mixer/loader 

Dry Flowable (Open Mixing) for Groundboom on Sweet Corn	

Long Sleeves,

Long Pants,

Gloves,  plus Coveralls and a Dust/Mist Respirator	

Dermal	

0.78	

200	

0.047	

High	

0.04	

60	

0.0048	

1.7	

350

Inhalation	

0.78	

200	

0.00015	

High	

1.0	

60	

0.00039	

1.7	

4400

		Total:	

0.0052	

1.7	

330

3. Mixer/loader 

Dry Flowable (Open Mixing) for Groundboom on Sweet Corn	

Long Sleeves,

Long Pants,

Gloves,  plus water-soluble packets	

Dermal	

0.78	

200	

0.0098	

High	

0.04	

60	

0.0010	

1.7	

1700

Inhalation	

0.78	

200	

0.00024	

High	

1.0	

60	

0.00062	

1.7	

2700

                                                                        
                                                                        
                                                                        
                                                           Total:	

0.00162	

1.7	

1000

P1 PDaily Dose =[Application Rate (lb ai/A) x Acres Treated (A/day) x
Unit Exposure(mg/lb ai handled) x Absorption Factor]/Body Weight

P2P Short- and Intermediate Term MOE = Short- and Intermediate Term
NOAEL (1.7 mg/kg/day)/Daily Dose.

P3 PMOE does not reach MOE of 300, and therefore is of concern to HED. 

7.2  Occupational Postapplication Exposure

Flufenacet uses subject to this action involve preplant, pre-emergence
and some post-emergence applications.  Potential postapplication
exposures from preplant and pre-emergence applications  are usually
considered to be negligible.  However, because the proposal does include
a post-emergence use, a postapplication exposure/risk assessment has
been performed.  While exposure is expected to be minimal, a risk
assessment was performed for potential postapplication dermal exposure
to scouts, and field workers performing irrigation.  Inhalation exposure
is expected to be negligible.  Because this herbicide is not registered
for residential or public use sites, a non-occupational postapplication
risk assessment for residential or recreational settings has not been
performed.  

There were no chemical-specific data with which to estimate
postapplication exposure of agricultural workers to dislodgeable
residues of flufenacet.  Therefore, theoretical estimates of exposure,
based on surrogate studies, have been conducted.  The ExpoSAC (Policy
003.1, Rev. 7 Aug. 2000, Regarding Agricultural Transfer Coefficients;
Amended ExpoSAC Meeting notes - 13 Sept 01) lists a number of possible
postapplication agricultural activities relative to the subject crops
that result in potential pesticide exposure to agricultural workers. 
Transfer coefficients (TCs) used in this assessment are derived from
data in surrogate exposure studies conducted during the various
activities listed.  TCs expressed as cm²/hr are identified for each of
the postapplication, agricultural activities.  The data from these
studies are proprietary and compensation issues with ARTF may need to be
addressed.  It is the intention of HED’s ExpoSAC that this policy will
be periodically updated to incorporate additional information about
agricultural practices in crops and new data on TCs.  Much of this
information will originate from exposure studies currently being
conducted by the ARTF, from further analysis of studies already
submitted to the Agency, and from studies in the published scientific
literature.

Since no chemical-specific DFR data are available, postapplication
worker exposure is estimated using the HED procedure that assumes 20% of
the application rate is available as dislodgeable foliar residue on the
day of treatment.  The estimates provided are for
short/intermediate-term dermal exposures (1 day-6 months), and are
considered to be screening level estimates (i.e., conservative).  

The short- and intermediate-term MOEs for postapplication exposure on
day zero range from 460 to 4000.  Since the calculated MOEs are greater
than 300 on the day of application, they DO NOT exceed HED’s level of
concern, and the interim WPS REI of 12 hours is sufficient to protect
workers from excessive exposure.

A summary of the postapplication exposure/risk assessment is presented
in Table 10.



Table 10.  Exposure and Risk Assessment for Occupational Postapplication
Activities

Crops	

Application Rate

(lb ai/A)	

Post-application Day (t)	

Fraction of ai Retained on the Foliage	

Fraction of Residue That Dissipates Daily	

Dislodgeable 

Foliar Residue

(ug/cmP2P) P1P	

Dermal Transfer 

CoefficientP 2P

(cmP2P/hr)	

Exposure Time 

(hrs/day)	

Dermal

Absorption Factor P3P	

Body Wt

(kg)	

 Daily Dose P4P

(mg/kg/day)	

Short-/

Intermed.

