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Indoxacarb and its R-enantiomer; 75:25 mixture (DPX MP062) (DuPont). March 17, 2004. Pesticide tolerance petition. Federal Register.

http://www.epa.gov/fedrgstr/EPA-PEST/2004/March/Day-17/p550.htm

[Federal Register: March 17, 2004 (Volume 69, Number 52)]
[Notices]
[Page 12664-12670]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr17mr04-68]
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ENVIRONMENTAL PROTECTION AGENCY
[OPP-2004-0034; FRL-7345-2]
Indoxacarb; Notice of Filing a Pesticide Petition to Establish a
Tolerance for a Certain Pesticide Chemical in or on Food
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.
DATES: Comments, identified by docket ID number OPP-2004-0034, must be
received on or before April 16, 2004.
ADDRESSES: Comments may be submitted electronically, by mail, or
through hand delivery/courier. Follow the detailed instructions as
provided in Unit I. of the SUPPLEMENTARY INFORMATION.
FOR FURTHER INFORMATION CONTACT: Rita Kumar, Registration Division
(7505C), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone
number: (703) 308-8291; e-mail address: kumar.rita@epa.gov.

SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, or pesticide manufacturer.
Potentially affected entities may include, but are not limited to:
• Crop production (NAICS 111)
• Animal production (NAICS 112)
• Food manufacturing (NAICS 311)
• Pesticide manufacturing (NAICS 32532)
This listing is not intended to be exhaustive, but rather provide a
guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. North American Industrial Classification System (NAICS) codes
shave been provided to assist you and others in determining whether
this action might apply to certain entities. If you have any questions
regarding the applicability of this action to a particular entity,
consult the person listed under FOR FURTHER INFORMATION CONTACT.
B. How Can I Get Copies of this Document and Other Related Information?
1. Docket. EPA has established an official public docket for this
action under docket ID number OPP-2004-0034. The official public docket
consists of the documents specifically referenced in this action, any
public comments received, and other information related to this action.
Although, a part of the official docket, the public docket does not
include Confidential Business Information (CBI) or other information
whose disclosure is restricted by statute. The official public docket
is the collection of materials that is available for public viewing at
the Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall #2, 1921 Jefferson Davis Hwy., Arlington, VA. This
docket facility is open from 8:30 a.m. to 4 p.m., Monday through
Friday, excluding legal holidays. The docket telephone number is (703)
305-5805.
2. Electronic access. You may access this Federal Register document
electronically through the EPA Internet under the ``Federal Register''
listings at http://www.epa.gov/fedrgstr/.
An electronic version of the public docket is available through
EPA's electronic public docket and comment system, EPA Dockets. You may
use EPA Dockets at http://www.epa.gov/edocket/ to submit or view public
comments, access the index listing of the contents of the official
public docket, and to access those documents in the public docket that
are available electronically. Although, not all docket materials may be
available electronically, you may still access any of the publicly
available docket materials through the docket facility identified in
Unit I.B.1. Once in the system, select ``search,'' then key in the
appropriate docket ID number.
Certain types of information will not be placed in the EPA Dockets.
Information claimed as CBI and other information whose disclosure is
restricted by statute, which is not included in the official public
docket, will not be available for public viewing in EPA's electronic
public docket. EPA's policy is that copyrighted material will
[[Page 12665]]
not be placed in EPA's electronic public docket but will be available
only in printed, paper form in the official public docket. To the
extent feasible, publicly available docket materials will be made
available in EPA's electronic public docket. When a document is
selected from the index list in EPA Dockets, the system will identify
whether the document is available for viewing in EPA's electronic
public docket. Although, not all docket materials may be available
electronically, you may still access any of the publicly available
docket materials through the docket facility identified in Unit I.B.
EPA intends to work towards providing electronic access to all of the
publicly available docket materials through EPA's electronic public
docket.
For public commenters, it is important to note that EPA's policy is
that public comments, whether submitted electronically or on paper,
will be made available for public viewing in EPA's electronic public
docket as EPA receives them and without change, unless the comment
contains copyrighted material, CBI, or other information whose
disclosure is restricted by statute. When EPA identifies a comment
containing copyrighted material, EPA will provide a reference to that
material in the version of the comment that is placed in EPA's
electronic public docket. The entire printed comment, including the
copyrighted material, will be available in the public docket.
Public comments submitted on computer disks that are mailed or
delivered to the docket will be transferred to EPA's electronic public
docket. Public comments that are mailed or delivered to the docket will
be scanned and placed in EPA's electronic public docket. Where
practical, physical objects will be photographed, and the photograph
will be placed in EPA's electronic public docket along with a brief
description written by the docket staff.

