Document ID: EPA-HQ-OPP-2008-0360-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-06-17T04:00Z

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE
PETITIONS PUBLISHED IN THE FEDERAL REGISTER  (x/xx/2008)

EPA Registration Division contact: Richard Gebken (703) 305-6701

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.

[IR-4]

[PP# xxxxxx]

	EPA has received a pesticide petition ([PP # xxxxxxx]) from Nichino
America, Inc. (NAI) 4550 New Linden Hill Road, Suite 501 Wilmington, DE
19808 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.
511 by establishing a tolerance for residues of buprofezin in or on the
raw agricultural commodities: brassicas, head and stem group 5A at 7.0
parts per million (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 metabolic profile of buprofezin has been
elucidated in a wide range of crops, including tomatoes, lettuce,
cotton, and citrus.   In citrus, although buprofezin was a major
component of the residue, a chromatographically well-defined region of
radioactivity, clearly associated with polar conjugates, was observed.
Mass spectrometry identified the principal polar residue as a hexose
conjugate of BF4 (buprofezin hydroxylated in the t-butyl group).
Although the conjugate was resistant to enzyme hydrolysis, acid
hydrolysis of the polar fraction released predominantly BF26 with minor
amounts of BF9 and BF12. The same compounds were observed following acid
hydrolysis of a standard of BF4 clearly indicating that BF4 is the
conjugated metabolite existing in citrus. Although only limited
metabolism was observed in lettuce and cotton, trace levels of similar
metabolites, including the conjugate BF4 were observed indicating that
the metabolic pathway does not differ with plant species.

	2. Analytical method. The proposed analytical method involves
extraction, partition, clean-up and detection of residues by gas
chromatography using nitrogen phosphorous detection.  ADVANCE \d 4 

      3. Magnitude of residues. Field trials were conducted on broccoli
and cabbage, with buprofezin, the principal residue of concern, in the
required geographic regions in the United States at the maximum rate and
minimum application and the minimum preharvest interval.  The highest
average residue value for broccoli and cabbage were 1.375 and 3.285
parts per million (ppm), respectively.   The requested tolerances are
adequately supported.

B. Toxicological Profile

1. Acute toxicity.  “NA-Remove”

	2. Genotoxicty. “NA-Remove” 

	3. Reproductive and developmental toxicity. “NA-Remove” 

	4. Subchronic toxicity. “NA-Remove” 

	5. Chronic toxicity. “NA-Remove” 

	1. An extensive battery of toxicology studies has been conducted with
buprofezin.  EPA has evaluated the available toxicity data and
considered its validity, completeness, and reliability as well as the
relationship of the results of the studies to human risk  The nature of
the toxic effects caused by buprofezin is discussed in Unit III.A. of
the Final Rule on Buprofezin Pesticide Tolerance published in the
Federal Register on September 5, 2001 (66 FR 46381) (FRL-6796-6).   An
assessment of toxic effects caused by buprofezin including the
toxicological endpoints of concern is also discussed in Unit III.A. and
Unit III B. of the Federal Register dated June 25, 2003   (FRL-7310-7)
(68 FR 37765).

2. Animal metabolism. The metabolism of buprofezin has been extensively
studied in various species of animals and fish. Buprofezin has several
groups that can metabolize in a variety of ways thus potentially
producing a very large number of metabolites. Extensive metabolism to
many minor metabolites was observed in all the animal species.
Metabolism in fish was, however, much more limited and clearly defined.
Although not all metabolic intermediates have been detected in all the
species, the major routes of metabolism have been identified in animals
and fish and a consistent pattern is observed throughout these species.
The proposed metabolic pathway was provided in the tolerance petition,
PP 0F6087. For convenience, degradates are referred to by an internal
code: BF 1 through 13. Corresponding chemical structures were provided
in the tolerance petition, PP 0F6087.

