Document ID: EPA-HQ-OPP-2009-0980-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2011-02-02T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date:	   January 4, 2011

 

SUBJECT:	Revised Fluazifop-P-Butyl.  Amended Human Health Risk
Assessment to Support Use on Bananas, Citrus, Grapes, Sugar Beets, and
the Establishment of a Tolerance on Imported Potatoes.  

PC Code:  122809	DP Barcode:  385178 

Decision No.:  423996	Registration No.:  100-1001

Petition No.: 9F7624 & 9E7651	Regulatory Action: New Use Registration

Risk Assessment Type: Human Health	Case No.: 2285

TXR No.: NA	CAS No.: 79241-46-6

MRID No.: 47874601-06 & 47920401-05	40 CFR: 180.411

FROM:	Peter Savoia, Chemist

		Seyed Tadayon, Chemist

		William A. Irwin, PhD, Toxicologist

		Danette Drew, Chemist

		Risk Assessment Branch V

		Health Effects Division (7509P)

		

THRU:	Jack Arthur, Branch Chief

		Risk Assessment Branch V

		Health Effects Division (7509P)

		

TO:	Kathryn Montague/Michael Walsh, RM

		Herbicide Branch 

		Registration Division (7505P)

		

This risk assessment revises the September 1, 2010 version (D371092) by
providing a more complete characterization of uncertainties/data gaps. 
Syngenta Crop Protection, Inc. has submitted petition No. 9F7624
requesting to allow for the use of fluazifop-P-butyl (PC Code 122809) on
bananas, citrus, grapes, and sugar beets.  In addition to these new crop
uses, Syngenta has also submitted petition No. 9E7651 which proposes
that an import tolerance for fluazifop-P-butyl be established on
potatoes.  To address these proposed new uses, this document is HED’s
amended human health risk assessment incorporating the Syngenta proposed
new uses.  It therefore contains updated sections of the HED Human
Health Risk Assessment of September 2008 (DP No. D347515, P. Savoia,
09/18/2008).  In doing so, the following sections which include residue
chemistry, drinking water exposure, dietary exposure, aggregate risk
assessment, and occupational exposure have been updated to reflect the
proposed new uses.  Information contained in the September 2008 risk
assessment remains unchanged unless specifically noted in this
memorandum.  

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc202162117"  1.0	Executive
Summary	4 

  HYPERLINK \l "_Toc202162118"  2.0	Background	11 

  HYPERLINK \l "_Toc202162122"  3.0	Summary of Proposed Uses	11 

  HYPERLINK \l "_Toc202162151"  4.0	Hazard Characterization and FQPA
Considerations	12 

  HYPERLINK \l "_Toc202162153"  4.1 	Toxicology Studies Available for
Analysis	13 

  HYPERLINK \l "_Toc202162153"  4.2 	Absorption, Distribution,
Metabolism and Elimination (ADME)	14 

  HYPERLINK \l "_Toc202162153"  4.2.1 	Dermal Absorption	15 

  HYPERLINK \l "_Toc202162153"  4.3	Toxicological Effects	16 

  HYPERLINK \l "_Toc202162153"  4.4	FQPA Safety Factor	17 

  HYPERLINK \l "_Toc202162153"  4.4.1	Completeness of toxicology
Database	18 

  HYPERLINK \l "_Toc202162153"  4.4.2	Evidence of Neurotoxicity	19 

  HYPERLINK \l "_Toc202162153"  4.4.3	Evidence of
Sensitivity/Suspectibility in the Developing or Young Animal	19 

  HYPERLINK \l "_Toc202162153"  4.4.4	Residual Uncertainty in Exposure
Database	20 

  HYPERLINK \l "_Toc202162153"  4.4.4.1	HED’s Levels of Concern (LOC)
21 

  HYPERLINK \l "_Toc202162153"  4.5	Toxicity Endpoint and Point of
Departure Selections	21 

  HYPERLINK \l "_Toc202162153"  4.5.1	Dose-Response Assessment	23 

  HYPERLINK \l "_Toc202162153"  4.5.2	Recommendation for Combining
Routes of Exposures for Risk Assessment	23 

  HYPERLINK \l "_Toc202162153"  4.5.3	Cancer Classification and Risk
Assessment Recommendation	23 

  HYPERLINK \l "_Toc202162153"  4.5.3.1	Carcenogenic Potential in Rats
24 

  HYPERLINK \l "_Toc202162153"  4.5.3.2	Carcenogenicity Syudy in
Hampsters	26 

  HYPERLINK \l "_Toc202162153"  4.5.3.3	Classification of Carcenogenic
Potential	27 

  HYPERLINK \l "_Toc202162153"  4.5.4	Summary of Points of Departure And
Toxicity Endpoints Used In Human Risk Assessment	27 

  HYPERLINK \l "_Toc202162153"  4.6	Endocrine Disruption	28 

  HYPERLINK \l "_Toc202162152"  5.0	Metabolism	29 

  HYPERLINK \l "_Toc202162153"  5.1	Nature of the Residue - Plants	29 

  HYPERLINK \l "_Toc202162165"  5.2	Nature of the Residue - Animals	29 

5.3     Meat, Milk, Poultry and Eggs	29

5.4     Analytical Methods	30

  HYPERLINK \l "_Toc202162165"  5.5	Storage Stability Update	30 

  HYPERLINK \l "_Toc202162165"  5.6	Magnitude of Residue in Food Update
31 

  HYPERLINK \l "_Toc202162165"  5.7	Processing Factors	34 

  HYPERLINK \l "_Toc202162165"  5.8	Rotational Crops	37 

  HYPERLINK \l "_Toc202162165"  5.9	Proposed and Recommended Tolerances 
37 

  HYPERLINK \l "_Toc202162168"  6.0	Exposure Characterization/Assessment
Section Update	39 

6.1  HYPERLINK \l "_Toc202162165"   	Dietary Exposure/Pathway	39

	6.1.1    Acute and Chronic Dietary Exposure and Risk Update	39	

  HYPERLINK \l "_Toc202162169"  7.0	Water Exposure Risk/Pathway	41 

  HYPERLINK \l "_Toc202162173"  8.0	Residential Exposure Risk
Characterization	42 

  HYPERLINK \l "_Toc202162174"  9.0	Aggregate Risk Assessment and Risk
Characterization Updates	45 

  HYPERLINK \l "_Toc202162176"  10.0	Occupational Exposure/Pathway
Updates	46 

  HYPERLINK \l "_Toc202162177"  10.1	Handler Exposure and Risk	46 

  HYPERLINK \l "_Toc202162178"  10.2	Occupational Post-Application
Exposure and Risks	51 

  HYPERLINK \l "_Toc202162180"  11.0 	Data Needs and Label Requirements
53

	11.1     Toxicology	53	

	11.2     Residue Chemistry	53

	11.3     Occupational and Residential Exposure	53

12.0     References	53

   TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc202162117"  Appendix A
Hazard Identification and Endpoint Selection	57 

  HYPERLINK \l "_Toc202162153"  A.1	Toxicology Data Requirements	57 

  HYPERLINK \l "_Toc202162153"  A.2	Toxicity Profiles	59 

  HYPERLINK \l "_Toc202162153"  A.3	Hazard Identification and Endpoint
Selection	68 

  HYPERLINK \l "_Toc202162153"  A.3.1	Acute Reference Dose (aRfD) –
Females Age 13-49	68 

  HYPERLINK \l "_Toc202162153"  A.3.2	Acute Reference Dose (aRfD) –
General Population	68 

  HYPERLINK \l "_Toc202162153"  A.3.3	Chronic reference Dose (cRfD)	69 

  HYPERLINK \l "_Toc202162153"  A.3.4	Incidental Oral Exposure (Short-
and Intermediate-Term)	69 

  HYPERLINK \l "_Toc202162153"  A.3.5	Dermal Exposure (Short-,
Intermediate-, and Long-Term)	70 

  HYPERLINK \l "_Toc202162153"  A.3.6	Inhalation Exposure (Short-,
Intermediate-, and Long-Term)	72 

  HYPERLINK \l "_Toc202162153"  A.4	Executive Summaries	73 

  HYPERLINK \l "_Toc202162153"  A.5	Toxicology Data Required as a
Condition of Registration	74 

  HYPERLINK \l "_Toc202162165"   

 

1.0 Executive Summary

Fluazifop-P-butyl
[(R)-2-(4-((5-(trifluoromethyl)-2-pyridinyl)oxy)phenoxy)propanoic acid,
butyl ester] is a selective herbicide used for the post-emergence
control of perennial and annual weed grasses.  It works by interfering
with fatty acid synthesis by inhibiting the enzyme acetyl CoA
carboxylase, an adenosine triphosphate (ATP) dependent enzyme.  It
accumulates in the meristems of roots and shoots, root rhizomes and
stolons in susceptible plants.  This active ingredient is the resolved
isomer (R enantiomer) of fluazifop-butyl (PC code 122805) which has
since been cancelled resulting in only fluazifop-P-butyl to be supported
for re-registration.  Fluazifop-P-butyl end-use products are registered
in the United States to Syngenta Crop Protection, Inc. under the trade
names Fusilade®, Fusion®, Oramec®, Tornado®, and Typhoon®.    

Fluazifop-butyl isomers are List B chemicals with parent and
fluazifop-acid (free and conjugated) regulated for tolerance expression
as the residues of concern used to determine misuse (DP No. D319907, S.
L. Kinard, 08/17/2005).  It is currently registered for use on
asparagus, carrot, coffee, cotton, endive (escarole), garlic, macadamia
nut, onion, pecan, pepper, rhubarb, soybeans, stone fruits, sweet
potato, and yam.  It is also currently registered for use on lawns as a
weed control application.  

Tolerances are established under 40 CFR §180.411(a) for residues of the
herbicide fluazifop-P-butyl which include both the free and conjugated
forms of its resolved isomer expressed as fluazifop.

There are no Section 18 emergency exemptions in effect but
fluazifop-P-butyl tolerances are likewise established under 40 CFR
§180.411(c) which carry regional restrictions expressed as fluazifop. 

To further develop the use of fluazifop-P-butyl, Syngenta has submitted
petition No. 9F7624 for establishing permanent tolerances in/on bananas,
citrus, grapes, and sugar beets.  The end-use product relevant for this
petition request is Fusilade® DX Herbicide (EPA Reg. No. 100-1070), an
emulsifiable concentrate formulation containing 24.5% ai of
fluazifop-P-butyl (equivalent to 2 lb ai/gal).  It is proposed for use
as multiple foliar or vineyard/orchard floor applications made at
maximum seasonal rates of 1.125 lb ai/A for bananas, grapes, and citrus
and 0.75 lb ai/A for sugar beets.  Applications are to be made with an
adjuvant using ground or aerial equipment at Pre-Harvest Intervals
(PHIs) which range from 0 days on treatments made to bananas up to 90
days for sugar beets.

In addition, petition No. 9E7651 is also being put forward by Syngenta
which requests that an import tolerance for fluazifop-P-butyl be
established on potatoes.  The end-use products relevant for this
petition request are the VENTURE L and Fusilade® MAX(X) herbicide
Emulsifiable Concentrate (EC) formulations.  These end-use products are
identical with both of them containing approximately 14.0%
fluazifop-P-butyl active ingredient (ai) equivalent to 125 g ai/L.  For
this action, Syngenta has requested to amend the label of the VENTURE L
product by adding this new use on potatoes in Canada.  Treatments of
these products are to be made as a single foliar spray application not
to exceed the maximum labeled rate of 250 g ai/ha timed at PHIs of 45 or
90 days.

This HED document provides a summary of the findings from the data
evaluation and subsequent assessment of human health risk resulting from
these submissions.  Prior actions made to develop the fluazifop-P-butyl
herbicide active ingredient (ai) have identified a number of studies
that are required for completing data gaps.  In accordance, a number of
Data Call-In (DCI) submissions have been provided by the registrant in
order to satisfy these database requirements.  These studies are as
follows:

• Carrot and endive nature of residue studies, test guideline
860.1300. 

• Ruminant and poultry nature of residue studies, test guideline
860.1300. 

• Radiovalidation study made for the tolerance enforcement method
proposed for analyzing plants,                         test guideline
860.1340. 

• Method validation study made for the tolerance enforcement method
proposed for analyzing poultry, eggs and livestock, test guideline
860.1340.

• Cattle and poultry feeding studies, test guideline 860.1480.

• Confined rotational crop study, test guideline 860.1850. 

An assessment of these studies is currently in progress and when
completed, will be addressed in a separate memorandum.  Should the
results of the studies submitted in response to the registration DCI
impact the conclusions reached in this summation, appropriate changes
will be made at that time.  

Hazard Assessment

Fluazifop-P-butyl has low acute toxicity by the oral, dermal and
inhalation

routes, and mildly irritating to the eye and skin, and is not a skin
sensitizer. Sub-chronic and

chronic toxicity studies with fluazifop-P-butyl show that the rat is
more

sensitive to toxic effects than the dog, rabbit or hamster, possibly due
to longer retention time of

the major metabolite (fluazifop acid) in the rat. The liver and kidney
are the target organs and

the toxicity is expressed as liver toxicity in the presence of
peroxisome proliferation and

exacerbation of age related kidney toxicity. An acute dietary endpoint
for females 13-49 years of age was selected from a developmental
toxicity study in rats, based on diaphragmatic hernia (LOAEL=50
mg/kg/day). No appropriate endpoint attributable to a single dose was
identified for the general U.S. population. The short-term incidental
oral endpoint was selected from the developmental toxicity studies in
rats and is based on maternal body weight gain decrement (NOAEL=100
mg/kg/day). The chronic dietary (all populations), intermediate-term
dermal and inhalation, and intermediate term incidental oral endpoints
were selected from the two-generation reproduction study in rats based
on decreased spleen, testes and epididymal weights in males, and
decreased uterine and pituitary weights in females (NOAEL=0.74
mg/kg/day). This endpoint was also utilized for the intermediate &
long-term dermal and inhalation exposures (1 to >6 months). The
short-term dermal and inhalation endpoints used in the assessment were
selected from the developmental toxicity studies in rats based on
decreased fetal weights, hydroureter and delayed ossification (NOAEL=2
mg/kg/day). Though this endpoint was selected by the Hazard
Identification Risk Assessment Committee specifically for females 13-49
years of age, and a separate, higher, dose/endpoint was selected for all
other population sub-groups from the developmental toxicity studies in
rats, based on maternal weight gain decrement, HED chose to use the
female-specific endpoint for all population sub-groups. By using the
lower dose/endpoint approach for all population sub-groups, the risk
assessment is protective of the toxic effects seen at higher doses.
Because oral NOAELs were selected for dermal and inhalation endpoints,
dermal absorption factors, calculated from a dermal absorption and
pharmacokinetic study in

humans, of 2% for high exposures and 9% for low exposures were used for
oral-dermal route-to route

extrapolation, and 100% absorption was used for inhalation exposure.
Fluazifop-P-butyl is

classified as “not likely to be carcinogenic to humans” and no
mutagenic potential was observed

in adequate in vivo and in vitro studies with fluazifop-P-butyl.

Though increased susceptibility of offspring was observed in rats, the
degree of concern is low.

The endpoint of concern (delayed ossifications) is a well defined
endpoint based on five

developmental toxicity studies and the NOAEL/LOAEL(s) are much lower
dose levels than

resulted in the malformations. A developmental endpoint of concern for a
single-dose effect

(diaphragmatic hernia) is used for assessing acute dietary risk.
However, the 2-generation reproduction study in rats did not reveal
increased susceptibility of the offspring. No increased offspring
sensitivity over parent was seen the rabbit pre-natal developmental
studies or the post-natal reproduction study Therefore, there is no
residual uncertainty for pre and/or post natal toxicity. The Assessment
team concluded that there was not a concern for neurotoxicity resulting
from exposure to fluazifop-P-butyl at relevant exposure levels. There
was no evidence of clinical signs indicative of neurotoxicity,
neuropathology or immunotoxicity in the available studies. Marginal
increases in brain weights at termination were seen in a sub-chronic
toxicity study in rats and a carcinogenicity study in hamsters, but only
at high doses.  HED concluded that there is not a concern for
developmental neurotoxicity resulting from exposure to
fluazifop-P-butyl. The Agency concluded that the toxicology database is
complete for FQPA assessment and that outstanding studies are not likely
to have an endpoint of less than 0.74 mg/kg/day. Therefore, the FQPA 10X
uncertainty factor need not be retained for susceptibility or data base
uncertainty concerns. 

Residue Chemistry

The Fluazifop-P-Butyl Residue Chapter of the TRED (DP No. 319907, S. L.
Kinard, 08/17/2005) concluded that the nature of the residue in soybeans
is adequately understood.  No new plant metabolism studies for the
proposed new use crops were submitted as part of the current petition. 
It has been concluded that for tolerance expression, parent and
fluazifop-acid (free and conjugated) are the residues of concern since
they are adequate to determine misuse (DP No. D298939, S. L. Kinard,
06/22/2004).  For this action, there are no residue chemistry issues
that would preclude the conditional registration of the requested uses
of fluazifop in/on bananas, citrus, grapes and grape processed
commodities, or sugar beet.  An unconditional registration may be
appropriate upon determination of the adequacy of a new citrus
processing study.  In regard to the establishment of a tolerance for
fluazifop-P-butyl in/on imported potato commodities, registration can be
granted for this requested use.  There are adequate analytical methods
available for carrying out data collection efforts and enforcing all
recommended tolerances.

Residential Exposure and Risk Estimates

Short-term (1-30 days) residential exposure may occur from its use in
post-emergent control of weed grasses on turf.  For adults, exposure may
occur from homeowner application of fluazifop-P-butyl products (dermal
and inhalation routes) and from contact with treated turf (dermal)
following application.  For children, post-application exposures (dermal
and incidental oral) can occur from contact with treated turf.  Adult
applicator and post-application risks were combined in the assessment. 
Likewise, risks to children from dermal plus hand-to-mouth,
object-to-mouth, and soil ingestion exposures were combined for
scenarios involving post-application contact with treated turf.  

For fluazifop-P-butyl, residential risk estimates were determined using
the Margins of Exposure (MOEs) approach made as a ratio of the
toxicological point of departure to the body burden.  By means of this
technique, aggregate risk estimates were made using the most
conservative endpoints, high-end exposures, and worst-case scenarios. 
Estimated risks for residential handlers and short-term post-application
exposures, as well as those involving children, all yielded MOEs above
100 which are not of concern to HED.  

Based upon these proposed new uses for this action, the existing
residential fluazifop-P-butyl use patterns will not be affected.  As a
result, HED’s most recent residential risk assessment will require no
revision with its conclusions remaining relevant and appropriate (DP No.
D291905, M. Collantes, 11/29/2004).     

   

Dietary Exposure and Risk Estimates

(DEEM-FCID™) were subsequently conducted for fluazifop-P-butyl (DP No.
D379452, S. Tadayon, 08/09/2010).  This modeling effort uses food
consumption data from the U.S. Department of Agriculture’s Continuing
Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998
to calculate dietary risk.  These analyses were performed to support the
Section 3 registration of fluazifop-P-butyl on bananas, citrus, grapes
and grape processed commodities, as well as sugar beets.  Also included
in this determination are all uses which would be relevant to the
establishment of an import tolerance made for fluazifop-P-butyl on
potatoes.  The proposed new crop uses were added into the residue file
for all previously registered commodities so that a current evaluation
of dietary exposure could be made.  

DEEM-FCID™ model form a careful evaluation of exposure for
fluazifop-P-butyl.  The acute dietary assessment was limited to the
females 13-49 years of age population subgroup.  This is the only
population subgroup for which an appropriate toxic endpoint attributable
to a single dose was identified.  For females 13-49 years of age, acute
dietary risk was estimated to be only 13 % of the aPAD with an exposure
of 0.0641 mg/Kg/day.  In conjunction, the refined chronic analysis
likewise yielded risk estimates well below the 100% of the cPAD
threshold level of concern for each population subgroup.  For the most
highly exposed population subgroup, children 1-2 years of age, chronic
dietary risk was estimated to be 40% of the cPAD with an exposure of
0.0030 mg/Kg/day.  In all, the dietary risks for combined food and
drinking water exposure from the proposed expanded uses of
fluazifop-P-butyl are not of concern.  

Drinking Water Exposure and Risk Estimates

The potential human exposure to fluazifop-P-butyl in drinking water was
likewise re-evaluated by EFED to support the proposed new crop uses
being requested by Syngenta for risk assessment purposes.  For this
assessment, EECs in both ground and surface water were estimated using
the Tier I SCIGROW and Tier II PRZM/EXAMS models, respectively (DP Nos.
D371093 & D371094, W. J Shaughnessy, 05/25/2010).  These modeling
efforts indicate that the most significant levels of fluazifop-P-butyl
would likely be found in surface water resulting from applications made
to bananas and plantains.  Corresponding drinking water levels of
fluazifop-P-butyl resulted in estimated concentrations of 33.4 µg/L and
6.6 µg/L for acute and chronic exposures respectively.  As such, these
concentration estimates provided by EFED indicate that the proposed new
uses would result in greater water exposures relative to those which
were previously determined.  However, as stated above, when combined
with exposures through food, combined drinking water and food exposures
are not of concern.

  

Aggregate Exposure and Risk Estimates

To ensure risk characterization efforts are all inclusive, HED
aggregated the exposures/risks from food, drinking water, and
residential (oral, dermal & inhalation) sources.  This evaluation is
typically made by adding together the exposures from each source for
comparison to a quantitative estimate of hazard (NOAEL, PAD, etc.), or
just by simply aggregating the risks themselves.  When aggregating
various sources of exposures and risks, HED gives consideration to both
the route and duration of exposure.  

    

For this action, the proposed new uses of fluazifop-P-butyl were found
to slightly increase total exposures through food, and significantly
increase exposures through drinking water.  Based upon this outcome, the
impact on dietary exposure is the only occurrence which would
necessitate updating the current aggregate short-term risk assessment in
place for this herbicide.  To complete this evaluation, aggregate risk
assessments were carried out for the most likely exposure scenarios
resulting from the existing and expanded uses of fluazifop-P-butyl. 
These scenarios are for combined acute (1-day) exposures made through
food and drinking water, as well as combined chronic exposures occurring
through food and drinking water.  In addition, the short-term aggregate
exposures resulting from food, drinking water, and residential uses were
considered.                   

DEEM-FCID™ modeling.  DEEM-FCID™ modeling was also used to determine
estimates of aggregate risk from combined chronic fluazifop-P-butyl
exposures in food and drinking water as well.  A detailed discussion of
these findings evaluating the expanded use of fluazifop-P-butyl is
therefore provided in the Section 6.1.1 Acute and Chronic Dietary
Exposure and Risk Update of this memorandum.  As for the short-term
(1-30 days in duration) aggregate risk assessment, it was made as an
estimate of potential exposures from food, drinking water, and home
lawns.  High-end estimates of exposure resulting from treatment of lawns
along with average exposures from food and drinking water were used to
form this evaluation.  For this short-term aggregate risk assessment,
aggregate MOEs of  150 for adults and 250 for children (1 – 2 years of
age) were obtained which are well above the level of concern of 100
indicating there are no concerns resulting from the proposed expanded
uses of fluazifop-P-butyl.  

Occupational Exposure Estimates

The new crop uses proposed with this petition are for the Fusilade® DX
Herbicide (EPA Reg. No. 100-1070), an EC formulation containing 24.5% ai
of fluazifop-P-butyl (equivalent to 2 lb ai/gal).  Its expanded use will
employ multiple foliar or vineyard/orchard floor applications at maximum
seasonal rates of 1.125 lb ai/A for bananas, grapes, and citrus and 0.75
lb ai/A for sugar beets.  Applications are to be made using an adjuvant
and applied with either ground or aerial equipment.  Labeling
instructions propose PHIs for the requested new uses which range from 0
days on treatments made to bananas up to 90 days for sugar beet
applications.  In accordance, occupational handlers and post-application
workers can become exposed to fluazifop-P-butyl at short- or
intermediate-term durations through its use. 

For the new crop uses being proposed in this action, the expanded use of
fluazifop-P-butyl will support commercial agricultural efforts in
controlling grass weeds through limited foliar application.  

Occupational exposures/risks were addressed in the prior HED human
health risk assessment made to support the new uses to dry beans and
peanuts (DP No. D347515, P. Savoia, 09/18/2008).  For this current
action, a new evaluation of the occupational exposure/risk pathway was
performed herein to ensure worker protection safeguards (DP No. D379451,
S. Tadayon, 06/23/2008).  This accounts for potential exposure to
fluazifop-P-butyl during mixing, loading, and application activities
pertinent to the existing and proposed new uses.  

Most occupational activities will involve worker contacts with the
herbicide requiring the consideration of dermal and inhalation exposure
when evaluating risk.  Dermal absorption factors of 2% and 9% were
determined for fluazifop-P-butyl depending on high versus low levels of
exposure respectively.  Re-entry intervals have been assessed using both
values.  HED believes that prior dermal absorption studies demonstrate
saturation of the skin if the mass per unit area exceeds a certain
level.  Given this, use of the 9% factor in combination with high levels
of exposure would result in a conservative estimate of risk.            
        

No long-term exposures are expected for the general agricultural
use-patterns of fluazifop-P-butyl, therefore, no long-term risks were
assessed.  Estimated risks for occupational handlers determined for
short-/intermediate-term exposures yielded total MOEs greater than 100,
with some scenarios requiring additional personal protection above
baseline (e.g., engineering controls for mixer/loaders).  In reaching or
exceeding the LOC of 100, the resulting MOEs indicate these risks are
not of concern.  Most of the proposed new uses are ground directed
applications where no crop foliage is being treated.  Currently, HED has
no Transfer Coefficients (TCs) or other data to assess post-application
dermal exposures to soil by occupational workers.  As a result, this
post-application exposure and risk to occupational workers was not
quantitatively assessed.  However, in assessing the applications made to
sugar beets and potatoes where workers can come in contact with foliage,
these risks are not of concern since the resulting MOEs where found to
exceed 100.     

Environmental Justice

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations,"   HYPERLINK
"http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pd
f" 
http://www.epa.gov/compliance/resources/policies/ej/exec_order_12898.pdf
.  The Office of Pesticide Programs (OPP) typically considers the
highest potential exposures from the legal use of a pesticide when
conducting human health risk assessments, including, but not limited to,
people who obtain drinking water from sources near agricultural areas,
the variability of diets within the U.S. (including different ages,
regions, and ethnicities), and people who may be exposed when harvesting
crops.  Should these highest exposures indicate potential risks of
concern, OPP further refines the risk assessments to ensure that the
risk estimates are based on the best available information.

