Document ID: EPA-HQ-OPP-2007-0504-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-08-01T04:00Z

<EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  (1/1/2007)>

<EPA Registration Division contact: [insert name and telephone number
with area code]>

 

<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 and brackets, i.e., “[insert
company name],” with the information specific to your action.>

<TEMPLATE:>

<[Dow AgroSciences]>

<[Insert petition number]>

<	EPA has received a pesticide petition ([insert petition number]) from
[Dow AgroSciences], [9330 Zionsville Road, Indianapolis, IN, 46268]
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.>

)>

<	1. by establishing a tolerance for residues of>

	[isoxaben] in or on the raw agricultural commodity [grape; grape,
juice; and grape, raisin] at [0.01] parts per million (ppm); in or on
the raw agricultural commodity [nut, tree, group and pistachio] at
[0.03] parts per million (ppm); in or on the raw agricultural commodity
[almond, hulls] at [0.35] parts per million (ppm); AND

<

	2. to request a waiver for the requirement of a tolerance for
[isoxaben] in or on the raw agricultural commodity [cattle, meat
byproducts; meat and milk].

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 nature of the residue in plants (grapes and
cereals) has been determined using radiolabeled isoxaben and is
adequately understood for the purposes of these tolerances.  The results
of the plant and animal metabolism studies and toxicity testing indicate
that the total toxic residue to be regulated is isoxaben.]

>

<	2. Analytical method. [There is a practical method (liquid
chromatography with positive ion atmospheric pressure chemical
ionization tandem mass spectrometry (LC/MS/MS)) for detection of
isoxaben residues.  The limit of detection (LOD) and limit of
quantitation (LOQ) are 0.003 µg/g and 0.01 µg/g, respectively and are
suitable for detecting and measuring levels of isoxaben in or on food
and allows monitoring of food with residues at or above the level set
for these tolerances.  The method has an independent laboratory
validation.]>

<	3. Magnitude of residues. [The proposed tolerances for isoxaben are
supported by MOR trials conducted in grapes, almonds and pecans.  The
magnitude of residues of isoxaben were determined following a single
maximum application of Gallery* 75 DF herbicide which is a water
dispersible granular.  A similar design was used in all three studies so
that one trial in each study was a decline trial and also each trial had
one control plot and two treated plots.  Applications were made to the
orchard or vineyard floor and resulting residues in the portions of the
plants consumed by humans are predominantly below the LOD and all but
two individual values were below the LOQ.  The farming practices and
environmental conditions were typical of those used in the production of
these crops.  For grapes, 12 trials were conducted in Washington,
California and New York; all residue values were below the LOQ in grapes
and ranged from no detects (ND) to 0.0085 ppm.  No concentration of
residues was measured upon processing to raisins or juice.  For the five
almond trials conducted in California, residue values ranged from no
detects to 0.015 ppm in the nutmeat and 0.0073 to 0.30 ppm in the hulls.
 For pecans, five trials were conducted in Georgia, Louisiana and Texas;
all residue values were non-detects, with the exception of one value;
that residue was just above the LOD at 0.0031 ppm.]>

<B. Toxicological Profile>

<	1. Acute toxicity.  [Isoxaben is not considered acutely toxic via
ingestion, inhalation or dermal exposure.  The acute oral LD50 for
isoxaben is >5000 mg/kg-bw in the rat, mouse and dogs; acute dermal LD50
in rabbit >2000 mg/kg-bw; the 4-hr inhalation LC50 for rats was 2.93
mg/L air.  No skin sensitization has been observed.  Isoxaben does not
produce significant eye or skin irritation.  No acute endpoint has been
established for further risk assessment.  In addition, all current
end-use product labels for both dry flowables and fertilizer
formulations carry the lowest signal word of “Caution”. ]>

<	2. Genotoxicity: [Isoxaben yielded negative results in a battery of in
vitro and in vivo tests for mutagenicity and other forms of
genotoxicity.  Initially, the micronucleus assays in mice gave a weakly
positive result but findings were not deemed to be dose-related> and
were of questionable biological significance.  A more recent mouse bone
marrow micronucleus test gave negative results and isoxaben showed no
genotoxic potential.]

