Document ID: EPA-HQ-OPP-2011-0758-0011
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-07-25T04:00Z

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

<EPA Registration Division contact: Laura Nollen, (703) 305-7390

Interregional Research Project Number 4 (IR-4) 

Petition Number (PP#) 2E8020>

 

<	EPA has received a pesticide petition, PP# 2E8020, from IR-4, Rutgers,
The State University of New Jersey, 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 180.498 by establishing a tolerance for residues of
sulfentrazone
(N-[2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2
,4-triazol-1-yl]phenyl]-methanesulfonamide) and its metabolites
3-hydroxymethyl-sulfentrazone
(N-[2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-hydroxymethyl-5-oxo
-1H-1,2,4-triazol-1-yl]phenyl]methanesulfonamide) and 3-desmethyl
sulfentrazone
(N-[2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazo
l-1-yl]phenyl]methanesulfonamide) in or on the raw agricultural
commodity soybean, vegetable, succulent (Edamame) at 0.15 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 sulfentrazone in plants is
adequately understood for the existing and proposed tolerances. Crop
residues found after the pre-emergence and the pending proposed
post-emergence uses were similar in that the major metabolites were
3-hydroxymethyl sulfentrazone and 3-desmethyl sulfentrazone. In
rotational crops, sulfentrazone is metabolized via four different
pathways: (i) Oxidation of the 3-methyl group to form 3-hydroxymethyl
sulfentrazone, followed by further oxidation to form sulfentrazone
carboxylic acid which is decarboxylated to 3-desmethyl sulfentrazone;
(ii) hydrolysis of the trifluoromethyl group to form desdifluoromethyl
sulfentrazone which is oxidized and decarboxylated to form
desdifluoromethyl desmethyl sulfentrazone; (iii) hydrolysis of the
sulfonamide group to form desmethylsulfonyl sulfentrazone; and (iv)
scission of the phenyl and triazole rings to produce methyl triazole.
The corresponding phenyl metabolites are believed to remain bound. EPA
determined that tolerances based on the parent and 3-hydroxymethyl
sulfentrazone are therefore appropriate.>

<	2. Analytical method. There is a practical analytical method for
detecting and measuring levels of sulfentrazone and its metabolites in
or on food with a limit of quantitation that allows monitoring of food
with residues at or above the levels set or proposed in the
tolerances.  The analytical enforcement method for sulfentrazone was
used with minor modification that eliminated several clean-up and
derivatization steps that was required for GC/MSD but not for
LC/MS/MS.  The analytical method for sulfentrazone involves separate
analyses for parent and its metabolites.  The parent is analyzed by
evaporation and reconstitution of the sample prior to analysis by
LC/MS/MS GC/ECD.  The metabolites samples were refluxed in the presence
of acid and cleaned up with solid phase extraction prior to analysis by
LC/MS/MS.

>

<	3. Magnitude of residues. Sulfentrazone was applied to succulent pea
and succulent lima bean trials in the appropriate EPA regions.  The RACs
were harvested at the appropriate growth stages. The subsequent analyses
of the RACs determined that the residues of sulfentrazone and its
metabolites would not exceed the established tolerances. IR-4 is
requesting that the extrapolation of this data be used in support of the
proposed tolerance in vegetable soybean (edamame).>

<B. Toxicological Profile>

<	1. Acute toxicity.  A battery of acute toxicity studies placed
technical sulfentrazone in Toxicity Categories III and IV. No evidence
of sensitization was observed following dermal application in guinea
pigs. In an acute neurotoxicity study in rats at gavage doses of 0, 750,
or 2,000 mg/kg, a NOEL of 250 mg/kg and a LOEL of 750 mg/kg were based
upon increased incidences of clinical signs, Functional Observation
Battery (FOB) findings, and decreased motor activity which were reversed
by day 14 post-dose. There was no evidence of neuropathology.>

<	2. Genotoxicty. A reverse gene mutation assay (salmonella typhimurium)
yielded negative results, both with and without metabolic activation.  A
mouse lymphoma forward gene mutation assay yielded negative results with
equivocal results without activation.  A mouse micronucleus assay test
was negative following intraperitoneal injection of 340 mg/kg.>