Cumulative 

 

FQPA requires that EPA consider “available information” concerning
the cumulative effects of a particular pesticide’s residues and
“other substances that have a common mechanism of toxicity.” The
Agency considers other substances because low-level exposures to
multiple chemical substances that cause a common toxic effect by a
common mechanism could lead to the same adverse health effect, as would
a higher level of exposure to any of the substances individually. Risks
summarized in this document are those that result only from the use of
fluazifop. The Food Quality Protection Act (FQPA) requires that 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.” 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 fluazifop and any other substances. In addition, fluazifop
does not appear to produce a toxic metabolite produced by other
substances which have tolerances in the U.S. Therefore, for the purposes
of tolerance reassessment, EPA has not assumed that fluazifop shares a
common mechanism of toxicity with other compounds.

  SEQ CHAPTER \h \r 1 Recommendations for Tolerances/Registration

Provided the petitioner submits revised Sections B and F (see Section
11.0), HED concludes that the toxicological, residue chemistry and
occupational/residential databases support a conditional registration
and establishment of permanent tolerances for the proposed new uses of
fluazifop-P-butyl.

Tolerances are to be established for residues of the herbicide
fluazifop-P-butyl, including its metabolites and degradates, in or on
the commodities listed below.  Compliance with the tolerance levels
specified below is to be determined by measuring only the sum of
fluazifop-P-butyl,
butyl(R)-2-[4-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenoxy]propanoate,
and the free and conjugated forms of the resolved isomer of fluazifop,
(R)-2-[4-[[5-(trifluoromethyl)-2-pyridinyl]oxy]phenoxy]propanoic acid,
calculated as the stoichiometric equivalent of fluazifop, in or on the
commodity.

Banana	0.01 ppm

Fruit, citrus, group 10	0.03 ppm

Citrus, oil	30.0 ppm

Citrus, dried pulp	0.40 ppm

Citrus, juice	0.06 ppm

Grape	0.01 ppm

Beet, sugar, root	0.25 ppm

Beet, sugar, dried pulp	1.0 ppm

Beet, sugar, molasses	3.5 ppm

Potato	1.0 ppm

Potato, chips	2.0 ppm

Potato, granules/flakes	4.0 ppm

Registration of these tolerances should be made conditionally until the
remaining data deficiencies described in Section 11.0 are satisfied.  An
unconditional registration may be appropriate upon determination of the
adequacy of a new citrus processing study (see requirements under
Processed Food and Feed).  

2.0	 Background

In August of 2005, HED completed a human health risk assessment of the
fluazifop-P-butyl herbicide active ingredient for Tolerance Reassessment
Eligibility Decision (DP No. D316891, D. Locke, 08/29/2005).  Following
this risk assessment, Syngenta Crop Protection, Inc. submitted petition
No. 7F7289 which requested to allow for the post-emergence use of
fluazifop-P-butyl on dry beans and peanuts.  Along with these two new
crop uses, the registrant also proposed in this petition to allow
fluazifop-P-butyl treatments made on soybeans to include post-bloom
application.   In response to this action, HED has conducted a
subsequent risk assessment to support all existing uses as well as the
new crop treatments which were requested (DP No. D347515, P. Savoia,
09/18/2008).

For this current registration action, new data characterizing the
magnitude of the residue in plants were appropriately provided by the
registrant to support the additional crop uses which are being proposed.
 There were no new toxicological studies, public health, residential, or
occupational data provided in the Syngenta submission.  Therefore, the
presentation of the toxicity database, points of departure, and hazard
characterization presented in section 4.0, while more streamlined, are
substantively the same as those appearing in recent previous
assessments.  The assessment of residential exposures and risks are
similarly based upon the relevant information provided in the August
2005 tolerance reassessment (DP No. D316891, D. Locke, 08/29/2005).   

To establish permanent tolerances for residues of fluazifop-P-butyl on
banana, citrus, grape, and sugar beet RACs as well as an imported
potatoes, this memorandum updates the prior risk assessments noted.  It
provides residue chemistry, dietary exposure, aggregate risk assessment,
and occupational risk assessment updates to reflect the new crop uses
which are being proposed.  In doing so, all information and/or
conclusions contained in the August 2005 and September 2008 HED human
health risk assessments will therefore remain unchanged unless otherwise
noted in this memorandum. 

Summary of Proposed Uses

The expanded use of fluazifop-P-butyl will utilize the Fusilade® DX
Herbicide for multiple foliar or vineyard/orchard floor applications at
maximum seasonal rates of 1.125 lb ai/A for bananas, grapes, and citrus
and 0.75 lb ai/A for sugar beets.  This product can be applied with an
adjuvant using ground or aerial equipment at PHIs which range from 0
days on treatments made to bananas up to 90 days for sugar beet
applications.  For the new use requested on potatoes, the VENTURE L
product will be utilized as a single foliar spray not to exceed the
maximum labeled rate of 250 g ai/ha timed at a PHI of 45 or 90 days.  In
using this product, spray mist and drift is to be avoided with
applications never to be made by aircraft or within 15 m of fish bearing
waters.  A detailed summary of the proposed new uses on bananas, grapes,
citrus, potatoes and sugar beets is presented below in Table 1 for
review.   

Table 1.   Summary of Directions for Use of Fluazifop-P-butyl.

Applic. Timing, Type, and Equip. 	Formulation

[EPA Reg. No.]	Maximum Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Banana 

Ground and Aerial.	Fusilade® DX Herbicide,

2 lb/gal EC

[100-1070]	0.375	3	1.125	0	A minimum 30-day RTI is specified. 

Citrus

Ground and Aerial.	Fusilade® DX Herbicide,

2 lb/gal EC

[100-1070]	0.375	3	1.125	14	A minimum 21-day RTI is specified.

Grape

Ground and Aerial.	Fusilade® DX Herbicide,

2 lb/gal EC

[100-1070]	0.375	3	1.125	50	A minimum 14-day RTI is specified.

Sugar Beet

Ground and Aerial.	Fusilade® DX Herbicide,

2 lb/gal EC

[100-1070]	0.375	2	0.75	90	A minimum 14-day RTI is specified.

Potato

Post-emergence

Ground.	Venture L®  Herbicide,

125 g ai/L EC

[Canadian Reg. No.: 21209]	0.275	1	0.275	45 or 90	May be mixed with
Lexone or sencore formulations for early post emergent application.

The general label use directions of the Fusilade® DX Herbicide specify
that:  (1) adjuvants (crop oil concentrate, non-ionic surfactant, or
other approved adjuvants) plus liquid nitrogen fertilizer may be used on
soybeans; (2) ground and aerial applications are to be made in a minimum
of 5 gal/A; (3) for chemigation (sprinkler irrigation), adjuvants are
not to be used in the manner described for use in conventional
applications or applied with a system connected to a public water
system; and (4) the restricted-entry interval is 12 hours.  Rotational
grass crops such as corn, sorghum and cereals are not to be planted
within 60 days of last application.

For the VENTURE L product, general label use directions specify that it
will be less effective when weeds are not growing rapidly because of
stress from lack of moisture, excessive moisture, flooding, low
temperature and/or very low humidity.  Treatments should be applied to
actively growing grass weeds that have 3 to 5 fully developed leaves for
best results.  Spray mist and drift is to be avoided with applications
never to be made by aircraft or within 15 m of fish bearing waters.  The
use of adjuvants (crop oil concentrate, non-ionic surfactant, or other
approved adjuvants) plus liquid nitrogen fertilizer may be used on
specified crops such as soybeans and potatoes.  

4.0	Hazard Characterization and FQPA Considerations

The 2005 risk assessment contained a thorough description of toxicology
profile for fluazifop-P-butyl (DP No. D316891, D. Locke, 08/29/2005).
The data base is adequate for FQPA assessment, endpoint selection, and
dose-response evaluation for fluazifop-P-butyl and the fluazifop mixed
isomers. 

4.1	Toxicology Studies Available for Analysis

The toxicity database on fluazifop-butyl is essentially complete with
sufficient toxicity data on fluazifop-P-butyl to show similar responses
in animal toxicity studies.  The toxicity database is adequate for FQPA
assessment, endpoint selection and dose-response evaluation of both
products.  Fluazifop-P-butyl has low volatility, is not an eye or skin
irritant in acute or 21-day dermal studies, and is not a skin
sensitizer.  Fluazifop-P-butyl is likely to show similar toxicity by the
inhalation route and the oral route, because it is metabolized by blood
to the acid form and excreted as the acid form.  The use pattern and
exposure pattern for the residential handler show high MOEs, well above
the level of concern using endpoints based on oral exposure.  The data
are relatively consistent among the rat with fluazifop-butyl and
fluazifop-P-butyl, dog with fluazifop-butyl, and the hamster with
fluazifop-P-butyl, probably with some within-animal variation, although
all endpoints were not evaluated with all species with fluazifop-P-butyl
and its mixed isomers. 

Data from the following studies were used to evaluate the hazard
potential of fluazifop-P-butyl:

Acute:	Oral, Dermal, Inhalation, Eye and skin irritation, Dermal
sensitization with fluazifop-butyl and fluazifop-P-butyl

Subchronic:	Oral rat with fluazifop-butyl and fluazifop-P-butyl, Oral
dog with fluazifop-butyl, Dermal 21-day rabbit with fluazifop-butyl,
Inhalation - no studies available.

Chronic: 	Chronic/Cancer rat with fluazifop-butyl, Cancer hamster with
fluazifop-P-butyl, Oral dog with fluazifop-butyl

Developmental:	Two in the Sprague Dawley rat with fluazifop-butyl and
three in the Wistar rat with fluazifop-P-butyl.  One in the NZW Rabbit
with fluazifop-butyl and one in the NZW rabbit with fluazifop-P-butyl.

Reproduction:	Two-generation in rats with fluazifop-butyl

Metabolism:	Rat, human and dog with fluazifop-butyl and comparative in
the rat with fluazifop-butyl and fluazifop-P-butyl, and hamsters with
fluazifop-P-butyl.

Dermal Penetration:     Human study (ethics of study cleared)

Literature Studies:	Literature studies regarding information for which
similar, but more detailed, reports were submitted to the Agency.

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

Fluazifop-butyl is a herbicide with mixed isomeric [RS] content, while
fluazifop-P-butyl is the purified [R] enantiomer, the only herbicide
supported for re-registration.  Metabolism studies have been conducted
in the rat with fluazifop-butyl, and absorption, excretion and
confirmatory metabolism studies in the dog with fluazifop-butyl, and
hamster with fluazifop-P-butyl.  Comparative metabolism studies in the
rat show that both fluazifop-P-butyl and fluazifop-butyl mixed isomers
are rapidly hydrolyzed to fluazifop acid and the [S] enantiomer is
rapidly converted to the [R] enantiomer in the blood, yielding similar
toxicities within animal variation.  In characterizing this herbicide
active ingredient, fluazifop-P-butyl is the purified (R) enantiomer of
the mixed isomeric (RS) fluazifop-butyl product. Fluazifop-butyl (PC
code 122805) has since been cancelled resulting in only
fluazifop-P-butyl (PC code 122809) currently being supported for
re-registration.  In vivo, the S-isomer quickly converts to the
R-isomer. A 50:50 mixture of the two isomers quickly converts to 97%
R-isomer in vivo. Given this distinction, the toxicological data-base on
fluazifop-butyl is complete with sufficient data available showing
equivalence of fluazifop-butyl (FB, PC code 122805) for
fluazifop-P-butyl (FPB, PC code 122809) in animal toxicity.  The
toxicity data-base is therefore adequate to carry out FQPA assessment,
endpoint selection, and dose-response evaluation for both chemicals.
Peroxisome proliferation was shown in rat and mouse, and to a lesser
extent in the hamster, in vivo, and human liver cells, in vitro.  

Oral dog and female rat studies show similar results.  Fluazifop-butyl
is rapidly absorbed through the gut after oral dosing and the ester
linkage is hydrolyzed to produce the fluazifop acid in the blood. No
parent fluazifop-ester was detected in plasma at any time. Male rats
show similar fluazifop acid excretion to the female, but excretion is
slower because fluazifop is excreted in the bile, resulting in a higher
% in the feces of males rats.  The greater toxicity in male rats may be
due to the longer retention time. In rats, the blood half-lives after
intravenous administration ranged from 2.7-43 hours for 1 mg/kg and 1000
mg/kg doses, respectively. Based on radioactivity recovered in the urine
after 1 mg/kg oral dosing in rats, absorption was extensive in females
(75-89%), but was less so in males (49-51%).  Furthermore, excretion in
the urine was rapid in females, 66-83% dose within 1 day post-dose. 
Conversely, excretion was slower in males, largely taking place over a 3
day period post-dose in urine (41-43% dose) and feces (26-27% dose). 
Over the 7 day post-dose period in rats, relatively little of the dose
was excreted in the feces of females (3-11%), while 35% dose was
excreted in the feces of males.  Residual fluazifop acid appears to be
retained in the body fat (<1% to 8% in the rat) and speculated to be
esterified to mono- or di-glycerides.  This small amount of residual
material, if released, was too low to be accurately detectable in the
urine.  This residual material is relatively immobile and may be
toxicologically insignificant, since multiple dosing studies show that
fluazifop-butyl does not accumulate in the body and is not a carcinogen.
In hamsters dosed orally, 72-82% of the administered radioactivity was
excreted by males and 82-88% by females within 12 hours of dosing.  Over
the 72-hour collection period, the majority of the radiolabel was
excreted in the urine (70-83% for males; 76-93% for females) and feces
(11-24% for males; 10-16% for females), irrespective of dose.  The
hamsters had low levels of radiolabel in the tissues and carcasses
(0.18-0.43% of the given dose).  

In a metabolism study (MRID# 00131464)(Fluazifop-butyl, 99.6% a.i,
Y00083/012/003) were administered to 3 male humans in a single dose in
corn oil on a sugar cube at a dose level of 0.07 mg/kg.  The results
from the study were consistent with the studies in rats and dogs.  That
fluazifop-butyl is rapidly absorbed, hydrolyzed to the free acid and
excreted mostly in the urine as the free acid, with minor amounts of
conjugates of the free acid (conjugates unidentified in humans).  The
one-half life in the men studied was closer to that found in female
rats, which lacked the delayed excretion characteristic of male rats
possibly being due to biliary recycling in male rats.  If the toxicity
of fluazifop-butyl is related to delayed excretion time seen in male
rats, then the rapid excretion in men in the current study may suggest
that the toxicity in men is more closely related to the dog and female
rats where the excretion time is also short.  In toxicity studies in
rats, toxicity in males was always more severe than in females.   Only
hydrolyzed fluazifop-butyl or the free acid was detectable in plasma and
the free acid and its conjugate were detected in urine.  The excretion
of the test material was complete within 7 days, with plasma levels
being undetectable within 72-144 hours (3-6 days) and with urine levels
being undetectable at 96-144 hours (4-6 days).  Total recoveries of
fluazifop as the conjugate and the free acid in the urine from each of
the 3 men were 80%, 93% and 92% (Mean 88.3%) of the dose and 1-4%, 6%
and 23% as a conjugate, respectively.  The ethics of this human study
was cleared in the memo “Ethics Review of Fluazifop-Butyl Absorption,
Distribution and Metabolism Study” (K Sherman, August 13, 2010).

4.2.1	Dermal Absorption

In a dermal absorption and pharmacokinetic study in humans (MRID#
46082918, ethics of study cleared, Lowe MF, Carley JM, June 10, 2006),
six men/dose (age 18-45; weight 60-90 kg) were exposed dermally with 2
mg or 200 mg of 0.05% or a 5.0% (w/v) solution of fluazifop-butyl in a
formulation.  The washes, T-shirts, plasma and urine samples were
analyzed for fluazifop-butyl or fluazifop acid.

Most of the applied dose appeared to be in the stratum corneum and
easily removed (the unrecovered test material was speculated to be in
the outer layers of the skin). Recovery of test material was good, a
mean of 93.4% ± a standard deviation of 13% at the 2 mg dose and mean
of 83.2% ± a standard deviation of 21% at the 200 mg dose.  Peak plasma
levels were shown to occur 24 to 31 hours after application in these
men.  The one half-life for excretion was about 18 hours. In the 2005
risk assessment, HED (D316891) modified the study author’s percentage
absorption via scaling the amount recovered material to 100%, yielding
absorption factors of 8.6% and 1.9% at the 2 mg dose and 200 mg dose,
respectively.

4.3	Toxicological Effects

Fluazifop-P-butyl herbicidal specificity is by inhibiting acetyl CoA
carboxylase (a key enzyme in plant fatty acid synthesis and required for
maintaining membranes in functioning condition). Fluazifop-P-butyl has
low volatility proving no indication of being an eye or skin irritant in
acute or 21-day dermal studies, and is not a skin sensitizer. 
Fluazifop-P-butyl shows similar toxicity by both the inhalation and oral
routes because of its metabolization by blood into the acid form and
excretion in this manner.  The liver and kidney have demonstrated to be
its target organs expressed for the most part as liver toxicity in the
presence of peroxisome proliferation and exacerbation of age-related
kidney toxicity.  These data are reasonably consistent among the rat
with fluazifop-butyl and fluazifop-P-butyl, dog with fluazifop-butyl,
and hamster with fluazifop-P-butyl.  Although all endpoints were not
tested in all species using both compounds, some disparities may be
evident probably within animal variation.  In general, there were no
carcinogenicity concerns in any acceptable studies in the rat with
fluazifop-butyl or in the hamster for fluazifop-P-butyl.  The hamster
was selected for cancer study because liver peroxisome prolifieration
more closely resembled what was found for human liver cells.  There were
no mutagenicity concerns evident for fluazifop-butyl or
fluazifop-P-butyl. 

The current risk assessment is based on the most sensitive endpoints
(decreased testes and epididymal weights in male rats and decreased
pituitary and uterine weights in females) in the most sensitive species.
 The reproduction study male/female NOAELs are 0.74 and 0.88 mg/kg/day
while the LOAELs are 5.8 and 7.1 mg/kg/day, respectively.

A rat developmental study exhibiting diaphragmatic hernia effects was
used as the basis to select the acute dietary endpoint for females 13-49
years of age.  In contrast, there was no appropriate endpoint which
correlated to a single dose identifiable for the general U.S.
population.  The short-term incidental oral endpoint was selected based
upon a maternal body weight gain decrement exhibited in the
developmental toxicity studies performed on rats.  The chronic dietary
(all populations), intermediate-term dermal and inhalation, as well as
the intermediate-term incidental oral endpoints, were selected from the
2-generation reproduction study in rats.  This study was significant in
exhibiting decreased testes, and epididymal weights in males along with
decreased uterine and pituitary weights in females.  In regard to the
short-term dermal and inhalation endpoints used in this assessment, the
developmental toxicity studies performed on rats were used as the basis
for endpoint selection.  These studies were notable in exhibiting
decreased fetal weights, as well as hydroureter and delayed ossification
effects.          

In summarizing the available toxicity data on fluazifop-P-butyl, the
established toxicity endpoints for risk assessment are presented below
in Appendix A2 for review (DP No. D316891, D. Locke, 08/29/2005). There
were no concerns for neurotoxicity resulting from fluazifop-P-butyl
which were evident at relevant exposure levels.  There was also no
evidence of clinical signs which would indicate neurotoxicity or
neuropathology in the available studies, however, the Revised Part 158
Data Requirements list the acute and 90-day neurotoxicity studies as
mandatory.  Marginal increases in brain weights at termination were
observed in a sub-chronic toxicity study in rats, and in a
carcinogenicity study performed on hamsters, but only at higher doses.  

For fluazifop, there were some indications of potential immunotoxicity
in the form of thymic involution, altered spleen weights,
lymphadenopathy and bone marrow myelogram changes in dogs treated orally
(capsule) with 25 mg/kg/day (mid-dose) and 125 mg/kg/day (high-dose)
fluazifop for 55 weeks.  However, these effects are not of concern
because: (1) thymic involution was of slight severity in only 1 female
treated with the mid-dose.  In addition, the response was equivocal in
the males as there was no dose-response relationship (incidence and
severity) and controls also exhibited thymic involution.  One control
dog had severe thymic involution.  Also, the colony of dogs used in the
study had excessive health problems that may have impacted normal immune
status; (2) the statistical and biological significance of the
alterations in spleen weights could not be assessed because of the large
variation of the weights in control dogs.  Also, the alterations were
inconsistent between dogs that died (these dogs displayed increased
adrenal weights) and dogs that survived (these dogs displayed decreased
adrenal weights); (3) lymphadenopathy was observed only at the high dose
(125 mg/kg/day) and the response is questionable since the colony of
dogs used in the study had excessive health problems that included
lymphadenopathy;  (4) the bone marrow myelogram changes were discounted
by an HED Peer Review Committee which determined that the changes were
small and variable and not dose related.  In addition, the colony of
dogs used in the study exhibited health problems that may have impacted
the normal immune system; and (5) none of the potential immunological
signs in the dog were seen in a chronic study of the rat, the most
sensitive species. HED considered the results of the chronic dog study
to be unreliable due to fact that the animals were unhealthy, so that
apparent immunotoxic effects were observed in some untreated control
animals.  Moreover, no immunotoxic effects were observed in the
sub-chronic dog study; a study where healthy animals were used. HED
therefore believes that the available data do not warrant an additional
10X be applied to the uncertainty factor used for estimating risk at
this time.  An immunotoxicity study (870.7800) must be performed on
fluazifop-P-butyl, under 40 CFR Part 158, so that its immunotoxic
potential can be fully evaluated.

4.4	FQPA Safety Factor

No increased offspring sensitivity over parent was seen the rabbit
pre-natal developmental studies or the post-natal reproduction study and
no evidence of neurotoxicity was observed.  Although malformed fetuses
were seen at high dose levels in the absence of maternal toxicity in the
rat developmental toxicity studies, the definitive developmental
endpoint in five developmental studies was selected based delayed
ossification and fetal weight decrement at much lower doses (100 fold
lower).  

There is an adequate toxicity database for fluazifop-P-butyl and
exposure data are complete or are estimated based on data that
reasonably account for potential exposures. There is no evidence of
susceptibility following in utero and/or post-natal exposure in the
2-generation rat reproduction study (parental NOAEL=0.74 mg/kg/day and
offspring NOAEL=7.1 mg/kg/day). There are no residual uncertainties
pertaining to pre- and post-natal toxicity and no developmental
neurotoxicity or immunotoxicity concerns were revealed in past studies. 
The chronic dietary (food and drinking water) exposure assessments are
conservative.  The dietary and residential assessments are based on
reliable data and will not underestimate exposure/risk.  Based on these
data and conclusions, the FQPA Safety Factor can be reduced to 1X. 

90-Day dermal and inhalation toxicity studies are also required to
confirm the PODs selected for assessing dermal and inhalation exposures
based on route-to-route extrapolations from oral studies. 
Fluazifop-P-butyl is expected to show similar toxicity by the inhalation
and oral routes because of its metabolism by blood into the acid form
and excretion in this manner.  The NOAEL from the available 28-day
dermal study is considerably higher (100 mg/kg/day). 

Although a point of departure from an oral study was used to assess
residential handler inhalation risks for fluazifop-P-butyl, EPA does not
believe this aggregate risk assessment is under-protective of adult
handlers.  Handler MOEs based on the extrapolated endpoint are quite
high (14,000 to 1.1 million), and the contribution of residential
exposure to aggregate risk is small.  Therefore, even if an inhalation
study were to provide a lower point of departure than the oral study,
it’s not expected to have a significant impact on aggregate risk. 

4.4.1	Completeness of the Toxicology Database

The toxicity database for fluazifop-P-butyl is complete except for acute
and sub-chronic neurotoxicity studies and immunotoxicity testing. 
Recent changes to 40 CFR §158 make these studies (OPPTS Guideline
870.7800) required for pesticide registration.  A 90-day dermal study
and 90-day inhalation study have also been requested for purposes of
further evaluation and confirmation of the oral PODs route-to-route
extrapolations used for these potential exposure routes.
Fluazifop-P-butyl is likely to show similar toxicity by both the
inhalation and oral routes because of its metabolization by blood into
the acid form and excretion in this manner.  The short-term dermal and
short-term inhalation endpoints utilized the developmental toxicity
study data with a NOAEL of 2.0 mg/kg/day, since it was more protective
than the 28-day dermal study endpoint of 100 mg/kg/day.  Although
neurotoxicity studies have not yet been submitted, there is no evidence
of neurotoxicity in any study in the toxicity database for
fluazifop-P-butyl. In the absence of specific immunotoxicity studies,
EPA has evaluated the available fluazifop-P-butyl toxicity database to
determine whether an additional database uncertainty factor is needed to
account for potential immunotoxicity. No evidence of immunotoxicity was
found in the most sensitive species, as described previously. The
complete description for the lack of immunotoxicity testing not
warranting a 10X FQPA factor is described in the memo
“Fluazifop-P-Butyl.  Rationale for Reducing the 10X Safety Factor to
1X for Lack of an Immunotoxicity Study.  Addendum to Fluazifop-P-Butyl
Risk Assessment for Dry Beans, Peanuts, and Soybeans [D347515, P. Savoia
et al., 19-SEP-2008], J. Liccione, January 23, 2009, DP Barcode: 
359779.

Due to the lack of evidence of neurotoxicity and immunotoxicity for
fluazifop-P-butyl, EPA does not believe that conducting immunotoxicity
and acute and sub-chronic neurotoxicity testing will result in a NOAEL
less than that to derive the current cRfD of 0.0074 mg/kg bw/day. 
Likewise, the oral POD selected for residential dermal and inhalation
routes of exposure (Developmental NOAEL=2.0 mg/kg/day) is believed to be
protective.  Residential MOEs are large (14,000) and fluazifop-p-butyl
is expected to show similar toxicity by both the inhalation and oral
routes because of its metabolization by blood into the acid form and
excretion in this manner.  Consequently, the EPA believes the existing
data are sufficient for endpoint selection for exposure/risk assessment
scenarios and for evaluation of the requirements under the FQPA, and an
additional database uncertainty factor does not need to be applied.

In the case of fluazifop-p-butyl, the 2008 risk assessment included a
table that listed decreased spleen weights in male rats in the
two-generation reproduction rat study as one of the effects observed at
the LOAEL for several endpoints.  However, upon closer examination of
the effects seen, HED has determined that the spleen weight effect
should not be cited as a toxicological effect at the study LOAEL for the
following reasons: 1) the apparent spleen effect was marginal, only
observed in one generation of male rats, and relatively independent of
dose, 2) the apparent spleen effect was not observed in the chronic
carcinogenicity rat study, and 3) histological examination of the spleen
tissue did not indicate that any changes were occurring on a cellular
level.  Based on these detailed considerations, HED now concludes that
it is inappropriate to list spleen weight as a toxicological effect at
the LOAEL of the two-generation rat reproduction study.