C. How and to Whom Do I Submit Comments?
You may submit comments electronically, by mail, or through hand
delivery/courier. To ensure proper receipt by EPA, identify the
appropriate docket ID number in the subject line on the first page of
your comment. Please ensure that your comments are submitted within the
specified comment period. Comments received after the close of the
comment period will be marked ``late.'' EPA is not required to consider
these late comments. If you wish to submit CBI or information that is
otherwise protected by statute, please follow the instructions in Unit
I.D. Do not use EPA Dockets or e-mail to submit CBI or information
protected by statute.
1. Electronically. If you submit an electronic comment as
prescribed in this unit, EPA recommends that you include your name,
mailing address, and an e-mail address or other contact information in
the body of your comment. Also, include this contact information on the
outside of any disk or CD ROM you submit, and in any cover letter
accompanying the disk or CD ROM. This ensures that you can be
identified as the submitter of the comment and allows EPA to contact
you in case EPA cannot read your comment due to technical difficulties
or needs further information on the substance of your comment. EPA's
policy is that EPA will not edit your comment, and any identifying or
contact information provided in the body of a comment will be included
as part of the comment that is placed in the official public docket,
and made available in EPA's electronic public docket. If EPA cannot
read your comment due to technical difficulties and cannot contact you
for clarification, EPA may not be able to consider your comment.
i. EPA Dockets. Your use of EPA's electronic public docket to
submit comments to EPA electronically is EPA's preferred method for
receiving comments. Go directly to EPA Dockets at http://www.epa.gov/
edocket/, and follow the online instructions for submitting comments.
Once in the system, select ``search,'' then key in docket ID number
OPP-2004-0034. The system is an ``anonymous access'' system, which
means EPA will not know your identity, e-mail address, or other contact
information unless you provide it in the body of your comment.
ii. E-mail. Comments may be sent by e-mail to opp-docket@epa.gov,
Attention: Docket ID number OPP-2004-0034. In contrast to EPA's
electronic public docket, EPA's e-mail system is not an ``anonymous
access'' system. If you send an e-mail comment directly to the docket
without going through EPA's electronic public docket, EPA's e-mail
system automatically captures your e-mail address. E-mail addresses
that are automatically captured by EPA's e-mail system are included as
part of the comment that is placed in the official public docket, and
made available in EPA's electronic public docket.
iii. Disk or CD ROM. You may submit comments on a disk or CD ROM
that you mail to the mailing address identified in Unit I.C.2. These
electronic submissions will be accepted in WordPerfect or ASCII file
format. Avoid the use of special characters and any form of encryption.
2. By mail. Send your comments to: Public Information and Records
Integrity Branch (PIRIB) (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460-0001, Attention: Docket ID number OPP-2004-0034.
3. By hand delivery or courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Office of Pesticide
Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall
#2, 1921 Jefferson Davis Hwy., Arlington, VA, Attention: Docket
ID number OPP-2004-0034. Such deliveries are only accepted during the
docket's normal hours of operation as identified in Unit I.B.1.

D. How Should I Submit CBI to the Agency?
Do not submit information that you consider to be CBI
electronically through EPA's electronic public docket or by e-mail. You
may claim information that you submit to EPA as CBI by marking any part
or all of that information as CBI (if you submit CBI on disk or CD ROM,
mark the outside of the disk or CD ROM as CBI and then identify
electronically within the disk or CD ROM the specific information that
is CBI). Information so marked will not be disclosed except in
accordance with procedures set forth in 40 CFR part 2.
In addition to one complete version of the comment that includes
any information claimed as CBI, a copy of the comment that does not
contain the information claimed as CBI must be submitted for inclusion
in the public docket and EPA's electronic public docket. If you submit
the copy that does not contain CBI on disk or CD ROM, mark the outside
of the disk or CD ROM clearly that it does not contain CBI. Information
not marked as CBI will be included in the public docket and EPA's
electronic public docket without prior notice. If you have any
questions about CBI or the procedures for claiming CBI, please consult
the person listed under FOR FURTHER INFORMATION CONTACT.
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you used
that support your views.
[[Page 12666]]
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in this notice.
7. To ensure proper receipt by EPA, be sure to identify the docket
ID number assigned to this action in the subject line on the first page
of your response. You may also provide the name, date, and Federal
Register citation.

