Document ID: EPA-HQ-OPP-2006-0789-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-10-20T04:00Z

<>

<EPA Registration Division contact: Jim Tompkins, Registration Division
(7505P), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW., Washington, DC 20460–0001; telephone
number:

(703) 305–5697; e-mail address: tompkins.jim@epa.gov. >

 

<Arysta LifeScience North America Corporation>

<PP 6F7112>

	EPA has received a pesticide petition (PP 6F7112) from Arysta
LifeScience North America Corporation, 15401 Weston Parkway, Suite 150,
Cary, NC 27513 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 

<	flucarbazone sodium:
4,5-dihydro-3-methoxy-4-methyl-5-oxo-N-[[2-(trifluoromethoxy)phenyl]sulf
onyl]-1H-1,2,4-triazole 1-carboxamide, sodium salt; and its N-desmethyl
metabolite in or on the raw agricultural commodities (RACs):

Commodity	Parts per million

Wheat, forage	0.30

Wheat, grain	0.01

Wheat, hay	0.10

Wheat, straw	0.05

and combined residues of flucarbazone-sodium and its metabolites
converted to 2-(trifluoromethoxy)benzene sulfonamide and calculated as
flucarbazone-sodium in or on the raw agricultural commodities:

Commodity	Parts per million

Milk	0.005

Meat and meat byproducts except liver

(cattle, goats, sheep, horses, hogs)	0.01

Liver (cattle, goats, sheep, horses, hogs)	1.50

EPA has determined that the petition contains data or information
regarding the elements set forth in section 408 (d)(2) of the 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 flucarbazone-sodium in wheat
was rapid and extensive. Little or no parent flucarbazone-sodium was
found in the RACs. A primary metabolic pathway in wheat involved the
N-demethylation of flucarbazone-sodium to give N-desmethyl
flucarbazone-sodium. N-desmethyl flucarbazone-sodium was found in all of
the wheat RACs. The N-desmethyl flucarbazone-sodium was then either
hydrolyzed or conjugated with glucose. Another primary metabolic pathway
was hydrolysis of flucarbazone-sodium yielding sulfonic acid and
sulfonamide which were isolated, and N,O-dimethyl triazolinone which was
not isolated. Other metabolites were then subsequently formed by
oxidative reactions, hydrolytic reactions, and conjugation.>

<	2. Analytical method. --i. Plants. The proposed tolerance expression
is parent flucarbazone-sodium and N-desmethyl flucarbazone-sodium. An
analytical method was developed to measure these two analytes in plant
matrices. This method was validated in wheat tissues. The
flucarbazone-sodium and N-desmethyl flucarbazone-sodium residues are
extracted from the wheat samples with 0.05 M NH4OH by accelerated
solvent extraction (ASE). The extracts are purified by a combination of
C-18 solid phase extraction (SPE) and ethylene diamine-N-propyl (PSA)
SPE. The resultant analytes are detected by liquid chromatography/tandem
mass spectroscopy (lc/ms/ms) and quantified against known amounts of
deuterated internal standards. The method limit of quantitation (LOQ) is
0.01 milligram/kilogram (mg/kg) of either analyte in all wheat matrices.
The method limit of detection (LOD) is 0.005 mg/kg of either analyte in
all wheat matrices.

     ii. Animals. An analytical method was developed to measure the
residues of flucarbazone-sodium in animal tissues and milk. Since the
flucarbazone-sodium-related residues were present in ruminant tissues as
a mixture of bound, conjugated, and unconjugated residues, a method was
developed that simultaneously extracted and hydrolyzed the majority of
the flucarbazone-sodium-related residues to flucarbazone-sodium
sulfonamide. The flucarbazone-sodium residues are simultaneously
hydrolyzed to flucarbazone-sodium sulfonamide and extracted from the
animal tissues and milk by heating with 8% trifluoroacetic acid (TFA) in
water. The analysis of fat was complicated by the large quantities of
lipids that were released during hydrolysis and extraction. Therefore,
the flucarbazone-sodium residues are extracted into acetonitrile/water
(9:1) before they are hydrolyzed to flucarbazone-sodium sulfonamide.
After conversion to flucarbazone-sodium sulfonamide, the residues are
purified and partitioned. The residues are detected by lc/ms/ms and
quantified against known amounts of deuterated internal standards. The
LOQ in the tissues and milk is 0.020 and 0.005 mg/kg, respectively. The
estimated LOD (3x highest background response) in the liver, muscle, and
milk is 0.014, 0.002 and 0.004 mg/kg, respectively. The recoveries of
flucarbazone-sodium were determined in all tissues and milk after
fortification with flucarbazone-sodium. The average recoveries of
flucarbazone-sodium from liver fortified at 0.020 and 0.100 mg/kg were
104 and 100%, respectively. The average recoveries of
flucarbazone-sodium from muscle fortified at 0.020 and 0.100 mg/kg were
97 and 102%, respectively. In milk, the average recoveries of
flucarbazone-sodium at fortifications of 0.005, 0.010, and 0.050 mg/kg
were 111 (after correction for background in the control samples, the
average recovery was 92%), 97 and 91%, respectively. An independent
laboratory validation of the analytical method was performed. The method
was successfully validated indicating that the method could be
satisfactorily run by following the written procedure.>