The Assessment team concluded that the toxicology database for
fluazifop-butyl and fluazifop-P-butyl is complete for FQPA evaluation
and that the current NOAEL of 0.74 mg/kg/day is sufficiently protective,
since no immunotoxicity nor neurotoxicity were observed in previous
studies.  Acceptable developmental toxicity studies in rats and rabbits
on fluazifop-butyl and fluazifop-P-butyl are available in addition to an
acceptable 2-generation reproduction study in rats.  Studies on
fluazifop-butyl may be used to support fluazifop-P-butyl due to
equivalency in toxicity. A more comprehensive description of these data
needs is listed in Appendix A3.

4.4.2	Evidence of Neurotoxicity

The assessment team concluded that there was not a concern for
neurotoxicity resulting from exposure to fluazifop-P-butyl at relevant
exposure levels.  There was no evidence of clinical signs indicative of
neurotoxicity or neuropathology in the available studies.  Marginal
increases in brain weights at termination were seen in a sub-chronic
toxicity study in a rats and a carcinogenicity study in hamsters, but
only at high doses. A developmental neurotoxicity study is not required
at this time.

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

There is no concern for increased susceptibility to offspring following
pre- and postnatal exposure to rats or in utero exposure in rabbits.

There is no indication of developmental neurotoxicity resulting from
exposure to fluazifop-P-butyl with the current data sets, so this study
will not be requested at this time.  Evidence that supports not
requiring a DNT study include there was no developmental or central
nervous system malformations seen in any of the developmental toxicity
studies with rats or rabbits and no evidence of neurotoxicity or
neuropathology in adult animals in the available studies. The
toxicological significance of the marginal increases in brain weights at
high doses is unknown in the absence of corroborative histopathological
lesions. The assessment team concluded that there is not a concern for
developmental neurotoxicity resulting from exposure to fluazifop-butyl
or fluazifop-P-butyl.  The toxicology database is adequate for hazard
characterization and endpoint selection.  Therefore, no database
uncertainty factors are needed for any database deficiencies.

The data base included 7 developmental toxicity studies: 2 with
fluazifop-butyl in Sprague-Dawley rats; 3 with fluazifop-P-butyl in
Wistar rats; 1 with fluazifop-butyl in New Zealand rabbits; and 1 with
fluazifop-P-butyl in New Zealand rabbits.  These studies are summarized
below:

The NOAEL/LOAEL in the five rat developmental toxicity studies was
determined by a weight of evidence criteria mainly around consistency of
delayed ossification, delayed development of the urinary tract, and
diaphragmatic hernias.  Although, delayed ossification was seen in some
studies at lower doses, they were inconsistent (i.e., low incidence of
delayed ossification in controls compared to historical controls, large
variation in historical controls, the delayed ossification was not
clearly dose related, and litter incidence was not statistically
significant). 

The LOAEL is 5.0 mg/kg/day based on decreased fetal weight and increased
incidence of hydroureter in fetuses and litters, and delayed
ossification in a 160 litter/group developmental toxicity study (MRID#
00088858).  This LOAEL is also supported by a dose-related increased
fetal incidence in partially ossified sternebrae and sternebrae
bipartite, 5th (MRID# 46082913, 46082903), and statistically significant
increased incidence of fetuses and litters with interparietals,
occipitals and parietals partially ossified, calcaneum not ossified and
increased manus and pes scores at 5.0 mg/kg/day (MRID# 46082903 and
46158401).  The NOAEL of 1.0 mg/kg/day in the 160 litter per group study
was not selected and a NOAEL of 2.0 mg/kg/day from the Wistar rat
studies was selected.  Since apparent effects noted at 0.05 and 1.0
mg/kg/day were either not dose related, concurrent controls were low,
the effects were lower than the historical control range, or were not
statistically significant in litters, and 2 developmental studies that
included a 2 mg/kg/day dose group failed to elicit a dose dependant
response, a NOAEL of 2.0 mg/kg/day was selected.

The overall rat studies showed a NOAEL/LOAEL of 2.0/5.0 mg/kg/day.  The
NOAEL/ LOAEL was chosen from among MRID# 0008858, 46082903, 46082913 and
46518401.  For a single dose effect, the NOAEL/LOAELs are 50/200
mg/kg/day based on the diaphragmatic hernia malformations.

The maternal toxicity NOAEL/LOAEL of 100/300 mg/kg/day was based a
combination of factors.  There was a clear effect on maternal weight
decrement at 300 mg/kg/day in the Wistar rat studies and a clear NOAEL
at 100 mg/kg/day in the Wistar rat studies.  Although, the maternal
weight decrement in the Sprague Dawley rat was shown to be due to gravid
uterine weight decrement, it was not completely clear that maternal
toxicity was not expressed at 200 mg/kg/day.  Therefore the maternal
NOAEL was chosen among the three Wistar rat developmental toxicity
studies to remove this ambiguity in maternal toxicity.

While there was quantitative evidence of increased susceptibility in the
fetuses of rats exposed in utero to fluazifop-butyl and
fluazifop-P-butyl, the degree of concern is low based on the following
considerations: the endpoint of concern (delayed ossifications) is
considered to be a developmental delay as opposed to a malformation or
variation which is considered to be more serious in nature; there were
considerable variations in the incidences among the five studies; the
NOAELs/LOAELs for this effect were well defined and consistent across
these studies; and a developmental endpoint of concern (diaphragmatic
hernia) is used for assessing acute dietary risk. Also, in a
two-generation reproduction toxicity study in rats, there was no
evidence (quantitative or qualitative) of increased susceptibility
following in utero exposures to rabbits or following pre-and/or
post-natal toxicity. Therefore, there is no residual uncertainty for pre
and/or post natal toxicity.

4.4.4	Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database.  Since the
dietary and non-dietary exposure estimates were based on several
conservative assumptions, HED does not believe that the exposure
estimates are underestimated.

 plus water analyses were performed with the DEEM-FCID™ model, which
assumes that all drinking water will contain fluazifop-P-butyl at the
highest estimated drinking water concentration (EDWC) levels modeled by
EFED for ground water or surface water.  For these reasons it can be
concluded that the dietary analysis does not underestimate risk from
exposure to fluazifop-P-butyl.

4.4.4.1      HED’s Levels of Concern (LOC) tc \l3 "4.4.11 HED’s
Levels of Concern (LOC) 

Summary of HED’s LOCs for risk assessment.  MOEs that are less than
the LOCs are of concern.

Route

               

Duration	

Short-Term

(1-30 Days)	

Intermediate-Term

(1 - 6 Months)	

 Long-Term

(> 6 Months)

Occupational (Worker) Exposure

Dermal	

100	

100	

100

Inhalation	

100	

100	

100

Residential (Non-Dietary) Exposure

Oral	

100	

100	

N/A

Dermal (All Populations)	

100	

100	

100

Inhalation (All Populations)	

100	

100	

100

For Occupational exposure:  This is based on the conventional
uncertainty factor of 100X (10X for interspecies extrapolation and 10X
for intra-species variation).

For Residential exposure:  This is based on the conventional uncertainty
factor of 100X (1X for FQPA, 10X for interspecies extrapolation and 10X
for intra-species variation).

4.5	Toxicity Endpoint and Point of Departure Selections

The details for selecting toxicity endpoints and points of departure for
various exposure scenarios are presented in the appendix A2. 

An acute dietary endpoint for females 13-49 years of age was selected
from a developmental toxicity study in rats, based on diaphragmatic
hernia.  No appropriate endpoint attributable to a single dose was
identified for the general U.S. population.  The short-term incidental
oral endpoint was selected from the developmental toxicity studies in
rats and is based on maternal body weight gain decrement.  The chronic
dietary (all populations), intermediate-term dermal and inhalation, and
intermediate-term incidental oral endpoints were selected from the
2-generation reproduction study in rats based on decreased testes and
epididymal weights in males, and decreased uterine and pituitary weights
in females.  The short-term dermal and inhalation endpoints used in the
assessment were selected from the developmental toxicity studies in rats
based on decreased fetal weights, hydroureter and delayed ossification. 
Though this endpoint was selected by the Hazard Identification Risk
Assessment Committee specifically for females 13-49 years of age, and a
separate, higher, dose/endpoint was selected for all other population
subgroups from the developmental toxicity studies in rats, based on
maternal weight gain decrement, the fluazifop-P-butyl assessment team
chose to use the female-specific endpoint for all population subgroups
for initial screening.  By using the lower dose/endpoint approach for
all population subgroups, the risk assessment is protective of the toxic
effects seen at higher doses.  This approach is particularly appropriate
as a screening level assessment to determine if there are any potential
risks of concern.  Oral NOAELs were selected for dermal and inhalation
endpoints.  Dermal absorption factors, calculated from a dermal
absorption and pharmacokinetic study in humans, of 1.9% for high
exposures and 8.6% for low exposures were used for oral-dermal
route-to-route extrapolation, and 100% absorption was used for
inhalation exposure.  Fluazifop-P-butyl is classified as “not likely
to be carcinogenic to humans” and no mutagenic potential was observed
in adequate in vivo and in vitro studies with fluazifop-butyl and
fluazifop-P-butyl.

4.5.1	Dose-Response Assessment

The decreased testes weight and decreased epididymal weight in PO and F1
adult rats showed a marginally adequate dose response. The statistically
significant decrease in both organs could potentially have resulted from
a decreased sperm count.  The cancer study in hamsters showed a good
dose-response in testes weight decrement.  Since the statistically
significant effects were seen in the male P0 and F1 parents and in the
hamster study, the effects were considered treatment related.  The
testicular endpoint from the reproduction study was selected for the
chronic RfD, intermediate-term oral incidental exposure, intermediate
and long-term dermal and inhalation exposure.  Other studies showed
testes weight decrement and epididymal effects at higher dose levels,
but there were only equivocal histological effects shown.  Although
extensive short-term studies on the testes weight decrement and
epididymal effects were conducted, all failed to show that the effect
was incidental or find an explanation for the effect.  However, the more
sensitive studies on sperm parameters, such as sperm motility and sperm
count, were not among the extra studies conducted.  An acceptable
negative study of sufficient duration on sperm parameters would add
confidence to the possibility that the testes and epididymal weight
decrement seen in the rat reproduction study were incidental and not
reproducible.  

The uterine weight decrement seen in the reproduction study showed a
good dose-response and was supported by a dose-response in the pituitary
weight decrement at the same doses.  In addition, in the hamster,
hyperplasia in the ovary was seen at high dose levels.  One of the
sub-chronic studies in the rat with fluazifop-P-butyl showed testicular
weight decrement, while the other one with fluazifop-butyl did not at
approximately the same doses as in the reproduction study (at the
highest dose tested in the sub-chronic study with fluazifop-butyl
absolute testes weights were increased 30%).  The reason is unknown, but
may be due to animal variation or other unknown factors such as edema. 

The testes and epididymal weight decrement and uterine and ovarian
effects suggest possible endocrine related effects.  However, negative
in vitro studies suggest estrogen and androgen hormones were not
involved.  Agonistic and antagonistic studies with fluazifop-butyl,
fluazifop-P-butyl and the fluazifop acid metabolite were conducted in
yeast cells containing human estrogen and androgen receptors.  No
receptor activity was found with any of the test materials over a
sufficiently wide concentration range.  	

The acute RfD and short-term incidental oral, and short-term dermal and
inhalation exposure endpoints were selected from the developmental data
base which includes 7 developmental toxicity studies: 2 with
fluazifop-butyl in Sprague-Dawley rats; 3 with fluazifop-P-butyl in
Wistar rats; 1 with fluazifop-butyl in New Zealand rabbits; and 1 with
fluazifop-P-butyl in New Zealand rabbits.  There was evidence
(quantitative) of increased susceptibility in the fetuses of two strains
of rats exposed in utero to fluazifop-butyl.  Diaphragmatic hernia was
seen at the highest dose tested in the Sprague Dawley rat and other
developmental toxicity, characterized as delays in skeletal
ossifications, were seen in the absence of maternal toxicity relatively
consistently in all five rat studies.  However, the concern is low for
the increased susceptibility seen in the rats based on the endpoint of
concern (delayed ossifications).  This developmental delay occurred at a
lower dose level than the malformations.  The delayed ossification in a
given parameter showed considerable variation in the incidence among the
five studies requiring a weight of evidence to determine the appropriate
NOAEL/LOAEL among the five rat studies.  There was no evidence
(quantitative or qualitative) of increased susceptibility following in
utero exposures to rabbits.

The dose-related liver and kidney toxicity shown in the older
sub-chronic and chronic studies was expressed as exacerbation of age
related kidney toxicity.  Tests show that this toxicity was in the
presence of peroxisome proliferation.  However, the extensive and age
related nephropathy in control groups complicate this conclusion with
regard to the kidney.  A possible treatment related slight increase in
chronic nephropathy was noted only at the highest dose tested in the
more recent study of reproduction in the rat. 

The uncertainty factors used with all endpoints were 10X for
inter-species extrapolation and 10X for intra-species variation for a
total of 100X.

4.5.2	Recommendation for Combining Routes of Exposures for Risk
Assessment

As per FQPA, 1996, when there are potential residential exposures to the
pesticide, aggregate risk assessment must consider exposures from three
major routes: oral, dermal and inhalation.  The fluazifop-P-butyl team
chose to aggregate high-end exposures using conservative endpoints for a
screening level assessment.  If the resulting assessment showed risks of
concern, further refinements would have been incorporated into the
assessment but, it was not necessary.  

4.5.3	Cancer Classification and Risk Assessment Recommendation

The assessment team, in accordance with the 1999 Draft Carcinogen Risk
Assessment Guideline (April, 1999) classified fluazifop-butyl and
fluazifop-P-butyl as “Not likely to be carcinogenic in humans,”
based on the lack of evidence of carcinogenicity in rats and hamsters. 
Progressive chronic nephropathy was observed in both rats and hamsters,
but there was no statistically significant incidence of malignant and/or
benign tumors seen at any dose in either study.

A carcinogenicity study in mice was not conducted.  Peroxisome
proliferation in the mouse was at levels much higher than in the hamster
at comparable dose levels.  Therefore, a carcinogenicity study in
hamsters was conducted instead.  The hamster was chosen because
peroxisome proliferation in vivo and in vitro was more comparable to
that found in human cell culture.

The assessment team concluded that there is not a concern for
mutagenicity resulting from exposure to fluazifop-P-butyl.  The database
for mutagenicity is considered adequate based on pre-1991 guidelines. 
No mutagenic potential was seen in adequately conducted  pre-1991
guideline mutagenicity studies (in vivo and in vitro) on
fluazifop-P-butyl or fluazifop-butyl.  A structural analogue
{haloxyfop-methyl [methyl
2-[4-[[3-chloro-5-(trifluromethyl)-2-pyridinyl]
oxy]phenoxy]propinonate]} of fluazifop-P-butyl also showed no mutagenic
potential.

4.5.3.1 Carcinogenic Potential in Rats

In a combined chronic/carcinogenicity study (MRID# 41563703) PP009
(fluazifop-butyl, 94.8% a.i., batch/lot # 14, Reference C4915, CTL
Y00082/001/005)] was administered to [(60 Wistar rats/sex/group in the
diet at dose levels of 0, 2, 10, 80 or 250 ppm (equivalent to 0, 0.10,
0.51, 4.15 or 12.29 mg/kg bw/day for males and 0.127, 0.65, 5.20 or 16.0
for females) for 106 or 107 days, respectively.  Additional groups of 10
rats/sex/group were administered the test material in an analogous
manner for 52 weeks prior to an interim sacrifice.  

Clinical signs were characteristic of rats, except respiratory distress,
nasal and ocular discharge were seen among some males at 80 and among
some males and females at 250 ppm from week 29 to 55.  These signs were
accompanied by body weight loss and death in the seriously affected
males at 80 and 250 ppm and in the seriously affected females at 250
ppm.    

Body weight gain of males and females, not dying, were increased
significantly up to week 28 at 80 (14% in males and 19% in females) and
250 ppm (10% in males and 20% in females) and in males week 29-44 at 250
ppm (26%), thereafter body weight gain was nominally increased in males
at 10, 80 and 250 ppm and nominally increased in females from week
29-108 at 2, 10, 80 and 250 ppm.  There was an overall nominal body
weight gain increase in males and females at the three top dose levels
for the 106 weeks of the study.  However, male (-79 g to -123 g versus
-101 in control males) and female (-9 g to -24 g versus -24g in control
females) rats lost body weight between week 81-85 and at the end of the
study.  No differences from control were seen in food consumption, food
efficiency, water consumption or urinalysis among the groups. 

There appeared to be a dose related increased mortality among males at
80 and 250 ppm (33% at 80 ppm and 34% at 250 ppm versus 14% in control)
and among females (21% at 250 ppm versus 4% in control) during the first
52 weeks of the study.  Overall mortality at cumulative termination
appeared to be increased in males at 80 and 250 ppm (88%-86% versus 68%
in control) and in females at 250 ppm (65% versus 45% in controls).  The
report stated that the death occurring up to week 52 was caused by
respiratory problems exacerbated by test material related nephropathy
(all grades) in nearly 100% of the affected males dying at 80 and 250
ppm and 87% of the affected females dying at 250 ppm.  No dose-related
mortality was seen from week 52 to termination.

Dose-related nephropathology, slight, moderate and marked, but not
otherwise specified was seen in the animals dying or killed in extremis
during the first 52 weeks of the study.  This nephropathy was seen in
control, 2, 10, 80 and 250 ppm group animals; 9/10, 9/9, 6/6, 22/23, and
24/24, respectively in males and  0/3, 0/1, 1/6, 1/ 2 and 13/15,
respectively in females dying or killed in extremis.  Treatment may have
exacerbated the nephropathy.  In animals sacrificed at termination,
geriatric nephropathy was seen in nearly all surviving animals [23/24
(96%) HDT versus 30/31 (97%) in control males] and [20/24 (83%) HDT
versus 19/24 (79%) control females].   Gastrointestinal tract lesions
appeared to be increased slightly at 250 ppm in males and females.   

At ophthalmological examination, increased keratitis was seen in males
(5/20) at 250 ppm.  Since this observation was not seen in females and
did not appear to be dose related at lower dose levels, the study
authors questioned the toxicological significance of the finding.     

Hematological parameters showed slight changes in males at 80 and 250
ppm.  Decreased hematocrit (6-8%), hemoglobin concentration (3-4%) and
erythrocyte count (6-8%) were slightly but statistically significant at
week 12 and 25 and nominally decreased at week 78 at 80 ppm and 250 ppm.
 Hemosiderosis was found only in the spleens of one female each in
control, 2, 80 and 250 ppm groups.  Blood chemistries showed increased
cholesterol (about 85% to 107%) at various times of analyses up to 78
weeks in males and females, but not after 100 weeks in females at 250
ppm; males showed a nominal decrease in cholesterol after 100 weeks at
the same dose.  Albumin showed statistically significantly decreases of
about 24% in males and females at 250 ppm. Bone smears on males and
female rats were similar to controls at week 52 or 106, but many smears
in all groups could not be evaluated.

Decreased absolute (16%) and relative (17%) liver weights were
statistically significant in males at 250 ppm at terminal sacrifice, and
increased absolute (40%) and relative (37%) ovarian weights were
significant at termination at 250 ppm; animals with ovarian cysts and
masses were excluded from these calculations.  Testes and seminal
vesicle weight did not differ from control weight at terminal sacrifice,
but were nominally decreased at 250 ppm.  At the 52 week interim
sacrifice, absolute and relative kidney (Abs. 29%) and thyroid (Abs.
33%) weights were significantly increased in males, but not in females
at 250 ppm.   Absolute (31%) and relative (24%) testes weight showed a
treatment related decrease at 250 ppm at the 52 week sacrifice.  Ovarian
weights were nominally increased at 250 ppm and 52 weeks.  Ovaries,
possibly enlarged by cysts, appeared to have an increased incidence in
the 250 ppm group than in control. 

The LOAEL in males is 80 ppm (4.15 mg/kg/day) based on increased
mortality and nephropathy from start to week 52 of the study.  The NOAEL
is 10 ppm (0.51 mg/kg/day in males).   The LOAEL in females is 250 ppm
(16.0 mg/kg/day) based on increased morality and nephropathy during the
first 52 weeks of the study and increased ovarian weight and ovarian
cysts at termination.    The NOAEL was 80 ppm (5.2 mg/kg/day) for
females.

At the doses tested, there was no treatment related increase in tumor
incidence when compared to controls.  The only statistically significant
neoplasia seen in the study was an increase in male adrenal
phaeochromocytomas at 80 ppm, but not at 250 ppm. The incidence of
adrenal phaeochromocytoma bearing males (left or right adrenal was
calculated from the individual animal data) in control, 2, 10, 80 or 250
ppm were, respectively, 5/70, 3/70, 2/70, 11*/70 and 7/70 for males that
died or were sacrificed. [* Significant at p < 0.019 by a Peto analysis,
when the 80 ppm group was compared with control]   None of these adrenal
tumors were seen at the interim sacrifice.    This
chronic/carcinogenicity study in the rat is ACCEPTABLE (GUIDELINE) and
satisfies the guideline requirement for a chronic/carcinogenicity study
OPPTS 870.4300); OECD 453] in the rat.  This study was upgraded from
supplementary (TXR#009746) to acceptable by a 3/12/1996 peer review
committee (TXR# 011840).  The confusion in TXR# 009746 over which
enantiomer was studied is corrected from [R] in TXR# 009746 to [RS]. 
The test material studied was PP009, the [RS] racemic mixture.  The
conclusions take precedence over previous conclusions.  

4.5.3.2 Carcinogenicity Study in Hamsters

In a carcinogenicity study (MRID# 45345401, 46082905)
[fluazifop-P-butyl, 91.6% a.i., batch/lot# P23] was administered to 63
Golden Syrian hamsters/sex/dose in the diet at dose levels of 0, 0, 200,
750 or 3000 ppm (mean of measured test material consumption equivalent
to 0, 0, 12.5, 47.4 or 193.6 mg/kg bw/day for males and 0, 0, 12.1, 45.5
or 181.4 mg/kgbw/day for females, page 25 of 45345401) for 80 weeks.  Of
these animals, 12/sex/group were designated for interim sacrifice on
week 53.  Two control groups were included.

There were no significant definitive body weight changes or meaningful
food consumption or food efficiency differences from control in males or
females during the study.  There was an increased frequency of a
clinical observation at 3000 ppm (“thin”) (13 versus 5 in control). 
Survival was unchanged statistically, but females showed a slight
nominal decrease at 3000 ppm (70.6% versus 78.5% in pooled control).  

Probably no biologically-significant hematological effects were seen in
the study.  Statistically significant decreases in white cell count in
interim sacrificed males (22%-23%) at 750 ppm and 3000 ppm and in
terminal females (17%) at 3000 ppm were observed.  The remaining
statistically significant hematological changes at 3000 ppm were minor
and probably not biologically significant.  No clinical chemistry
analysis was conducted. 

Testes weights were decreased at 750 and 3000 ppm and liver and kidney
weights were increased in males and females at 3000 ppm.  In males,
absolute and adjusted testes weights were decreased in a dose related
manner and statistically significantly reduced (p < 0.01) at 750 (abs 8%
and adj 10%) and 3000 ppm (abs 20% and adj 19%).  In males, adjusted
liver weight was statistically significantly elevated at 750 (5%) and
3000 ppm (7%), but the absolute weight was not elevated at any dose
level.  In males and females, a kidney weight (males 11% and females 9%)
and adjusted kidney weights (males 11% and females 9%) were
statistically significantly elevated in the 3000 ppm group, only.  In
females absolute liver weight was statistically significantly elevated
at all dose levels (9%-38%), but adjusted liver weights (34%) were
significantly elevated only at 3000 ppm.  Slight absolute and adjusted
brain weight increases (2.5% and 1.6%) respectively in males and females
at 3000 ppm are of unknown biological significance.     

Non-neoplastic microscopic histological findings were increased in the
epididymis, testes, eyes, livers and gall bladder in males and in
females, ovarian stroma cell/sex cord hyperplasia was increased at 750
and 3000 ppm.  In males dose related incidences were seen at 750 ppm of
reduced spermatozoa in epididymis (24% versus 8% in pooled controls),
increased incidences of testicular tubule degeneration (37% versus 7% in
pooled controls), increased incidences of eye cataract changes (31% in
males at 750 ppm versus 16% in pooled controls), increased incidences of
male liver mononuclear cell infiltration (35% versus 20% in pooled
controls) and increased incidences of gall bladder stones (73% versus
31% in pooled controls) in males and in females at 3000 ppm (41% versus
13% in pooled controls).  The incidence of chronic nephropathy was
nominally increased in males and females at all dose levels.  In females
dose-related increased incidences were seen at 750 ppm in ovarian
stroma/sex cord hyperplasia (14%versus 6% in pooled controls).

The LOAEL for systemic effects is 750 ppm (equivalent to 47.4 mg/kg/day
in males and 45.5 mg/kg/day in females) based on increased incidence of
males with reduced sperm, testicular degeneration, eye cataract changes,
liver inflammation and gall stones and in females increased incidences
of ovarian stroma cell/sex cord hyperplasia.  The NOAEL is 200 ppm
(equivalent to 12.5 mg/kg/day in males and 12.1 mg/kg/day in females.  

No dose-related tumors were seen in males.  Benign ovarian stroma
cell/sex cord tumors were statistically significantly elevated at the
3000 ppm 5/51 (9.8%) versus 3/103 (2.9%) in pooled controls.  However,
when the incidences of malignant and benign tumors were combined, no
significant differences were seen at any dose.   It was concluded that
fluazifop-butyl, [R] isomer is not carcinogenic at the dose levels
studied.   Dosing was adequate in males and females as indicated by the
kidney weight increase and histological findings in eyes [cataracts],
liver [inflammation], gall bladder [gall stones], the testes [tubular
degeneration] and epididymis [reduced spermatozoa] of males, and in
females by the ovarian findings [hyperplasia and adenomas], gall bladder
[gall stones] and the severity of progressive chronic nephropathy at
3000 ppm (HDT). The carcinogenicity study [MRID#46082901, but not
45345401] in the hamster is ACCEPTABLE (guideline) and does satisfy the
guideline requirement for a carcinogenicity study [OPPTS 870.4200; OECD
451] in hamsters.

4.5.3.3 Classification of Carcinogenic Potential

The assessment team, in accordance with the 1999 Draft Carcinogen Risk
Assessment Guideline (April, 1999) classified fluazifop-butyl and
fluazifop-P-butyl as “Not likely to be carcinogenic in humans,”
based on the lack of evidence of carcinogenicity in rats and hamsters.