	3. Metabolite toxicology. 

	i. Metabolism in rats.  The major metabolite found in rat excreta was
parent buprofezin in addition to several compounds formed after
extensive metabolism. Whereas plant metabolism appeared restricted
mainly to oxidation of the tertiary butyl group, oxidation of the butyl
group and hydroxylation of the phenyl ring were both observed in rats.
Oxidation of the t-butyl group proceeded beyond an alcohol to an acid
and was accompanied by ring opening. The most extensively metabolized
compound identified in rats was BF23 (acetylated p-aminophenol).

	ii. Metabolism in ruminants and hens. Residue levels were low (0.05
ppm) in all ruminant and poultry tissues and commodities, following
treatment at exaggerated rates (approximately 20x and 7,500x the
anticipated dietary burden, respectively). The only exceptions were cow
liver (1.21 ppm), cow kidney (0.41 ppm), hen liver (0.15 ppm), and egg
yolk (0.11 ppm). Extensive metabolism was observed in both species with
a large number of minor metabolites being produced.  The principal
metabolites identified in the cow were BF2 and BF23, indicating that the
major pathway of degradation in ruminants is hydroxylation of the phenyl
ring followed by opening and degradation of the heterocyclic ring. The
identification of trace levels of BF13 confirms this pathway. As in
rats, BF23 was the most extensively metabolized compound identified.
Trace levels of BF12 were also detected. This indicates that the
parallel pathway of heterocyclic ring opening without hydroxylation of
the phenyl ring is also in operation. Similarly in hens, the identified
metabolites were derived from degradation of the heterocyclic ring
either with (BF13) or without (BF9 and BF12) phenyl ring hydroxylation. 
No single unidentified compound accounted for more than 6% of the total
residue in any animal tissue or commodity, with the exception of a
component comprising 8.7% of egg white. The total residue in egg white
was, however, only 0.02 ppm even at this highly exaggerated dose rate.

	 iii. Metabolism in fish. Analysis of fish tissues, following a
bioaccumulation study, found a much simpler metabolic profile.
Buprofezin was present in both edible and non-edible tissues, but the
principle metabolites were polar conjugates of BF4. Trace levels of BF12
were also detected.

	4. Endocrine disruption. No special studies have been conducted to
investigate the potential of buprofezin to induce estrogenic or other
endocrine effects. The standard battery of required toxicity studies has
been completed. These studies include an evaluation of the potential
effects on reproduction and development and an evaluation of the
pathology of the endocrine organs following repeated or long-term
exposure. These studies are generally considered to be sufficient to
detect any endocrine effects. The only effect noted on endocrine organs
was an increased incidence of follicular cell hypertrophy and C-cell
hyperplasia of the thyroid gland in rats administered buprofezin. 
Buprofezin also caused mild to moderate hepatotoxic effects at this
dietary concentration.  The effect on the thyroid isconsistent with an
increased turnover of T3/T4 in the liver with a resultant rise in TSH
secretion (due to the hepatotoxicity). The rat is known to be much more
susceptible than humans to these effects due to the very rapid turnover
of thyroxine in the blood in rats (12 hours vs. about 5-9 days in
humans). Therefore, the thyroid pathological  changes which have been
noted following administration of high doses of buprofezin are
considered to be of minimal relevance to human risk assessment,
particularly considering the low levels of buprofezin to which humans
are likely to be exposed.

C. Aggregate Exposure

	1. Dietary exposure. Acute and chronic dietary risk analyses were
conducted to estimate to potential buprofezin residues in/on the
following crops: avocado, banana, bell and non-bell peppers, broccoli,
brussel sprouts, cabbage, cauliflower, canistel, celery, spinach,
cotton, grape, grape raisin, longan, lychee, mango, papaya, mamey
sapote, Spanish lime, head lettuce, leaf lettuce, snap bean, fruiting
vegetables, cucurbit vegetables, citrus fruits, pome fruits, stone
fruits, almond, pistachio, olive, and strawberry, and meat and milk,
using LifeLine™ version 4.3.   Residue estimates for water consumption
were based on PRZM3/EXAMs and SCIGROW models and exposure assessments
using LifeLineTM version 4.3.  

