Document ID: EPA-HQ-OPP-2014-0852-0002
Agency: epa
Document Type: Notice
Title: Notice of Filing for 3F8206, Request to establish a tolerance for residues of the herbicide safener [fluxofenim (CAS Reg. No. 88485-37-4)] in or on the raw agricultural commodity [grain sorghum, grain; grain sorghum, forage; and grain sorghum, fodder] at [0.01; 0.01; and 0.01] parts per million (ppm), respectively.
Posted Date: 2015-04-06T04:00Z

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

EPA Registration Division contact: [P.V. Shah, 703-308-1846]

INSTRUCTIONS:  Please utilize this outline in preparing the pesticide
petition.  In cases where the outline element does not apply, please
insert “NA-Remove” and maintain the outline. Please do not change
the margins, font, or format in your pesticide petition. Simply replace
the instructions that appear in green, i.e., “[insert company
name],” with the information specific to your action.

TEMPLATE:

[Syngenta Crop Protection, LLC]

[3F8206]

	EPA has received a pesticide petition (3F8206) from [Syngenta Crop
Protection, LLC], [P.O. Box 81300, Greensboro NC 27419] requesting,
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 the herbicide safener [fluxofenim (CAS Reg.
No. 88485-37-4)] in or on the raw agricultural commodity [grain sorghum,
grain; grain sorghum, forage; and grain sorghum, fodder] at [0.01; 0.01;
and 0.01] parts per million (ppm), respectively.  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. [Plant metabolism information is not included. 
There are no detectable residues even following applications with
exaggerated rates (5X).]

	2. Analytical method. [Analytical Method GRM063.01A provides a reliable
determination of CGA 133205 (fluxofenim) by LC-MS/MS in grain sorghum
raw agricultural commodities with a limit of quatification of 0.01 ppm.]

	3. Magnitude of residues. [A Magnitude of Residue Study conducted on
field grown grain sorghum is included in this submission indicating that
nominal and 5X product label rates resulted in no detectable fluxofenim
residues in grain sorghum grain, forage or fodder with a limit of
detection of 0.01 ppm.]

B. Toxicological Profile

	1. Acute toxicity.  [Fluxofenim technical: acute oral toxicity LD50 =
667mg/kg; acute dermal toxicity LD50 = 1544 mg/kg; acute inhalation
toxicity LD50 > 1.12 mg/l; acute eye irritation classification =
moderately/mildly irritating; acute dermal irritation classification =
slight irritant; not a dermal sensitizer.]

	2. Genotoxicty. [Fluxofenim is not mutagenic in the Ames test at
concentrations up to the cytotoxic and inhibitory limits of 500
ug/plate.  An in vitro study on the ability of fluxofenim to cause DNA
damage in isolated hepatocytes was negative, as was a sudy on the
potential of fluxofenim to cause chromosomal damage in a mouse
micronucleus test.]

	3. Reproductive and developmental toxicity. [In a dose range-finding
study in rat, fluxofenim was administered orally by gavage to 5 groups
of rats (10 females per group) once daily at doses of 5, 25, 50, 100 or
150 mg/kg on gestational days 6-15.  An additional group of rats (10
females) received vehicle (10 ml/kg/day) and served as controls. 
Maternal toxicity was observed at ≥ 25 mg/kg evidenced by body weight
losses at ≥ 50 mg/kg and reductions in body weight and feed
consumption at ≥ 25 mg/kg.  Reproductive findings included decreases
in the number of live fetuses, marked increases in the number of
resorptions and post-implantation losses at ≥ 100 mg/kg.  Slight to
moderate decreases in fetal weights were observed in the 50 and 100
mg/kg treated groups.  These reductions in fetal weights were considered
secondary to the compound induced maternal toxicity and were reflective
of a slight fetal developmental delay.  No treatment related effects
were noted at 5 mg/kg.  Based on these findings, the maternal NOEL was 5
mg/kg/day, while the fetal NOEL was 25 mg/kg/day.