<	3. Reproductive and developmental toxicity. A prenatal oral
developmental toxicity study in the rat with dose levels at 25.0 or 50.0
mg/kg/day established a maternal NOEL of 25 mg/kg/day based on decreased
body weight gain, increased spleen weight, and microscopic changes in
the spleen, and a fetal NOEL of 10 mg/kg/day was based on fetal death,
reduced body weights, and alterations in skeletal development at higher
doses.  A supplemental oral developmental toxicity study conducted in
rats at oral dose levels of 25.0 and 50.0 mg/kg/day to test for cardiac
effects at the request of the EPA, did not reveal any significant
effects on fetal cardiac development. The results of this study
confirmed the maternal and fetal findings of the previously conducted
developmental study on sulfentrazone in rats and did not alter the study
conclusions.

In a dermal developmental study in the rat at doses of 0, 5, 25, 50, 100
and 250 mg/kg/day, a maternal (systemic) No Observed Adverse Effect
Level (NOAEL) was established at 250 mg/kg/day. Significant
treatment-related increases in the fetal and litter incidences of
incompletely ossified lumbar vertebral arches, hypoplastic or wavy ribs,
and incompletely ossified or nonossified ischia or pubes occurred at the
high-dose (250 mg/kg/day). An additional significant increase in the
high-dose fetal incidence of variations in the sternebrae (incompletely
ossified or unossified) was not judged to be treatment-related. At 250
mg/kg/day, the mean numbers of thoracic vertebral and rib ossification
sites were significantly decreased, a high-dose effect of treatment with
sulfentrazone consistent with the significant treatment-related
hypoplasia observed in the skeletal evaluation of the ribs. Therefore,
the developmental (fetal) Lowest Observed Effect Level (LOEL) is 250
mg/kg/day based on decreased fetal body weight; increased incidences of
fetal variations: hypoplastic or wavy ribs, incompletely ossified lumbar
vertebral arches, and incompletely ossified ischia or pubes; and reduced
number of thoracic vertebral and rib ossification sites. The
developmental (fetal) NOEL is 100 mg/kg/day.

A developmental toxicity study in rabbits was conducted at gavage dose
levels of 0, 100, 250, or 375 mg/kg/day. Treatment-related incidences of
decreased feces and hematuria were noted at 250 mg/kg/day or greater. In
addition, at the 375 mg/kg/day dose level, five rabbits aborted.
Significant reductions in mean body weight change were observed for the
dosing period (GD 7- 19) and for the study duration (GD 0-29, both
before and after adjustment for gravid uterine weight) at the 250 and
375 mg/kg/day dose levels. Therefore, the maternal (systemic) LOEL is
250 mg/kg/day, based upon increased abortions, clinical signs (hematuria
and decreased feces), and reduced body weight gain. The maternal
(systemic) NOEL is 100 mg/kg/day. Skeletal evaluation in fetuses
revealed dose- and treatment-related findings at the 375 mg/kg/day dose
level. These included significant increases in both the fetal and litter
incidences of fused caudal vertebrae (a malformation) and of partially
fused nasal bones (a variation). In addition, at 375 mg/kg/day,
significant treatment-related reductions in ossification site averages
were observed for metacarpals and both fore- and hindpaw phalanges.
Therefore, the developmental (fetal) LOEL is 250 mg/kg/day, based upon
increased resorptions, decreased live fetuses per litter, and decreased
fetal weight. The developmental (fetal) NOEL is 100 mg/kg/day.

A two-generation reproduction study in the rat at dietary levels of 14,
33, or 46 mg/kg/day in males and 16, 40, or 56 mg/kg/day in females
established a NOEL for systemic and reproductive/developmental
parameters of 14 mg/kg/day for males and 16 mg/kg/day for females. The
LOEL for systemic and reproductive/development parameters was 33
mg/kg/day for males and 40 mg/kg/day for females. Systemic effects were
comprised of decreased body weight gains, while
reproductive/developmental effect at the LOEL included degeneration
and/or atrophy in the testes, with epididymal sperm deficits, in the
second (F1) generation males. Male fertility in the F1 generation was
reduced at higher doses; litter size, pup survival, and pup body weight
for both generations were also effected at higher doses.

