Document ID: EPA-HQ-OPP-2014-0878-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-04-06T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  

EPA Registration Division contact: Susan Lewis; (703)305-7090

Inter-Regional Research Project Number 4 (IR-4 Project)

Petition 4E8328

	EPA has received a pesticide petition (4E8328) from Interregional
Research Project No. 4 (IR-4), 500 College Road East, Suite 201 W,
Princeton, NJ 08540 proposing, pursuant to section 408(d) of the
Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to
amend 40 CFR part 180 by establishing a tolerance for residues of
fluazifop-p-butyl in or on the raw agricultural commodities: lettuce,
head and leaf at 5.0 parts per million (ppm);  strawberry at 3.0 ppm;
onion, green at 1.5 ppm; grass hay at 15 ppm; grass forage at 4.0 ppm;
caneberry subgroup 13-07A at 0.05 ppm; bushberry subgroup 13-07B at 0.3
ppm; tuberous and corm vegetables (except for potato) subgroup 1D at 1.5
ppm; small fruit vine climbing, except for fuzzy kiwifruit subgroup
13-07F, 0.03 ppm; and onion, bulb subgroup 3-07A at 0.5 ppm and amending
a tolerance for residues of fluazifop-p-butyl in or on rhubarb, from 0.5
ppm to 0.4 ppm. Upon the approval of the aforementioned tolerances, IR-4
requests removal of the existing tolerances for grape at 0.01 ppm;
onion, bulb at 0.5 ppm; and sweet potato, roots at 0.05 ppm.  EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408 (d) (2) of FDDCA; however, EPA has not
fully evaluated the sufficiency of the submitted data at this time or
whether the data supports granting of the petition. Additional data may
be needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. The metabolism of fluazifop-p-butyl is adequately
understood for the purpose of the proposed amended tolerance.

	2. Analytical method. Syngenta has developed and validated analytical
methodology for enforcement purposes.  This method has been submitted to
the Agency and is in PAM Vol. II, Method II.  An extensive database of
method validation data using this method on various crop commodities is
available.

3. Magnitude of residues. Complete residue data to support the requested
amended tolerance are submitted with this petition. The requested
tolerances are adequately supported.  These studies were conducted per
EPA Test Guidelines 860 Series.

B. Toxicological Profile

	1. Acute toxicity. Fluazifop-p-butyl technical and the end-use
formulation have low acute toxicity by oral, dermal and inhalation
exposure routes.  For fluazifop-p-butyl technical, the oral LD50 in rats
is 3680 mg/kg for males and 2451 mg/kg for females.  The rabbit dermal
toxicity LD50 is >2000 mg/kg and the rat inhalation LD50 is 1.7 mg/l
air.  Fluazifop-p-butyl technical is mildly irritating to the rabbit eye
and slightly irritating to rabbit skin.  Fluazifop-p-butyl technical is
not a skin sensitizer.

	2. Genotoxicty. Fluazifop-p-butyl has been tested for its potential to
induce gene mutation and chromosomal changes in different test systems. 
Fluazifop-p-butyl was negative in bacterial reverse gene mutation assays
and in mouse lymphoma mammalian cell mutation assays.  Fluazifop-p-butyl
was negative in in vitro chromosomal aberrations assay in human blood
lymphocytes and was negative in the in vivo mouse micronucleus test.

	3. Reproductive and developmental toxicity. A number of developmental
toxicity studies have been conducted.  Based on an HED review of all
relevant data, the Agency concluded that the degree of concern is low. 
The overall NOAEL for the rat studies is 2.0 mg/kg/day and the LOAEL is
5.0 mg/kg/day.  For single dose effects, the NOAEL is 50 mg/kg/day and
the LOAEL is 200 mg/day based on diaphragmatic hernia malformations.

4. Subchronic toxicity. Fluazifop-p-butyl was evaluated in a number of
subchronic studies.  In a 90-day rat oral toxicity study the NOAEL was
0.5 mg/kg/day.  Effects at higher doses included decreased spleen and
testicular weight and decreased hematological parameters in males. 
Fluazifop-p-butyl was also evaluated in a 90-day oral toxicity study
with hamsters.  The NOAEL was 78.3 mg/kg/day, based on decreased body
weight and body weight gain as well as food efficiency in males at
higher doses levels.  Signs of liver toxicity and centrilobular
eosinophilia were observed in males and females.  No dermal toxicity
study was conducted; however, the study was conducted with a similar
compound, fluazifop-butyl.  In a 21/28 day dermal rabbit study conducted
with fluazifop-butyl, the NOAEL was 100 mg/kg/day.  LOAEL was 500
mg/kg/day based on the death of a male.