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

Table 1a        Summary of Toxicological Doses and Endpoints for
Fluazifop-P-butyl+

Exposure

Scenario	Dose Used in Risk Assessment, UF	FQPA SF and Level of Concern
for Risk Assessment	Study and Toxicological Effects

Acute Dietary*

(Females 13-49 years of age)	NOAEL = 50 mg/kg/day

UF = 100

Acute RfD = 0.50 mg/kg/day	FQPA SF = 1X

aPAD = 

0.50 mg/kg/day	Developmental Toxicity in Rats

Developmental LOAEL = 200 mg/kg/day based on diaphragmatic hernia.

Acute Dietary

(General population including infants and children)	An appropriate
endpoint attributable to a single dose was not identified in the
available studies including the developmental toxicity studies.

Chronic Dietary

(All populations)	NOAEL= 0.74 mg/kg/day

UF = 100

Chronic RfD = 

0.0074 mg/kg/day	FQPA SF = 1X

cPAD =

 0.0074 mg/kg/day	Two-Generation Reproduction in Rats

LOAEL = 5.8 mg/kg/day in males and 7.1 in females based on decreased
testes & epididymal weights in males, and uterine & pituitary weights in
females.

Short-Term Incidental Oral (1-30 days)	Maternal 

NOAEL = 100 mg/kg/day	Residential LOC for MOE = 100

Occupational = N/A	Developmental Toxicity in Rats

Maternal LOAEL = 300 mg/kg/day based on maternal body weight gain
decrement during GD 7-16.

Intermediate-Term Incidental Oral (1-6 months)	Parental/Systemic NOAEL =
0.74 mg/kg/day	Residential LOC for MOE = 100

Occupational = N/A	Two-Generation Reproduction in Rats

LOAEL = 5.8 mg/kg/day in males and 7.1 in females based on decreased
testes & epididymal weights in males, and uterine & pituitary weights in
females.

Short-Term Dermal (1 to 30 days)	Developmental NOAEL = 2.0 mg/kg/day
Residential LOC for MOE = 100

Occupational LOC for MOE = 100	Developmental Toxicity in Rats

LOAEL = 5.0 mg/kg/day based on fetal weight decrement, hydroureter, and
delayed ossification.

Intermediate- & Long-Term Dermal (1 to >6 months)a	Parental/Systemic
NOAEL = 0.74 mg/kg/day	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	Two-Generation Reproduction in Rats

LOAEL = 5.8 mg/kg/day in males and 7.1 in females based on decreased
testes & epididymal weights in males, and uterine & pituitary weights in
females.

Short-Term Inhalation (1 to 30 days) b	Developmental NOAEL = 2.0
mg/kg/day	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	Developmental Toxicity in Rats

LOAEL = 5.0 mg/kg/day based on fetal weight decrement, hydroureter, and
delayed ossification.

Intermediate- & Long-Term Inhalation (1 to >6 months)b	Parental/Systemic
NOAEL = 0.74 mg/kg/day	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	Two-Generation Reproduction in Rats

LOAEL = 5.8 mg/kg/day in males and 7.1 in females based on decreased
testes & epididymal weights in males, and uterine & pituitary weights in
females.

Cancer (oral, dermal, inhalation)	Not likely to be carcinogenic to
humans.

* Selected by the Assessment team for Females 13-49 years of age.  +
Table taken from DP Barcode:  359779, J Liccione, Jan. 23, 2009

a Use either 9% (low exposure scenario) or 2% (high exposure scenario)
for route-to-route extrapolations 

b Absorption via the inhalation route is presumed to be equivalent to
oral absorption. 

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 

4.6   Endocrine Disruption

In the available studies on fluazifop–P-butyl, there was no estrogen,
androgen and/or thyroid mediated toxicity shown.  No androgen/estrogen
agonist or antagonist activity was detected for fluazifop-P-butyl or its
acid metabolite. Fluazifop-P-butyl is not among the group of 58
pesticide active ingredients on the initial list to be screened under
the Endocrine Disruption Screening Program. 

As required under FFDCA section 408(p), EPA has developed the Endocrine
Disruptor Screening Program (EDSP) to determine whether certain
substances (including pesticide active and other ingredients) may have
an effect in humans or wildlife similar to an effect produced by a
“naturally occurring estrogen, or other such endocrine effects as the
Administrator may designate.”  The EDSP employs a two-tiered approach
to making the statutorily required determinations. Tier 1 consists of a
battery of 11 screening assays to identify the potential of a chemical
substance to interact with the estrogen, androgen, or thyroid (E, A, or
T) hormonal systems.  Chemicals that go through Tier 1 screening and are
found to have the potential to interact with E, A, or T hormonal systems
will proceed to the next stage of the EDSP where EPA will determine
which, if any, of the Tier 2 tests are necessary based on the available
data. Tier 2 testing is designed to identify any adverse endocrine
related effects caused by the substance, and establish a dose-response
relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA has issued test orders/data
call-ins for the first group of 67 chemicals, which contains 58
pesticide active ingredients and 9 inert ingredients.  This list of
chemicals was selected based on the potential for human exposure through
pathways such as food and water, residential activity, and certain
post-application agricultural scenarios.  This list should not be
construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and
procedures, the list of 67 chemicals, the test guidelines and the Tier 1
screening battery, please visit the website:  http://www.epa.gov/endo/.

5.0	Metabolism 

5.1	Nature of the Residue – Plants

 

		Fluazifop-P-butyl 

The Fluazifop-P-Butyl Residue Chapter of the TRED (DP No. 319907, S. L.
Kinard, 08/17/2005) concluded that the nature of the residue in soybeans
is adequately understood.  No new plant metabolism studies for the
proposed new use crops were submitted as part of the current petition. 
The MARC has determined that for tolerance expression, parent and
fluazifop-acid (free and conjugated) are the residues of concern since
they are adequate to determine misuse.  The MARC also concluded that the
residues of concern in plants for risk assessment are parent,
fluazifop-acid (free and conjugated), 5-trifluoromethyl-2-pyridone, and
2-(4-hydroxyphenoxy) propionic acid (free and conjugated).  

5.2	Nature of the Residue - Animals

The MARC has concluded that for tolerance expression and risk
assessment, parent and fluazifop-acid (free and conjugated) are the
residues of concern since they are adequate to determine misuse.   SEQ
CHAPTER \h \r 1 

5.3	Meat, Milk, Poultry, and Eggs

In evaluating the data provided to support this petition, the
establishment of tolerance limits will be recommended for several RACs
commonly recognized for use as livestock feedstuffs.  This would include
establishing tolerance limits for sugar beet tops, citrus dried pulp and
potatoes as requested in part with this action.  Although in the
assessment of prior actions sugar beet tops would have comprised a large
portion of the beef and dairy cattle diet, it is no longer a factor for
consideration in the calculation of dietary burden.  For the citrus
dried pulp commodity, the tolerance of this livestock feed is being
tentatively set following the concentration factor of 4x determined from
the processing data that were provided.  In comparing the resulting
limit of 0.40 ppm for this commodity to the 2.5 ppm residue level of the
soybean roughage now being fed, a net increase in the contribution of
dietary burden to livestock will not result.  In regard to potato RACs,
this use will be only established as an import tolerance which will not
result in making this commodity a contributor to the dietary burden of
cattle.  

Given these circumstances, it will not be necessary to provide a
re-calculation of dietary burden in support of this action.  The prior
calculations tentatively depicting the secondary transfer of
fluazifop-P-butyl residues to meat, milk, poultry, and eggs made for the
uses established on dry beans and peanuts remain current (DP No.
D348246, D. Soderberg, 09/16/2008).

5.4	Analytical Methods

There are adequate residue analytical methods listed in PAM II for
tolerance enforcement and data collection.    SEQ CHAPTER \h \r 1 For
the enforcement of tolerances for fluazifop-P-butyl residues of concern,
a High Performance Liquid Chromatography/Ultra-Violet Spectrometry
(HPLC/UV) method is available for crop commodities.  In conjunction,
HPLC/UV and Gas Chromatography/Mass Spectrometry (GC/MS) methods are
available for milk and animal commodities.  The stated quantitation
limits are 0.02-0.05 ppm for crop commodities, 0.01 ppm for milk, and
0.02 ppm for animal tissues.  In addition, the FDA PESTDATA database
dated 11/01 (PAM Volume I, Appendix I) indicates that fluazifop-butyl
(only) is completely recovered using Multiresidue Methods Sections 302
(Luke Method; Protocol D) and 303 (Mills, Onley, and Gaither Method;
Protocol E, nonfatty food).  It is important to note that none of these
methods can distinguish the optical isomers of fluazifop-butyl or
fluazifop.

To support PP#9F7624, the banana, citrus, grape, and sugar beet field
trial samples were analyzed for residues of total fluazifop
(fluazifop-P-butyl, fluazifop free and conjugated) using either a GC/MS
or Fluorine-19 Nuclear Magnetic Resonance (19F NMR) protocol.  These
procedures provide a total determination by hydrolyzing the fluazifop
ester or acid conjugates and then derivatizing them to form the
fluazifop methyl ester for quantitation with residues being reported as
fluazifop.  For PP#9E7561, the potato field trial samples were analyzed
for residues of total fluazifop using a High Performance Liquid
Chromatography/Mass Spectrometry/Mass Spectrometry (HPLC/MS/MS)
protocol.  This procedure is a common moiety method which works by
hydrolyzing the fluazifop ester or acid conjugates so that a total
determination can be made.  In all, these protocols are adequate for
data collection based upon acceptable method validation and concurrent
method recoveries.  

5.5	Storage Stability Update

Storage stability data have been reviewed in conjunction with earlier
actions undertaken for fluazifop-P-butyl which indicate that its
residues are stable in a number of crop commodities.  As such, its
stability has been investigated in a wide variety of frozen crop
commodities and documented in several prior reports generated by
Syngenta.  These reports demonstrate that residues of fluazifop are
stable in/on soybeans, sugar beets, green beans, strawberries, oilseed
rape, coffee, cauliflower, onions, potatoes, peanuts, macadamia nuts,
tomatoes, endive, and celery for durations of 3 to 28 months (DP No.
D348246, D. Soderberg, 09/16/2008).  Given the results obtained from
these prior studies, these data are adequate in directly supporting or
can be translated to corroborate the sample storage intervals incurred
in these field trials.  Although no data were provided to substantiate
the holding times that were incurred for many of the processed
commodities tested, none are needed since these analyses were made
within thirty (30) days of production.  As such, there are adequate data
to support all of the sample storage conditions and durations that were
incurred for all of the RACs tested in part for these petition requests
(PP#9F7624 & PP#9E7561).  However, no data were provided to substantiate
the holding times that were incurred for any of the potato processed
commodities which were analyzed.  Data are available which demonstrate
fluazifop-P-butyl is stable in a wide variety of frozen crop commodities
including potatoes.  As such, HED expects fluazifop to be stable in the
frozen potato processed commodities noted but data should be provided to
confirm its stability in these fractions.    

5.6	Magnitude of Residue in Food Update

The data described below are from the HED residue chemistry chapter made
for PP#9F7624 which requests to allow new uses of fluazifop-P-butyl to
be made on bananas, citrus, grapes, and sugar beets (DP No. D380017, P.
Savoia, 08/31/2010).  In addition, data are also presented from the
accompanying HED residue chemistry chapter made for PP#9E7651 which
proposes the establishment of an import tolerance for fluazifop-P-butyl
on potatoes (DP No. D372408, P. Savoia, 08/31/2010).  These results are
adequate to support each of the proposed new crop uses put forward in
these petition requests.

Banana results

To determine the magnitude of fluazifop-P-butyl residue, five (5) field
trials were conducted in/on bagged and unbagged bananas in the United
States during the 1999 growing season.  The trials were conducted in
Zone 3 (1 trial in Florida) and Zone 13 (4 trials in Hawaii).  For each
trial, three applications of the 2 lb/gal EC formulation of
fluazifop-P-butyl were made at a target rate of 0.375 lbs
fluazifop-p-butyl/acre for a total seasonal rate of 1.125 lb a.i./acre. 
All applications were made in spray volumes of 17 to 29 gal/A (GPA)
using ground-based equipment.  An adjuvant was added to the spray
mixture for all applications (non-ionic surfactant or crop oil
concentrate).  Each test site consisted of a control and treated plot
for both bagged and unbagged bananas.  Applications were made by
broadcast spray to the soil at 60, 30, and 0 days prior to normal
harvest.  Banana whole fruit samples were collected at the normal
harvest which was immediately following the last application (PHI of 0
days).  

The banana field trial results demonstrate the application of the
fluazifop-P-butyl herbicide made at the 1x maximum directed labeled use
rate.  It was appropriately carried out in line with the requirements
set forth in the OPPTS 860.1500 Residue Chemistry Test Guidelines for
bananas.  Following three applications of fluazifop-p-butyl at a
seasonal target application rate of 1.125 lbs ai/A, residue levels
(reported as total fluazifop) were below the LOQ (0.01 ppm) in all
bagged and unbagged samples of whole bananas (PHI of 0 days).  Based on
concurrent recoveries, an acceptable method was used for the
quantitation of total fluazifop in/on unbagged and bagged bananas. 
Adequate stability data available for other similar crops can be
translated to substantiate the storage conditions and durations that
were incurred in this study.  These data which were reported are
adequate to support the proposed seasonal use pattern on bananas (MRID
No. 47874601, P. Savoia, 08/31/2010).  

Citrus results 

To determine the magnitude of fluazifop-P-butyl residue in/on citrus
RACs, twenty-three (23) field trial studies were provided by the
registrant in support of this petition request.  In accordance, MRID No.
41373705 contains 15 field trials and MRID No. 47874602 provides an
additional 8 more to satisfy the data requirement for a total of 23
studies in all.  For the data submission which contained the 15 field
trials, these studies were conducted in the United States during the
1986 growing season.  It is comprised of 5 trials made for oranges (zone
3; Florida) along with 5 trials each carried out for grapefruits and
lemons (2 trials in zone 3; Florida, 1 trial zone 6; Texas & 2 trials in
zone 10; California & Arizona).  The treated test plots in this study
received 2 to 3 applications of the 2 lb/gal EC formulation of
fluazifop-P-butyl made at 21 day RTIs for a total seasonal rate of 1.5
lb ai/acre to 2.25 lb ai/acre.  In regard to the data submission
containing the 8 field trials that were made, these studies were
conducted in the United States during the 2000 growing season.  It
consisted of 7 trials made for oranges (3 trials in zone 3; Florida, 1
trial in zone 6; Texas & 3 trials in zone 10; California & Arizona)
along with 1 trial carried out on grapefruit (1 trial in zone 3;
Florida).  The treated test plots in this study each received 3
applications of the 2 lb/gal EC formulation of fluazifop-P-butyl at
19-21 day RTIs for a total seasonal rate of 1.125 lb ai/acre.

The number and locations of the field trials were made in accordance
with OPPTS Guideline 860.1500 for oranges, grapefruit, and lemons.  The
trials generally reflect the proposed maximum seasonal use pattern,
although the trials made in 1986 (MRID No. 41373705) were performed at a
1.3x and 2x greater rate.  For the data submission which contained the
15 field trials carried out in 1986, an 19F NMR instrumental technique
was used to carry out these analyses.  Following the treatment program
made at a seasonal target application rate of 1.5 lbs ai/A to 2.25 lb
ai/A, residue levels (reported as total fluazifop) were below the LOQ
(0.03 ppm) in oranges, grapefruit and lemon (PHI 14 days).  In regard to
the data submission containing the 8 field trials that were made, a
GC/MS instrumental technique was used to carry out these analyses.  For
this treatment program of 3 applications made at a seasonal targeted
rate of 1.125 lbs ai/A, residue levels (reported as total fluazifop)
were below the LOQ (0.01 ppm) in oranges and grapefruit (PHI of 12 to 14
days).  Based on concurrent recoveries of fortified oranges, grapefruit,
and lemons, the methods used for these analyses were adequate for data
collection.  Adequate stability data available for other similar crops
can be translated to substantiate the storage conditions and durations
that were incurred in this study.  These data which were reported are
adequate to support the proposed seasonal use pattern on citrus
commodities (MRID No. 47874602, P. Savoia, 08/31/2010).

Grape results

To determine the magnitude of fluazifop-P-butyl residue in/on grapes,
twelve (12) were conducted in the United States during the 2000 growing
season.  For this study, the trials were carried out in zone 1 (2
trials; New York), zone 10 (8 trials: California), and zone 11 (2
trials; Oregon & Washington).  

Separate untreated control and treated test plots were established at
each trial site.  At each test location, three broadcast spray
applications of the 2 lb/gal EC formulation of fluazifop-P-butyl were
made to the vineyard floor beneath the grape vines at a target
application rate of 0.375 lb ai/A/application, for a total target
seasonal rate of 1.125 lb ai/A.  Applications were made 12 to 15 days
apart in spray volumes of 10 to 30 gal/A at 9 trial sites and 8 to 10
gal/A at 3 trial sites.  Adjuvants (non-ionic surfactant or crop oil
concentrate) were used at all the sites and the grapes subsequently
harvested at a PHI of 49-50 days.  

The grape field trial results demonstrate the application of the
fluazifop-P-butyl herbicide made at the 1x maximum directed labeled use
rate.  It was appropriately carried out in line with the requirements
set forth in the OPPTS 860.1500 Residue Chemistry Test Guidelines for
grapes.  Following the last of three vineyard floor applications made
with the 2 lb/gal EC formulation at a total rate of 1.11 to 1.16 lb
ai/A/season, residue levels (reported as total fluazifop) were <LOQ
(0.01 ppm) in/on grapes (PHI of 49 to 50 days).  Based upon acceptable
method validation and concurrent method recoveries, the protocol used
for these analyses was adequate for data collection.  Adequate stability
data available for other similar crops can be translated to substantiate
the storage conditions and durations that were incurred in this study. 
These data which were reported are adequate to support the proposed
seasonal use pattern on grape commodities (MRID No. 47874604, P. Savoia,
08/31/2010).

Sugar beet results

To determine the magnitude of fluazifop-P-butyl residue in/on sugar
beets, twelve (12) field trials were conducted in the United States
during the 2000 growing season.  For this study, trials were carried out
in zones 5 (2 trials; Minnesota, 2 trials; North Dakota & 1 trial;
Wisconsin), 7 (1 trial: Nebraska), 8 (1 trial; Kansas), 9 (1 trial;
Montana), 10 (2 trials; California), and 11 (2 trials; Idaho &
Washington).  Separate untreated control and treated test plots were
established at each trial site.  At each test location, two foliar
broadcast spray applications of the 2 lb/gal EC formulation of
fluazifop-P-butyl were made to sugar beets at a target application rate
of 0.375 lb ai/A/application, for a total target seasonal rate of 0.75
lb ai/A.  Applications were made at 12- to 14-day retreatment intervals
in spray volumes of 10 to 30 gal/A at 9 trial sites and 8 to 10 gal/A at
the other 3 trial sites.  Adjuvants (non-ionic surfactant or crop oil
concentrate) were used at all sites and the sugar beets subsequently
harvested at a PHI of 89 to 90 days.  

The sugar beet field trial results demonstrate the application of the
fluazifop-P-butyl herbicide made at the 1x maximum directed labeled use
rate.  It was appropriately carried out in line with the requirements
set forth in the OPPTS 860.1500 Residue Chemistry Test Guidelines for
sugar beets.  For the application program tested, samples were harvested
89 to 90 days after the last of two broadcast foliar applications made
with the 2 lb/gal EC formulation at total rates of 0.747-0.764 lb
ai/A/season.  In accordance, maximum residues of total fluazifop were
found to be 1.45 ppm in/on sugar beet tops and at 0.23 ppm for the
roots.  Based upon acceptable method validation and concurrent method
recoveries, the protocol used for these analyses was adequate for data
collection.  Adequate stability data are available for this RAC to
substantiate the storage conditions and durations that were incurred for
this study.  These data which were reported are adequate to support the
proposed seasonal use pattern on sugar beet commodities (MRID No.
47874603, P. Savoia, 08/31/2010).

Potato results 

To establish a new import tolerance for the residues of
fluazifop-P-butyl in/on potatoes, field trial studies were conducted
within the various geographic/climatological production regions of
Canada.  In accordance, MRID No. 47920402 contains 13 field trials and
MRID No. 47920403 provides an additional 3 more to satisfy the Canadian
requirement for a total of 16 studies in all.  For the data submission
which contained the 13 field trials, these studies were carried out in
Canadian growing zones 1, 1A, 5, 5B, 7A, 12 and 14 during the 2008
growing season.  As such, two trials were held at New Glasgow, Elm
Creek, and Malden along with single ones made at Albany, Branchton, St.
Marc-sur-Richeilieu, Taber, Abbotsford, Minto, and Innisfall.  In regard
to the data submission containing the 3 field trials that were made,
these studies were held at Hunter River (2 trials) and Portage la
Prairie (1 trial) in Canada during the 2007 growing season.  Each trial
site was managed according to the practices routinely followed by
Canadian commercial producers for cultivating potatoes.  Test plots were
sufficiently large enough to provide a 1 Kg sample of mature potato
tubers to be collected from at least six (6) different plants.  At each
study location, market quality potato samples were cultivated using both
untreated control and treated test plots.  Each treated test plot
received a single application of the VENTURE L end-use product applied
at the maximum labeled rate of 250 g ai/ha so that late seasonal
treatments made at a PHI of 45 days could be evaluated.  

The potato field trial results demonstrate the application of the
fluazifop-P-butyl herbicide made at the 1x maximum directed labeled use
rate.  The number and location of field trials were sufficient in scope
since they were undertaken in line with the requirements set forth in
the PMRA Regulatory Directive to evaluate this use.  Following a single
treatment of the VENTURE L EC formulation of fluazifop made at the
maximum seasonal rate of 250 g ai/ha, total residue levels were observed
ranging at levels between <0.0033 - 0.61 ppm (PHI of 45 days ± 1 day). 
The treatment regimen also appropriately included two (2) residue
decline studies made at the New Glasgow and Elm Creek sites with samples
collected at -7, 0, +7, +14 and +21 days of normal commercial harvest. 
The results generated in the two decline studies illustrate demonstrate
that concentrations of fluazifop will in fact decrease as greater PHIs
for treatment are followed.  Based upon acceptable method validation and
concurrent method recoveries, the protocol used for these analyses was
adequate for data collection.  Adequate stability data are available to
show that fluazifop residues are stable in frozen potatoes stored at
-18°C for 18 months which substantiate the storage conditions and
durations that were incurred in these studies.  These data which were
reported are adequate to support the proposed seasonal use pattern on
sugar beet commodities (MRID Nos. 47920402 & 47920403, P. Savoia,
08/31/2010).

5.7	Processing Factors

 

The data described below are from the HED residue chemistry chapter made
for PP#9F7624 which requests to allow new uses of fluazifop-P-butyl to
be made on bananas, citrus, grapes, and sugar beets (DP No. D380017, P.
Savoia, 08/31/2010).  In addition, data are also presented from the
accompanying HED residue chemistry chapter made for PP#9E7651 which
proposes the establishment of an import tolerance for fluazifop-P-butyl
on potatoes (DP No. D372408, P. Savoia, 08/31/2010).  These results are
adequate to determine residue concentration factors for processed
fractions to support the new crop uses put forward in these petition
requests.

Citrus processed commodity results

To determine residue concentration factors in citrus processed
fractions, a single trial on oranges was conducted in Florida during the
1986 growing season using the 2 lb/gal EC formulation of
fluazifop-P-butyl.  For this test program, three applications were made
at the nominal rate of 3.75 lb ai/A/application, for a total seasonal
rate of 11.25 lb ai/A (10x the maximum proposed seasonal rate for
citrus).  Applications were made at 21 day intervals using ground
equipment, with the spray directed to the ground beneath and around the
trees.  Samples of oranges were harvested 14 days after the last
application and processed into chopped peel, dried pulp, molasses,
juice, and oil.

Total fluazifop residues were <LOQ (0.03 ppm) in/on the whole oranges
treated with fluazifop-P-butyl at a total of 11.25 lb ai/A.  Following
processing of the whole oranges, total fluazifop residues were 1.7 ppm
in chopped peel, 2.6 ppm in dried pulp, 0.09 ppm in molasses and oil,
and <LOQ (0.03 ppm) in juice.  Based on these data, processing factors
would be 87x in dried pulp, 3x in oil, and <1x in juice.  However, the
Petitioner states that processing factor in dried pulp in unreasonable
considering that oranges contain about 86% water.  Therefore, the
Petitioner calculated processing factors by assuming that the residue in
the whole oranges was 0.65 ppm, as calculated from the total residue
found in the processed commodities and the weight of the starting
oranges.  The resulting reported processing factors were 4x for dried
pulp, 2.6x for peel, 1.7x for molasses, and 0.14x for oil.

EPA previously concluded that proposed tolerances in citrus fruit and
dried citrus cannot be determined (DEB No. 6343, M. J. Bradley,
08/15/1990).  Rather then attempting to upgrade these results, it would
be prudent for the petitioner to provide a new study given the age of
this data submission.  To satisfy the establishment of tolerances for
the citrus processed commodities, the theoretical concentration factors
are therefore used for setting the pertinent limits on juice (2x) and
oil (1000x).  These factors along with the citrus HAFT of 0.03 ppm,
determine that an appropriate fluazifop-P-butyl tolerance for citrus
juice would be 0.06 ppm and 30.0 ppm for the oil fraction.  In regard to
citrus dried pulp, there is no theoretical concentration factor
determined for this processed commodity.  However, in a recent action
made for chlorantraniliprole, a snap-shot of 27 pesticides having citrus
dried pulp limits was made to determine a practical maximum
concentration factor for this processed commodity (DP No. D361791, D.
Rate, 01/08/2010).  This determination found that concentration factors
range between 2-13x for the citrus dried pulp tolerances which were
examined.  Therefore, using the maximum concentration factor of 13x for
fluazifop, a resulting tolerance of 0.40 ppm should be set for the
citrus dried pulp processed commodity (D385205, P. Savoia, 01/04/11)    
  

Grape processed commodity results 

To determine residue concentration factors in grape processed fractions,
a single field trial was conducted during the 2000 growing season in
Zone 10 (1 trial in CA).  Separate untreated control and treated test
plots were established at the trial site.  Three broadcast spray
applications of the 2 lb/gal EC formulation of fluazifop-P-butyl were
made to the vineyard floor beneath the grape vines to conduct this
trial.  Treatments were made at a target application rate of 1.875 lb
ai/A/application, with a 14-day retreatment interval (RTI), for a total
target seasonal rate of 5.63 lb ai/A (5x the maximum application rate). 
Grapes were harvested 50 days after final treatment.  The grape RACs
were processed into grape juice and raisins.