Term Dermal

MOE P5P

Corn 	

0.78	

0	

0.2	

0.1	

1.75	

scout: 400P6P	

8	

0.04	

60	

0.0037	

460

irrigate: 100P7P

0.0009	

1800

Grasses Grown for Seed	

0.44	

0	

0.2	

0.1	

0.987	

scout: 400P6P	

8	

0.04	

60	

0.0021	

800

irrigate: 100P7P

0.0005	

3000

Wheat	

0.34	

0	

0.2	

0.1	

0.763	

scout: 400 P6P	

8	

0.04	

60	

0.0016	

1000

irrigate: 100P7P

0.0004	

4000

P1 P Dislodgeable Foliar ResidueB Postapplication day B(ug/cmP2P) =
Application rate (lb ai/A) x Fraction of ai Retained on the Foliage x
(1- Fraction of Residue that Dissipates Daily)B PBpostapplication dayP x
 4.54E+8 ug/lb x 24.7E-9 A/cmP2

P2 P Harvesting corn, soybeans and wheat by mechanical means is assumed
to result in negligible dermal exposure.

P3P  For short- and intermediate-term dermal risk assessment, the dermal
absorption factor of 4% was applied because the endpoint chosen for this
risk assessment was derived from an oral  toxicity study.

P4P  Daily Dose = (Dislodgeable Foliar Residue x  Absorption Factor  x
0.001 mg/ug  x Dermal Transfer Coefficient x Exposure Time)/Body weight 

P5P  MOE = NOAEL/Daily Dose          Short-/Intermediate-Term Dermal
NOAEL = 1.7 mg/kg/day

P6P  Low end  value from ARF009

P7P  Central value from MRID 426891 [Note that there was no value for
irrigation of low crop height, minimal foliage plants under Field/row
crop, tall.  Therefore the value for irrigating crops with this profile
was obtained from the Field/row crop, low/medium as a best fit for the
post-emergence use pattern proposed for flufenacet.]         P          
                                                        

7.3  Incidents

The OPP Incidents Database includes 39 entries for flufenacet.  Most
entries describe adverse reactions of unknown origin, such as rash,
hives and headache.

8.0  DATA NEEDS/LABEL REQUIREMENTS

8.1 Chemistry

1.	Successful agency Petition Method Validation (PMV) of the livestock
analytical enforcement method is needed.  HED has requested ACB to
perform this PMV.

2.	Bridging studies (side-by-side field trials) are needed to compare
the SC formulation (Define PTMP SC, EPA Reg. No. 264-819) and the DF
formulation (Define PTMP DF Herbicide EPA Reg. No. 264-765) on field
corn for the midseason use (i.e., broadcast early postemergence
application at the 5th leaf collar stage).  Three side-by-side field
trials should be conducted for field corn.

3a.	A revised Section F is needed to specify kidney tolerances of 0.05
ppm for cattle, goat, horse, hog, and sheep.

3b.	A revised Section F is needed to specify tolerances for corn, sweet,
forage (0.45 ppm); corn, sweet, stover (0.30 ppm); corn, field, forage
(0.45 ppm); corn, field stover (0.30 ppm); wheat, forage (6.0 ppm);
wheat, hay (1.2 ppm); wheat, straw (0.35 ppm);  wheat, grain (0.60 ppm);
wheat, bran (0.80 ppm); grass, forage (7.0 ppm); and grass, hay (0.40
ppm).

3c.	Based on the available field trial data, tolerances for indirect or
inadvertent residue in rotational crops under §180.527(d) should be
revised.  The correct tolerance levels and commodity definitions are as
follows: 0.10 ppm for cereal, grain, crop group 15, except rice; 2.0 ppm
for cereal, grain, forage, fodder and straw, crop group 16, except rice;
2.0 ppm for alfalfa, forage; 2.0 for alfalfa, hay; 0.10 ppm for alfalfa,
seed; 2.0 ppm for clover, forage; 2.0 ppm for clover, hay; and 2.0 ppm
for grass, forage, fodder and hay, crop group 17.