5. Chronic toxicity. The Agency has classified fluazifop-p-butyl as not
likely to be carcinogenic in humans.  In a hamster carcinogenicity study
the NOAEL was 12.5 mg/kg/day for males and 12.1 mg/kg/day for females. 
In a combined carcinogenicity/chronic toxicity study in Wistar rats, in
males the LOAEL was 80 ppm (4.15 mg/kg/day) and the NOAEL was 10 ppm
(0.51 mg/kg/day).  For females the LOAEL was 250 ppm (16.0 mg/kg/day)
and the NOAEL was 80 ppm (5.2 mg/kg/day).

6. Animal metabolism. The metabolism of fluazifop-p-butyl in rats is
adequately understood.

	7. Metabolite toxicology. The major metabolites of fluazifop-p-butyl
are fluazifop acid (free and conjugated), 5-trifluromethyl-2-pyridone
and 2-(4-hydroxyphenoxy) propionic acid (free and conjugated).  Based on
their structures, these compounds are likely to be significantly less
toxic than parent.

	8. Endocrine disruption. There is no indication of endocrine disruption
potential from the fluazifop-p-butyl toxicology data. There is no
hormonal disruption or evidence of developmental or reproductive
toxicity in the absence of maternal toxicity. Furthermore, the chemical
structure of fluazifop-p-butyl indicates that it is unlikely to disrupt
mammalian hormones.

C. Aggregate Exposure

	1. Dietary exposure. Acute (Tier I), short-term, and chronic (Tier III)
aggregate exposure evaluations were performed for fluazifop-P-butyl
using the Dietary Exposure Evaluation Model (DEEM-FCID™, version 3.16)
software from Exponent.  All consumption data for these assessments were
taken from the National Health and Nutrition Examination Survey/“What
We Eat in America” (NHANES/WWEIA) dietary survey conducted in
2003-2008.  These exposure assessments included all currently registered
uses of fluazifop-P-butyl as well as proposed IR-4 uses on caneberry,
lettuce, blueberry, rhubarb, grasses grown for seed, strawberry, sweet
potato and green onions.  The Tier I acute assessments incorporated
established or proposed tolerances (40CFR180.411) in or on a variety of
agricultural commodities including meat, milk and eggs; percent of crop
treated values were conservatively estimated to be 100% for all uses in
the acute assessments.  The Tier III chronic assessments incorporated
field trial residue values where fluazifop-P-butyl was applied at the
maximum intended use rate and samples were harvested at the minimum
pre-harvest interval (PHI) to obtain the maximum expected residues. 
Estimated percent crop treated (%CT) values were incorporated into the
Tier III chronic assessments based upon economic, pest, and competitive
pressures.  Anticipated residues in meat, milk and eggs were calculated
by constructing theoretical nutritionally balanced diets and used in the
chronic risk assessments.  Empirically derived or DEEMTM (version 7.87)
default processing factors were input into the DEEM-FCID™ software. 
Drinking water estimates were included directly into the dietary
exposure assessment using the higher of the estimated drinking water
concentrations (EDWCs) for surface and ground water.

	i. Food. Acute Exposure. The acute assessment was performed for females
(13-49 years old) subpopulation, as this subpopulation was the only one
for which an acute endpoint was determined.  The acute dietary risk
assessment was performed with an acute reference dose (aRfD) of 0.50
mg/kg-bw/day based on a developmental toxicity study in rats with an
acute no observed adverse effect level (NOAEL) of 50 mg/kg/day and an
uncertainly factor of 100X to account for intra- and interspecies
variations.  No additional FQPA safety factor was applied.  For the
purpose of aggregate risk assessment, the exposure value was expressed
in terms of margin of exposure (MOE), which was calculated by dividing
the NOAEL by the exposure for the females (13-49 years old) subgroup. 
In addition, exposure was expressed as a percent of the acute reference
dose (% aRfD).  Acute food exposure to the females (13-49 years old)
subpopulation resulted in a MOE of 777 (12.9% of the aRfD of 0.5
mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and
since EPA generally has no concern for exposures above the benchmark or
below 100% of the aRfD, Syngenta believes that there is a reasonable
certainty that no harm will result from acute dietary (food) exposure to
residues arising from all current, pending and proposed uses of
fluazifop-P-butyl.

