Document ID: EPA-HQ-OPP-2006-0821-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2006-10-11T04:00Z

Summary of Petition 

    The petitioner summary of the pesticide petition is printed below as
required by section 408(d)(3) of the FFDCA. The summary of the petition
was prepared by the petitioner and represent the views of the
petitioner. EPA is publishing the petition summary verbatim without
editing it in any way. The petition summary announces the availability
of a description of the analytical methods available to EPA for the
detection and measurement of the pesticide chemical residues or an

explanation of why no such method is needed.

Interregional Research Project Number 4 (IR-4)

PP 5E6979, 5E6980 and 5E6981

 

EPA has received a revision to pesticide petitions (5E6979, 5E6980 and
5E6981) from the Interregional Research Project #4 (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 FFDCA,
21 U.S.C. 346a(d), to amend 40 CFR 180.511 by establishing a tolerance
for residues of buprofezin   ADVANCE \d4
(2-[(1,1-dimethylethyl)imino]tetrahydro-3-(1-methylethyl)-5-
phenyl-4H-1,3,5-thiadiazin-4-one) in or on the following raw
agricultural commodities (RACs):

PP 5E6979 proposes the establishment of tolerances for stone fruit crop
group 12 (except peaches and nectarines) at 2.0 ppm.

PP 5E6980 proposes the establishment of tolerances for black sapote,
canistel, mamey sapote, mango, papaya, sapodilla, star apple, at 0.80
parts per million ppm (ppm).

      PP 5E6981 proposes an increase of  tolerance on grapes to 0.80
part per              million (ppm) and for raisins 1.2  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 the FFDCA; 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.   Nichino America,
Inc. 4550 New Linden Hill Road Wilmington, DE 19808  is the registrant
for buprofezin with the EPA and prepared and submitted the following
summary of information, data, and arguments in support of the pesticide
petitions.  This summary does not necessarily reflect the findings of
the EPA.  

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 \d4 

3.  Magnitude of residues-i. Plums. Six field trials on plums and
thirteen field trials on cherries were conducted.  The highest average
residue value for plums treated with buprofezin (HAFT) was 0.55 ppm, and
for cherries 1.32  ppm.  Dried plum samples had an average residue of
0.21 ppm, compared to a mean of 0.7 ppm in fresh plum from the same
trial, suggesting a 3X concentration factor and which would be covered
in the stone fruit crop group.  A tolerance of 2 ppm are being proposed
for the stone fruit crop group 12, except peaches, and are adequately
supported. ii.  Three field trials on papaya in Florida were conducted
to support a geographically-limited tolerance. The HAFT was 0.65 ppm
with the three day PHI.  A tolerance of 0.8 ppm is proposed for the
tolerance on papaya, star apple, black sapote, mango, sapodilla,
canistel, and mamey sapote are adequately supported. iii. Grapes. Field
trials on wine grapes and table grapes were conducted with buprofezin,
the principal residue of concern, in eight sites at the maximum rate,
applications, and the minimum preharvest interval of 7 days.  The
highest average residue value for grapes treated with buprofezin (HAFT)
was 0.70 ppm.  Using the EPA concentration factor of 1.5x, the residues
in raisins would be 1.05 ppm.  A tolerance of 0.8 ppm is proposed for
the tolerance on grapes and a tolerance of 1.2 ppm for raisins, and are
adequately supported.

B. Toxicological Profile

An extensive battery of toxicology studies has been conducted with
buprofezin.  An assessment of toxic effects caused by buprofezin is
discussed in the Federal Register of April 8, 2005 (70  FR 17901)
(FRL-7691-8).

1. 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.

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 meta- bolites 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 path-

way. As in rats, BF23 was the most extensively metabolized compound
identi- fied. 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
bioaccumu-lation 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.

2. Endocrine disruption. No special studies have been conducted to
investi-gate 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 con- sidered 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 is consistent 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: almonds, apricot, avocado, banana, canistel, cherry,
cotton, grape, grape raisin, longan, lychee, mango, papaya, mamey
sapote, Spanish lime, head lettuce, leaf lettuce, nectarine, plum,
prune, snap bean, tomato, cucurbit vegetables, citrus oil, citrus
orange, citrus grapefruit, citrus lemon, pistachio, pome fruit, apples,
pome fruit pear, and peach, and for animal kidney, fat, liver, meat, and
meat-by-products and milk,  using the Lifeline TM Version 3.0, which
incorporates food consumption data as reported by respondents in the
USDA 1994-1996 and 1998 Nationwide Continuing Surveys of Food Intake by
Individuals (CSFII), and accumulated exposure to the chemical for each
commodity.  