In a rabbit dose range-finding study, fluxofenim was administered orally
to two groups (4 females per group) at daily doses of 300 or 700 mg/kg. 
Mortality rates of 100% were observed in both dosed groups by the third
day of dosing.  Death was preceded by decreased/no stool, lethargy and
anorexia in all compound-treated animals.  Due to early death of does,
embryotoxicity could not be evaluated in this exploratory study.

≥ 15 mg/kg and were limited to slight mean body weight loss at 30
mg/kg and decrease in daily food consumption at ≥ 15 mg/kg.  Fetal
pathology findings were limited to an increased incidence of a minor
skeletal variation (not ossified centrum/vertebrae) observed at 30
mg/kg.  This minor skeletal variation was considered to be associated
with compound-induced maternal toxicity.  Fluxofenim was well tolerated
by animals receiving 1 mg/kg.  Based on these findings, the maternal
NOEL was set at 1 mg/kg, while 15 mg/kg was determined to be the fetal
NOEL.]

	4. Subchronic toxicity. [In a dose range-finding study in the dog,
groups of 2 dogs of each sex were administered capsules to provide doses
of 5, 50, 100 and 150 mg/kg/day and 2 dogs of each sex were fed constant
dietary concentrations of 2500 ppm fluxofenim for 4 weeks.  Severe
toxicity, evidenced by emaciation, lack of appetite and emesis was
observed in the two top dose groups.  In addition, decreased body weight
gain was observed at ≥ 50 mg/kg/day.  Microscopic findings in the
liver (centrilobular necrosis), kidney (interstitial inflammation), and
hematopoietic system (hypoerythropoiesis in the sternal bone marrow)
were reported at doses of  ≥ 100 mg/kg/day.  No clinical toxicity or
histopathologic changes were observed at the lowest test dose.  The NOEL
for this study was 5 mg/kg/day.

In a 90 day dog study, groups of 4 dogs of each sex were administered
fluxofenim in capsules at doses of 0, 0.4, 4, 20 or 40 mg/kg/day. 
Administration of up to 40 mg/kg/day did not produce mortality or
significant changes in body weight, body weight gain, food consumption,
clinical observations or clinical chemistry parameters. 
Treatment-related effects were observed only in the top dose group and
included effects in organ weights in females (thyroid, liver and
kidney), and changes on hematological parameters in both sexes
(decreased mean corpuscular hemoglobin concentration and decreased red
blood cell count).  The NOEL for this study was 20 mg/kg/day.

In order to determine appropriate dietary concentrations of fluxofenim
for a subsequent sub-chronic toxicity study, a dose range-finding study
was conducted in the rat at feeding levels of 0, 100, 500, 1000, 2500,
and 5000 ppm for 4 weeks.  Treatment induced mortality at the highest
dose (5000 ppm).  Decreases in body weight and food consumption, and
increased incidence of clinical observations suggestive of general
toxicity were reported in all treated animals with the exception of the
lowest dose tested (100 ppm).  Based upon the body weight changes
observed at 500 and 1000 ppm, the recommended top dose for a subsequent
90 day sub-chronic study was set at 500 ppm.

In the 90 day oral study in rat, groups of 10 rats of each sex were fed
constant dietary concentrations of 0, 10, 30, 150 or 300 ppm fluxofenim
for 90 days.  No mortality or clinical signs of toxicity were observed,
and there were no necropsy or histopathology findings suggestive ofa
relationship to treatment with fluxofenim for any tissues or organs
examined.  Male body weights were decreased after week 9 of exposure and
absolute and relative (to body) kidney weights were increased in females
receiving 30 ppm and above.  Based on kidney weight changes, the
NOEL’s were 10 and 30 ppm for females and males, respectively.  