Chronic Exposure. The chronic assessment was run using DEEM-FCID™
software, average field trial residue values and %CT values.  The
chronic dietary risk assessment was performed for all population
subgroups with a chronic reference dose (cRfD)  of 0.0074 mg/kg-bw/day
based on a two-generation reproduction study in rats with a NOAEL of
0.74 mg/kg/day and an uncertainly factor of 100X to account for intra-
and interspecies variations.  No additional FQPA safety factor was
applied.  For the purpose of the aggregate risk assessment, the exposure
values were expressed in terms of MOE, which was calculated by dividing
the NOAEL by the exposure for each population subgroup.  In addition,
exposure was expressed as a percent of the chronic reference dose (%
cRfD).  Chronic food exposure to the U.S. population resulted in a MOE
of 1,154 (8.7% of the cRfD of 0.0074 mg/kg-bw/day).  Chronic food
exposure to children 1-2 years old, the most exposed population
subgroup, resulted in a MOE of 350 (28.6% of the cRfD of 0.0074
mg/kg-bw/day).  Since the Benchmark MOE for this assessment was 100 and
since EPA generally has no concern for exposures above the benchmark or
below 100% of the cRfD, Syngenta believes that there is a reasonable
certainty that no harm will result from chronic dietary (food) exposure
to residues arising from all current, pending and proposed uses of
fluazifop-P-butyl.

Cancer. Fluazifop-p-butyl has been classified as “not likely
carcinogen to humans”.  Therefore no dietary cancer assessment was
performed.

	ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs)
of fluazifop-P-butyl (evaluated as fluazifop-p-acid, the acid degradate
of fluazifop-P-butyl) were determined using Tier l model SCI-GROW which
estimates pesticide concentration in ground water and Tier II PRZM/EXAMS
which estimates pesticide concentration in surface water.  EDWCs of
fluazifop-p-acid from the currently registered uses as well as the
proposed IR-4 uses on caneberry, lettuce, blueberry, rhubarb, grasses
grown for seed, strawberry, sweet potato and green onions were
determined.  For ground water, SCI-GROW provided an EDWC of 0.255 ppb
(acute and chronic) based on the currently registered uses on tree
fruits (apricots, cherries, nectarines, peaches, plums, prunes), pecans,
non-bearing crops, ornamentals, bananas, citrus, and grapes.   For
surface water, PRZM/EXAMS provided an acute EDWC of 44.6 ppb based on
the currently registered use on citrus and a chronic EDWC of 6.58 ppb
based on the currently registered use on grapes.  No Percent Cropped
Area (PCA) adjustments were made to the surface water EDWCs.  The
surface water EDWCs were used for risk assessment purposes.   

Acute Exposure from Drinking Water.  The acute surface water EDWC of
44.6 ppb was input directly into the DEEM-FCID™ software as “water,
direct and indirect, all sources” to model the acute drinking water
exposures.  Exposure contributions at the 95.0%-ile of exposures were
determined by taking the difference between the aggregate (food +
drinking water) exposures and the food (alone) exposures.  Acute
drinking water exposure to the females (13-49 years old) subpopulation
resulted in a MOE of 62,500 (0.2% of the aRfD of 0.50 mg/kg-bw/day). 
Since the Benchmark MOE for this assessment was 100 and since EPA
generally has no concern for exposures below 100% of the aRfD, Syngenta
believes that there is a reasonable certainty that no harm will result
from acute drinking water exposure to residues arising from the current,
pending and proposed uses for fluazifop-P-butyl.

Chronic Exposure from Drinking Water: The chronic surface water EDWC of
6.58 ppb was input directly into the DEEM-FCID™ software as “water,
direct and indirect, all sources” to model the chronic drinking water
exposures.  Chronic drinking water exposure to the U.S. population
resulted in a MOE of 5,371 (1.9% of the cRfD of 0.0074 mg/kg-bw/day). 
Chronic drinking water exposure to the most exposed sub-population
(infants, <1 year old) resulted in a MOE of 2,083 (4.8% of the cRfD of
0.0074 mg/kg-bw/day).  Since the Benchmark MOE for this assessment was
100 and since EPA generally has no concern for exposures below 100% of
the cRfD, Syngenta believes that there is a reasonable certainty that no
harm will result from chronic drinking water exposure to residues
arising from the current, pending and proposed uses for
fluazifop-P-butyl.