Total fluazifop residues were found to be <LOQ (0.01 ppm) in/on the
grape RAC harvested 50 days after the last of three treatments made at a
5x seasonal application rate (5.64 lb ai/A/season).  Total fluazifop
residues were also found to be <LOQ (0.01 ppm) in/on the grape juice and
raisin processed grape fractions.  As such, the observed processing
factors for grape juice and raisins are less than the theoretical
concentration factor of 4.7x for raisins (based on the loss of water on
processing grapes into raisins; OPPTS 860.1520, Table 1) and 1.2x for
grape juice (based on separation of components; OPPTS 860.1520, Table
3).  These data indicate that total fluazifop residues do not appear to
concentrate in raisins or grape juice.  These data are adequate for
determining residue concentration factors for the grape processed
commodities (MRID No. 47874605, P. Savoia, 08/31/2010).  

Sugar beet processed commodity results 

To determine residue concentration factors in sugar beet processed
fractions, a single field trial was conducted during the 2000 growing
season in Zone 11 (1 trial in WA).  Separate untreated control and
treated test plots were established at the trial site.  Two foliar
broadcast spray applications using the 2 lb/gal EC formulation of
fluazifop-P-butyl were made to sugar beets to conduct this trial. 
Treatments were made at a target application rate of 1.875 lb
ai/A/application, with a 14-day RTI, for a total target seasonal rate of
3.75 lb ai/A (5x the maximum application rate).  Sugar beets were
harvested 90 days after final treatment.  The sugar beet RAC was
processed into refined sugar, dry pulp and molasses.

Average total fluazifop residues were found to be 0.86 ppm in/on the
sugar beet RAC (root) harvested 90 days after the last of two broadcast
foliar treatments made at a 5x seasonal application rate (3.79 lb
ai/A/season).  In processed sugar beet fractions, average total
fluazifop residues were found to be 0.31 ppm in refined sugar, 3.35 ppm
in the dry pulp, and 12 ppm in molasses.  A comparison of the residues
in the RAC with those in each processed fraction resulted in
concentration factors of 0.36x for refined sugar, 3.9x for dry pulp, and
14x for molasses.  These concentration factors are consistent with the
theoretical concentration factor of 12.5x for sugar (based on separation
of components; OPPTS 860.1520, Table 3) and the maximum observed
concentration factor of 20x (OPPTS 860.1520, Table 4) for dry pulp and
molasses.  These data indicate that total fluazifop residues do not
appear to concentrate in sugar beet refined sugar, but may concentrate
in sugar beet dried pulp and sugar beet molasses (MRID No. 47874606, P.
Savoia, 08/31/2010).

Potato processed commodity results

To determine residue concentration factors in potato processed
fractions, ZENECA AGRO based in Frankfurt held six (6) field trials at
separate sites within Germany to cultivate potatoes during the 1993
growing season.  No details concerning the varieties of potatoes that
were grown, the use of any maintenance pesticides and fertilizers, soil
chemistry, weather data, or the use of supplemental irrigation was
provided.  The data submission only noted that each test location
received an application of the Fusilade end-use product formulation of
fluazifop-P-butyl applied at a late seasonal Pre-Harvest Interval (PHI)
of six weeks.  These treatments were made at the targeted amount of 375
g ai/ha in order to provide each test plot with a total seasonal
application that was equivalent to 1.5x the maximum labeled use rate. 
For this program, the field samples from the two trials observed with
the highest residues of total fluazifop were processed into potato
peels, cooked potatoes, chips and dried flakes for testing.  

The results in this data submission provide a determination of residue
concentration factors for fluazifop-P-butyl in potato processed
commodities.  It was appropriately carried out in line with the
recommendations set forth in the OPPTS 860.1520 Residue Chemistry Test
Guidelines for evaluating the concentration of residues in processed
commodities.  Processing of the potato RAC bearing quantifiable residues
of fluazifop resulted in no concentration of residues in the peel (1.1x
processing factor).  However, total fluazifop residues were found to
concentrate in potato chips and dried flakes at a processing factor of
3.3x, and 6.4x, respectively.  These results indicate that total
fluazifop residues do not appear to concentrate in the potato peels, but
may do so in the chips and granules/flakes processed fractions.  In all,
these data are adequate for determining residue concentration factors
for potato processed commodities (MRID No. 47920405, P. Savoia,
08/31/2010).  

5.8	Rotational Crops

For these actions (PP#9F7624 & PP#9E7651), no new rotational crop data
are required. 

5.9	Proposed and Recommended Tolerances

In a meeting on March 3, 2004, the MARC concluded that for tolerance
expression, parent and fluazifop-acid (free and conjugated) are the
residues of concern since they are adequate to determine misuse (DP No.
D298939, S. L. Kinard, 06/22/2004).  An acceptable soybean metabolism
study is available along with new studies made to a root crop and leafy
vegetable which are currently undergoing Agency review.  In accordance,
tolerances are established under 40 CFR §180.411(a)(1) and (c)(1) for
residues of fluazifop-butyl, including free and conjugated fluazifop,
expressed as fluazifop.  For fluazifop-P-butyl, including free and
conjugated fluazifop (R isomer), tolerances are likewise established
under 40 CFR §180.411(a)(2) and (c)(2) with residues expressed as
fluazifop.  Its registered uses include dry beans, carrot, cotton,
endive (escarole), macadamia nut, onion, peanut, pecan, soybean,
spinach, stone fruit, and sweet potato.  It also carries tolerances with
regional registrations on asparagus, coffee, pepper, and rhubarb along
with being registered for use on lawns as a weed control application.

For PP#9F7624, field trials on bananas, citrus, grapes, and sugar beets
along with corresponding studies made on the relevant processed
commodities were submitted to support this action.  In evaluating the
field trials provided by the registrant, these studies were found to be
adequate in satisfying these residue chemistry data requirements.  In
regard to the banana, grape, and citrus RACs, residues levels in all of
the treated samples analyzed were found to be below the LOQ of the test
method.  As such, the proposed tolerance of 0.01 ppm specified by the
registrant for bananas and grapes is acceptable.  Following this
approach a revised tolerance of 0.03 ppm for citrus based upon the
corresponding LOQ of the test method is therefore recommended instead of
the 0.05 ppm level proposed by the registrant.  Total fluazifop residues
in/on sugar beet RACs were found to be readily quantifiable at levels
greater then the LOQ of the test method.  The residue data for sugar
beets were entered into the Agency’s tolerance spreadsheet as
specified by the Guidance for Setting Pesticide Tolerances Based on
Field Trial Data SOP to determine an appropriate tolerance level
(Appendix I).  The spreadsheet provides a best estimate of a tolerance
at 0.25 ppm for sugar beet roots.  In regard to sugar beet tops, no
tolerance will be required for this commodity since it is no longer
considered to be a significant food or feed item.

In evaluating of the corresponding processing study data that were
provided, it can be concluded that no additional tolerances are needed
for grape juice and raisins as well as sugar beet refined sugar. 
However, residues of fluazifop were found to concentrate in sugar beet
dry pulp (3.9x) and sugar beet molasses (14x).  Based on the sugar beet
root HAFT of 0.22 ppm and the processing factors calculated for dried
pulp and molasses, expected residues in these fractions are 0.86 ppm and
3.1 ppm, respectively.  As a result, the tolerances of 1.0 ppm in dried
pulp and 3.5 ppm for molasses proposed by the registrant are adequate
for these sugar beet processed commodities.  

For the citrus processed commodities, the petitioner has also proposed
tolerances of 0.40 ppm in dried pulp along with 0.05 ppm in juice and
oil.  However, EPA previously concluded that proposed tolerances in
citrus fruit and dried citrus cannot be determined (DEB No. 6343, M. J.
Bradley, 08/15/1990).  Rather then attempting to upgrade these results,
it would be prudent for the petitioner to provide a new study given the
age of this data submission.  To satisfy the establishment of tolerances
for the citrus processed commodities, the theoretical concentration
factors are therefore used for setting the pertinent limits on juice
(2x) and oil (1000x).  These factors along with the citrus HAFT of 0.03
ppm, determine that an appropriate fluazifop-P-butyl tolerance for
citrus juice would be 0.06 ppm and 30.0 ppm for the oil fraction.  In
regard to citrus dried pulp, there is no theoretical concentration
factor determined for this processed commodity.  Using the maximum
concentration factor of 13x calculated in the recent chlorantraniliprole
action along with the citrus HAFT of 0.03 ppm, setting a
fluazifop-P-butyl tolerance of 0.40 for dried pulp would be relevant for
this fraction.

For PP#9E7651, field trials on potatoes along with a corresponding study
made on its pertinent processed commodities were submitted to support
this action.  In evaluating the field trials provided by the registrant,
these studies were found to be adequate in satisfying these residue
chemistry data requirements.  Total fluazifop residues in/on the potato
RAC were found to be readily quantifiable at levels greater then the LOQ
of the test method.  In accordance, the Agency’s Guidance for Setting
Pesticide Tolerances Based on Field Trial Data was utilized for
determining appropriate tolerance levels for potato tubers.  Based on
these calculations, the proposed potato tolerance of 0.25 in roots is
adequate and a limit of 1.0 ppm for tops is recommended.  In regard to
the corresponding processing study data that were provided, it can be
concluded that no additional tolerances are needed for the peel. 
However, residues of fluazifop were found to concentrate in potato chips
(3.3x) and dried flakes (6.4x).  Based on the potato HAFT of 0.55 ppm
and the processing factors calculated for chips and dried flakes,
expected residues in these fractions are 1.82 ppm and 3.52 ppm,
respectively.  As a result, the tolerances of 2.0 ppm in chips and 4.0
ppm for dried flakes are recommended for these potato processed
commodities.

The available residue data provided for fluazifop-P-butyl are adequate
to support the establishment of permanent tolerances on bananas, citrus,
grapes, and sugar beets along with an import limit on potatoes.  There
are no Codex, Canadian or Mexican established Maximum Residue Limits
(MRLs) for residues of fluazifop-P-butyl in/on bananas, citrus, grapes,
sugar beets, and potatoes.  However, PP#9E7651 is being put forward as a
request for the establishment of import tolerances on potato commodities
which will be cultivated in Canada.  As noted, there are no established
MRLs for residues of fluazifop-P-butyl in/on potatoes in Canada but the
promulgation of regulatory levels by PMRA are in the process of being
finalized.  As a result, international harmonization with Canada is a
consideration for this data evaluation concerning the establishment of
import tolerances on potato commodities.  In all, the proposed
tolerances should therefore be revised to reflect the recommended
tolerance levels and correct commodity definitions specified below in
Table 2.

Table 2. 	Tolerance Summary for Fluazifop-P-butyl.

Commodity	Established Tolerance (ppm)	Proposed Tolerance (ppm)
Recommended Tolerance (ppm)	Comments; Correct Commodity Definition

Tolerances Proposed for 40 CFR §180.411(a)(1)

Bananas	--	0.01	0.01

	Citrus	--	0.05	0.03	Fruit, citrus, group 10

Citrus, oil	--	0.05	30.0

	Citrus, dried pulp	--	0.40	0.40

	Citrus, juice	--	0.05	0.06

	Grape	--	0.01	0.01

	Beet, sugar, root	--	0.25	0.25

	Beet, sugar, top	--	1.5	None	Removed from Table 1 Feedstuffs, June 2008

Beet, sugar, dried pulp	--	1.0	1.0

	Beet, sugar, molasses	--	3.5	3.5

	Potato, tubers	--	1.1	1.0	Potato

Potato, chips	--	3.0	2.0

	Potato, granules/flakes	--	5.0	4.0

	Note; the establishment of a tolerance on banana includes the plantain
raw agricultural commodity.

6.0	Exposure Characterization/Assessment Section Update  

6.1	Dietary Exposure/Pathway

6.1.1	Acute and Chronic Dietary Exposure and Risk Update 

Revised acute and chronic dietary exposure assessments using the version
2.03 Dietary Exposure Evaluation Model (DEEM-FCID™) were conducted for
fluazifop-P-butyl (DP No. D379452, S. Tadayon, 08/09/2010).  This
modeling effort uses food consumption data from the U.S. Department of
Agriculture’s Continuing Surveys of Food Intakes by Individuals
(CSFII) from 1994-1996 and 1998 to calculate dietary risk.  These
analyses were performed to support the Section 3 registration of
fluazifop-P-butyl on bananas, citrus, grapes and grape processed
commodities, as well as sugar beets.  Also included in this
determination are all uses relevant to the establishment of an import
tolerance made for fluazifop-P-butyl on potatoes.  These new crop uses
were incorporated into the residue data of file inputs for all other
registered commodities to render a current evaluation of dietary
exposure.  

The resulting acute and chronic risk assessments which include both food
and water are conservative evaluations.  For the acute dietary exposure
assessment, tolerance level residues with a ratio adjustment to account
for additional metabolites of concern were used with the assumption that
100% of all crops are treated.  Where applicable, DEEM 7.81 processing
factors were utilized for the applicable commodities to reflect the
possible altering of residue levels through the manufacture of other
food forms such as meal and flour.  For all other commodities, the
default adjustment factor of 1.0 was used to weight the processing
effects of alternate food forms. 

 

In contrast, percent crop treated estimates determined by BEAD along
with the average residue levels observed in the applicable field trial
studies with ratio adjustment was used to carry out the refined chronic
analysis.  Default processing factors along with the measured potato
processing factors were used to weight the effects of alternate food
forms for chronic assessment.  For both determinations, drinking water
estimates were incorporated directly into these analyses using the EECs
generated by EFED to complete the combined dietary exposure assessments.

  

Results of Acute and Chronic Dietary Exposure Analysis

Acute and chronic dietary risk analyses were made with the DEEM-FCID™
model to form a careful evaluation of exposure for fluazifop-P-butyl. 
The acute dietary assessment focuses on the population subgroup, females
13-49 years of age.  This is the only population subgroup for which an
appropriate toxic endpoint attributable to a single dose was identified.
 For this population subgroup, female 13-49 years of age, acute dietary
risk was estimated to be only 13 % of the aPAD with an exposure of
0.0641 mg/Kg/day.  No acute dietary endpoint attributable to a single
dose was identified for general population including infants and
children.  This assessment concludes that for all supported registered
commodities and new uses, the acute food plus water dietary risk
estimates are below the Agency’s level of concern (<100 % aPAD). 

In conjunction, the refined chronic analysis performed concludes that
for all commodities, the resulting food plus water dietary risk is below
the Agency’s level of concern (<100 %cPAD) for the U.S. population
(12% cPAD with an exposure of 0.009 mg/kg/day) and all population
subgroups.  The most highly exposed population subgroup in the chronic
dietary exposure analysis performed was for children 1-2 years of age
(40% cPAD with an exposure of 0.003 mg/kg/day).  An overview summarizing
the results of the acute and chronic dietary assessments with the
population subgroup having the highest exposure being noted in bold is
presented below in Table 3. 

 Table 3.  Summary of Acute & Chronic Dietary Exposure for
Fluazifop-P-butyl1

Population Subgroup	Acute Dietary2  (95th Percentile)	Chronic Dietary3

	Dietary Exposure (mg/kg/day)	% aRfD	Dietary Exposure

(mg/kg/day)	% cRfD

General U.S. Population	

N/A4	

N/A	0.0009	12

All Infants 

	0.0015	20

Children 1-2 years old

	0.003	40

Children 3-5 years old

	0.0022	30

Children 6-12 years old

	0.0014	19

Youth 13-19 years old

	0.0008	11

Adults 20-49 years old

	0.007	8.9

Adults 50+ years old

	0.0006	8.7

Females 13-49 years old	0.0641	13	0.0006	8.6

1 Fluazifop-P-butyl is not a likely human carcinogen based on lack of
evidence of carcinogenicity in rats and mice; therefore, a 

  dietary cancer exposure and risk analysis was not conducted.

2 Acute dietary analysis derived from a 0.50 mg/kg/day aRfD.

3 Chronic dietary analysis derived from a 0.0074 mg/kg/day cRfD.

4 N/A – None Applicable.

7.0	Water Exposure Risk/Pathway

To address the proposed new crop uses for this action (PP#9F7624), the
potential human exposure to fluazifop-P-butyl in drinking water was
subsequently re-evaluated (DP Nos. D371093 & D371094, W. J Shaughnessy,
05/25/2010).  This modeling was updated to reflect updated application
rates based on acid equivalents, applications with two and four total
applications, and half-lives calculated using the linear/natural log
equation.  It was carried out by EFED to support risk assessment efforts
for the Section 3 registration of fluazifop-p-butyl for use on bananas,
citrus, grapes, and sugar beets.

Ground water EECs were modeled using Tier I SCIGROW (version 2.3, dated
July 29, 2003) and surface water EECs with Tier II PRZM (Pesticide Root
Zone Model; vers. 3.12.2, May 12, 2005) and EXAMS (EXposure Analysis
Modeling System; Vers. 2.98.04.06).  The resulting EECs represent
exposure to fluazifop-acid, with assumptions that fluazifop-acid may be
present in the R or S form or as a mixture of the enantiomers. 
Fluazifop-butyl (PC Code 122805) was detected in both surface water and
ground water samples at low concentrations in Spain (<0.2 µg/L)
indicating that exposure to fluazifop-butyl in drinking water is
possible.  However, based on the metabolism studies fluazifop-acid is
still expected to be the primary component present in drinking water
(Martinez et al. 2000).  Fluazifop-acid was not detected in a
non-targeted ground water monitoring study (MRID No. 40439401).

The results of this updated modeling analyses performed by EFED is
presented below in Table 4 for review.  The results of current
assessment are higher than 2008 assessment (DP No. D347521, K. White,
08/04/2008).  For aerial applications the highest surface water EECs
reported for peak, 1 in 10 year average, and the 30 year average as
estimated by PRZM/EXAMS for all crop use scenarios were 33.4, 6.6 ppb,
and 4.4 ppb, respectively.  For ground applications the highest EECs for
peak, 1 in 10 year average, and the 30 year average were 32.1 ppb, 5.8
ppb, and 3.1 ppb, respectively.  SCI-GROW estimated the concentration of
fluazifop-acid in shallow ground water sources to be 1.56 ppb.  The
difference between the 2008 and current assessment results can be
attributed to a proposed increase in the maximum number of allowable
applications (i.e., 3 vs. 2), and differences in crop use scenarios used
in the two assessments.

Table 4.  Summary of the highest predicted surface and ground water
concentrations for the drinking water assessment for the use of
fluazifop-p-butyl on bananas, plantains, citrus, grapes, and sugar
beets. 

Use	Estimated Drinking Water Concentration of Fluazifop-Acid (g/L)

	Acute or Peak	1 in 10 year Average (Noncancer Chronic)	30 year Average
(Cancer Chronic) 

Aerial Applications 	Surface Water

Bananas & Plantains	33.4	6.2	3.2

Citrus	28.5	5.4	3.7

Grapes	19.8	6.6	4.4

Sugar Beets	13.0	4.8	3.3

Ground Applications	Surface Water

Bananas & Plantains	32.1	5.8	2.7

Citrus	27.3	5.1	2.8

Grapes	16.6	5.3	3.1

Sugar Beets	10.6	3.9	2.3

 	Ground Water

All Uses	1.56	1.56	1.56

The resulting modeling estimates indicate that the most significant
levels of fluazifop-P-butyl would likely be found in surface water
resulting from applications made to bananas and plantains.  These new
EECs were then appropriately used to complete this updated risk
assessment.           

8.0	Residential Exposure Risk Characterization  				

Non-dietary, non-occupational exposure was addressed in the HED
tolerance reassessment made for the fluazifop-P-butyl herbicide in
August 2005 (DP No. D316891, D. Locke, 08/29/2005).  Upon completion of
this human health risk assessment, no new information on residential
exposure has been submitted.  For this action, the existing residential
application of fluazifop-P-butyl will not be impacted because the
proposed new uses will only augment commercial agricultural practices. 
Sections of the prior residential analyses made for fluazifop-P-butyl
are therefore repeated to allow for the transparent calculation of
aggregate risk required to support the proposed new uses. 

Non-Occupational (Residential) Handler Exposure and Risks

Fluazifop-P-butyl is a registered herbicide for residential use on
turfgrass and broadleaf ornamentals for the post-emergent control of
weed grasses.  It is used in this manner as a total grass weed control
in a number of outdoor environments such as on lawns, walks, driveways,
and ornamental planting beds.  Homeowners that apply fluazifop-P-butyl
products may therefore become exposed for short-term durations via the
dermal and inhalation routes.  There are several residential handler
exposure scenarios given the types of equipment and techniques for
applying fluazifop-P-butyl based upon anticipated use patterns and
current labeling instructions.  The exposure scenarios developed for
residential handlers of fluazifop-P-butyl are as follows:     

Liquid Concentrate: Low Pressure Handwand.

Liquid Concentrate: Hose-end Sprayer.

Liquid Concentrate: Watering Can.

Ready-to-Use (RTU) Formulations: Sprinkling Application.

Ready-to-Use (RTU) Formulations: Trigger-pump Sprayer.

The results for residential handlers of fluazifop-P-butyl were found to
yield MOEs above 100 which indicate no risks are of concern. The results
from these exposure and risk calculations are presented below in Table 5
which are taken from the HED August 2005 tolerance reassessment.

Table 5.  Summary of Residential Handler Risks from Fluazifop-P-butyl.

Exposure Scenario	Target	Appl. Ratea	Area Treated Dailyb	Dermal Unit
Exposure (mg/lb ai)	Inhalation Unit Exposure (g/lb ai)	Dermal Dose
(mg/Kg/day)	Inhalation Dose (mg/Kg/day)	MOE (HED’s level of concern =
100)

Derd	Inhl.e	Der + Inhl.

Mixer/Loader/Applicator

Mixing/Loading/Applying Liquid Conc. with Low Press. Handwand (1)	Walks,
drives, patios & fences	0.0056 lb ai/gal	5 gallons	56	3.8	0.0024
0.0000018	850	1.1 x 106	850

Mixing/Loading/Applying Liquid Conc. with Hose-end Sprayer (2)	Walks,
drives, patios, fences & lawns	0.98 lb ai/acre	0.5 acre	11	17	0.0081
0.00014	250	14000	240

Mixing/Loading/Applying Liquid Conc. with Watering Can (3)	Walks,
drives, patios & fences	0.0056 lb ai/gal	5 gallons	11	17	0.00046
0.0000079	4300	250000	4300

Loading/

Applying RTU Liquid with Watering Can (4)	In/around ornamental plants  &
ground cover	0.04 lb ai/gal	1 gallon	11	17	0.00066	0.000011	3000	180000
3000

Loading/

Applying RTU Liquid with Trigger Pump Sprayer (5)	In/around ornamental
plants  & ground cover	0.04 lb ai/gal	1 gallon	13.5	123	0.00081	0.000082
2500	24000	2200

a  Application rates are the maximum application rates determined from
EPA registered labels for fluazifop-P-butyl. 

b  Amount handled per day values are EPA estimates. Attire is
short-sleeve shirt, short pants, and no gloves and no respirator. 

c  Dermal MOE = NOAEL (2 mg/kg/day) / dermal daily dose (mg/kg/day),
where dermal dose = daily unit exposure (mg/lb ai)  x     application
rate amount handled per day  / body weight (60 kg female adult). 

d Inhalation MOE = NOAEL (2 mg/kg/day) / inhalation daily dose
(mg/kg/day), where inhalation dose = daily unit exposure (µg/lb ai) x
application rate x amount handled per day x conversion factor (1
mg/1,000 g)/body weight (60 Kg adult female).  

Residential Post-Application Exposure and Risks

Fluazifop-P-butyl can be used in a number of residential areas which may
be frequented by the general population such as on home lawns.  This
provides the potential for dermal (adults and children) and incidental
oral exposure (children) following residential applications of
fluazifop-P-butyl.  For these purposes, exposure and risk estimates were
derived using the HED Standard Operating Procedures for Residential
Exposure Assessments (draft December 18, 1997).   In accordance, the
following fluazifop-P-butyl post-application risk scenarios were
assessed for children:

Residential Turf (High Contact Activities).

Hand to Mouth Activity on Turf.

Object to Mouth Activity on Turf.

Incidental Soil Ingestion.

The results for residential post-application exposures were found to
yield MOEs above 100 which indicate that no risks are of concern. The
results from these exposure and risk calculations are presented below in
Table 6 which are taken from the HED August 2005 tolerance reassessment.

Table 6.  Fluazifop-P-butyl Post-Application Risk Estimates for
Children.

Exposure Scenario	Route of Exposure	Application Rate (lb ai/acre)	MOE on
Day 0 (HED’s level of concern = 100)

Residential Turf (High Contact Activities) 	Dermal 	0.98 (lawn
renovation) 	260 

0.09 (established turf) 	2,900 

0.075 (turf) 	170,000 

Hand to Mouth Activity on Turf 	Oral 	0.98 (lawn renovation) 	6,800 

0.09 (established turf) 	74,000 

0.075 (turf) 	89,000 

Object to Mouth Activity on Turf 	Oral 	0.98 (lawn renovation) 	27,000 

0.09 (established turf) 	300,000 

0.075 (turf) 	360,000 

Incidental Soil Ingestion 	Oral 	0.98 (lawn renovation) 	2,000,000 

0.09 (established turf) 	22,000,000 

0.075 (turf) 	26,000,000 

Fluazifop-P-butyl Post-Application Risk Estimates for Adults.

High Contact Lawn Activities	

Dermal	

0.98 (lawn renovation)	

380

0.09 (established turf)	

4,200

0.075 (turf)	

5,000

Mowing Turf	

Dermal	

0.09 (established turf)	

26,000

0.075 (turf)	

32,000

Golf Course	

Dermal	

0.09 (established turf)	

13,000

0.075 (turf)	

16,000

Spray Drift

Spray drift is always a potential source of exposure to residents who
may be nearby to spraying operations.  This is particularly the case
with aerial application, but could also be a potential source of
exposure from ground application methods to a lesser extent.  Labeling
instructions for fluazifop-P-butyl specify that it is registered for use
on several major agricultural crops, including cotton, soybeans,
fruit/nut trees, and vegetable crops.  As such, it may be applied with
aircraft, ground-boom, or air-blast equipment.  As indicated in this
assessment, fluazifop-P-butyl can be directly applied to residential
turf, which will not result in exposures of concern.   Based on this
assessment, HED believes that it is unlikely that there is a higher
potential for risk from exposure to spray drift from agricultural uses
of this active ingredient.