II. What Action is the Agency Taking?
EPA has received a pesticide petition as follows proposing the
establishment and/or amendment of regulations for residues of a certain
pesticide chemical in or on various food commodities under section 408
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that this petition contains data or information
regarding the elements set forth in FFDCA section 408(d)(2); 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.
List of Subjects
Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated:February 27, 2004.
Lois Rossi,
Director, Registration Division, Office of Pesticide Programs.

Summary of Petition

The petitioner's summary of the pesticide petition is printed below
as required by FFDCA section 408(d)(3). The summary of the petition was
prepared by E. I. DuPont de Nemours and Company, and represents the
view of the petitioner. 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.

E. I. DuPont de Nemours and Company
PP 3G6797
EPA has received a pesticide petition (PP 3G6797) from E. I. DuPont
de Nemours and Company, DuPont Crop Protection, Wilmington, DE,
proposing pursuant to section 408(d) of the Federal Food, Drug, and
Cosmetic Act, 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing a temporary tolerance for combined residues of indoxacarb,
[(S)-methyl 7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-
(trifluoromethoxy)phenyl]
amino]carbonyl]indeno
[1,2e][1,3,4]oxadiazine-4a(3H)-carboxylate]
and its R-enantiomer (R)-
methyl 7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)
phenyl]amino]carbonyl]indeno [1,2-e]
[1,3,4]
oxadiazine-4a(3H)-
carboxylate]
in a 75:25 mixture (DPX MP062), respectively, in or on the
raw agricultural commodity as follows: cherry, sweet, 1 part per
million (ppm) and cherry, tart, 1 ppm. An analytical enforcement method
(LC-UV) is available for determining plant residues. 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 support granting of the petition. Additional data may be
needed before EPA rules on the petition. This action is in response to
university extension specialists, IR-4 and DuPont Crop Protection's
combined efforts to generate the information necessary for use of the
reduced risk pesticide, indoxacarb, on cherries for the control of plum
curculio. This proposed temporary tolerance supports an Experimental
Use Permit (EUP) under section 5 of the Federal Insecticide,
Fungicide,and Rodenticide Act (FIFRA) authorizing use of indoxacarb on
cherries in the state of Michigan. This regulation proposes to
establish a maximum permissible level for residues of indoxacarb in
this food commodity pursuant to section 408(e) of FFDCA, as amended by
FQPA.

A. Residue Chemistry
The active ingredient in the end-use formulation, Avaunt, is a
75:25 mixture of two isomers, indoxacarb (DPX-KN128) and IN-KN127. Only
one of the isomers, indoxacarb (DPX-KN128), has insecticidal activity.
Since the insecticidal efficacy is based on the concentration of
indoxacarb (DPX-KN128), the application rates have been normalized on
an indoxacarb (DPX-KN128) basis. The proposed tolerance expression
includes both indoxacarb (DPX-KN128) and IN-KN127 and the residue
method does not distinguish between the enantiomers; therefore,
residues are reported as the sum of indoxacarb (DPX-KN128) combined
with IN-KN127. Residues of indoxacarb (DPX-KN128)combined with IN-KN127
will be referred to as ``KN128/KN127.''