Mild skin irritation was noted in a 5-day dermal toxicity study at doses
as low as 1 mg/kg.  A 21 day dermal study was conducted with rabbit with
peanut oil as the vehicle followed by a 21 day dermal study in rabbit to
determine the effects of the peanut oil on the results.  The studies are
summarized in extracts from a Status Report dated October 12, 1990 from
EPA, Office of Toxic Substances, indicating that:

The submitter noted that the test compound “has been reported to cause
treatment-related kidney changes…” and that these “renal changes
[were] characterized by cytoplasmic vacuplation of cortical tubules,
tubular dilation, and the presence of tubular casts and/or tubular
basophilia… in male rabbits at dermal doses of 0.125, 125 and 400
mg/kg and in females in the mid- and high-dose groups…” 

Ciba-Geigy sent a letter to OTS November 19, 1990 indicating that a
repeat study was planned for the 21 day rabbit dermal study to try to
determin the influence of the suspension vehicle, peanut oil, on the
results of the study.  The repeat study was completed at doses of 0.05,
0.125, or 125 mg/kg/day.  The test substance was applied neat, and an
extra treatment was included with 0.125 mg/kg applied in a peanut oil
suspension.  Peanut oil alone and water alone were used as controls. 
The report summary includes:

Treatment-related effects were limited to dermal changes that were
observed in all CGA 133205 [fluxofenim] treated groups and the control
sites treated with peanut oil, and included: 1) slight to severe dermal
irritation (erythema, papules, thickened skin, atonia or flaking) in
both sexes; and 2) microscopic evidence of minimal to moderate
acanthosis with hperkeratosis and inflammation.  In general, the effects
of CGA 133205 applied as neat material were slight or mild in severity
at 0.05 and 0.125 mg/kg, but more severe at 125 mg/kg.  Moderate dermal
irritation was observed with CGA 133205 administered as a suspension in
peanut oil (0.125 mg/kg), but these changes were essentially
indistinguishable from that of the corresponding control. Since there
were no systemic effects seen at any dose in this study, the NOEL for
systemic changes was 125 mg/kg; however, a dermal NOEL was not achieved
for this study.]

	5. Chronic toxicity. [No chronic toxicity is provided.]

	6. Animal metabolism. [No animal metabolism data is provided.]

	7. Metabolite toxicology. [No metabolite data is provided.]

	8. Endocrine disruption. [Fluxofenim does not belong to a class of
chemicals known or suspected of having adverse effects on the endocrine
system.]

C. Aggregate Exposure

	1. Dietary exposure. [Tier I acute and chronic dietary exposure
assessments were performed for fluxofenim using the Dietary Exposure
Evaluation Model (DEEM-FCID™ Version 3.16) from Exponent and
consumption data from the USDA NHANES “What We Eat in America”
survey, 2003-2008.  These fluxofenim exposure assessments included the
sole current use for fluxofenim on grain sorghum.  These assessments
utilized estimated tolerances from field trial residue data where
fluxofenim was applied at the maximum intended seed dressing use rate;
samples were harvested at the minimum pre-harvest interval (PHI) to
obtain maximum residues.  All processing factors utilized DEEM-FCIDTM
Version 7.87 defaults.  The percent of crop treated value was assumed to
be 100%.  Secondary residues in livestock commodities were
conservatively estimated based on “maximum reasonably balanced
diets” and transfer information from a rat metabolism study.]

	i. Food. [Acute exposure.  The acute dietary (food only) risk
assessment for females 13-49 years old (the only population subgroup for
which an acute toxicological endpoint has been established) was
performed using an acute reference dose (aRfD) of 0.01 mg/kg-bw/day,
based upon a rat teratology study with a no observed adverse effect
level (NOAEL) of 1.0 mg/kg-bw/day and an uncertainty factor (UF) of 100X
for intra- and inter-species variations; no additional FQPA safety
factor was applied.  For the purpose of the 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 each
population subgroup.  In addition, exposure was expressed as a percent
of the acute reference dose (%aRfD).  Acute food exposure to the females
13-49 years subpopulation resulted in a MOE of 260,032 (0.1% of the aRfD
of 0.01 mg/kg-bw/day).  The Benchmark MOE for this assessment was 100. 