<	3. Magnitude of residues. Field trials were conducted with wheat at 36
locations to evaluate the quantity of flucarbazone-sodium residues in
wheat forage, hay, straw, and grain following treatment with
flucarbazone-sodium 70WG at a rate of 30 grams active
ingredient/hectacre (g a.i./ha). The highest average field trial (HAFT)
residue detected in forage, hay, and straw were 0.27, 0.08, and 0.04
mg/kg, respectively. Residues of flucarbazone-sodium were <0.01 mg/kg in
wheat grain.>

<B. Toxicological Profile>

<	1. Acute toxicity.  --i. Flucarbazone-sodium is not toxic to fasted
rats following a single oral administration. The oral lethal dose (LD50)
is >5,000 mg/kg body weight (bwt) for males and females.

    ii. Flucarbazone-sodium is not toxic to rats following a single
dermal application. The dermal LD50 is >5,000 mg/kg bwt for males and
females.

    iii. An acute inhalation study with rats showed low toxicity with a
4-hour dust aerosol lethal concentration (LC50) >5,130 mg/m3 air for
males and females.

    iv. An eye irritation study in rabbits showed only very slight,
reversible irritation.

    v. A dermal irritation study in rabbits showed flucarbazone-sodium
is not irritating to skin.

    vi. Flucarbazone-sodium has no skin sensitizing potential under the
conditions of the maximization test in guinea pigs.>

<	2. Genotoxicty.  The genotoxic action of flucarbazone-sodium was
studied in bacteria and mammalian cells with the aid of various in vitro
test systems (Salmonella microsome test, hypoxanthine guanine
phophoribosyl transferase (HGPRT) test with Chinese hamster V79 cells,
cytogenetic study with Chinese hamster V79 cells and unscheduled DNA
synthesis test) and in one in vivo test (micronucleus test). None of the
tests revealed any evidence of a mutagenic or genotoxic potential of
flucarbazone-sodium. The compound did not induce point mutation, DNA
damage, or chromosome aberration.>

<	3. Reproductive and developmental toxicity. In a 2-generation
reproduction study, Wistar rats were administered dietary levels of
flucarbazone-sodium at levels of 0, 50, 4,000, and 20,000/12,000 ppm
(dose reduction week 6). The no observed adverse effect levels (NOAELs)
for reproductive parameters was established at 4,000 ppm, based on
slight reduction in pup weight development at 12,000 ppm. The NOAELs
established for parental males and females were 4,000 and 50 ppm,
respectively.

    i. A developmental toxicity study was conducted with Sprague-Dawley
rats via oral gavage of flucarbazone-sodium at levels of 0, 100, 300,
and 1,000 mg/kg bwt/day on days 6 through 19 of gestation. There were no
signs of maternal toxicity, embryotoxicity, fetotoxicity, or
teratogenicity at the level of 1,000 mg/kg bwt/day. Therefore, the
maternal and developmental NOAELs for rats were established at >1,000
mg/kg bwt/day, the limit dose for this study type.

    ii. Himalayan rabbits were administered flucarbazone-sodium at
levels of 0, 100, 300, 500, or 1,000 mg/kg bwt by oral gavage days 6
through 28 post coitum in a test for developmental toxicity. A maternal
NOAEL of 100 mg/kg bwt/day was established based on clinical findings,
bwt loss, decreased feed consumption, gastrointestinal changes,
increased liver weights and fatty liver changes at 300 mg/kg bwt/day.
The gestation rate NOAEL of 100 mg/kg bwt/day was based on one abortion
(assessed as secondary due to maternal toxicity) at 300 mg/kg bwt/day.
The NOAEL for fetal parameters of 300 mg/kg bwt/day was based on
decreased fetal weights and delayed ossification at 500 mg/kg bwt/day.
No teratogenic potential of flucarbazone-sodium was evident in rabbits.>

