Document ID: EPA-HQ-OPP-2014-0879-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2015-03-06T05:00Z

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EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE
PETITION 

EPA Registration Division contact: Sidney Jackson, (703) 305-7610

Docket I.D. Number: EPA-HQ-OPP-2014-0879

Interregional Research Project Number 4 (IR-4)

Pesticide Petition Number: PP# 4E8330

EPA has received a pesticide petition (PP# 4E8330) from Interregional
Research Project No. 4 (IR-4), 500 College Road East, Suite 201 W,
Princeton, NJ 08540  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, penoxsulam (2-(2,2-difluoroethoxy)-N-(5,8-dimethoxy[1,2,4]
triazolo[1,5-c]pyrimidin-2-yl)-6-(trifluoromethyl)benzenesulfonamide)
in/on the following raw agricultural commodities: Fruit, Pome, group
11-10 at 0.01 parts per million (ppm), Fruit, Stone, group 12-12 at 0.01
ppm, Fruit, Small, Vine Climbing, subgroup 13-07F, except Fuzzy
Kiwifruit at 0.01 ppm, Nut, Tree, group 14-12 at 0.01 ppm, Olive at 0.01
ppm, and Pomegranate at 0.01 ppm.  In addition, the petitioner proposes
based upon the establishment of the new tolerances above, removal of
existing tolerances at 40 CFR 180.605 for Grape at 0.01 ppm, Nut, tree,
group 14 at 0.01 ppm and Pistachio at 0.01 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 support granting of the petition.  Additional data may be
needed before EPA rules on the petition.

A. Residue Chemistry

	1. Plant metabolism. Based on results of the metabolism studies in
plants that are summarized below, it is concluded that the residue
definition in plants is the parent compound alone, penoxsulam.  

A nature of residue study (NOR) was conducted in grapes using a soil
application of penoxsulam.  Penoxsulam, 14C-labeled either in the
2-position on the triazolopyrimidine ring (TP) or uniformly labeled in
the phenyl-ring (Ph), was applied as a broadcast spray onto soil around
established grape vines at a single application rate of approximately 20
g a.i./ha.  The soil in this study was a sandy clay loam.  Application
was made when grapes vines were at growth stage BBCH 55 (early
flowering).  After application, the plots were irrigated with 1 cm of
water daily for 7 days.  Grapes and leaves were harvested at 118 days
after application. 

Mature grapes contained residues below the limit of quantification
(0.0008 µg/g penoxsulam equivalents).  The PH-label and TP-label leaves
collected at maturity contained 0.016 µg/g and 0.013 µg/g penoxsulam
equivalents, respectively.  In the mature leaves, approximately 65% of
the leaf TRR was extractable with neutral solvent, of which
approximately half partitioned into organic solvent.  The majority of
the organic phase was identified as numerous low-level metabolites,
while the aqueous phase consisted of primarily polar, solvent-front
residues.  The residue was characterized as low-level degradates,
tentatively including the 5-hydroxy-penoxsulam and the
dihydroxy-penoxsulam metabolites.

In summary, very low levels of soil-applied penoxsulam and degradates
are taken up by the vine.  No penoxsulam was detected in the leaves, and
due to the low TRR levels in the grapes, no penoxsulam is predicted
there either.  The residue was characterized as low-level degradates,
tentatively including the 5-hydroxy-penoxsulam and the
dihydroxy-penoxsulam metabolites.

Metabolism studies in livestock animals with 14C-labeled penoxsulam
(2-position on the triazolopyrimidine ring or uniformly labeled in the
phenyl ring) at a concentration equivalent to about 10 ppm in the diet
indicated that approximately 99% of the administered dose was eliminated
in the excreta.  The low levels of residues (0.002-0.07 ppm) in fat and
edible tissues, milk or eggs demonstrate that residues due to penoxsulam
would not accumulate in the animals.  Additionally, the dose levels in
these studies are about 200 to 1000 times higher than the theoretical
maximum exposure in the animal diet of rice commodities treated with
penoxsulam, therefore, livestock feeding studies are not considered
necessary.