9.0 	Aggregate Risk Assessment and Risk Characterization Updates

In compliance with FQPA, HED must consider and aggregate (add) the risks
whenever there are potential residential exposures to a pesticide active
ingredient.  In doing so, the pesticide risks from the three (3) major
potential sources of exposure (food, drinking water & residential use)
are evaluated collectively.  This assessment is made by adding together
the exposures from these relevant sources and comparing them to
quantitative estimates of hazard (NOAEL, PAD, etc.), or the risks
themselves can be aggregated.  When aggregating exposures and risks from
various sources, HED will routinely consider both the route and duration
of exposure.

ith DEEM-FCID™ modeling described beforehand.  Estimated drinking
water concentrations provided by EFED were directly incorporated into
the assessment.  

Acute and Chronic Aggregate Risk Assessments (Food & Drinking Water)

For a detailed discussion of the acute and chronic aggregate risk
assessments of food and drinking water exposure, refer to Section 6.1.1
in this memorandum for the analyses made with DEEM-FCID™ modeling. 
These assessments concluded that for all supported registered
commodities and new uses, the food plus water dietary risk estimates for
acute and chronic exposure are both below the Agency’s level of
concern (<100 %  of the aPAD & cPAD). 

Short-Term Aggregate Risk Assessments

Short-term aggregate risk assessments are made to estimate the potential
effects from exposures which can occur from 1 to 30 days in duration. 
For fluazifop-P-butyl, there are a number of short-term exposure
scenarios which could be aggregated.  In doing so, only the most likely
occurrences were combined so that a conservative (high-end)
determination would be made.  For adults, HED combined the average
chronic food and drinking water exposures with handler (dermal and
inhalation) and postapplication exposures on treated turf (dermal).  For
children, HED combined the average chronic food and drinking water
exposures with postapplication dermal and incidental oral
(hand-to-mouth, object-to-mouth, soil ingestion) from contact with
treated turf.  The results from this assessment are presented below in
Table 7 for review.  These results indicate that short-term aggregate
risks are not of concern for fluazifop-P-butyl.

Table 7.  Short-Term Aggregate Risk 

Population	Short-Term Scenario1 	Aggregate MOE (food and residential)7 

	HED’s Aggregate LOC2 	MOE food + water3 	MOE incidental oral4 	MOE
dermal5 	MOE inhalation6 

	Gen. U.S. Population 	100 	110,000 	NA 	150 	14,000 	150

Adult Female	100 	170,000 	NA 	150 	14,000 	150

Child	100 	33,000 	5,500 	260 	NA 	250

1  Level of Concern (LOC) along with the Margin of Exposure (MOE) for
incidental oral, dermal, and inhalation see DP No. D316891, D. Locke,
08/29/2005.  MOE for food + water see Table 3 of this memorandum.

2  Level of Concern (LOC) is 100 based on 10X for inter-species
extrapolation and 10X for intra-species variation. 

3  MOE food + water = [(short-term oral NOAEL 100 mg/kg/day)/(chronic
dietary exposure)] 

Chronic dietary exposure: General U.S. Pop.= 0.002309 mg/kg/day; Females
13-49 yrs = 0.001823 mg/kg/day; Children 1-2 yrs. = 0.005994 mg/kg/day.

4  MOE incidental oral = [(short-term incidental oral NOAEL 100
mg/kg/day)/(child residential exposure)] Child residential exposure:
Hand-to-mouth = 0.015 mg/kg/day; Object-to-mouth = 0.0037 mg/kg/day;
Incidental soil ingestion = 0.000049 mg/kg/day. 

5  MOE dermal = [(short-term dermal NOAEL 2 mg/kg/day)/(high-end dermal
residential exposure)] Dermal exposure: Adults = handler 0.0081
mg/kg/day + postapp 0.0053 mg/kg/day; Child = 0.0076 mg/kg/day. 

6  MOE inhalation = [(inhalation NOAEL 2 mg/kg/day)/(high-end inhalation
residential exposure)] Inhalation exposure: Adult = handler 0.00014
mg/kg/day.

7 Aggregate MOE (food + water + residential) = 1÷[ [(1÷MOE food +
water) + (1÷MOE incidental oral) + (1÷MOEdermal) + (1÷MOE
inhalation)]].

Intermediate-Term Aggregate Risk Assessments

All residential/recreational exposures are anticipated to be short-term
in duration (DP No. D316891, D. Locke, 08/29/2005).

Long-Term Aggregate Risk Assessments

Long-term aggregate risks are captured under the chronic dietary risk
assessment previously discussed.  As stated above, no long-term
residential exposures are anticipated for fluazifop-P-butyl.

  

10.0	Occupational Exposure/Pathway  

The new crop uses which are proposed will be made with the Fusilade® DX
Herbicide (EPA Reg. No. 100-1070) EC formulation containing 24.5%
fluazifop-P-butyl ai (equivalent to 2 lb ai/gal).  Its expanded use will
employ multiple foliar or vineyard/orchard floor applications at maximum
seasonal rates of 1.125 lb ai/A for bananas, grapes, and citrus and 0.75
lb ai/A for sugar beets.  Applications are to be made with an adjuvant
using ground or aerial equipment at Pre-Harvest Intervals (PHIs) which
range from 0 days on treatments made to bananas up to 90 days for sugar
beets.  In accordance, occupational handlers and post-application
workers can become exposed to fluazifop-P-butyl at short- or
intermediate-term durations through its use. 

For the new crop uses being proposed in this action, the expanded use of
fluazifop-P-butyl will support commercial agricultural efforts in
controlling grass weeds through limited foliar application.  

Occupational exposures/risks were not addressed in the prior HED human
health risk assessment to support tolerance reassessment (DP No.
D316891, D. Locke, 08/29/2005).  An evaluation of the occupational
exposure/risk pathway was performed herein to ensure worker protection
safeguards (DP No. D379451, S. Tadayon, 06/23/2010).  

10.1	Handler Exposure and Risk

For the new crop uses being proposed, agricultural workers may likely
become exposed to fluazifop-P-butyl through a number of different
application activities.  There is a potential for exposure to
fluazifop-P-butyl during mixing, loading, and application activities. 
As such, a short-/intermediate-term risk assessment to evaluate exposure
using the applicable endpoints selected by the HIARC (06/15/2004) was
performed.  In doing so, the following worker scenarios were identified
for the uses being proposed:

Mixer/Loader:  

Mixing/Loading Liquid Concentrates for Aerial Applications (PHED) 

Mixing Loading Liquid Concentrates for Chemigation Applications (PHED) 

Mixing Loading Liquid Concentrates for Groundboom Applications (PHED) 

Applicators

Applying Sprays via Aerial Equipment (PHED) 

Applying Sprays via Groundboom Equipment (PHED) 

Mixer/Loader/Applicator

1.   Mixing/Loading/Applying with Handgun Sprayer (ORETF data)

Flaggers

Flagging for Aerial Spray Applications (PHED) 

To estimate risks from occupational exposures associated with these new
uses, HED used dermal absorption data from a study involving human
volunteers (Woolen, BH, 1991, "Fluazifop-butyl - Dermal Absorption and
Pharmacokinetics in man following single dose of 2 mg and 200 mg"). 
This study has had the appropriate ethical review and been deemed
acceptable for use in human health risk assessment (Lowe, MF, June 10,
2006, Initial Ethics Review of a Human Study of Dermal Absorption and
Pharmacokinetics of Fluazifop-Butyl").  This study provides two
estimates of dermal absorption for fluazifop-butyl, 2% and 9 %.  The
study indicates that the rate of absorption of fluazifop-butyl through
the skin is dependent on the level of exposure or dose applied to the
skin.  Specifically, low levels of exposure result in higher rates of
absorption (9%), and high levels of exposure result in lower rates of
absorption (2%). HED's HIARC determined that the data were acceptable
and both factors could be used for risk assessment (Report of the Hazard
Identification Assessment Review Committee for Fluazifop-P-butyl, D.
Anderson, 05/20/2004).   

HED's TOX SAC met on 08/28/2008 to reconsider the use of both factors in
risk assessment.  The TOX SAC reconfirmed the appropriateness of the use
of both factors for risk assessment because there is high confidence in
the data as they come from a study using humans.  In addition, the TOX
SAC concurred that the use of the 9% dermal absorption factor across all
scenarios is conservative given the results of the dermal absorption
study in humans, which indicates that as exposures to fluazifop-butyl on
the skin increase, the skin becomes saturated and the percentage of
dermal absorption decreases.  More specifically, a high dose results in
a chemical build up on the skin.  This chemical build up acts as a
shield and therefore prevents further absorption of the chemical.  As a
result, there is a lowering of the dermal absorption factor (2%) at
higher doses.  Conversely, a scenario in which there is a low daily dose
allows the chemical to absorb into the skin without the shielding effect
from chemical build up.  As a result, a higher dermal absorption factor
(9%) is observed at low daily doses.

Following this approach, a range of risk estimates (MOEs) for
occupational exposures associated with the new uses, one set of MOEs
based on 9% dermal absorption and a second set of MOEs based on 2%
dermal absorption were determined.  The TOX SAC considered this a unique
circumstance in which available human data could be used to provide a
range of risk estimates.  In this manner, the use of 2% absorption is
considered a refinement.  The non-cancer risk or margin of exposure
(MOE) for all time durations was calculated as follows:                 
                                                                        
   

                        

MOE 		=  	        NOAEL (mg/Kg/day)               	

Dermal or Inhalation Daily Dose (mg/Kg/day)   

                                                      		

The levels of concern for occupational workers are MOEs of 100 for
dermal and inhalation risk.

The adverse effects seen in both the dermal and inhalation studies were
similar; therefore, the

MOEs were combined to identify a total risk.  All
short/intermediate-term MOEs calculated for the mixer/loader are greater
than 100 at the engineering control level.  These MOEs do not exceed
HED’s level of concern.  In characterizing these risks, the dermal
toxicity study associates a 9% dermal absorption factor with a dermal
dose of 0.02 mg/Kg/day, and a 2% dermal absorption factor with a dermal
dose of 2.6 mg/Kg/day.  As a result, occupational exposures for the new
uses of fluazifop-P-butyl were found to range from a high of 0.07
mg/Kg/day to a low of 0.006 mg/Kg/day.  To illustrate these findings,
the results of occupation handler risk assessment are presented below in
Tables 8 and 9 for review.  This analysis has determined that exposures
greater thean 0.1 mg/Kg/day represent high doses and the use of the 2%
dermal absorption factor would be most appropriate for these exposure
scenarios (high pressure handwand).  Alternately, exposures less than
0.1 mg/Kg/day represent low doses and application of the 9% dermal
adsorption factor for these scenarios (all other scenarios) would be
more appropriate.Table 8.  Short-Term Fluazifop-P-butyl Occupational
Handler Risks

Exposure Scenario	Crop or Target	Application Ratea (lb ai/A)	Area
Treated Dailyb(A/gal)	Dermal Dose (mg/Kg/day) 	Dermal

Absorption Factor	Total MOEc

Baseline+ Gloved	Eng Conte

Mixer/Loader

Mixing/Loading Liquid for Aerial and Applications	Potato, sugar beet
0.375 	350	4.53E-03	9%	280	NA

Mixing/Loading Liquid for chemigation Applications 	Potato, sugar beet
0.375 	350 	4.53E-03	9%	280	NA

Mixing/Loading Liquid for Groundboom Applications 	Potato, sugar beet,
citrus, grape, banana, plantains	0.375	80	1.04E-03	9%	1223	NA

Applicator

Applying Sprays via Aerial Equipment 	Potato, sugar beet	0.375	350
9.84E-04	9%	No Data	1765

Applying Sprays via Groundboom Equipment 	Potato, sugar beet, citrus,
grape, banana, plantains	0.375	80	6.30E-04	9%	2000	NA

Mixer/Loader/Applicator

Handgun Sprayer (ORETF)	Citrus, grape, banana, plantains	0.375	25
6.33E-03	9%	303	NA

Flagger

Flagging for Aerial Spray Applications 	Potato, sugar beet	0.375	350 
2.17E-03	9%	682	NA

NA	Not assessed since an acceptable risk is achieved

a	Application rates are the maximum application rates determined from
proposed labels for fluazifop- P- butyl

b	Amount handled per day values are HED estimates of acres treated per
day based on Exposure SAC SOP #9 “Standard Values for Daily Acres
Treated in Agriculture,” industry sources, and HED estimates.	

c	Short-term Inhalation and dermal MOE = NOAEL (2.mg/kg/day) /
inhalation or dermal daily dose (mg/kg/day), where ;

	Dermal dose = daily unit exposure (μg/lb ai) x application rate x
amount handled per day x 9% dermal absorption factor (since all the
dermal dose values were less then 0.1 mg/Kg/day a value of 9% dermal
absorption factor was used)/body weight (60 Kg).

	Inhalation dose = daily unit exposure (μg/lb ai)  x application rate x
amount handled per day x conversion factor (1 mg/1,000 μg/body weight
(60 Kg).

	  SEQ CHAPTER \h \r 1 Total MOE = NOAEL / (Dermal dose + Inhalation
Dose)

d 	PPE- long pants, long sleeved shirt shoes and glove .

e	Engineering Controls is closed mixing/loading system, enclosed cab, or
enclosed cockpit.

Table 9.  Intermediate-Term Fluazifop-P-butyl Occupational Handler
Risks

Exposure Scenario	Crop or Target	Application Ratea

lb ai/A	Area Treated Dailyb (A/gal)	Dermal

Dose (mg/Kg/day) 	Dermal

Absorption Factor	Total MOEc

Baseline+ Gloved	Eng Conte

Mixer/Loader

Mixing/Loading Liquid for Aerial and Applications	Potato, sugar beet
0.375	350	3.88E-03	9%	114	NA

Mixing/Loading Liquid for Chemigation Applications 	Potato, sugar beet
0.375 	350 	3.88E-03	9%	114	NA

Mixing/Loading Liquids for Groundboom Applications 	Potato, sugar beet,
citrus, grape, banana, plantains	0.375	80	8.87E-04	9%	198	NA

Applicator

Applying Sprays via Aerial Equipment 	Potato, sugar beet	0.375	350
8.44E-04	9%	No Data	746

Applying Sprays via Groundboom Equipment 	Potato, sugar beet, citrus,
grape, banana, plantains	0.375	80	5.40E-04	9%	813	NA

Mixer/Loader/Applicator

Handgun Sprayer (ORETF)	Citrus, grape, banana, plantains	0.375	25
5.42E-03	9%	130	NA

Flagger

Flagging for Aerial Sprays Applications 	Potato, sugar beet	0.375	350
1.86E-03	9%	282	NA

NA	Not assessed since an acceptable risk is achieved

a	Application rates are the maximum application rates determined from
proposed labels for fluazifop- p- butyl

b	Amount handled per day values are HED estimates of acres treated per
day based on Exposure SAC SOP #9 “Standard Values for Daily Acres
Treated in Agriculture,” , and HED estimates.	

c	Intermediate-term inhalation and dermal MOE = NOAEL (0.74mg/Kg/day) /
inhalation or dermal daily dose (mg/Kg/day), where;

Dermal dose  = daily unit exposure (μg/lb ai) x application rate x
amount handled per day  x  9% dermal absorption factor (since all the
dermal dose values were less then 0.1 mg/Kg/day a value of 9% dermal
absorption factor was used)/body weight (70 Kg).    SEQ CHAPTER \h \r 1 

	Inhalation dose = daily unit exposure (μg/lb ai)  x application rate x
amount handled per day  x conversion factor (1mg/1,000 μg /body weight
(70 Kg).    SEQ CHAPTER \h \r 1  

	Total MOE = NOAEL / (Dermal dose + Inhalation Dose)

d	Baseline attire is single layer and no gloves/no respirator.

e	Engineering Controls is closed mixing/loading system, enclosed cab, or
enclosed cockpit.	

10.2	Occupational Post-Application Exposure and Risks

Most of the proposed new uses of fluazifop-P-butyl are ground-directed
applications where no crop foliage is treated.  Currently, HED has no
TCs or other data to assess post-application dermal exposures to soil by
occupational workers.  For citrus, grapes, bananas, and plantains, the
fluazifop-P-butyl label prohibits spraying on the foliage. 
Consequently, for these proposed soil-directed uses, post-application
exposures and risks to occupational workers were not quantitatively
assessed.  Alternately, for potatoes and sugar beets, the
fluazifop-P-butyl label allows for spraying on the foliage to occur. 
Therefore, for these proposed uses, post-application exposures and risks
to occupational workers were quantitatively assessed. 

HED’s post-application exposure estimates are based on a surrogate
approach due to the lack of chemical-specific data for
fluazifop-P-butyl.  The maximum application rate is used in this
assessment, while assumptions regarding Dislodgeable Foliar Residues
(DFR) and workday duration are believed to be average values.  Twenty
percent of the residues are assumed available for transfer.  Dissipation
of foliar residues is assumed to occur at the rate of 10% of the
application rate per day.  The workday duration is assumed to be 8
hours.  These risk estimates are characterized as central to high-end.

Most post-application activities will involve frequent contacts made
with the foliage of treated crops requiring the consideration of dermal
exposure when evaluating re-entry risks.  For any given activity, the
extent of exposure will depend on the amount of residue on the foliage,
the intensity of the contact made with the foliage, and the duration of
contact.  Dermal absorption factors of 2% and 9% were determined for
fluazifop-P-butyl depending on low versus high exposures, respectively. 
Re-entry intervals have been assessed using both values.  HED believes
that prior dermal absorption studies demonstrate saturation if the mass
per unit area exceeds a certain level.  Given this, use of the 9% factor
in combination with high levels of exposure would result in providing a
conservative estimate of risk.                     

  Nevertheless, the MOEs are ≥ 100 for short- and intermediate-term
scouting activities with REIs of 3 and 10 days, respectively, when a
conservative dermal absorption factor of 9% is assumed.  A summary of
the Post-application Exposure and Risk Assessment made herein is
presented below in Table 10 for review.

 

Table 10.  Fluazifop-P-butyl Exposure and Risk Assessment for
Occupational Post-Application Activities.

Crops1

	Application Rate

(lb ai/A)

	Dislodgeable Foliar Residue

(ug/cm2)2	Dermal Transfer  Coefficient3 (cm2/hr)	Short-Term  (2%DAF)4
Intermediate-Term4 (2%DAF)

MOE	REI (days)	MOE	REI (days)

Potato, sugar beet	0.375	0.84 (day 0)

0.61 (day 3)

0.29 (day 10)	High end activities Scouting 2500	360	0	155	0

	Low end activities (Irrigation) 100	8900	0	3800	0

	Dermal Transfer  Coefficient (cm2/hr)	Short-Term (9% DAF)
Intermediate-Term (9%DAF)

MOE	REI (days)	MOE	REI (days)

	High end activities Scouting 2500	110	3	100	10

	Low end activities (Irrigation) 100	1985	0	875	0

1. Crop types are taken from the HED Science Advisory Council (SAC) for
Exposure Policy 003.1 (August 2000).

2. Dislodgeable Foliar Residue Postapplication day (ug/cm2) =
Application rate (lb ai/A) x Fraction of ai Retained on the Foliage x
(1- Fraction of Residue that Dissipates Daily) postapplication day x
4.54E+8 ug/lb x 4.7E-9 A/cm2

3. Transfer coefficients are taken from the HED Science Advisory Council
(SAC) for Exposure Policy 003.1 (August 2000), which include data
supplied by the Agricultural Reentry Task Force.

4. For short- and intermediate-term dermal risk assessment, the dermal
absorption factor of 2% and 9% were applied because the endpoint chosen
for this risk assessment was derived from an oral toxicity study.11.0
Data Needs and Label Requirements  TC \l1 "10.0	Data Needs and Label
Requirements 

Toxicology

See Appendix A.5 for list of studies and rational for requirements.  TC
\l2 "10.1	Toxicology 

11.2	Residue Chemistry  TC \l2 "10.2	Residue Chemistry 

860.1200 Directions for Use

The submitted bridging study data made for the Venture L and Fusilade
Maxx EC formulations show that when they are applied to potatoes at 1x
the maximum seasonal rate, the resulting residues will be similar.  If
the registrant so chooses, a revised section B could be submitted which
includes this use for both product formulations.  

860.1380 Storage Stability

Adequate storage stability data are available to support sample storage
conditions that were incurred for the potato RAC, but none have been
provided for the processed commodities.  This is required since the
processed commodities do not appear to have been analyzed within thirty
(30) days of production.

860.1520 Processed Food and Feed

The submitted citrus processing study is not acceptable having been
previously concluded by the Agency to be inadequate (DEB No. 6343, M. J.
Bradley, 08/15/1990).  Rather then attempting to upgrade these results,
it would be prudent for the petitioner to provide a new study given the
age of this data submission.

860.1550 Proposed Tolerances

The proposed tolerances should be revised to reflect the recommended
tolerance levels and correct commodity definitions as specified in Table
2 of this memorandum.  

11.3	Occupational and Residential Exposure  TC \l2 "10.3	Occupational
and Residential Exposure 

None

12.0	References

DP No.:	D347515

Subject:	Fluazifop-P-Butyl.  Amended Human Health Risk Assessment to
Support Use on Dry Beans, Peanuts, and the Post-Bloom Application to
Soybeans.

From:	P. Savoia

To:	J. Miller & J. Stone

Dated:		09/19/2008

MRID Nos.:	47285501-47285505

DP No.:	D319907

Subject:	Fluazifop-P-butyl.  REVISED TRED – Report on FQPA Tolerance
Reassessment Progress and Interim Risk Management Decisions.  Residue
Chemistry Considerations.  Case No. 2285.

From:	S. L. Kinard

To:	D. Locke

Dated:	08/17/2005

MRID Nos.:	00093840-1, 00093843, 00093845, 00137763, 00144014, 00151494,
00157191, 001517193, 40140401, 40241901, 40341601, 40361104, 40361108,
40361111, 40693108, 40725701, 40831303-5, 40831307, 40831309-10,
41018001, 41373703.

DP No.:	D298939

Subject:	Fluazifop-P-butyl.  Report of the Metabolism Assessment Review
Committee. 

From:	S. L. Kinard

To:	Y. Donovan

Dated:	03/17/2004

MRID No.:	None

DP No.:	D291905

Subject:	Fluazifop-P-butyl: Revised Residential Exposure Assessment and
Recommendations for the Tolerance Reassessment Eligibility Decision
(TRED) Document. 

From:	M. Collantes

To:	D. Locke

Dated:	08/10/2004

MRID No.:	None

DP No.:	D379452

Subject:	Fluazifop-P-butyl Acute and Chronic Aggregate Dietary (Food and
Drinking Water) Exposure and Risk assessment for the Section 3
Registration Action to add uses on Banana, Plantains, Citrus, Grapes,
Potato and Sugar beet.  

From:	S. Tadayon

To:	P. Savoia

Dated:	08/09/2010

MRID No.:	None

DP Nos.:	D371093 and D371904 

Subject:	Drinking Water Assessment for the Section 3 registration of
Fluazifop-P-butyl for New Use on Bananas, Plantains, Citrus, Grapes, and
Sugar Beets

From:	Wm. J. Shaughnessy

To:	J. Miller and M. Walsh

Dated:	05/25/2010

MRID No.:	None

DP No.:	D379451

Subject:	Occupational Risk Assessment to Support Request for a Section 3
registration of New Uses of Fluazifop-P-butyl

From:	S. Tadayon

To:	P. Savoia

Dated:	06/23/2010

MRID No.:	None

DP No.:	D316891

Subject:	Fluazifop-P-butyl.  REVISED HED Chapter of the Tolerance
Reassessment Eligibility Document (TRED).  PC Code: 122809, Case #2285,
DP No. D316891.

From:	D. Locke

To:	L. Wormell

Dated:	08/17/2005

MRID No.:	None

DP No.:	D348246

Subject:	Fluazifop-P-Butyl. Section 3 Registration Request to Add New
Uses on Beans (Dry), Peanuts and Soybeans. Summary of Analytical
Chemistry and Residue Data.

From:	D. Soderberg

To:	J. Miller

Dated:	09/16/2008

MRID Nos.:	47285501-05; 46412503

DP No.:	D385205

Subject:	Fluazifop-P-Butyl.  Amended Section 3 Registration Request to
Add New Uses on Bananas, Citrus, Grapes, and Sugar beets.  Summary of
Analytical Chemistry and Residue Data. 

From:	P. Savoia

To:	K. Montague and M. Walsh

Dated:	01/04/2011

MRID Nos.:	47874601-47874606 

DP No.:	D372408

Subject:	Fluazifop-P-Butyl.  Request for the Registration of a Reduced
Pre-Harvest Interval for Application of the Venture L End-Use Product on
Potatoes.  Summary of Analytical Chemistry and Residue Data.

From:	P. Savoia

To:	K. Montague and M. Walsh

Date:	08/31/2010

MRID Nos.:	47920401-47920401	

MRID No.:	47874601.  Kleinschmidt M., M.M. Miller. (2000)
Fluazifop-P-Butyl – Residue Levels in Banana from Trials Carried Out
in the United States During 1999 (Final Report).  Report Number RR
00-43B. Study Number FLUA-99-MR-01.  Unpublished study prepared by
Syngenta Crop Protection, Inc.  79 pages.

MRID No.:	47874602.  Stewart, ER. (2001) Fluazifop-P-butyl – Residue
Levels on Citrus from Trials Conducted in the United States During 2000
(Final Report).  Report Number RR 00-63B.  Study Number FLUA-00-MR-03. 
Unpublished study prepared by Syngenta Crop Protection, Inc.  126 pages.

MRID No.:	47874604.  Stewart, E. (2001) Fluazifop-P-Butyl - Residue
Levels on Grapes from Trials Conducted in the United States During 2000
(Final Report).  Report Number RR 00-062B.  Study Number FLUA-00MR-02. 
Unpublished study prepared by Syngenta Crop Protection, Inc.  158 pages.

MRID No.:	47874603.  Stewart, E. (2001) Fluazifop-P-Butyl - Residue
Levels on Sugar Beets from Trials Conducted in the United States During
2000 (Final Report).  Report Number RR 00-066B.  Study Number
FLUA-00-MR-06.  Unpublished study prepared by Syngenta Crop Protection,
Inc.  177 pages.

MRID No.:	47920402  Sagan, K.  (2009) Fluazifop EC (A12791B) – Residue
Levels on Potatoes from Trials Conducted in Canada During 2008; Final
Report.  Laboratory Project ID Report Number: CER02608/08.  Task Number:
TK0021556.  Unpublished study prepared by ALS Laboratory Group Canada,
Atlantic Agri Tech., Inc., ICMS, Inc., and Syngenta Crop Protection,
Inc.  194 pages.

MRID No.:	47920403  Sagan, K.  (2008) Fluazifop EC (A12791B) – Residue
Levels on Potatoes from Trials Conducted in Canada During 2007; Final
Report.  Laboratory Project ID Report Number: CER02606/07.  Task Number:
TK0021557.  Unpublished study prepared by ALS Laboratory Group Canada,
Atlantic Agri Tech., Inc., ICMS, Inc., and Syngenta Crop Protection,
Inc.  118 pages.