A supplemental two-generation rat reproduction study was conducted at
dietary intake levels of 50, 100, 200, or 500 ppm with a NOEL for
reproductive parameters of 200 ppm. This study confirmed the
reproductive/developmental effects observed in the first two-generation
reproductive toxicity study. It was the conclusion of the RfD/Peer
Review Committee that, under the conditions of the studies reviewed,
sulfentrazone caused developmental and reproductive toxicity. The
results of these studies elicited a high level of concern by the
Committee, since the developmental toxicity studies demonstrated
embryo/fetal toxicity at treatment levels that were not maternally
toxic, and significant toxic effects were observed primarily in the
second generation animals of the reproduction study. Because these
animals had been exposed to sulfentrazone in utero, the possibility that
the observed reproductive toxicity resulted from a developmental and/or
genotoxic mechanism was suggested.>

<	4. Subchronic toxicity. A 90-day subchronic toxicity study was
conducted in rats, with dietary intake levels of 0, 3.3, 6.7, 19.9,
65.8, 199.3, or 534.9 mg/kg/day for males and 0, 4, 7.7, 23.1, 78.1,
230.5, or 404.3 milligrams/kilograms/day (mg/kg/day) for females
respectively. No Observed Effect Levels (NOELs) of 19.9 mg/kg/day in
males and 23.1 mg/kg/day in females were based on clinical anemia.  

A 90-day subchronic feeding study was conducted in mice by dietary admix
at doses of 0, 10.3, 17.8, 60.0, 108.4, or 194.4 mg/kg/day for males and
0, 13.9, 29.0, 79.8, 143.6, or 257.0 mg/kg/day for females,
respectively. NOELs of 60 mg/kg/day (males) and 79.8 mg/kg/day (females)
were based on decreases in body weights and/or gains; decreased
erythrocytes, hemoglobin and hematocrit values; and splenic microscopic
pathology.

In a 90-day subchronic feeding study in dogs administered by dietary
admix at doses of 0, 10, 28, or 57 mg/kg/day for males and 0, 10, 28, or
73 mg/kg/day for females, a NOEL of 28 mg/kg/day was determined for both
males and females based on decreases in hemoglobin and hematocrit,
elevated alkaline phosphatase levels, increased liver weights and
microscopic liver as well as splenic changes.

A 90-day subchronic neurotoxicity study in the rat was conducted at
dietary levels of 30, 150, or 265 mg/kg/day in males, and 37, 180, or
292 mg/kg/day in females, with a NOEL of 30 mg/kg/day in males and 37
mg/kg/day in females. The LOEL was 150 mg/kg/day for males and 180
mg/kg/day for females based on increased incidences of clinical signs,
decreased body weights, body weight gains, and food consumption in
females and increased motor activity in females at week 13. There were
no neurohistopathological effects on the peripheral or central nervous
system.>

<	5. Chronic toxicity. A 12-month feeding study in dogs was dosed at
levels of 0.0, 24.9, or 61.2 mg/kg/day for male dogs and 0.0, 10.4,
29.6, or 61.9 mg/kg/day for female dogs in the control through high-dose
groups, respectively, with a NOEL of 24.9 mg/kg/day for males and 29.6
mg/kg/day for females based on hematology effects and microscopic liver
changes.

An 18-month feeding/carcinogenicity study in mice was conducted with
dietary intake of 0, 46.6, 93.9, 160.5, or 337.6 mg/kg/day for males and
0, 58.0, 116.9, 198.0, or 407.1 mg/kg/day for females. A NOEL of 93.9
mg/kg/day in males and 116.9 mg/kg/day in females was based on decreases
in hemoglobin and hematocrit. There were no treatment-related increases
in tumors of any kind observed at any dose level.