	2. Analytical method. [In the Magnitude of Residue (MOR) studies
conducted in Pome Fruit and Stone Fruit to support tolerances proposed
in this petition, residues of penoxsulam were determined using the
analytical method GRM 04.09.  Residues of penoxsulam were extracted from
the crop samples by homogenizing and shaking with an acetonitrile/water
solution (80:20 v/v).  An aliquot was diluted with 0.1N HCl and purified
using a 96-well polymeric-reverse phase extraction (SPE) plate.  The SPE
plate was washed with a 40/60 methanol/water solution and eluted with
acetonitrile into a 96-well plate containing an
acetonitrile/methanol/water mobile phase (15:15:70 containing 0.1%
acetic acid) and a stable isotope internal standard.  The final solution
was analyzed by liquid chromatography with positive-ion electrospray
tandem mass spectrometry (LC/MS/MS).  The limit of detection (LOD) and
limit of quantitation (LOQ) are 0.003 µg/g and 0.010 µg/g,
respectively.

	3. Magnitude of residues. The proposed tolerances (Section F) are
supported by MOR studies in grapes, almonds and pecans conducted in the
U.S.  Trials were conducted in almonds and pecans to support a tolerance
for the nut tree crop group (Nuts, tree, group 14) including pistachios,
and almond hulls.  Additionally, trials were conducted in grapes to
support a tolerance for grapes.

B. Toxicological Profile

	1. Acute toxicity.  The acute toxicity of penoxsulam is considered low.
 The acute oral and dermal lethal dose (LD)50s were greater than 5000
milligram per kilogram (mg/kg), while the acute inhalation lethal
concentration (LC)50 was greater than the highest attainable aerosol
concentration (3.50 mg/L).  Only very slight, transient dermal
irritation was seen, and mild eye irritation was noted. Penoxsulam was
negative for skin sensitization in a Magnussen and Kligman maximization
test involving intradermal injection of penoxsulam with an adjuvant.

	2. Genotoxicty. Penoxsulam was negative for genotoxicity when tested in
in vitro and in vivo systems.

	3. Reproductive and developmental toxicity. Penoxsulam did not have any
effect on reproductive parameters at dose levels that induced
treatment-related effects in parental rats.  At the highest dosage
tested (300 mg/kg/day), body weights and weight gains in both males and
females were depressed, liver and/or kidney weights were increased, and
histologic changes were noted in the liver (males) and kidneys
(females).  At 100 mg/kg/day, increased liver weights were recorded in
males, with no histologic correlate, and histologic changes noted in the
kidneys of females.  Transient decreases in pup body weights were seen
at the highest dosage tested, but dietary concentrations were targeted
for adults and consumption of treated diets by the pups resulted in dose
levels to the pups approximately 3-fold higher than in adults.  A
teratogenic potential was not demonstrated for penoxsulam in either rats
or rabbits.

	4. Subchronic toxicity. Dietary exposure to penoxsulam identified the
liver and/or urinary tract (kidneys and bladder) as target organs in
rats, mice and dogs following 4-week and 13-week administration. 
Effects on the liver were reflected in increased liver weights and
hepatocellular hypertrophy, but these effects were not associated with
increases in mixed function oxidase (MFO) enzyme activity.  Effects
noted in the kidneys included crystal deposition, most likely from
precipitation of penoxsulam from the urine, with resultant irritation,
inflammation and hyperplasia of renal pelvic transitional epithelium. 
Other than the crystal deposition in the kidneys, all effects following
subchronic exposure to rats appeared to be reversible.  Very high doses
were associated with significant decreases in body weight and weight
gain, and feed consumption.

	5. Chronic toxicity. Chronic exposure in the dog indicated that the
renal effects were not exacerbated with long-term exposure.  Following
long-term exposure in rats, the kidneys and urinary bladder were the
primary target organs.  Histologic changes seen at the end of 2-years of
exposure consisted of inflammation and hyperplasia of the renal pelvic
transitional epithelium, crystal deposition in the kidneys and urinary
bladder, and hyperplasia of the mucosa of the urinary bladder.  In the
mouse, the liver was the primary target organ, and histologic changes
consisted of hepatocellular hypertrophy.  There were no
treatment-related increases in tumors in either rats or mice.  The
incidence of mononuclear cell leukemia (Fischer rat leukemia) was
increased in all groups of treated male rats compared to the concurrent
controls.  However, the incidences in the treated groups were identical
across a 50-fold increase in dosage, and well within the range of
control values reported in the literature. Penoxsulam was classified as
having “Suggestive Evidence of Carcinogenicity, but Not Sufficient to
Assess Human Carcinogenic Potential”. EPA has concluded that cancer
risk associated with penoxsulam is negligible.