	i. Food. The acute dietary exposure was based on the following
assumptions: residues at tolerance levels, 100% crop treated, and
DEEM™ (ver. 7.76) default processing factors for all
registered/proposed commodities (Tier 1).  The Hazard Identification
Assessment Review Committee (HIARC) met on 15-February-2000 and
determined the endpoint selection for buprofezin (HED Doc. No. 014093)
and subsequently on 22-October-2002 to evaluate the potential for
increased susceptibility of infants and children from exposure to
buprofezin.  Based on toxicological considerations, the special FQPA
safety factor was set at 1X when assessing acute and chronic dietary
exposures.  The acute dietary aPAD (acute population adjusted dose) was
set at 2.0 mg/kg/day for females aged 13-50 years old based on a
developmental toxicity study in rats that had an oral NOEL of 200
mg/kg/day.  The chronic dietary cPAD (chronic Population Adjusted Dose)
was determined to be 0.01 mg/kg/day for the general population based on
a oral NOAEL of 1.0 mg/kg/day in the two-year rat chronic/oncogenicity
study.  The uncertainty factor of 30 was used to account for
interspecies and intraspecies variations.  An additional 10x database
uncertainty factor was applied.  The resultant safety factor used to
establish the cPAD was 300.  The cPAD was set at 0.0033 mg/kg/day.  
Since the only evidence of carcinogenicity was ‘suggestive’, this
endpoint was not deemed relevant to this assessment. 

Using tolerance values for exposure and a default value of 100% crop
treated, the resulting food exposure estimate for females 13-49 years
old was 6% of the acute RfD. No acute endpoint was identified for the
remaining population subgroups.  

The chronic dietary exposure used the following % crop treated:  100%
broccoli, brussel sprouts, cabbage, cauliflower, cranberry, olive, 67%
head lettuce and radicchio; 63% leaf lettuce, 100%, pepper, okra; 42%
raw tomato, 25% processed tomato; 39% for strawberry; 60% nectarines, 35
% plums,  40% apricots, 76% cherries; 30% spinach; 21 % grapes and 1%
grape raisin; 18% celery and leaf petioles;  5% cantaloupe; 2.5% crop
treated for avocado, cotton seed, tomato, 1% cottonseed, tomato, olive,
almond, pistachio, casaba, honeydew, watermelon, and all other cucurbit
crop group, all citrus crop group, exclusive of oranges 1 %; 13% for
peaches; 100% for oranges, apples, pear; and 0.1% for all the other
commodities.  For most crops the average field trial residues at maximum
label rates and minimum PHI's with no reduction factors for common
washing, cooking, or preparation practices were used for the assessment.
 For a few crops, tolerance values were used.  For apples, pears, and
oranges the USDA Pesticide Data Program (PDP) residues were used.  The
food exposure estimates from residues of buprofezin for the U.S.
population was 68.2 % of the chronic population adjusted dose (cPAD).
The subpopulation with the highest exposure were children ages 1-2 with
93.7% of the cPAD used. These can be considered conservative values. 

	

	ii. Drinking water. The residue of concern in drinking water was
determined to be buprofezin.  There are no established maximum
contaminant levels or health advisory levels for residues of buprofezin
in drinking water.  In the absence of comprehensive water monitoring
data, the Agency uses the FQPA Index Reservoir Screening Tool or the
Pesticide Root ZoneModel/Exposure Analysis Modeling System (PRZM/EXAMS)
to produce estimates of pesticide concentrations in an index resevoir.  
The SCI-GROW model is used to predict pesticide concentrations in
shallow ground water. For a screening-level assessment for surface water
EPA will use FIRST (a tier 1 model) before using PRZM/EXAMS (a tier 2
model). The FIRST model is a subset of the PRZM/EXAMS model that uses a
specific high-end runoff scenario for pesticides. Both FIRST and
PRZM/EXAMS incorporate an index reservoir environment, and both models
include a percent crop area factor as an adjustment to account for the
maximum percent crop coverage within a watershed or drainage basin.

None of these models include consideration of the impact processing
(mixing, dilution, or treatment) of raw water for distribution as
drinking water would likely have on the removal of pesticides from the
source water. The primary use of these models by the Agency at this
stage is to provide a screen for sorting out pesticides for which it is
unlikely that drinking water concentrations would exceed human health
levels of concern.