4. 	Reference standards for flufenacet, FOE oxalate, and FOE sulfonic
acid (sodium salt) are currently available at the EPA National Pesticide
Standards Repository.  However, a standard for the FOE thioglycolate
sulfoxide metabolite is not available and should be submitted to the
National Pesticide Standards Repository/Analytical Chemistry Branch/OPP,
701 Mapes Road, Fort George G. Meade, MD 20755-5350.

8.2  Toxicology

The HIARC determined that a special comparative sensitivity study on
thyroid hormone levels in neonatal and adult rats should be required
(see above), based on the changes seen in thyroid hormones in multiple
species in adult toxicity studies.  The HIARC also noted that
neuropathology evaluations (morphometric measurements) could be included
in the protocol for the comparative sensitivity study.  The registrant
should consult with the Agency in developing the protocol for that
study.  UA request for a waiver to the requirement for this study has
been submitted to the Agency by the registrant, Bayer CropScience (MRID#
46575701, May 25, 2005).  A preliminary review of this submission
indicates that support for a study waiver is not sufficient and that the
requirement for a special comparative sensitivity study on thyroid
levels remains.  Formal completion of the waiver review is forthcoming
and will be presented in a separate HED memorandum.U

A 28-day inhalation toxicity study in rats is needed.  UA request for a
waiver to the requirement for this study has been submitted to the
Agency.  HED has reviewed the submission and has determined that the
rationale proposed does not support granting this waiver (J. Arthur, DP#
318557 et al., 09/01/06).

cc RAB3 Reading File.

ATTACHMENT 1 – Optional Endpoint Selection Table for CFR

Summary of Toxicological Dose and Endpoints for Flufenacet

Exposure

Scenario	

Dose Used in Risk Assessment, UF 	

FQPA SF* and Level of Concern for Risk Assessment	

Study and Toxicological Effects

Acute Dietary

(General population including infants and children)	

LOAEL = 1.7 mg/kg/day

UF = 1000X

	

FQPA SF = 10X

aPAD = 0.0017  mg/kg/day

aRfD = 0.0017	

Developmental Neurotoxicity study in rats.

LOAEL = 1.7 mg/kg/day based on decreased body weight/body weight gain,
and missing morphometric measurements in caudate/putamen, in pups.

Chronic Dietary

(All populations)	

LOAEL= 1.7 mg/kg/day

UF = 1000

	

FQPA SF = 1X

cPAD = 0.0017 mg/kg/day

cRfD = 0.0017	

Developmental Neurotoxicity study in rats.

LOAEL = 1.7 mg/kg/day based on decreased body weight/body weight gain in
pups.

Short-Term 

Incidental Oral (1-30 days)

	

LOAEL= 1.7 mg/kg/day	

Residential LOC for MOE =NA 

Occupational = NA	

Developmental Neurotoxicity study in rats.

LOAEL = 1.7 mg/kg/day based on decreased body weight/body weight gain in
pups.

Intermediate-Term 

Incidental Oral (1- 6 months)

	

NOAEL= 1.7 mg/kg/day	

Residential LOC for MOE =NA

Occupational = NA	

Developmental Neurotoxicity study in rats.

LOAEL = 1.7 mg/kg/day based on decreased body weight/body weight gain in
pups.

Short-Term Dermal (1 to 30 days)	

Oral study LOAEL= 

1.7 mg/kg/day

(dermal absorption rate = 4%)	

Occupational LOC for MOE = 300 

Residential LOC for MOE = NA	

Developmental Neurotoxicity study in rats.

LOAEL = 1.7 mg/kg/day based on decreased body weight/body weight gain in
pups.

Intermediate-Term

Dermal (1 to 6 months)	

Oral  study LOAEL= 

1.7 mg/kg/day

(dermal absorption rate = 4%)	

Occupational LOC for MOE = 300 

Residential LOC for MOE = NA	

Developmental Neurotoxicity study in rats.

LOAEL = 1.7 mg/kg/day based on decreased body weight/body weight gain in
pups.