2. Food.  The acute dietary exposure was based on the following
assumptions: for all registered proposed commodities residues were at
tolerance levels, 100% crop treated, and EPA default  processing
factors,  with exceptions based on processing studies when available.
EPA had previously set the FQPA safety factor 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 and an FQPA safety factor (SF) of 1X.  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, and a FQPA
safety factor (SF) of 1X .  The uncertainty fact or of 100 was used to
account for interspecies and intraspecies variations.  Since the only
evidence of carcinogenicity was ‘suggestive’, this endpoint was not
deemed relevant to this assessment.

The resulting food exposure estimate for  females 13-49 years old was 

6.13 % of the Population Adjusted Dose (aPAD) at the 95th percentile and
a MOE of 1630. Exposure to this subpopulation was estimated to be 0.123
mg/kg/day.  No acute endpoint was identified for the remaining
population subgroups. The acute exposure was based on tolerance level
exposures and assuming 100% of the crops were treated.

      The chronic dietary exposure was based on the following
assumptions:  

% crop treated, maximum average values from the magnitude of the residue
studies for buprofezin for crops where the EPA had already established 
tolerances and  crop tolerances for the new proposed tolerances for the
following crops: canistel, mango, papaya, sapodilla, mamey sapote,
grapes, apricots, cherry, nectarines, and plums.  In addition,
buprofezin conjugates were added to these values as specified in the EPA
Memorandum “Buprofezin-Acute and Chronic Dietary Exposure
Assessments”, dated 14 April-2004. Processing study concentration
factors were used when available and replaced the default values. The
food exposure estimates from residues of buprofezin  for the U.S.
population was 6.82 % and a MOE of 2360 of the chronic Population
Adjusted Dose (cPAD). Exposure to this subpopulation was estimated to be
0.000682 mg/kg/day.  The subpopulation with the highest exposure was
children 1-2 years old with 27.5 % of the cPAD used and a MOE of 464.
Exposure to this subpopulation was estimated to be 0.00275 mg/kg/day.
These are considered conservative values.	

3.	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 Zone

Model/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 estimated by the EPA in the Federal Register of April 8, 2005 the
Tier II PRZM (Pesticide Root Zone Model) and EXAMS (Exposure Analysis
Modeling Stystem (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.  Based on the model outputs,
the estimated environmental concentrations (EECs ) for buprofezin are
4.5 parts per billion (ppb) for acute and chronic exposure to ground
water are 19.2 ppb and 4.5 ppb for acute and chronic exposure,
respectively to surface water .  The acute Drinking Water Level of
Concern (DWLOC) was calculated based on an acute Population Adjusted
Dose (aPAD) of 2.0 mg/kg/day.  For the acute assessment, the females
(13-49) subpopulation generated an acute DWLOC of 56,310  ppb.  The
acute DWLOC is considerably higher than the acute EEC of 19 ppb. 
Chronic DWLOCs were calculated based on a chronic Population Adjusted
Dose (cPAD) of 0.01 mg/kg/day.   The children 1-2 years old
subpopulation generated the lowest chronic DWLOC of 72.5 ppb.  Thus, the
chronic DWLOC is higher than the chronic EEC of 4.5 ppb. 

4. Non-Dietary Exposure

 ADVANCE \d4 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. Cumulative
effects from substances with a common mechanism of toxicity. 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  ADVANCE \d4 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
will utilize at most 

6.13 % of the acute reference dose of females (13-49) and is likely to
be much less, as more realistic data and models are developed.  EPA
generally has no concern for exposures below 100% of the aPAD  Drinking
Water Levels of Comparison (DWLOC) were calculated based on an aPAD of
2.0 mg/kg/day.  After calculating DWLOCs and comparing them to the EECs
for surface and ground water, EPA does not expect the aggregate exposure
to exceed 100% of the aPAD.



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 0.000682 mg/kg/day and was 6.82
% of the estimated chronic population adjusted dose (cPAD).  Exposure to
potential residues in drinking water are expected to be negligible.
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 children ages 1-2, the
highest exposed population subgroup, was 0.00275 mg/kg/day 27.5 % (of
the cPAD).  Exposure to potential residues in drinking water is expected
to be negligible.  EPA has determined that reliable data support using
the standard margin of exposure (MOE) and uncertainty factor (100 for
combined interspecies and intraspecies variability) for buprofezin and
that an additional safety factor of 10 is not necessary to be protective
of infants and children.  EPA generally has no concern for exposures
below 100% of the cPAD.  The acute EEC of 19 ppb is considerably less
than the DWLOC of 56,310 ppb.  For the chronic assessment, the children
1-2 years old subpopulation generated the lowest chronic DWLOC of
approximately 72.5 ppb.  For the general population, the chronic DWLOC
of  326 ppb is higher than the chronic EEC of 4.5 ppb.  The Agency has
considered the potential aggregate exposure from food, water and
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

There are no Canadian or Mexican maximum residue limits (MRLs)
established for buprofezin in/on any of the commodities associated with
the current petition. There are Codex MRLs associated with cucumbers (1
ppm), oranges, sweet and sour (0.5 ppm),  and tomatoes (1 ppm).