DP No.:	None

Subject:	PP#0F3842/FAP#0H5596.  Fluazifop-P-butyl on Citrus.  Evaluation
of Analytical Methods and Residue Data.  MRID Nos. 41373701-06.  DEB No.
6343.  HED Project No. 0-0683.

From:	M. J. Bradley

To:	J. Miller

Dated:	08/15/1990

MRID Nos.:	41373701 - 41373706.

DP No.:	D361791

Subject:	Chlorantraniliprole.  Amended Section 3 Registration Request
for Uses on Various Field, Vegetable, and Fruit Crops and Discussion of
Future Registration and Tolerance Requests.  Summary of Analytical
Chemistry and Residue Data.

From:	D. Rate

To:	V. Eagle and K. Davis

Dated:	01/08/2010

MRID Nos.:	47588201-11 and 47588214-29

MRID No.:	47874605.  Stewart, E. (2001) Fluazifop-P-Butyl - Residue
Levels on Grape Juice and Raisins from a Trial Conducted in the United
States in 2000 (Final Report).  Report Number RR 00-067B.  Study Number
FLUA-00-PR-01.  Unpublished study prepared by Syngenta Crop Protection,
Inc.  124 pages.

MRID No.:	47874606.  Stewart, E. (2001) Fluazifop-P-Butyl - Residue
Levels on Sugar beet Sugar (Refined), Dry Pulp and Molasses from a Trial
Conducted in the United States During 2000 (Final Report). Report Number
RR 00-070B.  Study Number FLUA-00-PR-04.  Unpublished study prepared by
Syngenta Crop Protection, Inc.  134 pages.

MRID No.:	47920405  Sagan, K.  (1994) Determination of Residues of
Total-Fluazifop (Fluazifop-P-Butyl + Fluazifop-P) in Potatoes and their
Processed Products Federal Republic of Germany 1993.  Laboratory Project
ID Report Number: ICI-9301.  Study Number: Az. 13430/93.  Task Number:
TK0022593.  Unpublished study prepared by Dr. Specht & Partner Chemische
Laboratorien GMBH, and Syngenta Crop Protection, Inc.  66 pages.

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Initial Ethics Review of a Human Study of Dermal Absorption and
Pharmacokinetics of Fluazifop-Butyl (MRID 46082918). Lowe MF, Carley JM,
June 10, 2006

Ethics Review of Fluazifop-Butyl Absorption, Distribution, and
Metabolism Study (MRID 00131464). Sherman K, August 13, 2010

Fluazifop-P-Butyl.  Rationale for Reducing the 10X Safety Factor to 1X
for Lack of an Immunotoxicity Study.  Addendum to Fluazifop-P-Butyl Risk
Assessment for Dry Beans, Peanuts, and Soybeans [D347515, P. Savoia et
al., 19-SEP-2008], J. Liccione, January 23, 2009        DP Barcode: 
359779

Appendix A   Toxicology Data Requirements and Profile

A.1	Toxicology Data Requirements

The requirements (40 CFR 158.500) for food and non-food use for
fluazifop-P-butyl are in Table A1. Use of the new guideline numbers does
not imply that the new (1998) guideline protocols were used.

  Table A1:   Toxicology Data Requirements

	

Technical

	

Required	

Satisfied

870.1100	Acute Oral Toxicity	

870.1200	Acute Dermal Toxicity	

870.1300	Acute Inhalation Toxicity	

870.2400	Primary Eye Irritation	

870.2500	Primary Dermal Irritation	

870.2600	Dermal Sensitization		

yes

yes

yes

yes

yes

yes	

yes

yes

yes

yes

yes

yes

870.3100	Oral Sub-chronic (rodent)	

870.3150	Oral Sub-chronic (nonrodent)	

870.3200	21-Day Dermal	

870.3250	90-Day Dermal	

870.3465	90-Day/28-Day Inhalation		

yes

yes

yes

R

R	

yes

yes

yes 

no

no

870.3700a	Developmental Toxicity (rodent)	

870.3700b	Developmental Toxicity (nonrodent)	

870.3800	Reproduction		

yes

yes

yes	

yes

yes

yes 

870.4100a	Chronic Toxicity (rodent)	

870.4100b	Chronic Toxicity (nonrodent)	

870.4200a	Oncogenicity (rat)	

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

870.4200b	Oncogenicity (hamster)	

870.4300	Chronic/Oncogenicity
(rat)...........................................	

yes

yes

yes

yes

no

yes	

yes a

yes 

yes 

no b

yes 

yes

870.5100	Mutagenicity—Gene Mutation - bacterial	

870.5300	Mutagenicity—Gene Mutation - mammalian	

870.5375	Mutagenicity—Structural Chromosomal Aberrations	

870.5395	Mutagenicity—Other Genotoxic Effects		

yes

yes

yes

yes	

yes

yes

yes

yes

870.6100a	Acute Delayed Neurotox. (hen)	

870.6100b	90-Day Neurotoxicity (hen)	

870.6200a	Acute Neurotox. Screening Battery (rat)	

870.6200b	90-Day Neuro. Screening Battery (rat)	

870.6300	Developmental Neurotoxicity		

R

R

yes

yes

R	

yes c

yes c

no

no

no

870.7485	General Metabolism	

870.7600	Dermal Penetration		

yes

no	

yes

yes

870.7800   
Immunotoxicity..........................................................
...	            yes	              no

a Guideline 870.4300 satisfies this requirement.   b The study in the
hamster satisfies this requirement.    c Required for organophosphates
only.   d Reserved.       R: Required

A.2	Toxicity Profiles

 Table A.2.1            Acute Studies with Fluazifop-P-butyl (PC 122809)

Guideline No./ Study Type	

MRID No.	

Results	

Toxicity Category

870.1100 Acute oral toxicity/rats

(PP005; 93.7% & 86.3% )

	

00162440

(1984)	

LD50 = 3680 mg/kg for males rats

LD50 = 2451 mg/kg for female rats	

III

III

870.1200 Acute dermal toxicity/rabbits 

(PP005; 93.7% & 86.3%)	

00162440

(1984)	

LD50 > 2000 mg/kg or >1.73 mL/kg	

III

870.1300 Acute inhalation 1 toxicity/rats 

(PP005; 24.6%) CTL/P/3331	

41917904

(1991)	

LC50 > 1.7 mg/L	

III

870.2400 Acute eye irritation/rabbit 

(PP005; 86.3%) CTL/P/856	

00162441

(1983)	

Mild irritation, cleared within 3 days	

IV

870.2500 Acute dermal irritation/rabbit 

(PP005; 86.3%) CTL/P/856	

00162441

(1983)	

Slight irritation, cleared within 72 hours	

IV

870.2600 Skin sensitization/GP (PP005; 99.6%) 80/ILK026/349	

00162441

(1983)	

Not a skin sensitizer	

Table A.2.2  Subchronic, Chronic, Developmental, Reproductive and Other
Toxicity Profile on Fluazifop-      butyl [FB] and Fluazifop-P-butyl
[FPB].

Guideline No./ Study Type	

MRID No. (year)/ Classification /Doses	

Results

870.3100

90-Day oral toxicity (rat) with FB	

00093820 (1980)

Acceptable/guideline

0, 10, 100, 2000 ppm

M: 0, 0.7, 7.1, 144.5 mg/kg/day

F; 0, 0.8, 8.0, 161.9 mg/kg/day 	

NOAEL=0.7 mg/kg/day

LOAEL=7.1 mg/kg/day based on liver and kidney histopathology. 

870.3100

90-Day oral toxicity (rat) with FPB	

46158402 (1985)

Acceptable/guideline

0, 10, 100, 2000 ppm

—F: 0, 0.5, 5, 100 mg/kg/day 	

NOAEL=0.5 mg/kg/day

LOAEL=5 mg/kg/day based on decreased spleen weight and decreased
hematological parameters in males.  Dose related testicular weight
decrement and cholesterol depression were also seen.   

870.3150

90-Day oral toxicity (dog) with FB	

00093821 (1980)

Acceptable/guideline

0, 5, 25, 125/250 mg/kg/day	

NOAEL = 25 mg/kg/day

LOAEL = 125/250 mg/kg/day based on multiple pathologies in 3 dogs (2
males and 1 female) killed at 1 month dosed at 250 mg/kg/day.  Also seen
were body weight loss gut lesions, severe eye lesions and
hepatotoxicity.  In remaining surviving dogs dosed at 125 mg/kg/day,
mild to equivocal liver lesions were seen.  

870.3150

90-Day oral toxicity (hamster) with FPB	

46082902 (2001)

Acceptable/guideline

Males: 0, 19.5, 78.3 or 291.9 mg/kg/day

Females: 0, 19.9, 79.0 or 319.6 mg/kg/day	

NOAEL = M/F: 78.3/79.0 mg/kg/day

LOAEL = M/F: 291.9/319.6 mg/kg/day based on decreased body weight/body
weight gain and food efficiency in males and evidence of liver toxicity;
centrilobular eosinophilia/loss of glycogen in males and females. 

870.3200

21/28-Day dermal toxicity (rabbit) with FB	

00093819 (1980)

Acceptable/guideline

0, 100, 500, 2000 mg/kg/day	

NOAEL = 100 mg/kg/day

LOAEL = 500 mg/kg/day based on death in 1 male and at 2000 mg/kg/day,
death 4 males and 5 females, possibly due to kidney failure.

870.3700a

Prenatal developmental in (Sprague Dawley rats) with FB	

0008857, 92067047 (1981) Acceptable/guideline

0, 10, 50, 200 mg/kg/day 	

Maternal NOAEL = 200 mg/kg/day

LOAEL = None based on maternal weight decrement due to gravid uterine
weight decrement.

Developmental NOAEL=none

LOAEL=10 mg/kg/day based on delayed ossification.

Malformations NOAEL = 50 mg/kg/day

LOAEL = 200 mg/kg/day based on diaphragmatic hernia.

870.3700a Developmental toxicity (Sprague Dawley rat) with FB	

00088858, 92067048, 92967020 (1981)

Acceptable/guideline

0, 1.0, 5.0, 10, 200 mg/kg/day with FB	

Maternal NOAEL=200 mg/kg/day.

LOAEL=None based on maternal weight decrement partially explained by
gravid urine weight decrement. 

Developmental NOAEL=1 mg/kg/day.

LOAEL=5 mg/kg/day based on fetal weight decrement and increased
incidence of small fetuses and delayed ossification.

Malformations NOAEL= 10 mg/kg/day

LOAEL=200 mg/kg/day based on increased incidence of diaphragmatic
hernia. 

870.3700a Developmental toxicity (Wistar rats) with FPB 	

46158401 (1991) Acceptable/guideline

0, 0.5, 1.0, 20, 300 mg/kg/day	

Maternal NOAEL=20 mg/kg/day

LOAEL=300 mg/kg/day based on body weight gain decrement.

Developmental NOAEL=1.0 mg/kg/day

LOAEL=20 mg/kg/day based on delayed ossification in skull bones,
cervical arches and centrum in fetuses and litters and delayed
ossification in the manus and pes.

870.3700a Developmental Toxicity (Wistar rats) with FPB	

46082903 (1989)

Acceptable/guideline

0, 2, 5 or 100 mg/kg/day  	

Maternal NOAEL=100 mg/kg/day

LOAEL= None based no maternal toxicity.

Developmental NOAEL=2.0 mg/kg/day

LOAEL=5.0 mg/kg/day based on based on dose related delayed ossification
in skull bones [occipital and parietal] in fetuses and litters.

870.3700a Developmental Toxicity (Wistar rats) with FPB	

46082013 (1990)

Acceptable/guideline

0, 2.0, 5.0, 100 mg/kg/day 	

Maternal NOAEL=100 mg/kg/day

LOAEL= None based on no toxic effects

Developmental NOAEL=2.0 mg/kg/day

LOAEL=5.0 mg/kg/day based on delayed ossification in skull bones,
sternebrae bipartite, sternebrae and calcenum unossifided in fetuses and
litters.

The overall conclusions based on a weight of evidence on the five
studies of developmental toxicity in the rat were a NOAEL/LOAEL =
2.0/5.0 mg/kg/day based on fetal weight decrement and delayed
ossification. 

870.3700b Developmental toxicity (NZW rabbit) with FB	

00088856, 92067049, 92067021 (1981)

Acceptable/guideline

0, 10, 30, 90 mg/kg/day 	

Maternal NOAEL=30 mg/kg/day

LOAEL=90 mg/kg/day based on abortions.

Developmental NOAEL=30 mg/kg/day

LOAEL=90 mg/kg/day based on nominal increases in delayed ossification,
total litter loss, abortions, small fetuses, cloudy eyes all above mean
or range of historical controls

870.3700b Developmental toxicity (NZW rabbits) with FPB	

46082904 (1993)

Acceptable/guideline

0, 2, 10, 50 mg/kg/day 	

Maternal NOAEL=10 mg/kg/day

LOAEL=50 mg/kg/day based death, abortions and body weight loss

Developmental NOAEL=10 mg/kg/day

LOAEL=50 mg/kg/day based on increased incidence of 13th rib and delayed
ossification in sternebrae 2.

870.3800

Reproduction and fertility effects

(rats) with FB	

00088859, 92067050 (1981) Acceptable/guideline

0, 10, 80, 250  ppm

M/F: 0/0, 0.74/0.88, 5.8/7.1, 21.7/17.5 mg/kg/day 	

Parental/Systemic NOAEL = M/F 0.74/7.1 mg/kg/day

LOAEL = M/F 5.8/ 21.7 mg/kg/day based on decreased spleen wt. in males &
increased absolute & relative liver & kidney wts. & geriatric
nephropathy in females.

Offspring NOAEL = 7.1 mg/kg/day

LOAEL = 21.7 mg/kg/day based on pup viability in f1 and f2 pups during
lactational day 1, 4, 11, 18 & 25 and decreased f2 pup weight on
lactational day 25.

Reproductive NOAEL = M/F 0.74/0.88mg/kg/day

LOAEL = M/F 5.8/7.1 mg/kg/day based on decreased abs. & rel testes &
epididymal weight and in females decreased pituitary & uterine weights. 
Sperm counts not available.

Conclusions on the 2-generation study on reproduction in the Sprague
Dawley rat: The cause of the dose related testes wt decrease in the P0
and F1 generations has not been demonstrated, but no sperm counts,
morphology, motility have been conducted to date.  Extensive short term
studies on testes weight, testes histopathology, and endocrine effects
(MRID# 46082911, 46082916, 46082917, 46082920 & 46082920, see table
4.1d) failed to find the reason for the testes weight decrement in the
rat and hamster.  However, since the most sensitive tests for effects on
sperm were not conducted (sperm count, motility and morphology as
indicated in the 1996 guidelines), it is concluded that testes weight
decrement from possible decrements in sperm seen in the rat reproduction
and the chronic study in hamsters have not been adequately eliminated.
The histology on the testes does not support an effect, but histology is
insufficiently sensitive to detect a slight effect.    

870.4100a

Chronic toxicity

(rats)	

870.4300 satisfies the requirement	

870.4100b

Chronic toxicity (dog) with FB	

00131462, 00131463, 92067018 (1982)

Acceptable/guideline

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

NOAEL = 5 mg/kg/day

LOAEL = 25 mg/kg/day based on marginally increased incidence adrenal
fatty vacuolation & increased incidence of thymic involution and at 125
mg/kg/day death of 4/6 males and 2/6 females, eye, gastrointestinal
tract lesions, adrenal and bone marrow pathology & thymic involution.

870.4200

Carcinogenicity

(hamster) with FPB	

4534501, 46082905 (2001)

Acceptable/guideline

0, 0, 200, 750, 3000 ppm 

M: 0, 0, 12.5, 47.4, 193.6 mg/kg/day F: 0, 0, 12.1, 45.5, 181.4
mg/kg/day	

NOAEL =M/F 12.5/12.1 mg/kg/day

LOAEL = 47.5/45.5 mg/kg/day based on based on increased incidence of
males with reduced sperm, testicular degeneration, eye cataract changes,
liver inflamation and gall stones and in females, increased incidence of
ovarian stroma cell/sex chord hyperplasia.

No evidence of carcinogenicity

870.4300

Chronic/Carcinogenicity

(rat) with FB	

41563703 (1985)

Acceptable/guideline

0, 2, 10, 80, 250 ppm

M: 0, 0.10, 0.51, 4.15, 12.3 mg/kg/day

F: 0, 0.13, 0.65, 5.2, 16.0 mg/kg/day 	

NOAEL =M/F 0.51/5.2 mg/kg/day

LOAEL =M/F 4.15/16.0 mg/kg/day based on increased mortality &
nephropathy exacerbated by respiratory stress, and in females possible
increased basal and/or follicular/luteal cysts.

No evidence of carcinogenicity

870.6100a Acute neurotoxicity in hens with FB	

00093818 (1981)

Acceptable/guideline

0, 3750, 7500 or 15000 or 15000 mg/kg 	

Fluazifop-butyl exposed hens showed no evidence of delayed
neurotoxicity.

870.7485

Metabolism and pharmacokinetics

(rats) with FB	

00093822 through 00093828 (1981) 

Acceptable/guideline

1 mg/kg and 1000 mg/kg 	

Fluazifop-butyl is rapidly hydrolyzed to fluazifop acid by blood enzymes
and excreted as the acid and its conjugates in the urine of males and
females.  Due to biliary excretion parent compound, fluazifop acid and
its conjugates are excreted in the feces of males at much higher
proportions than in feces of the female.  Excretion was complete in 7
days, with the exception of small amounts in the fat in some rats.  

870.7600

Dermal penetration

(human)	

46082918	

A human study/NG satisfies guideline 870.7600.

Ethics of study cleared.

NG Comparative metabolism with  FB and FPB in rats	

00162445, 0012446 (1983) Acceptable/NG 

1 mg/kg 	

FB is hydrolyzed and the [S] enantiomer is converted to the [R]
enantiomer.  Whether fluazifop-butyl [RS] (50:50) or fluazifop-P-butyl
[S] (90:10) is administered, within a hour the blood contained a mixture
composed of fluazifop acid in a ratio of [R] 95% and [S] 3%.  The two
products behaved similarly and reached the same equilibrium within
experimental error.  

NG Plasma level time course with FB and FPB in rats	

46082910 (1998)

Acceptable/NG

200 mg/kg	

The time course of plasma levels and elimination of the acid metabolite
were similar for both fluazifop-butyl and fluazifop-P-butyl.  Plasma
levels of the acid from both isomers were much higher in males than in
females.  The data support previous studies. 

NG Absorption and excretion study in hamsters with FPB  	

46082923 (2002)

Acceptable/NG

0, 200, 750, 3000 ppm	

The study was conducted in two phases, Phase 1- single dose followed by
3 days of unlabeled test material and Phase 2 - 24 hour feeding of
labeled test material followed by 3 day of unlabeled test material. Data
were consistent with excretion data from other species.  The system
appeared saturated, since the ratio of the 3000/200 ppm dose levels was
much lower than the ratio of respective plasma levels, especially for
males.   

NG Absorption, excretion and tissue retention in mice with FB 	

46082925 (1992)

Acceptable/NG

1 and 150 mg/kg	

Male mice excreted proportionally more in feces and less in urine than
females.  Although males excreted more than females in the feces and
females excreted more than males in the urine, the difference between
males and female mice was smaller than with male and female rats.   The
study showed individual variability in excretion, similar to that found
in the rats and dogs, although analytical deviation may have explained
part of the variation.    

NG Absorption and excretion in dogs with FB	

0093829 (1981) 

Acceptable/NG

1 mg/kg	

One dog showed delayed absorption.  Excretion rate similar to females
rats.  No evidence of biliary excretion. 

NG Peroxisome proliferation in mice, rats, hamsters and humans with FPB	

46082919 (1988)

Acceptable/NG

0, 80, 250, 1000 or 2000 ppm 	

In vivo and in vitro peroxisome proliferation was studied in the mouse,
rat and hamster and in vitro human hepatocytes.  Proliferation in
hepatocytes from the greatest to the smallest was:  mice > rats >
hamster >> human.  No increase in cell replication was seen at any dose.

NG Androgen/estrogen activity with FPB & acid; FB & acid metabolite	

46082916 (2001)

Acceptable/NG

	

No agonist or antagonist activity was detected for FPB or FB or their
acid metabolites.  Using recombinant yeast strains expressing human
androgen receptor or estrogen receptor, the intrinsic androgenic,
anti-androgenic, estrogenic, anti-estrogenic activity of FPB, FB and
their respective acid metabolites have been assessed by absorbance in a
transcription assay.  Positive antagonists were hydrotamoxifen and
flutamide, which induced appropriate antagonic activity.  Agonistic
activity assessed by comparison to 17β-estradiol and
dihydrotestosterone; antagonic activity was assessed by inhibition of
17βestradiol and dihydrotestosterone activity.  No agonist or antagonic
activity was found within 7 orders of magnitude (oom) greater than the
conc. of estradiol transcription, 4 oom greater for inhibition of
estradiol transcription and 6 oom for agonistic activity of
dihydrotestosterone and up to 156 μM antagonist activity by a dose
related decrease in dihydrotestosterone-mediated androgenic activity.

NG Dermal absorption in humans with FB	

46082918

Acceptable/NG

2 mg & 200 mg/person	

Dermal absorption was 8.6% at 2 mg/person and 1.9% at 200 mg/person,
Ethics of study cleared

Table A2.3:  Mutagenicity Data Summaries on Fluazifop-butyl (FB) and
fluazifop-P-butyl (FPB) 

Adequacy of data base for Mutagenicity:  No mutagenic potential was seen
in adequately conducted  pre-1991 guideline mutagenicity studies (in
vivo and in vitro) on fluazifop-P-butyl [FPB] or fluazifop-butyl [FB].  
A structural analogue {haloxyfop-methyl [methyl
2-[4-[[3-chloro-5-(trifluromethyl)-2-pyridinyl]
oxy]phenoxy]propinonate]} of fluazifop-P-butyl showed no mutagenic
potential.  

1.  Gene Mutation

Guideline 870.5100, Ames/Salmonella typhimurium, reverse mutation

MRID#00162443

Acceptable 

Test material [FB]	

In a reverse gene mutation assay in bacteria (MRID#00162443, 92067023),
histidine deficient strains  TA98, TA100, TA1535, TA1537, TA1538 of S.
typhimurium were exposed to fluazifop-butyl (96.8% a.i., batch/lot# P25)
in the presence and absence of mammalian metabolic activation by plate
incorporation. 

Negative with and without S9 up to the limit dose of 5000 µg/plate. 

  

Guideline 870.5100, Ames/Salmonella typhimurium, reverse mutation

MRID#00162442

Acceptable 

Test material [FPB]	

In a reverse gene mutation assay in bacteria (MRID#00162442, 92067013),
histidine deficient strains  TA98, TA100, TA1535, TA1537, TA1538 of S.
typhimurium were exposed to fluazifop-butyl (93.6% a.i., batch/lot# P8)
in the presence and absence of mammalian metabolic activation by plate
incorporation. 

             Negative with and without S9 up to the limit dose of 5000
µg/plate (insoluble at 5000µg/plate). 

Guideline 870.5300, Mouse lymphoma cell test 

Acceptable 

Test material [FB]	

In a mammalian cell gene mutation assay (MRID# 00116678), heterozygous
TK+/- P 388 mouse lymphoma cells cultured in vitro were exposed to
fluazifop-butyl, (99.6% a.i., batch/lot # ADGM/1021/79) at
concentrations of 0, 0.25, 2.5, 25, 250 or 2500 µg/mL in the presence
and absence of mammalian metabolic activation, S9, for 30 minutes.  

              Negative with and without S9 up to cytotoxic doses.

Guideline 870.5300, Mouse lymphoma L5178Y TK+ test

Acceptable

Test material [FPB]	

In a mammalian cell gene mutation assay (MRID#46082906), mouse lymphoma
L5178Y TK+ cells in vitro were exposed 4 hr to fluazifop-P-butyl at 0,
100, 200, 500, 700, 1000 or 1500 µg/mL with and without S9 activation. 
In second assay the cells were exposed to 0, 100, 200, 500, 700 or 1000
µg/mL with and without S9 activation.  

Test was negative with and without S9 activation up to and including
excessive precipitation. 

2.  Cytogenetics

Guideline 870.5375; In vitro chromosomal aberrations in human blood
lymphocytes. (1985)

Acceptable

Test material: [FPB]	

In independently performed mammalian cell cytogenetic assays (chromosome
aberration) (MRID#41555202), lymphocyte cultures prepared from human
peripheral blood were exposed to fluazifop-p-butyl (R-enantiomer, 93.8%
a.i.; CTL reference # Y02746/001/008) in dimethyl sulfoxide for 4 hours
at concentrations of 0, 1, 10, 100, 500, or 1000 µg/mL both in the
presence and absence of S9-activation.  Cells were harvested at 27 hours
after initiation of treatment.

        The was no evidence of chromosome aberration induced over
background in the presence or absence of S9-activation at toxic doses.

Guideline 870.5385, In vivo rat mammalian cytogenetics; bone marrow
chromosomal aberrations (1980)

Acceptable 

Test material: [FB]	

In independent bone marrow chromosome aberration assays (MRID#00088861),
10 male CD rats/dose were treated via oral gavage (10 mL/kg) either once
(acute) or daily for 5 consecutive days (sub-acute) with fluazifop-butyl
(94.5% a.i.; Lot/Batch #: CTL Compound code: Y00083/001/006), in corn
oil at doses of 0, 21.0, 67.2, or 210.0 mg/kg.  Bone marrow cells were
harvested at 6 or 24 hours after treatment in the acute study, and at 6
hours after treatment in the sub-acute study. 

         There was no evidence of chromosome aberration induced over
background at toxic doses.

Guideline 870.5450, Mouse Dominant lethal test (1980)

Unacceptable: Top dose not sufficiently toxic

Test material: [FB]	

In a dominant lethal assay (MRID#00088862) [PP009, fluazifop-butyl 
(97.0% a.i., batch/lot # 310M)] was administered to 25 CD-1 male
mice/group by corn oil gavage (10 mL /kg) at dose levels of 0, 28.7,
91.8 or 287 mg/kg/day for 5 days for the first mating.  Based on the
results of the first mating, subsequent matings were based on 15 of the
25 dosed males.  These 15 males were mated with 30 females in 8 sets and
the females examined for dominant lethal effects (resorptions) at day 15
of pregnancy.  The investigators reported that fluazifop-butyl does not
cause dominant lethal effects in CD-1 mice up to and including 287
mg/kg/day for 5 days.    No toxicity demonstrated.

