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. <IP_ADDRESS>).  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.

Fluazifop, a grass-selective herbicide which inhibits acetyl-CoA
carboxylase in sensitive plant species.   HYPERLINK
"http://www.ncbi.nlm.nih.gov/pubmed?term=%22Walker%20KA%22%5BAuthor%5D"
Walker KA ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/pubmed?term=%22Ridley%20SM%22%5BAuthor%5D"
Ridley SM ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/pubmed?term=%22Lewis%20T%22%5BAuthor%5D"
Lewis T ,   HYPERLINK
"http://www.ncbi.nlm.nih.gov/pubmed?term=%22Harwood%20JL%22%5BAuthor%5D"
 Harwood JL .,   HYPERLINK
"javascript:AL_get(this,%20'jour',%20'Biochem%20J.');" \o "The
Biochemical journal."  Biochem J.  1988 Aug 15;254(1):307-10.

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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