1. Plant metabolism. The metabolism of indoxacarb in plants is
adequately understood to support these tolerances. Plant metabolism
studies in cotton, lettuce, and tomatoes showed no significant
metabolites. The only significant residue was parent compound.
2. Analytical method. The plant residue enforcement method detects
and quantitates indoxacarb in various matrices including sweet corn,
lettuce, tomato, broccoli, apple, grape, cottonseed, tomato, peanut and
soybean commodity samples by high performance liquid chromotography
using ultra-violet detection (HPLC-UV). The limit of quantitation in
the method allows monitoring of crops with indoxacarb residues at or
above the levels proposed in these tolerances.
3. Magnitude of residues. Cherries IR-4 with the support from
DuPont has conducted magnitude of residue trials in tart cherry for an
additional crop use for DuPont Avaunt insecticide (indoxacarb 30WG). An
initial seven field trials have been conducted, making four
applications at 7 (+ 1) day intervals with the last application 14 (+
2) days before harvest.
Two test plots were established at each test site. One plot was
untreated and provided control samples for analysis. The treated plot
received four foliar applications of Avaunt at the maximum expected
label use rate of 0.11 lb a.i./A/Application (6 oz. product/A). All
application rates were within ±5% of the target rate. Maximum residues of
KN128/KN127 in individual duplicate samples were 0.635 ppm at a
pre-harvest interval (PHI) of 14 days (range 0.005 0.635 ppm).

B. Toxicological Profile

1. Acute toxicity. Based on EPA criteria, indoxacarb is classified
as follows for Toxicity Categories:
[[Page 12667]]
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Guideline Title Results Category
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870.1100 Acute Oral Toxicity LD50: 1,730 milligrams/kilogram (mg/kg) Category II
(male rat)
LD50: 268 mg/kg (female rat)
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870.1200 Acute Dermal Toxicity LD50: >5,000 mg/kg (rat) Category IV
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870.1300 Acute Inhalation Toxicity LC50: >5.5 milligrams/liter (mg/L) Category IV
(male rat) (70% MUP)
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870.2400 Primary Eye Irritation Effects reversed within 72 hours Category III
(rabbit)
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870.2500 Primary Dermal Irritation No irritation (rabbit) Category IV
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870.2600 Skin Sensitization Sensitizer (guinea pig) ------------
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Formulated products are slightly less acutely toxic than
indoxacarb.

In an acute neurotoxicity study, indoxacarb exhibited decreased
forelimb grip strength, decreased foot splay, and some evidence of
slightly reduced motor activity, but only at the highest doses tested.
The no observed adverse effect level (NOAEL) was 100 mg/kg for males
and 12.5 mg/kg for females based on body weight effects in females >=50
mg/kg.

2. Genotoxicty. Indoxacarb has shown no genotoxic activity in the
following listed in-vitro and in-vivo tests:
i. Ames--Negative.
ii. In-vitro mammalian gene mutation Chinese hampster ovary/
hypoxanthine guanine phophoribopsyl transferase (CHO/HGPRT)--Negative.
iii. In-vitro unscheduled DNA synthesis--Negative.
iv. In-vitro chromosomal aberration--Negative.
v. In-vivo mouse micronucleus--Negative.

3. Reproductive and developmental toxicity. The results of a series
of studies indicated that there were no reproductive, developmental
orteratogenic hazards associated with the use of indoxacarb. In a 2-
generation rat reproduction study, the parental NOAEL was 1.5 mg/kg/
day. The parental NOAEL was based on observations of reduced weight
gain and food consumption for the higher concentration groups of the F0
generation and potential treatment-related changes in spleen weights
for the higher groups of the F1 generation. There was no effect on
mating or fertility. The NOAEL for fertility and reproduction was 6.4
mg/kg/day. The off spring NOAEL was 1.5 mg/kg/day, and was based on the
reduced mean pup weights noted for the F1 litters of the higher
concentration groups. The effects on pup weights occurred only at a
maternal effect level and may have been due to altered growth and
nutrition in the dams. In studies conducted to evaluate developmental
toxicity potential, indoxacarb was neither teratogenic nor uniquely
toxic to the conceptus (i.e., not considered a developmental toxin).
Developmental studies conducted in rats and rabbits demonstrated that
the rat was more susceptible than the rabbit to the maternal and fetal
effects of DPX- MP062. Developmental toxicity was observed only in the
presence of maternal toxicity. The NOAEL for maternal and fetal effects
in rats was 2 mg/kg/day based on body weight effects and decreased food
consumption at 4 mg/kg/day. The NOAEL for developmental effects in
fetuses was >4 mg/kg/day. In rabbits, the maternal and fetal NOAELs
were 500 mg/kg/day based on body weight effects, decreased food
consumption in dams and decreased weight and delayed ossification in
fetuses at 1,000 mg/kg/day.