	2. Non-dietary exposure. Fluazifop-P-butyl is a selective herbicide
used in the post-emergent control of grasses in agricultural,
ornamental, residential and recreational (golf course) settings.  A
residential exposure and risk assessment was performed for
Fluazifop-P-butyl uses on turf and ornamentals using the endpoints and
uncertainty factors established by the EPA.  The fluazifop-P-butyl
end-use products are formulated as both liquid concentrates and
ready-to-use (RTU) liquids.  Homeowners can apply the liquid
formulations using a low-pressure hand-wand (LPHW), hose-end sprayer,
backpack or watering can.  Homeowners can apply the RTU liquids using a
hose-end sprayer, trigger-pump sprayer, or watering can.  The homeowner
handler and residential post-application exposure and risks were
determined based on the highest use rates for all lawn and garden
products that contain fluazifop-P-butyl.  Based on the labels for the
various products containing fluazifop-P-butyl, there is a potential for
residential handler exposure from consumers making applications to home
lawns and ornamentals.  There is also a potential for post-application
residential exposure to adults and children re-entering treated lawns
and to adults and youths playing golf on treated turf.  A short-term
incidental oral NOAEL of 100 mg/kg/day, a short-term dermal NOAEL of 2
mg/kg/day and a short-term inhalation NOAEL of 2 mg/kg/day (all from a
developmental toxicity study in rats) were used in these residential
risk assessments.  Combined short-term MOEs were 231 for adult handlers
(backpack sprayer) and 128 for children 1-6 years old (post-application
risk); both are above the Benchmark MOE of 100 and do not exceed the
EPAs level of concern (LOC) of 100.

D. Cumulative Effects

Cumulative Exposure to Substances with a Common Mechanism of Toxicity. 
Section 408(b)(2)(D)(v) requires that, when considering whether to
establish, modify, or revoke a tolerance, the Agency consider
“available information” concerning the cumulative effects of a
particular pesticide’s residues and “other substances that have a
common mechanism of toxicity”.  The EPA does not have, at this time,
available data to determine whether fluazifop-P-butyl has a common
mechanism of toxicity with other substances or how to include this
pesticide in a cumulative risk assessment.  For the purposes of this
tolerance action, the EPA has not assumed that fluazifop-P-butyl has a
common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. Using the conservative assumptions described above,
and based on the completeness and reliability of the toxicity data,
current, pending and proposed uses of fluazifop-P-butyl resulted in an
acute aggregate MOE of 767 (13.0% of the aRfD of 0.5 mg/kg-bw/day) for
females 13-49 years old (the only population subgroup of concern).  A
short-term aggregate MOE of 128,370 (LOC = 100) and a chronic aggregate
MOE of 950 (10.6% of the cRfD of 0.0074 mg/kg-bw/day) was determined for
the U.S. population.  Since the aggregate MOEs exceed the Benchmark MOEs
of 100, Syngenta believes that there is a reasonable certainty that no
harm will result to the U.S. population from acute, short-term, or
chronic aggregate exposures arising from all current, pending and
proposed uses of fluazifop-P-butyl.

	2. Infants and children. Acute aggregate exposure calculations were not
performed for infants and children, since a relevant acute endpoint has
not been identified for these subgroups.  Using the conservative
assumptions described above, and based on the completeness and
reliability of the toxicity data, short-term aggregate MOE of 128 (LOC =
100) was determined for children 1-6 years old, and a chronic aggregate
MOE of 320 (31.3% of the cRfD of 0.0074 mg/kg-bw/day) was determined for
children 1-2 years old.  Since the aggregate MOEs exceed the Benchmark
MOE of 100, Syngenta believes that there is a reasonable certainty that
no harm will occur to infants or children from short-term and chronic
aggregate exposures arising from all current, pending and proposed uses
of fluazifop-P-butyl.

F. International Tolerances

There are currently no Maximum Residue Limits (MRLs) set for
fluazifop-P-butyl for crops by the Codex Alimentarius Commission however
international MRLs for fluazifop-P-butyl have been established for
various agricultural commodities.

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