3.  Other Genotoxicity

Guideline 870.5395; In vivo mouse micronucleus test (1983)

Acceptable 

Test material: [FB] and [FPB]

Acceptable	

In an in vivo mammalian cell mouse micronucleus assay (MRID#
0016244,92068014), C57BL/6J mice were administered FB or FPB at doses of
250 or 400 mg/kg and bone marrow removed after 24, 48 or 72 hours to
determine the frequency of MPCEP.  FB and FPB were tested up to 80% and
50% of the LD50 in mice.

        There were no adequate evidence of a positive response of
increased micronuclei over background with either fluazifop-butyl [FB]
or fluazifop-P-butyl [FPB] at toxic doses.

A.3	Hazard Identification and Endpoint Selection

A.3.1	Acute Reference Dose (aRfD) - Females age 13-49

In a developmental toxicity study (MRID# 00088857), fluazifop-butyl was
administered to 22 female CD Sprague Dawley strain rats/group in a corn
oil (2 ml/kg) gavage at dose levels of 0, 10, 50 or 200 mg/kg bw/day
from days 6 through 20 of gestation.  Diaphragmatic hernia was seen in 1
fetus at 10 mg/kg/day, none at 50 mg/kg/day and in 3 fetuses at 200
mg/kg/day.  No diaphragmatic hernia was seen in 2970 historical control
fetuses. In a subsequent study (discussed below) with a larger number of
litters (160 litter/group) diaphragmatic hernias were seen in 3 of 1113
control fetuses, 1 of  1081 fetuses at 1 mg/kg/day, 3 of 1073 fetuses at
5 mg/kg/day, 2 of 1064 fetuses at 10 mg/kg/day and in 59 of 1064 fetuses
(and 45/159 litters)at 200 mg/kg/day.  Since this anomaly was seen at a
higher incidence (3 fetuses) in the controls in this study and was not
replicated at the same dose in the second study, the single incidence of
diaphragmatic hernia at 10 mg/kg/day was considered to be an aberration
and not attributable to treatment.

In an another developmental toxicity study (MRID# 00088858)
fluazifop-butyl was administered to 159 or 160 female CD Sprague Dawley
strain rats/group in a corn oil (2 ml/kg) gavage at dose levels of 0,
1.0, 5.0, 10 or 200 mg/kg bw/day from day 6 through 20 of gestation. 
There was an increased incidence of diaphragmatic hernia were seen in
fetuses (5% versus 0.13% in control) and litters (43.4% versus 1.9%) at
200 mg/kg/day.

Dose and Endpoint for Establishing aRfD:  NOAEL is 50 mg/kg/day based on
the increased incidence of diaphragmatic hernia at 200 mg/kg/day.  

Uncertainty Factor (UF): 100.  This includes 10X for inter-species
extrapolation and 10X for intra-species variation.

Comments about Study/Endpoint/Uncertainty Factor:  The NOAEL selected is
based on the combined results of the two studies. In the two studies
conducted in the same strain of rats with an identical dosing regimen,
diaphragmatic hernias were seen at 200 mg/kg/day in both studies; none
were seen at 50 mg/kg/day in the second study (MRID# 00088858); and a
single incidence was seen at 10 mg/kg/day in the first study (MRID#
00088857).  The single incidence in the first study was not considered
to be treatment-related since the incidence was lower than that seen in
the control fetuses in the second study and was not replicated at the
same dose in the later study. Therefore, based on the combined doses
tested, 0, 1, 5, 10, 50, or 200 mg/kg/day, for this effect, the NOAEL is
50 mg/kg/day and the LOAEL is 200 mg/kg/day.  These values differ from
the study NOAEL/LOAEL.  This particular developmental effect is presumed
to occur after a single exposure and thus is appropriate for this
population subgroup (Females 13-49).

Acute RfD  (Female 13- 49) =  50  mg/kg (NOAEL)/100 (UF) =	0.50 mg/kg

A.3.2	Acute Reference Dose (aRfD) - General Population

An appropriate endpoint attributable to a single dose was not available
in the database including the developmental toxicity studies.

A.3.3	Chronic Reference Dose (cRfD) 

See Section 4.2.4 for a descriptive summary of the Two-Generation
Reproduction Study in rats (MRID# 00008859, 92067022 & 92067050).

Dose and Endpoint for Establishing cRfD:  NOAEL is 0.74 mg/kg/day based
on decreases in absolute and relative testes and epididymal weights in
males at 5.8 mg/kg/day (LOAEL).   

Uncertainty Factor(s):  100X (10X for inter species extrapolation and
10X for intra species variation.

Comments about Study/Endpoint/Uncertainty Factor: The
study/dose/endpoint is appropriate for the route (oral) and duration
(chronic) of concern.  Although the endpoint of concern in based on male
reproductive effects, decreases in pituitary and uterine weights were
seen in females at a comparable NOAEL (0.88 mg/kg/day) and LOAEL (7.1
mg/kg/day).   

Chronic RfD  =   0.74 mg/kg/day (NOAEL)/100 (UF) =   0.0074  mg/kg/day

A.3.4	Incidental Oral Exposure (Short- and Intermediate-Term)

Short-Term Incidental Oral Exposure (1-30 days) tc \l3 "4.4.4 
Short-Term Incidental Oral Exposure (1-30 days) 

See Section 4.2.3 for a descriptive summary of the Developmental
Toxicity Studies in rats (MRID# 46082913, 46158401, 46082903).  A brief
summary relevant to the endpoint selected is presented below.

In a developmental toxicity study (MRID# 46082913) fluazifop-P-butyl was
administered to Aderly Park strain of Wistar rats by gavage at dose
levels of 0, 2.0, 5.0 or 100 mg a.i./kgday from days 7 through 16 of
gestation.  No evidence of maternal toxicity was seen at any dose level.
For maternal toxicity, the NOAEL is 100 mg/kg/day (HDT) and a LOAEL was
not established.

In another developmental toxicity study (MRID# 46158401)
fluazifop-P-butyl was administered to Alderly Park strain of Wistar rats
by gavage at dose levels of 0, 0.5, 1.0, 20, or 300 mg/kg /day from days
7 through 16 of gestation.  Maternal toxicity at 300 mg/kg/day was
indicated by a body weight gain decrement of 19% during the dosing
period, GD 7-16.  Food consumption was decreased statistically
significantly at the same dose and food efficiency decreased 13%.  For
maternal toxicity, the NOAEL is 20 mg/kg/day and the LOAEL is 300
mg/kg/day based on decreases in body weight gain maternal animals.

In another developmental toxicity study (MRID# 46028903)
fluazifop-P-butyl was administered to Alderly Park strain of Wistar rats
by gavage at dose levels of 0, 2, 5 or 100 mg a.i./kgday from days 7
through 21 of gestation.  No maternal toxicity was seen.  For maternal
toxicity, the NOAEL is 100 mg/kg/day (HDT) and a LOAEL is not
established.

Dose and Endpoint for Risk Assessment: Maternal NOAEL of 100 mg/kg/day
based on decreases in body weight gain in maternal animals during the
dosing period (GD 7-16) at 300 mg/kg/day (LOAEL).

Comments about Study/Endpoint:  The maternal NOAEL is selected based on
the combined results of the two studies with support from the third
study. The first two studies were conducted in the same strain of rats
(Wistar) with identical dosing regimen (dosing during GD 7-16) in the
same laboratory.  The lower NOAEL (20 mg/kg/day) in the second study
(46158401) is an artifact of dose selection.  Additionally, the NOAEL is
supported by another study conducted in the same strain of rats with a
slightly longer dosing period (GD 7-21) where no maternal toxicity was
seen at 100 mg/kg/day, the highest dose tested (MRID# 46082903).  This
dose/endpoint is appropriate for the population (infants and children)
and duration (1-30 days) of concern.

Intermediate-Term Incidental Oral Exposure (1-6 months) tc \l3 "4.4.5 
Intermediate-Term Incidental Oral Exposure (1-6 months) 

See Section 4.2.4 for a descriptive summary of the Two-Generation
Reproduction Study in rats (MRID# 00008859, 92067022 & 92067050).

Dose and Endpoint for Establishing cRfD: NOAEL is 0.74 mg/kg/day based
on decreases in absolute and relative testes and epididymal weights in
males at 5.8 mg/kg/day (LOAEL).   

Comments about Study/Endpoint: The endpoint of concern was seen after
approximately 13-16 weeks of exposure and thus is appropriate for the
duration (1-6 months) of concern.  Although the endpoint of concern in
based on male reproductive effects, decreases in pituitary and uterine
weights were seen in females at a comparable NOAEL (0.88 mg/kg/day) and
LOAEL (7.1 mg/kg/day).  This endpoint is appropriate for the population
(infants and children) of concern.

A.3.5	Dermal Exposure (Short-, Intermediate- and Long-Term)

In a dermal absorption and pharmacokinetic study in humans (MRID#
46082918), six men (age 18-45; weight 60-90 kg)/dose were dosed dermally
with 2 mg or 200 mg of 0.05% or a 5.0% (w/v) solution of fluazifop-butyl
in a formulation.  Four ml of each solution was spread over 800 cm2 of
the backs of 6 men/dose level, allowed to dry and left un-occluded for 8
hours.  Plasma and urine was collected in multiple samples over a 264
hour period.  Plasma was collected hourly for 4 hours, every 2 hours for
12 hours and every 24 hours to the end.  Urines were collected every 4
hours for 12 hours and then every 24 hours to the end.  After 8 hours,
the application site was washed with water using cotton swabs and 3%
Teepol and covered with  a T-shirt over the application site until
morning.  At 24 hours after application the site was again washed with a
3% solution of Teepol. The washes, T-shirts, plasma and urine samples
were analyzed for fluazifop-butyl or fluazifop acid.

Most of the applied dose appeared to be in the stratum corneum and
easily removed. Recovery of test material was good, a mean of 93.4% ± a
standard deviation of 13% at the 2 mg dose and mean of 83.2% ± a
standard deviation of 21% at the 200 mg dose.  Peak plasma levels were
shown to occur 24 to 31 hours after application in these men.  The one
half-life for excretion was about 18 hours.  In arriving at these
percentages of recovery, the study authors added a correction to the
amount excreted in the urine (i.e. to the amount excreted up to 120
hours was added the amount excreted after 120 hours through a
2-compartment pharmacokinetic model).  However, this latter correction
was insignificantly small amounting about 0.008% of the 200 mg applied
to the skin.  HED modified the study author’s percentage absorption by
scaling the recovered material to 100%.  The modified dermal absorption
was calculated by two methods; (1) Unrecovered added to absorbed
material, and (2) Scaling recovered material to100%.  Method (1) yielded
absorption factors of 18.4% and 14.6% at the 2 mg dose and 200 mg dose,
respectively.  Method (2) yielded absorption factors of 8.6% and 1.9% at
the 2 mg dose and 200 mg dose, respectively.  Method (2) appeared to be
more reasonable because residual material (unrecovered) may have been
relatively immobile.  The unrecovered test material was speculated to be
in the outer layers of the skin and appeared to be easily removed.

Short-Term Dermal Exposure (1-30 days) tc \l3 "4.4.7  Short-Term Dermal
Exposure (1-30 days) 

See Sections 4.4.1 and 4.4.4 for a descriptive summary of the
Developmental Toxicity Studies in rats (MRID# 00088858, 46082903,
46082913, 46158401).  Though the Assessment team chose two short-term
dermal endpoints, one for females of child-bearing age based on concerns
for in utero effects, and another for all other population subgroups,
for regulatory purposes, the dose and endpoint for the most sensitive
population was used in the risk assessment for all population subgroups.
 Since females of child-bearing age cannot be excluded or treated
separately from the general population should regulatory and/or
mitigation measures be necessary, it is incumbent upon the Agency to
address the potential risks of the most sensitive population as
representative of the entire population.

The short-term dermal endpoint that the assessment team chose for the
general population, including infants and children, was selected from 3
developmental toxicity studies in rats (MRID# 46158401, 46082913 and
46082903).  See a description under Section 4.4.4 Short-term Incidental
Oral above.  The dose/endpoint chosen is the maternal NOAEL of 100
mg/kg/day based on decreases in body weight gain in maternal animals
during the dosing period (GD 7-16) at 300 mg/kg/day (LOAEL).  For the
reasons stated above, the risk assessment was conducted using the
short-term dermal endpoint selected for females 13-49 years of age.

Dose and Endpoint for Risk Assessment: Developmental NOAEL is 2.0
mg/kg/day based on fetal weight decrement, increased incidence of
hydroureter and delayed ossification at 5.0 mg/kg/day (LOAEL).

Comments about Study/Endpoint: The in utero effects are appropriate to
assess dermal risks for the population subgroup, Females 13-49 from
exposure to fluazifop-butyl.  This endpoint was selected because of the
developmental toxicity concerns seen consistently in rats and rabbits
via the oral route.  The team did not select the 21-day dermal toxicity
study in rabbits due to the concern for developmental toxicity which is
not evaluated in the dermal study.  In addition, dermal study would not
address the developmental concerns since the NOAEL (100 mg/kg/day) in
that study is considerably higher than the dermal equivalent dose (22
mg/kg/day) obtained using the oral dose (2.0 mg/kg/day) with a 9% dermal
absorption factor (2.0 ( 0.09 = 22). 

Since an oral NOAEL was selected, an appropriate dermal absorption
factor (i.e., 2% or 9%, exposure depended) was used for route-to-route
extrapolation. 

Intermediate and Long-Term Dermal Exposure (1-6 months & > 6 months) tc
\l3 "4.4.8	Intermediate and Long-Term Dermal Exposure (1-6 months & > 6
months) 

See Section 4.2.4 for a descriptive summary of the Two-Generation
Reproduction Study in rats (MRID# 00008859, 92067022 & 92067050).

Dose and Endpoint for Risk Assessment:  NOAEL is 0.74 mg/kg/day based on
decreases in absolute and relative testes and epididymal weights in
males at 5.8 mg/kg/day (LOAEL).   

Comments about Study/Endpoint: The endpoint of concern was seen after
approximately 13-16 weeks of exposure and thus is appropriate for the
duration (1-6 months) of concern.  Although the endpoint of concern in
based on male reproductive effects, decreases in pituitary and uterine
weights were seen in females at a comparable NOAEL (0.88 mg/kg/day) and
LOAEL (7.1 mg/kg/day).  These endpoints are appropriate for the general
population including infants and children.  Since an oral NOAEL was
selected an appropriate dermal absorption factor (i.e., 2% or 9%,
exposure depended) was used for route-to-route extrapolation.

A.3.6	Inhalation Exposure (Short-, Intermediate- and Long-Term) 

Short-Term Inhalation Exposure (1-30 days) tc \l3 "4.4.9  Short-Term
Inhalation Exposure (1-30 days) 

See Sections 4.4.1 and 4.4.4 for a descriptive summary of the
Developmental Toxicity Studies in rats (MRID# 00088858, 46082903,
46082913, 46158401).  Again, though the Assessment team chose two
short-term inhalation endpoints, one for females of child-bearing age
based on concerns for in utero effects, and another for all other
population subgroups, for regulatory purposes, the dose and endpoint for
the most sensitive population was used in the risk assessment.

Dose and Endpoint for Risk Assessment: Developmental NOAEL is 2.0
mg/kg/day based on fetal weight decrement, increased incidence of
hydroureter and delayed ossification at 5.0 mg/kg/day (LOAEL)

Comments about Study/Endpoint: The in utero effects are appropriate to
assess inhalation risks for the population subgroup, Females 13-49 years
from exposure to fluazifop-P-butyl.  This endpoint was selected because
of the developmental toxicity concerns seen consistently in rats and
rabbits via the oral route.  The Assessment team noted the absence of a
repeated exposure inhalation toxicity study.  For route-to-route
extrapolation, absorption via the inhalation route is assumed to be
equivalent to oral absorption.	

	Intermediate- and Long-Term Inhalation Exposure (1-6 months & > 6
months) tc \l3 "4.4.10	Intermediate- and Long-Term Inhalation Exposure
(1-6 months & > 6 months) 

See Section 4.2.4 for a descriptive summary of the Two-Generation
Reproduction Study in rats (MRID# 00008859, 92067022 & 92067050).

Dose and Endpoint for Risk Assessment:  NOAEL is 0.74 mg/kg/day based on
decreases in absolute and relative testes and epididymal weights in
males at 5.8 mg/kg/day (LOAEL).   

Comments about Study/Endpoint: The endpoint of concern was seen after
approximately 13-16 weeks of exposure and thus is appropriate for the
duration (1-6 months) of concern. Although the endpoint of concern is
based on male reproductive effects, decreases in pituitary and uterine
weights were seen in females at a comparable NOAEL (0.88 mg/kg/day) and
LOAEL (7.1 mg/kg/day).  These endpoints are appropriate for the general
population including infants and children.  Again, the Assessment team
noted the absence of a repeated exposure inhalation toxicity study.  For
route-to-route extrapolation, absorption via the inhalation route is
assumed to be equivalent to oral absorption.

A.4	Executive Summaries

	A detailed summary of the various study executive summaries are listed
in the document “Fluazifop-P-butyl: Revised HED Chapter of the
Tolerance Reassessment Eligibility Document (TRED)” (August 29, 2005,
PC Code: 122809, Case # 2285, DP Barcode: D316891).

A.5	Toxicology Data Required as a Condition of Registration

Guideline Number: 870.3250

Study Title:   90-Day Dermal Toxicity 

Rationale for Requiring the Data

As well as food uses, fluazifop-P-butyl has non-food, commerical and
residential uses, including roadsides, turf and shrub applications. The
sub-chronic (90-day) dermal toxicity study is a new data requirement
under 40 CFR Part 158 as a part of the data requirements for
registration of a pesticide for non-food use.

The dermal toxicity Test Guidelines (OPPTS.870.3250) is intended to
evaluate the toxic effects associated with continuous or repeated
exposures to a test substance for a period of 90-days. 

The Agency requests a 90-day dermal toxicity study for non-food use
pesticides because the dermal route will be the primary route of
exposures for chemicals designated with this use pattern (i.e.,
non-food). The Agency believes that this study is required because the
longer term oral studies (i.e., chronic or carcinogenicity studies)
which are required for food-use pesticides are usually not required for
non-food use pesticides.  A 21/28 day dermal toxicity test is
insufficient to identify potential hazards for non-food use pesticides
because of the concern for the longer duration exposure associated with
this use pattern. For example, professional applicators may be subjected
to repeated exposure during the 3 month period of peak summer usage. 
For this type of increased exposure, professional applicators may not be
adequately protected using data from a 21/28-day study. Additionally,
the 28-day dermal study revealed adverse responses such as an animal
death at the study LOAEL, suggesting that further dermal testing is
required to determine whether longer exposure may decrease the dermal
LOAEL and NOAEL values. 

Practical Utility of the Data

How will the data be used?  

A route specific (i.e., dermal) study will provide critical scientific
information needed to characterize potential hazard to the human
population exposed to the pesticide by the dermal route.  This study
will provide a dose and a toxicological endpoint of concern for
quantification of risks for dermal exposures. This study would eliminate
the uncertainties associated with the use of an oral study with a
default (100% oral equivalent) dermal absorption factor.  

In many cases, toxicity observed via the dermal route will be different
than toxicity observed via oral exposure,  due to absorption and
distribution of the toxic agent after exposure or differences in
metabolism (i.e., systemic versus local).  This means that the
route-to-route extrapolation (i.e., use of an oral dose/endpoint) in
risk assessment could result in under or over estimation of risks from
the dermal route.  

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

If the dermal toxicity study indicates that the test material poses
either a greater or lesser risk than that calculated using an oral dose,
(as used in the interim decision), the risk assessment would be revised
to reflect the magnitude of potential risk derived from the new data.
Also, the requested data would allow the Agency to determine if the
risks were over-estimated or under-estimated.  If the risks were
under-estimated, additional risk mitigation measures could be required. 
If the risks were over-estimated, risk mitigation measures could be
reduced.

Guideline Number: 870.3465

Study Title:   90-Day/28-Day Inhalation Toxicity 

Rationale for Requiring the Data

Conducting the inhalation study for 90 days, is requested by the Agency
because intermediate-term exposure to workers is expected based on
fluazifop-P-butyl's use pattern.  A longer-term inhalation study is
required in situations in which a specific concern exists for increased
hazard related to exposure via the inhalation route.  The 28-day
inhalation toxicity study evaluates the potential hazard of a pesticide
chemical following repeated inhalation exposures.  This study is
important for pesticides such as fluazifop-P-butyl with use patterns in
which there is potential for repeated human exposures (e.g.,
professional applicators, green house use, etc.) of periods of 28 days
or more.  The study design simulates one route of human exposure
(inhalation) to a pesticide, the animals are exposed (nose/whole body)
to aerosol concentrations of the test material for 6 hours/day, 5
days/week for 90/28 days.  A detailed toxicological examination
including the histopathology of the respiratory system is conducted. 
This route-specific study would provide data for hazard
characterization, dose response assessment, and a dose and endpoint for
assessing potential risks via the inhalation route.  

Practical Utility of the Data

How will the data be used?  

This study will identify hazard (i.e., provide a dose and endpoint)
following repeated inhalation exposures.  The results will be used in
risk assessments as appropriate.

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

A sub-chronic inhalation study could provide scientific information to
characterize potential hazard to the human respiratory system from
pesticide exposure.  In the case of fluazifop-P-butyl, there is no
acceptable inhalation study available.  A 90/28-day repeated exposure
study that follows the Test Guidelines (870.3465) will characterize
hazard and provide data for a more refined inhalation risk assessment.
Exposure time may be reduced 28 days pending exposure patterns,
plateauing of effects and considering the overall toxicity potential of
fluazifop. 

Guideline Number: 870.6200

Study Title:  Neurotoxicity Battery (Acute and Sub-Chronic Studies)

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the
data requirements for registration of a pesticide (food and non-food
uses). 

The Neurotoxicity Screening Battery (OPPTS 870.6200) is designed to
evaluate the potential adverse effects on the nervous system from
exposure to pesticide chemicals.  The Agency believes that the guideline
studies are inadequate in their assessment of behavioral effects and do
not use optimal methods to evaluate the potential toxicity to the
nervous tissue structure and function. To detect and characterize these
potential effects more fully, a battery of more sensitive testing is
required. The objective of this neurotoxicity battery testing is to
evaluate the incidence and severity of the functional and/or behavioral
effects, the level of motor activity, and the histopathology of the
nervous system. The acute neurotoxicity study is required to detect
possible effects resulting from a single exposure. The sub-chronic
neurotoxicity study is intended to detect possible effects resulting
from repeated or long-term exposures.

Practical Utility of the Data

How will the data be used?

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posure. These studies can provide data on a wide range of functional
tests for evaluating neurotoxicity including sensory effects,
neuromuscular effects, learning and memory and histopathology of the
nervous system  For example, animal studies with organophosphorous
chemicals  have shown neurotoxicity to be the primary toxic endpoints
(e.g., cholinesterase inhibition) of concern in rodents and non-rodents.
   These animal studies can be used to select endpoints and doses for
use in risk assessment of all exposure scenarios and are considered a
primary data source for reliable reference dose calculation. The Agency
has established an oral reference dose (RfD) for assessing dietary risks
for a number of chemicals (e.g., organophoshates and carbamates) where
neurotoxicity was the most sensitive endpoint of concern.

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

If the acute or sub-chronic neurotoxicity studies show that
fluazifop-P-butyl poses either a greater or a diminished risk than that
given in the interim decision’s conclusion, the risk assessment for
fluazifop-P-butyl may need to be revised to reflect the magnitude of
potential risk derived from the new data.

 

If the Agency does not have these data, a 10X database uncertainty
factor may be applied when conducting a risk assessment using the
currently available studies.

Guideline Number: 870.7800

Study Title:  Immunotoxicity

Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the
data requirements for registration of a pesticide (food and non-food
uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing and is designed to evaluate the potential of a
repeated chemical exposure to produce adverse effects (i.e. suppression)
on the immune system. Immunosuppression is a deficit in the ability of
the immune system to respond to a challenge of bacterial or viral
infections such as tuberculosis (TB), Severe Acquired Respiratory
Syndrome (SARS), or neoplasia.  Because the immune system is highly
complex, studies assessing functional immunotoxic endpoints are helpful
in fully characterizing a pesticide’s potential immunotoxicity.  These
data will be used in combination with data from hematology, lymphoid
organ weights, and histopathology in routine chronic or sub-chronic
toxicity studies to characterize potential immunotoxic effects.  

Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provide critical scientific information needed to
characterize potential hazard to the human population on the immune
system from pesticide exposure. Since epidemiologic data on the effects
of chemical exposures on immune parameters are limited and are
inadequate to characterize a pesticide’s potential immunotoxicity in
humans, animal studies are used as the most sensitive endpoint for risk
assessment.  These animal studies can be used to select endpoints and
doses for use in risk assessment of all exposure scenarios and are
considered a primary data source for reliable reference dose
calculation. For example, animal studies have demonstrated that
immunotoxicity in rodents is one of the more sensitive manifestations of
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental,
reproductive, and endocrinologic toxicities.  Additionally, the EPA has
established an oral reference dose (RfD) for tributyltin oxide (TBTO)
based on observed immunotoxicity in animal studies (IRIS, 1997).

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

If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

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

Appendix B.  Review of Human Research

Past fluazifop-P-butyl risk assessments rely in part on data from
studies in which adult human subjects were intentionally exposed to a
pesticide to determine their dermal exposure and pharmacokinetics.  Many
such studies, involving exposure to many different pesticides, comprise
generic pesticide exposure databases such as the Pesticide Handlers
Exposure Database (PHED), the Agricultural Reentry Task Force (ARTF)
Database, and the Outdoor Residential Exposure Task Force (ORETF)
Database.  EPA has reviewed all the studies supporting these
multi-pesticide generic exposure databases, and has found no clear and
convincing evidence that the conduct of any of them was either
fundamentally unethical or significantly deficient relative to the
ethical standards prevailing at the time the research was conducted. 
All applicable requirements of EPA’s Rule for the Protection of Human
Subjects of Research (40 CFR Part 26) have been satisfied, and there is
no regulatory barrier to continued reliance on these studies. The
fluazifop-butyl human dermal study (MRID 46082918) utilized in this risk
assessment was cleared for use in the memo “Initial Ethics Review of a
Human Study of Dermal Absorption and Pharmacokinetics of
Fluazifop-Butyl”, Lowe MF, Carley JM, June 10, 2006.

Fluazifop-P-Butyl	Human Health Risk Assessment to Support New Uses	DP
No.:  385178

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Fluazifop-P-Butyl	Human Health Risk Assessment to Support New Uses	DP
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