The estimated drinking water concentrations (EDWCs) in surface water
were determined using the Tier II PRZM (Pesticide Root Zone Model) and
EXAMS (Exposure Analysis Modeling System (PE4-PL, version 01).  PRZM is
used to simulate pesticide transport as a result of runoff and erosion
and spray drift from an agricultural field and EXAMS estimates
environmental fate and transport of pesticides in surface water.  The
EPA estimated that based on the maximum use pattern of two applications
to Florida citrus for the acute and long-term estimates.  The acute
EDWCs are 57.4 ppb, and for chronic 12.5 ppb.  The EPA estimated that
for cranberries, based on the maximum use pattern of two applications to
cranberry, the acute EDWC was 47.9 ppb.  In ground water, using Tier I
SCI-GROW, the acute level is 0.09 ppb and chronic is 0.09 ppb.  

	2. Non-dietary exposure. The term residential exposure is used in this
document to refer to non-occupational, non-dietary exposure (e.g. for
lawn and garden pest control, indoor pest control, termiticides, and
flea and tick control on pets). Buprofezin is not registered for use on
any sites that would result in residential exposure. 

D. Cumulative Effects

	A determination has not been made that buprofezin has a common
mechanism of toxicity with other substances. Buprofezin does not appear
to produce a common toxic metabolite with other substances. A cumulative
risk assessment was, therefore, not performed for this analysis. Section
408(b)(2)(D)(v) of FFDCA 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.'' Unlike other pesticides for which EPA
has followed a cumulative risk approach based on a common mechanism of
toxicity, EPA has not made a common mechanism of toxicity finding as to
buprofezin and any other substances and buprofezin does not appear to
produce a toxic metabolite produced by other substances. For the
purposes of this tolerance action, therefore, EPA has not assumed that
buprofezin has a common mechanism of toxicity with other substances. For
information regarding EPA's efforts to determine which chemicals have a
common mechanism of toxicity and to evaluate the cumulative effects of
such chemicals, see the policy statements released by EPA's OPP
concerning common mechanism determinations and procedures for cumulating
effects from substances found to have a common mechanism on EPA's web
site at     HYPERLINK "http://www.epa.gov/pesticides/cumulative/"   
ADVANCE \d 4 http://www.epa.gov/ pesticides/cumulative/ . 

E. Safety Determination

	1. U.S. population. 

i. Acute risk.  Using the conservative assumptions discussed above,
based on the completeness and reliability of the toxicity data, it is
concluded that aggregate exposure to the proposed uses of buprofezin are
estimated at 0.137 mg/kg/day and will utilize at most 6.8 % of the acute
reference dose of females (13-49).  This estimate is likely to be much
less, as more realistic data and models are developed.  Drinking water
and other water consumption (EDWC of 57.4 ppb) scenarios were included
in the dietary risk assessment modeling.  

ii. Chronic Risk.  Based on the toxicology data base and available
information on anticipated residues, the chronic dietary exposure to the
U.S. Population (total) was estimated as 0.00227 mg/kg/day and was 68.2
% of the estimated chronic population adjusted dose (cPAD). Drinking
water and other potential water consumption scenarios (EDWC of 12.5 ppb)
were included in the dietary risk assessment modeling. Based on these
assessments, it can be concluded that there is reasonable certainty of
no harm to the U.S. Population or any population subgroup from exposure
to buprofezin.  

   

	2. Infants and children. Chronic exposure to food and water to children
ages 1-2 infants, the highest exposed population subgroup, was 0.00312
mg/kg/day 

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non-occupational exposure routes and has concluded aggregate exposure is
not expected to exceed 100% of the chronic reference dose, and
consequently, has determined there is a reasonable certainty that no
harm will occur to infants and children from aggregate exposure to
residues of buprofezin.

F. International Tolerances

Canada, Codex, and Mexico do not have maximum residue limits for
residues of buprofezin in/on the proposed crops.  Therefore,
harmonization is not an issue.  

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