Long-Term Dermal (>6 months)	

Long term dermal exposure is not expected and there are no residential
uses at the present time.  Therefore, quantification of risk is not
required.

Short-Term Inhalation (1 to 30 days)

	

Inhalation (or oral) study LOAEL= 1.7 mg/kg/day

(inhalation absorption rate = 100%)	

Occupational LOC for MOE = 300 

Residential LOC for MOE = NA

	

Developmental Neurotoxicity study in rats.

LOAEL = 1.7 mg/kg/day based on decreased body weight/body weight gain in
pups.

Intermediate-Term Inhalation (1 to 6 months)

	

Inhalation (or oral) study LOAEL = 1.7 mg/kg/day

(inhalation absorption rate = 100%)	

Occupational LOC for MOE = 300 

Residential LOC for MOE = NA

	

Developmental Neurotoxicity study in rats.

LOAEL = 1.7 mg/kg/day based on decreased body
weight/b摯⁹敷杩瑨朠楡⁮湩瀠灵⹳܇䰍湯ⵧ敔浲䤠桮污
瑡潩⁮㸨‶潭瑮獨ܩ䰍湯⁧整浲椠桮污瑡潩⁮硥潰畳敲
椠⁳潮⁴硥数瑣摥愠摮琠敨敲愠敲渠⁯敲楳敤瑮慩⁬獵
獥愠⁴桴⁥牰獥湥⁴楴敭‮吠敨敲潦敲‬畱湡楴楦慣楴
湯漠⁦楲歳椠⁳潮⁴敲畱物摥ܮഇ慃据牥⠠牯污‬敤浲
污‬湩慨慬楴湯ܩ

É

Ú

:

x

ÿ

z

{

$

@

@

㄀Ĥ摧矅

hÅw

hÅw

@

@

&

@

@

@

@

@

@

@

@

@

@

@

 hd

@

@

@

@

h

h

h

h

 h

h

h

h

  h

h

h

h

h

gd

h

h

kd

@

@

$

@

@

$

@

@

$

@

@

$

@

œ

@

@

$

@

@

萏ﾦ葞ﾦ摧堁æ

옍

옍

摧┩Ï

@

î

 hž

@

@

옍

옍

$

kd

@

 ᰠࠀᄀやㇽĤ葠ﴰ摧慤©

ഀெ̀ː ᰠࠀ㄀Ĥ摧㈁ä

옍

$

$

@

@

Ff£

$

옍

옍

␱䀁Ȧ摧䮰-

␅؁Ĥ옍

옍

ഀெ̀ː ᰠࠀༀ좄ㇻĤ葞﯈

옍

ഀெ̀ː ᰠࠀ㄀Ĥ

$

Æ

ഀெ̀ː ᰠࠀᄀ킄㄂Ĥ葠ː

␅؁Ĥ옍

萏ː萑ﴰ␱䀁Ħ葞ː葠ﴰ摧䮰-

$

Æ

Æ

Æ

Æ

$

Æ

옍

옍

옍

옍

옍

옍

옍

옍

옍

옍

옍

옍

옍

옍

옍

옍

옍

옍

옍

$

Æ

옍

옍

옍

옍

옍

옍

옍

옍

옍

$

Æ

Æ

$

Æ

Æ

Æ

Æ

$

Æ

옍

옍

옍

Æ

$

Æ

옍

옍

옍

옍

옍

옍

옍

옍

옍

Æ

Æ

h 

h 

옍

Æ

Æ

Æ

Æ

Æ

Æ

Æ

Æ

Æ

Æ

Æ

Æ

Æ

Æ

Æ

Æ

Æ

Æ

Æ

Æ

Æ

옍

萏ː萑ﴰ␱䀁&葞ː葠ﴰ摧䮰-

옍

옍

œ

ਁ砃愀϶ｪ؀Because the cancer classification is ‘Not Likely’
these risk assessments are not required.

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL =
no-observed-adverse-effect-level, LOAEL =
lowest-observed-adverse-effect-level, PAD = population-adjusted dose (a
= acute, c = chronic) RfD = reference dose, MOE = margin of exposure,
LOC = level of concern, NA = Not Applicable/Not Required.

Page   PAGE  42  of   NUMPAGES  46 

Page   PAGE  46  of   NUMPAGES  46