<	4. Subchronic toxicity. --i. A 28-day dermal rabbit study established
a systemic NOAEL of ≥1,000 mg/kg bwt/day (the dermal limit dose) for
males and females. The local dermal effects, skin thickening, seen at
1,000 mg/kg were regarded as a result of mechanical friction and of no
toxicological relevance.

    ii. A 90-day rat feeding study defined a NOAEL at 250 ppm (17.6
mg/kg bwt/day) for males and 1,000 ppm (101.7 mg/kg bwt/day) for females
based on a decreased spleen weight in males at 1,000 ppm and on
immunologic changes at 4,000 ppm in females.

    iii. A 90-day feeding study with male and female B6C3F1 mice
established a NOAEL of 7,000 ppm (equivalent to >2,083, and 3,051 mg/kg
bwt/day for males and females, respectively). The dose of 7,000 ppm was
the highest dose tested (HDT).

    iv. A 90-day dog feeding study at levels of 0, 1,000, 5,000, and
50,000 ppm established a NOAEL of 1,000 ppm (equivalent to 33.8 mg/kg
bwt/day in males and 35.2 mg/kg bwt/day in females) based on decreased
thyroxine levels and increased thyroxine-binding capacity, macroscopic
and microscopic effects on the gastric mucosa and an eosinophilic
hepatocellular cytoplasm occurring at 5,000 ppm and above. The liver
enzyme induction at 1,000 ppm was assessed as a slight adaptive response
in the detoxification process of flucarbazone-sodium but not as an
adverse effect, due to the absence of clinical chemical changes that
would indicate liver damage and due to the absence of any
histopathologic liver changes at this dietary level.

    v. A 28-day (6 hours/day; 5 days/week) subacute inhalation toxicity
study was conducted with male and female Wistar rats exposed to mean
actual concentrations of 5.2, 30.0, 180.1 and 513.3 mg/m3 air. A NOAEL
of 5.2 mg/m3 air was established based on histopathological changes
observed at 30 mg/m3 air and above.>

<	5. Chronic toxicity. --i. A 2-year chronic toxicity/oncogenicity study
was conducted with male and female Wistar rats at dietary levels of 0,
2.5, 7.5, 125, and 1,000 mg/kg bwt. A NOAEL of 125 mg/kg was established
based on increased food consumption (both sexes) and lower bwts
(females) at 1,000 mg/kg. No carcinogenic potential was indicated.

    ii. B6C3F1 mice were administered flucarbazone-sodium via the diet
at levels of 0, 50, 1,000, and 7,000 ppm in a 2-year carcinogenicity
study. The NOAEL was established in males and females at 1,000 ppm
(equivalent to 275 and 459 mg/kg bwt/day, respectively) based on reduced
bwt gain in both sexes and on increased feed consumption in males at the
7,000 ppm level. No carcinogenic potential was indicated.

    iii. A 1-year feeding study in dogs at levels of 0, 200, 1,000, and
5,000 ppm established a NOAEL of 1,000 ppm for males (equal to 35.9
mg/kg bwt/day) based on decreased bwt development, increased ALAT- and
ASAT-levels and slightly increased N-demethylase levels. The NOAEL of
1,000 ppm for females (equal to 37.1 mg/kg bwt/day) was based on body
weight gain depression, increased N-demethylase levels, decreased T4
levels and marginally increased liver weight.>

<	6. Animal metabolism. Flucarbazone-sodium was metabolized via two
pathways. The major pathway involved the hydrolysis of the urea linkage
forming sulfonamide and N,O-dimethyltriazolinone. The sulfonamide was
shown to be the major metabolite in the blood, fat, liver, and muscle at
4 to 6 hours following oral administration of [phenyl-UL-14C]
flucarbazone-sodium. The sulfonamide was conjugated with glucuronic acid
or acetate [sulfonamide N-glucuronide or N-acetyl sulfonamide] or
hydroxylated and then conjugated with glucuronic acid to form
hydroxysulfonamide-O-glucuronide prior to elimination in the urine. A
minor pathway involved N-demethylation of flucarbazone-sodium to form
N-desmethyl flucarbazone-sodium followed by hydrolysis to form the
sulfonamide and O-methyltriazolinone. Demethylation of
N,O-dimethyltriazolinone led to the formation of N-methyltriazolinone,
O-methyltriazolinone, and ultimately, urazole; methyl urethane was
probably formed from the cleavage of O-methyltriazolinone.>

<	7. Metabolite toxicology. --i. The animal and plant metabolite
flucarbazone-sodium sulfonamide (trifluoromethoxysulfonamide) has a low
acute oral toxicity (LD50 >2,000 mg/kg bwt) in fasted rats.