Chronic exposure.  The chronic dietary (food only) risk assessment was
performed using a chronic reference dose (RfD) of 0.01 mg/kg-bw/day,
based on a 3-month rat study with a NOAEL of 1.0 mg/kg-bw/day and an
uncertainty factor of 100X for intra- and inter-species variations; no
additional FQPA safety factor was applied.  For the purpose of the
aggregate risk assessment, the exposure values were expressed in terms
of margin of exposure (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 exposures to the U.S. population resulted in a MOE of 446,964 (0.1%
of the cRfD of 0.01 mg/kg-bw/day).  Chronic food exposures to the most
sensitive subpopulation (children 1-2 years old) resulted in a MOE of
74,547 (0.1% of the cRfD of 0.01 mg/kg-bw/day).  The Benchmark MOE for
this assessment was 100.]

	ii. Drinking water. [The Estimated Drinking Water Concentrations
(EDWCs) of fluxofenim were determined using Tier 1 model SCI-GROW which
estimates pesticide concentrations in ground water and Tier 1 model
FIRST which estimates pesticide concentrations in surface water. 
Fluxofenim used as a seed dressing on sorghum provided a ground water
EDWC of 0.0419 ppb (acute and chronic) and surface water EDWCs of 0.325
ppb and 0.150 ppb for acute and chronic, respectively.  Since the
surface water EDWCs exceed the ground water EDWC, the surface water
values were used for risk assessment purposes and will be considered
protective for any ground water exposure concerns.  

Acute Exposure from Drinking Water.  The acute surface water EDWC of
0.325 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 95th %-ile of exposures were
determined by taking the difference between the aggregate (food +
drinking water) exposures and food (alone) exposures for each population
subgroup.  Acute drinking water exposure at the 95th %-ile for females
(13-49 years), the only population subgroup for which an acute
toxicological endpoint has been established, resulted in a MOE of 62,500
(0.2% of the aRfD of 0.01 mg/kg-bw/day).  The Benchmark MOE for this
assessment was 100.

Chronic Exposure from Drinking Water.  The chronic surface water EDWC of
0.150 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 318,343 (0.1% of the cRfD of 0.01 mg/kg-bw/day). 
Chronic drinking water exposure to the most exposed sub-population
(infants <1 year old) resulted in a MOE of 123,477 (0.1% of the cRfD of
0.01 mg/kg-bw/day).  The Benchmark MOE for this assessment was 100.]

	2. Non-dietary exposure. [Fluxofenim is not registered for any use that
would result in residential handler (mixer/loader/applicator) or
post-application exposures, therefore no post-application residential
assessments were performed.]

D. Cumulative Effects

	[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”.  For the purposes of this tolerance
action, the EPA has not determined that fluxofenim has a common
mechanism of toxicity with other substances.]

E. Safety Determination

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An acute toxicological endpoint has not been established for the general
U.S. population, so an acute aggregate exposure assessment was not
performed for the U.S. population.  Acute aggregate exposures to females
13-49 years resulted in a MOE of 51,239 (0.2% of the aRfD of 0.01
mg/kg-bw/day).  The chronic aggregate exposure assessment showed that
exposures from the current sorghum use for fluxofenim resulted in a MOE
of 185,936 (0.1% of the cRfD of 0.01 mg/kg-bw/day) for the U.S.
population, which exceeds the Benchmark MOE of 100.]

	2. Infants and children. [An acute toxicological endpoint has not been
established for infants and children, so an acute aggregate exposure
assessment was not performed for infants and children.  The chronic
aggregate exposure assessment showed that exposures from the current
sorghum use for fluxofenim resulted in a MOE of 55,725 (0.1% of the cRfD
of 0.01 mg/kg-bw/day) for children 1-2 years old, which exceeds the
Benchmark MOE of 100.]

F. International Tolerances

	[The Codex Alimentarius Commission (CODEX) has not established Maximum
Residue Limits (MRLs) for fluxofenim in any agricultural commodity.]

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