<	3. Reproductive and developmental toxicity. [The teratogenic potential
of isoxaben has been tested in rats and rabbits.  Based on the rabbit
study, a NOEL of 1000 mg/kg/day is assigned for developmental toxicity
and 320 mg/kg/day for maternal toxicity.  >A three generation study in
rats with doses at 0, 40, 200, or 1000 mg/kg/day resulted in maternal
and paternal toxicity in the higher doses; effects were also observed on
prenatal and postnatal development in the high dose group.  The NOEL for
maternal and paternal toxicity was 40 and 200 mg/kg/day respectively. 
The NOEL for development offspring was 200 mg/kg/day and for
reproduction was 1000 mg/kg/day.  No increased sensitivity for the young
is observed.]

<	4. Subchronic toxicity. [Several 90-day feeding studies have been
conducted in rats, mice and dogs.  The NOAEL threshold is established
for rats at > 94 mg/kg bw/day.  In mice, the NOEL is 15.5 mg/kg bw /day
and the NOEL for dogs is 110 mg/kg/day.  Result thresholds were based on
increased liver weight and/or increased hepatic p-nitroanisole
0-demethylase activity.  A 28-day dermal study in rabbits found
technical isoxaben to be non-irritating at 1000 mg/kg bw/day and no
evidence of systemic toxicity was observed.>

<	5. Chronic toxicity. [EPA has established the reference dose (RfD) for
isoxaben at 0.05 mg/kg/day for chronic risk assessment.  Studies in
dogs, rats and mice were reviewed and the resulting cRfD is
conservatively based on the 2-year rat feeding study in rats with a NOEL
of 5 mg/kg/day and applied uncertainty factor of 100 for both
interspecies extrapolation (10x) and intraspecies variability (10x). 
The critical effects associated with the threshold were increased BUN,
decreased serum AP (alkyl phosphatase) and AST (aspartate
aminotransferase); decreased food consumption efficiency; increased
heart/body weight.

Oncology data for both rats and mice is available.  Isoxaben is
currently classified as a Group C compound by the OPP Peer Review
committee on the basis of a statistically significant increase in benign
liver tumors in mice.  Estimates of human dietary oncogenic risk were
based on the agency’s previously established Q* value of 2.3x10-3
(mg/kg-day)-1.]>

<	6. Animal metabolism. [Isoxaben has been shown to be readily and
rapidly absorbed when orally administered, but also rapidly excreted
from tissues: total urinary and fecal excretion ranging from 70 to 100%
has been observed in series of studies and timeframes.  Two tissue
distribution studies in rats with single doses of 14C labeled isoxaben
investigated the distribution of the absorbed dose; both found the
highest levels in the GI tract congruent with the understanding of the
rapid fecal excretion.  About 10% of absorbed dose converted to 15 or
more metabolites excreted in the urine.  For dermal exposure: a dermal
absorption value of 11% has been observed.  Supplemental data from some
bovine NOR work demonstrates any meat or fat residues of isoxaben in
cattle would be constituted primarily of degradates and <10% of the
parent isoxaben.  Based on the understanding of metabolism in both rats
and the cow, the low potential dietary burden to cattle from almond
hulls should result in residues below the current limit of detection in
milk and fat.  Based on this information, a waiver from animal product
tolerances (cattle, meat byproducts; meat and milk) is sought.]>

<	7. Metabolite toxicology. [The residue of concern for tolerance
purposes has already been established as the parent material isoxaben. 
Thus, there is no need to address metabolite toxicity.]>

<	8. Endocrine disruption. [No reference of isoxaben as an endocrine
disruptor was found in a web search, nor do any of the existing toxicity
studies suggest that endocrine modulation is a concern for isoxaben. ]>

<C. Aggregate Exposure>

<	1. Dietary exposure. [The dietary assessment model DEEM-FCID version
2.16 was employed to assess chronic dietary risk.  DEEM estimates US
consumption patterns based on the Continuing Survey of Food Intake by
Individuals (CSFII) and EPA/USDA translation recipes from August 2002. 
A DEEM residue file for a Tier I Dietary assessment was prepared using
proposed tolerance values plus water values from the Tier I screening
models.  DEEM was used to assess percent of chronic RfD for
subpopulations and also lifetime cancer risk using the cRfD of 0.05
mg/kg/day and a Q* values of 0.0023 (mg/kg/day)-1, respectively.  An
acute endpoint was not identified for acute dietary exposure and risk
assessment, therefore, an acute dietary exposure assessment was not
performed.]>