In a 24-month chronic feeding/oncogenicity study in rats at dietary
doses of 0, 24.3, 40.0, 82.8, or 123.5 mg/kg/day for males and 20.0,
36.4, 67.0, or 124.7 mg/kg/day for females, an overall NOEL of mg/kg/day
in males and 36.4 mg/kg/day in females was based on hematology effects
and reduced body weights. There was no evidence of an oncogenic
response.>

<	6. Animal metabolism. A metabolism study in rats indicated that
approximately 84 to 104% of the orally administered dose of
sulfentrazone was excreted in the urine, and that the pooled urinary
radioactivity consisted almost entirely of 3-hydroxymethyl
sulfentrazone. Pooled fecal radioactivity showed that the major
metabolite consisted of 3-hydroxymethyl-sulfentrazone (1.26 to 2.55% of
the administered dose). The proposed metabolic pathway appeared to be
conversion of the parent compound mainly to
3-hydroxymethyl-sulfentrazone (excreted in urine and feces).>

<	7. Metabolite toxicology. NA - Remove.>

<	8. Endocrine disruption. An evaluation of the potential effects on the
endocrine systems of mammals has not been determined; however, no
evidence of such effects was reported in the chronic or reproductive
toxicology studies described above. There was no observed pathology of
the endocrine organs in these studies. There is no evidence at this time
that sulfentrazone causes endocrine effects.>

<C. Aggregate Exposure>

<	1. Dietary exposure. A short-term aggregate exposure assessment was
conducted to determine the total exposure to sulfentrazone residues from
both dietary and non-dietary routes.  Aggregate exposure to
sulfentrazone was evaluated for two separate products (crop herbicide
and residential lawn/turf herbicide).  Exposure from these two uses
occurred by multiple routes (dietary, dermal and incidental ingestion). 
Aggregation is conducted for dietary and non-dietary residential
exposures and it is to represent reasonable conditions of exposure. The
aggregate exposure estimates for all adults, adult females and toddlers
were less than 100% of the PAD.>

<	i. Food. The primary source for human exposure to sulfentrazone would
be from ingestion of both raw and processed agricultural commodities,
including all registered and pending crops.  In December 2010, the
Revised Acute and Chronic Aggregate Dietary (Food and Drinking Water)
Exposure and Risk Assessment for the Section 3 registration request to
add new uses on: Brassica, Head and Stem, Subgroup 5A; Brassica, Leafy
Greens, Subgroup 5B; Melon Subgroup 9A; Fruiting Vegetable, Group 8 and
Okra; Pea, Succulent; Flax; Strawberry; Tuberous and Corm Vegetable,
Subgroup 1C; and Miscellaneous Fruiting Vegetables was conducted by the
EPA Health Effects Division (PC Code 129081; DP Barcode D384090).  A
Tier 1 exposure analysis has been performed to estimate the exposure for
the U.S. general population as well as all adults, adult females, and
children (all ages) sub-populations for raw and processed commodities
that might be associated with sulfentrazone residue.  Field trial data
for registered and the pending minor crop uses, acceptable bridging
residue data, and consumption data from the USDA Continuing Surveys of
Food Intake by Individuals (CSFIIs) were inputs into the Dietary
Exposure Evaluation Model (DEEM) software - ver. 2.14.  No significant
additional dietary risk was identified for registered and pending minor
crops.>

<	ii. Drinking water. Based on the FIRST and SCI-GROW models the EECs of
sulfentrazone plus its major metabolite 3-carboxylic acid for acute
exposures are estimated to be 35.8 ppb for surface water and 26 ppb for
groundwater.  (Drinking Water Exposure Assessment for Section 3 New Use
Registration of Sulfentrazone on Head/Stem Brassica Subgroup 5A, Leafy
Greens Subgroup 5B, Melon Subgroup 9A, Fruiting Vegetable Group 8, Okra,
Succulent Pea, Strawberry and Tuberous/Corm Vegetables Subgroup 1C.  PC
Code No. 129081; DP Barcode: D349322; 8/28/2008).  The EECs for chronic
exposures are estimated to be 7.8 ppb for surface water and 26.0 ppb for
ground water>