	6. Animal metabolism. Orally administered penoxsulam is rapidly
absorbed, excreted and extensively metabolized in both male and female
rats, thus, indicating that penoxsulam is not expected to accumulate in
biological systems.  The majority of the residue was associated with the
parent, penoxsulam.  Several metabolites were also observed but the vast
majority were <1% of the administered dose.  The major route of
metabolism involves O-demethylation, producing the OH- Penoxsulam
metabolite followed by conjugation.

	7. Metabolite toxicology. A metabolism study with penoxsulam in rice
revealed the presence of the parent, a desmethylation metabolite (5-OH-
Penoxsulam), and two other polar metabolites, which may represent
conjugates of the desmethylated metabolite.  The 5-OH-Penoxsulam
metabolite and its glucuronide and glutathione conjugates have also been
identified in the plasma and liver of rats, therefore, plant metabolites
are considered of little toxicological concern.

	8. Endocrine disruption. Penoxsulam did not have any effects on
endocrine organs or tissues in mice, rats or dogs in any of the studies
conducted.  There were no indications of effects on fetal development in
either rats or rabbits, or on reproductive performance in rats.  Based
on the lack of any effects on the endocrine system, penoxsulam is not
considered an endocrine disrupter.

C. Aggregate Exposure

	1. Dietary exposure. Tier 1 dietary risk assessments were performed
using Dietary Exposure Evaluation Model software with the Food Commodity
Intake Database (DEEM-FCID™) software (version 3.14) to determine
consumption of Fruits, Pome group 11-10, and Fruits, Stone group 12-12,
Fruit, Small, Vine Climbing, Subgroup 13-07F, except Kiwifruit, olive
and pomegranate containing penoxsulam residues and to determine dietary
exposure resulting from consumption of Fruits, Pome group 11-10, and
Fruits, Stone group 12-12, Fruit, Small, Vine Climbing, Subgroup 13-07F,
except Kiwifruit, Olive and Pomegranate treated with penoxsulam.

	i. Food. Penoxsulam is registered for use as an herbicide on rice. 
Therefore, consumption of rice that has been treated with penoxsulam
could result in dietary exposures.  On September 24, 2004, EPA finalized
tolerances for penoxsulam in rice, grain (0.02 ppm) and rice, straw (0.5
ppm) (69 FR 57188-57197).  In establishing the tolerances for rice,
grain and rice, straw, EPA concluded that chronic dietary exposures were
<1% of the chronic population adjusted dose (cPAD), but exposure
estimates were not provided.  On July 25, 2007, EPA finalized tolerances
for penoxsulam in fish, and shellfish. On April 24, 2009 EPA finalized
tolerances for penoxsulam in or on almond hulls; grape; nut, tree, group
14; and pistachio. For the purposes of this aggregate assessment, it is
necessary to estimate dietary exposures of penoxsulam resulting from
tolerance level residues on rice, fish and shellfish, almond hulls;
grape; nut, tree, group 14; and pistachio in addition to the proposed
new uses.  Secondary residues in meat, milk and poultry were not
included because the transferability of penoxsulam to edible tissues is
quite low and tolerances are not required.  A chronic dietary exposure
and risk assessment for tolerance-level residues in existing and
proposed uses was performed using the DEEM-FCID™ software (version
3.14).  An acute dietary assessment was not performed because no
toxicity endpoint has been identified to evaluate acute dietary
exposures to penoxsulam (EPA, 2004).  To produce a conservative Tier 1
dietary risk assessment, tolerance-level residues were assumed for all
commodities, and 100 percent crop treated was assumed for all
commodities. Dietary penoxsulam exposures are low, accounting for less
than 6% of the cRfD (0.147 mg/kg/d) for all subpopulations.

	ii. Drinking water. The estimated drinking water concentrations (EDWCs)
for the herbicide penoxsulam in groundwater and surface water resulting
from ground spray applications in Tree crops have been calculated
according to EPA guidance.  For groundwater, EDWCs were derived using
the Screening Concentration in Ground Water (SCI-GROW) and Pesticide
Root Zone Model-Ground Water (PRZM-GW) models.  For surface water, the
PRZM- Exposure Analysis Modeling System (EXAMS) model was used. The
values generated were lower than the conservative values generated for
aquatic weed control. For the purpose of these assessments, 150 ppb was
used for the chronic exposure estimate for water, and this value was
incorporated as a single point estimate for both “water, direct, all
sources” and “water, indirect, all sources” within DEEM-FCIDTM
food categories exposure modeling.  Based on the conservative
assumptions used and using a cPAD of 0.147 mg/kg/day, the chronic
dietary exposure to penoxsulam from all registered and proposed uses and
drinking water, to all population subgroups is approximately <6% of the
cPAD.  All Infants have been identified as the most highly exposed
population subgroup yet utilizing only <6% of the cPAD.