<	i. Food. [A Tier I dietary assessment for use on grapes and nuts
employed the proposed tolerance values for grapes, grape juice, raisins,
all nuts in crop grouping 14 including pistachio with no adjustment for
percent crop treated.  MOR trials in grapes showed no concentration in
grape juice or raisins and therefore proposed tolerances for these
processed commodities are the same as for grapes; no processing factors
were included in the DEEM assessment.  The use of a tolerance level and
100% of crop treated clearly results in an overestimate of human
exposure and results in a conservative dietary assessment.]>

<	ii. Drinking water. [Assessment for potential exposure via water has
been conducted using the EPA's Office of Pesticide Programs guidance
document for appropriate environmental fate input values to the Tier I
aquatic exposure models SCI-GROW and FIRST.  Based on residential uses
with three 1 lb/A applications, 60 days apart, the resulting Tier I
output from SCI-GROW is a groundwater calculation of 2.96 ppb.  Output
from FIRST resulted in a Tier I chronic value of 7.84 ppb.  Therefore
the FIRST value of 0.00784 ppm was employed as the conservative drinking
water residue from both direct and indirect sources within the DEEM
calculator for dietary risk.]>

<	2. Non-dietary exposure. [Commercial and homeowner uses of isoxaben
products in residential settings can lead to non-dietary exposures.  To
determine the maximum exposure scenarios by product type, the isoxaben
labels were reviewed and two key application scenarios which represent
the range of potential exposures assessed for residential turf and
ornamentals: 1) homeowner application of granular fertilizers to lawns
and ornamentals and 2) commercial applications via broadcast of the dry
flowable formulation.  Tier I residential assessments based on the
EPA’s SOPs were conducted for chronic exposure scenarios which
included multiple routes of post-application exposure for children.  To
aggregate the final exposures for the general population and children,
the appropriate chronic yearly averages from the dietary and residential
assessments are summed.  For both children and adults, use of the dry
flowable product resulted in slightly higher exposure, thus estimated
exposures from the dry flowable are used from the residential
assessment.  The most sensitive subpopulation from the dietary
assessment (non-nursing infants) is used to represent children, and for
adults the dietary exposure for the general population is used.]>

<D. Cumulative Effects>

<	[Isoxaben is uniquely classed as a “benzamide”; no cumulative
assessment is deemed necessary.]>

<E. Safety Determination>

<	1. U.S. population. [For adults, the Tier I chronic dietary exposure
component was determined to be 1.7x10-4 mg/kg bw/day and the largest
contribution to the dietary exposure came from the Tier I estimate for
drinking water.  The predicted residential exposure was 4.2x10-5 mg/kg
bw/day, resulting in an aggregate total exposure of 2.1x10-4 mg/kg
bw/day.  This potential exposure represents 0.42 % of the cRfD and when
multiplied by the Q* value results in a potential cancer risk value of
4x10-7.  These estimated exposures and lifetime risks are understood to
be below the Agency’s concern, with lifetime risks on the order of
10-6 and exposures at less then one percent of the established chronic
reference dose.]>

<	2. Infants and children. [For children, the chronic dietary exposure
component was determined to be 6.8x10-4 mg/kg bw/day (non-nursing
infant), the most exposed population subgroup, and the largest
contribution to the dietary exposure came from the Tier I estimate for
drinking water.  The predicted residential exposure was 1.8x10-5 mg/kg
bw/day, resulting in an aggregate total exposure of 7.0x10-4 mg/kg
bw/day.  This potential exposure represents 1.4 % of the cRfD and when
multiplied by the Q* value results in a potential cancer risk value of
1.6x10-6.  These estimated exposures and lifetime risks are understood
to be below the Agency’s concern, with lifetime risks on the order of
10-6 and exposures at less then two percent of the established chronic
reference dose.]>

<F. International Tolerances>

<	[To the best of our knowledge, no corresponding MRLs have been
established for grapes or tree nuts by CODEX, Canada, or Japan.  No
harmonized EU MRL exists for grapes or nuts.  Several EU member states
have historic national MRLs for both grapes and nuts ranging from 0.01
to 0.02 ppm.  The US proposed food tolerances are covered under the
current Canadian default of 0.1 ppm; grapes are covered under the
Japanese default of 0.01 ppm.]>

* Trademark of Dow AgroSciences

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well i can't pick one cause we are doing both

Could make another heading here for "Oncology" or just leave under
chronic I suppose.