    ii. The plant metabolite flucarbazone-sodium sulfonamide lactate
conjugate has no acute oral toxicity (NOAEL: 5,000 mg/kg bwt) in fasted
rats.

    iii. The plant metabolite flucarbazone-sodium sulfonamide alanine
has no acute oral toxicity (NOAEL: 5,000 mg/kg bwt) in fasted rats.

    iv. The soil metabolite O-desmethyl flucarbazone-sodium has an acute
oral LD50 value in fasted male and female rats of >2,500 - <5,000 mg/kg
bwt.

    v. The plant, animal, and soil metabolite, MKH 10868
(flucarbazone-sodium sulfonic acid Na-salt), has no acute oral toxicity
(LD50 >5,000 mg/kg bwt) in fasted male and female rats.

    vi. MKH 10868 was considered non-mutagenic with and without S9 mix
in the plate incorporation as well as in the preincubation modification
of the Salmonella/microsome test.>

<	8. Endocrine disruption. There is no evidence to suggest that
flucarbazone-sodium has an effect on the endocrine system. Studies in
this data base include evaluation of the potential effects on
reproduction and development, and an evaluation of the pathology of the
endocrine organs following short- and long-term exposure. These studies
revealed no endocrine effects due to flucarbazone-sodium.>

<	9. Other Studies. --i. An acute neurotoxicity screening study in rats
established an overall NOAEL for males and females of 500 mg/kg based on
transient neurobehavioral effects. Evidence of toxicity was only slight
at a limit dose of 2,000 mg/kg and complete recovery occurred within 7
days following treatment.

    ii. A subchronic neurotoxicity screening study in rats established
an overall NOAEL of 2,000 ppm for males (equal to 147 mg/kg bwt/day) and
20,000 ppm (equal to 1,736 mg/kg bwt/day) for females based on a slight
decrease in bwt and food consumption. The NOAEL for microscopic lesions
was 20,000 ppm for males and females, the HDT. There was no evidence of
neurotoxicity at any dietary level.

    iii. A plaque-forming-cell assay (to investigate immunotoxicological
potential) was performed on rats after a 4-week dietary exposure. The
NOAEL of 20,000 ppm (equivalent to 2,205, and 2,556 mg/kg bwt/day in
males and females, respectively) was based on the lack of specific
effects in the HDT.

    iv. The immunotoxicity potential of flucarbazone-sodium was
additionally investigated in antibody plaque-cell forming assays and in
assays examining splenic T-cells, B-cells, and NK-cells after 4-week
dietary administrations in male and female rats at levels up to and
including 1,000 mg/kg bwt/day. There was no statistically significant
effect on the humoral immune system and no effects on splenic cell
populations, cell-mediated immune response or the innate immune response
in males or females. The NOAEL for immunotoxicity from these studies was
1,000 mg/kg bwt/day, the immunotoxicity limit dose.>

<C. Aggregate Exposure>

<	1. Dietary exposure. >

<	i. Food. Estimates of chronic dietary exposure to residues of
flucarbazone-sodium utilized the proposed tolerance-level residues for
wheat forage, wheat hay, wheat straw, wheat grain, meat, liver, and milk
of 0.30, 0.10, 0.05, 0.01, 0.01, 1.50, and 0.005 ppm, respectively.
Other assumptions were that 100% of the target crop would be treated
with flucarbazone-sodium and that no loss of residue would occur due to
processing and or cooking. A chronic reference dose (RfD) of 0.36
mg/kg/day was assumed based on the NOAEL of 35.9 mg/kg/day from the one
year dog feeding study. A safety factor of 100 was used based on
interspecies extrapolation (10x) and intraspecies variability (10x).
Using these conservative assumptions, dietary residues of
flucarbazone-sodium contribute 0.006659 mg/kg/day (2% of the RfD) for
children 1-6 years, the most sensitive sub-population. For the U.S.
population, the exposure was 0.002891 mg/kg/day (1% of the RfD). For
acute dietary exposure, the same conservative assumptions were made.
Based on the NOAEL of 300 mg/kg/day from the rabbit developmental
toxicity study, an acute RfD of 3.0 mg/kg/day was used to calculate the
acute dietary risk to the most exposed subgroup: females, 13 to 50 years
old. The acute dietary exposure from food to flucarbazone-sodium will
occupy <1% of the RfD for females, 13 to 50 years old.>

<	ii. Drinking Water. Given the post-emergence application pattern, low
use rates and rapid soil degradation of flucarbazone-sodium, the risk of
ground and surface water contamination and exposure via drinking water
is negligible. The surface water model generic expected environment
concentration (GENEEC) and the ground water model SCI-GROW were used to
determine whether drinking water from surface or ground water sources
represented a worst-case exposure scenario. These models predict
residues of flucarbazone-sodium would be higher in surface water.
Assuming a worst-case GENEEC scenario where residues of
flucarbazone-sodium occur in surface water used for drinking water at
the highest predicted acute and chronic concentrations, the risk from
exposure to residues of flucarbazone-sodium are well within EPA's
acceptable limits.