<	2. Non-dietary exposure. The primary source for human non-dietary
exposure to sulfentrazone will be from post-application exposure to
treated residential turfgrass.   The routes of sulfentrazone exposure
were dermal post-application exposure for adults and toddlers, and
post-application incidental ingestion of sulfentrazone due to the
hand-to-mouth behavior of toddlers.  A worst case short-term non-dietary
exposure analysis was conducted using algorithms and default factors
published in US EPA’s Standard Operating Procedures (SOPs) for
Residential Exposure Assessments.  The dermal exposure estimates for all
adults, adult females and toddlers were 0.013, 0.016 and 0.023
mg/kg/day, respectively.  The exposure estimate for incidental ingestion
due to hand-to-mouth behavior for toddlers was 0.0026 mg/kg/day. The
resulting total (combined oral and dermal since the relevant endpoints
both have the same effect) non-dietary exposure estimates were 0.013,
0.016 and 0.025 mg/kg/day for all adults, adult females and toddlers,
respectively.>

<D. Cumulative Effects>

<	The Agency will reach a tolerance decision based on the best currently
available and useable information, without regard to common mechanism
issues. In the case of sulfentrazone, EPA has determined that it does
not currently have the capability to apply the information in its files
to a resolution of common mechanism issues in a manner that would be
useful in a risk assessment. This tolerance determination therefore does
not take into account common mechanism issues. The Agency will reexamine
the tolerances for sulfentrazone, if reexamination is appropriate, after
the Agency has determined how to apply common mechanism issues to its
pesticide risk assessments.>

<E. Safety Determination>

<	1. US Population. An aPAD of 0.14 mg/kg/day was used in the acute
dietary risk assessment for females (13-49 yrs) based on an oral NOAEL
of 14 mg/kg/day with a composite  UF of 100X (UFA = 10X; UFH = 10X and
FQPA SF =1X). This NOAEL was derived from a 2-generation reproductive
toxicity study in rats based on offspring toxicity (i.e., reduced
prenatal viability (fetal & litter), reduced litter size, increased
number of stillborn pups, reduced pup and litter postnatal survival and
decreased pup body weights throughout lactation) observed at the LOAELs
of 33 (males) and 40 mg/kg/day (females). 

An aPAD of 2.5 mg/kg/day was used in the acute dietary risk assessment
for general population including infants and children based on an oral
NOAEL of 14 mg/kg/day with a composite UF of 100X (UFA = 10X; UFH = 10X
and FQPA SF =1X). This NOAEL was derived from an acute neurotoxicity rat
study based on increased incidence of clinical signs and FOB parameters
and decreased motor activity observed at the LOAEL of 750 mg/kg/day. 

An cPAD of 0.1 mg/kg/day was used in the chronic dietary risk assessment
for all populations based on an oral NOAEL of 10 mg/kg/day with a
composite UF of 100 X (UFA = 10X; UFH = 10X and FQPA SF =1X). This NOAEL
was derived from a prenatal developmental toxicity study in the rat
based upon decreased mean fetal weights, and retardation in skeletal
development evidenced by an increased number of litters with any
variation and by decreased number of caudal vertebral and metacarpal
ossification sites observed at the developmental LOAEL of 25 mg/kg/day.

Acute dietary exposure estimates at the 95th percentile for the U.S.
general population and all population subgroups are less than 1% aPAD. 
A lower aPAD for females 13-49 years old (0.14 mg/kg/day) was considered
in the dietary assessment, compared to all other population subgroups
(2.5 mg/kg/day).  The population subgroup with the greatest risk was
females 13-49 year old, which utilized less than 3% of the aPAD for that
sub-group.  Resulting chronic risk estimates are below HED’s level of
concern.  The US General Population category utilized less than 2% of
the cPAD.

2. Infants and Children.

Acute dietary exposure estimates at the 95th percentile for all Infants
and Children subgroups are less than 1% aPAD.  For chronic exposure, the
most highly exposed population subgroup was Non-nursing Infants, which
utilizes less than 5% of the cPAD. Resulting acute and chronic risk
estimates are below HED’s level of concern.]>

<F. International Tolerances>

<	There are no Codex Alimentarius Commission (Codex) Maximum Residue
Levels (MRLs) for sulfentrazone.>

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