	2. Non-dietary exposure. The residential exposure portion of the risk
assessment has been updated using current EPA practices.  The proposed
changes do not impact the previous human health assessment conclusion
for penoxsulam in which it was determined that the percentages of
chronic population adjusted dose for all population subgroups were less
than 100% and therefore do not exceed the Agency’s level of concern. 
The change in the dietary contribution and the estimated residential
exposures also do not change the conclusions of the previous assessment
regarding Short-Term and Intermediate-Term exposures; aggregate margin
of exposures (MOEs) remain acceptable. Thus, anticipated aggregate
exposures estimated with conservative assumptions regarding use patterns
of the full range of registered and proposed penoxsulam products are not
of concern.

D. Cumulative Effects

	Currently no common mechanism of toxicity has been found between
penoxsulam and any other substances EPA and penoxsulam does not appear
to produce a toxic metabolite produced by other substances. For the
purposes of this tolerance action, it is not assumed that penoxsulam has
a common mechanism of toxicity with other substances.

E. Safety Determination

	1. U.S. population. Using the conservative exposure assumptions
described above, and based on the completeness and reliability of the
toxicity data, the aggregate exposure to penoxsulam, as determined under
the guidance of the FQPA, will utilize less than 6% of the RfD from the
dietary exposure for all subgroups of the U.S. population.  Generally
and under the FQPA, the U.S. EPA has no concern for exposures below 100%
of the RfD because the RfD represents the level at or below which daily
dietary exposure over a lifetime will not pose appreciable risks to
human health.  Additionally, the chronic dietary exposure to penoxsulam
from all registered and proposed uses and drinking water, to all
population subgroups is approximately 6% of the cPAD.  Therefore, there
is a reasonable certainty that no harm will result to the general U.S.
population from aggregate exposure to penoxsulam residues from the
proposed use.

	2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of penoxsulam, data from
developmental toxicity studies in rats and rabbits and a
multi-generation reproduction study in the rat are considered.  The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from pesticide exposure during
prenatal development.  Reproduction studies provide information relating
to effects from exposure of both parents to the pesticide on the
reproductive capability and potential systemic toxicity of mating
animals and on various parameters associated with the well being of
offspring.

FFDCA section 408 provides that the U.S. EPA may apply an additional
safety factor for infants and children in the case of threshold effects
to account for pre- and post-natal toxicity and the completeness of the
database.  Based on the current toxicological data requirements, the
database for penoxsulam relative to pre- and post-natal effects for
children is complete.  Overall, penoxsulam had no effect on reproduction
or embryo-fetal development at any dosage tested.  No quantitative or
qualitative susceptibility was seen following pre- and post-natal
exposures.  In a rabbit developmental toxicity study, effects on
in-utero survival were observed only at a dose level where clear
maternal toxicity was seen.  In a 2-generation reproductive toxicity
study in rats, no effects on reproductive performance were observed and
effects on neonatal growth were seen only at a dose level where parental
toxicity was seen.  In addition, the no-observed adverse effect level
(NOAEL) in the chronic dog study (14.7 mg/kg/day), used to calculate the
chronic reference dose (RfD) (0.147 mg/kg/day), is already lower than
the NOAEL from the rabbit developmental study (25 mg/kg/day). 
Therefore, an additional FQPA uncertainty factor is not needed and the
RfD at 0.147 mg/kg/day is appropriate for assessing risk to infants and
children.  Using the conservative exposure assumptions previously
described, the percent RfD utilized by the potential exposure to
residues of penoxsulam is less than 6% for the population subgroup
predicted to be potentially the most highly exposed.  Based on the
aggregate exposure to penoxsulam, Dow AgroSciences concludes with
reasonable certainty that no harm will result to infants and children,
females 13+ years old and the prenatal development of infants.

F. International Tolerances

	A review of Maximum Residue Limits (MRLs) established globally
indicates that MRLs of 0.01 have been established in Japan for
penoxsulam in or on Pome Fruit, Stone Fruit, grapes, Almond, and Pecan.

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