    The GENEEC model predicted an acute surface water concentration of
flucarbazone-sodium of 1.45 μg/L. Assuming a 70 kilogram (kg) adult
drinks 2 liters/day containing 1.45 μg/L, the acute exposure would be
0.0000414 mg/kg/day for adults. Assuming a 10 kg child drinks 1
liter/day containing 1.45 μg/L, the exposure would be 0.000145
mg/kg/day. Based on the NOAEL of 300 mg/kg/day from the rabbit
developmental toxicity study and assuming a safety of 100 (10x for
interaspecies variability and 10x for interspecies extrapolation), the
MOE for adults of 72,500 and for children of 20,700 do not exceed EPA's
level of concern for adults or children. This assessment is based on the
GENEEC highest predicted acute concentration of flucarbazone-sodium in
drinking water using worst-case assumptions.

    Using GENEEC, the highest predicted chronic (60-day exposure)
concentration of flucarbazone-sodium was 1.44 μg/L. EPA interim policy
recommends that the 60-day GENEEC value to be divided by an adjustment
factor of 3 to obtain a value for chronic risk assessment calculations.
Therefore, a surface water value of 0.48 μg/L was used for chronic risk
assessment.  Assuming a 70 kg adult consumes 2 L of water per day
containing 0.48 μg/L of flucarbazone-sodium residues for a period of 70
years, less than 0.004% of the RfD was consumed from residues of
flucarbazone-sodium in surface water used for drinking water (worst-case
scenario). For a 10 kg child drinking 1 L of water per day containing
0.48 μg/L of flucarbazone-sodium residues, only 0.01% of the RfD was
consumed by drinking water.>

<	2. Non-dietary exposure. There are no current non-food uses for
flucarbazone-sodium registered under the Federal Insecticide, Fungicide,
and Rodenticide Act (FIFRA), as amended. No non-food uses are proposed
for flucarbazone-sodium. No non-dietary exposures are expected for the
general population.>

<D. Cumulative Effects>

<	Flucarbazone-sodium falls into the category of sulfonamide herbicides.
There is no information to suggest that any of this class of herbicides
has a common mechanism of mammalian toxicity or even produce similar
effects so it is not appropriate to combine exposures of
flucarbazone-sodium with other herbicides. Arysta LifeScience North
America Corporation is considering only the potential risk of
flucarbazone-sodium.>

<E. Safety Determination>

<	1. U.S. population. As presented previously, the exposure of the U.S.
general population to flucarbazone-sodium is low, and the risks, based
on comparisons to the reference dose, are minimal. The margins of safety
from the use of flucarbazone-sodium are well within EPA's acceptable
limits. Arysta LifeScience North America Corporation concludes that
there is a reasonable certainty that no harm will result to the U.S.
population from aggregate exposure to flucarbazone-sodium residues.>

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摧所/Ѐ1摧季fऀy and 2-generation reproduction studies were
considered in assessing the potential for additional sensitivity of
infants and children to residues of flucarbazone-sodium. The
developmental toxicity studies in rats and rabbits revealed no increased
sensitivity of rats or rabbits to in-utero exposure to
flucarbazone-sodium. The 2-generation reproduction study did not reveal
any increased sensitivity of rats to in-utero or postnatal exposure to
flucarbazone-sodium. Furthermore, none of the other toxicology studies
revealed any data demonstrating that young animals were more sensitive
to flucarbazone-sodium than adult animals. The data taken collectively
clearly demonstrate that application of a Food Quality Protection Act
(FQPA) uncertainty factor for increased sensitivity of infants and
children is not necessary for flucarbazone-sodium.>

<F. International Tolerances>

<	A default Maximum Residue Limit (MRL) of 0.01 ppm has been established
in Canada for residues of flucarbazone-sodium and its N-desmethyl
metabolite on wheat grain. This value is consistent with the tolerance
being proposed in the United States on wheat grain. There are no
harmonized MRLs at the European Union level and no Codex MRLs for this
compound on wheat at present. Therefore, no compatibility issues exist
with Codex in regard to the proposed U.S. tolerances.>