4. Subchronic toxicity. Subchronic (90-day) feeding studies were
conducted with rats, mice, and dogs. In a 90-day feeding study in rats,
the NOAEL was 3.1 and 2.1 mg/kg/day for males and females,
respectively. In male rats, the NOAEL was based on decreased body
weight and nutritional parameters, mild hemolytic anemia and decreased
total protein and globulin concentration. In female rats, the NOAEL was
based on decreased body weight and food efficiency. In a subchronic
neurotoxicity study in rats, there was no evidence of neurotoxicity at
11.9 and 6.09 mg/kg/day, the highest dose tested for males and females,
respectively. The subchronic NOAEL in dogs (5.0 mg/kg/day, modifying
factor (M/F) was based on hemolytic anemia. Erythrocyte values for most
dogs were within a range that would be considered normal for dogs in a
clinical setting. Mice were less sensitive to indoxacarb than the rats
or dogs. NOAELs (23 mg/kg/day, males, 16 mg/kg/day, females) were based
on mortality (males only); increased reticulocytes and Heinz bodies and
decreased body weight, weight gain, food consumption, food efficiency;
and increased clinical signs (leaning to one side and/or with abnormal
gait or mobility) (females only). In a 28-day repeated dose dermal
study, the NOAEL was 50 mg/kg/day based on decreased body weights, body
weight gains, food consumption, and food efficiency in females, and
changes in hematology parameters, the spleen and clinical signs of
toxicity in both sexes in rats.

5. Chronic toxicity. Chronic studies with indoxacarb were conducted
on rats, mice, and dogs to determine oncogenic potential and/or chronic
toxicity of the compound. Effects generally similar to those observed
in the 90-day studies were seen in the chronic studies. Indoxacarb was
not oncogenic in rats or mice. The chronic NOAEL in male rats was 5 mg/
kg/day based on body weight and nutritional effects. In females, the
NOAEL of 2.1 mg/kg/day was based on body weight and nutritional
changes, as well as biologically significant hematologic changes at 3.6
mg/kg/day and above. Hemolytic effects were present only through the 6-
month evaluation and only in females. The regenerative nature of
indoxacarb-induced hemolytic anemia was demonstrated by the absence of
significant changes in indicators of circulating erythrocyte mass at
later evaluations. In mice, the chronic NOAEL of 2.6 mg/kg/day for
males was based on deceased body weight and weight gain effects and
food efficiency at 13.8 mg/kg/day and above. The NOAEL for females was
4.0 mg/kg/day based on body weight nutritional effects, neurotoxicity,
and clinical signs at 20 mg/kg/day. In dogs, the chronic NOAEL was
about 2.3 and 2.4 mg/kg/day in males and females, respectively based on
hemolytic effects similar to those seen in the subchronic dog study.

6. Animal metabolism--i. Livestock animal metabolism. Animal
metabolism has been studied in the rat, hen, and
[[Page 12668]]
cow and is well understood. In contrast to crops, indoxacarb is
extensively metabolized in animals.
ii. Poultry. In poultry, hens were fed at 10 ppm/day for 5 days,
87-88% of the total administered dose was excreted; parent comprised
51-54% of the total dose in excreta. Concentration of residues in eggs
were low, 0.3-0.4 of the total dose, as was the concentration of
residues in muscle, 0.2% of the total dose. Parent and metabolite IN-
JT333 were not detected in egg whites; only insecticidally inactive
metabolites were identified. Parent and IN-JT333 were found in egg
yolks; however, their concentrations were very low, 0.01-0.02 ppm.
Concentrations of parent and IN-JT333 in muscle were at or below the
limit of quantitation, (LOQ) (0.01 ppm).

iii. Poultry feeding study. A poultry feeding study was not
conducted for the initial section 3 registration because finite
concentrations of residues would not be expected based on the low
concentration of residues in the metabolism study. However, the Agency
has required a poultry feeding study as a condition of registration for
indoxacarb. The study was submitted on October 31, 2003. Once the
Agency has determined the components of the tolerance expression,
poultry meat, fat, by products and egg tolerances will be proposed.

iv. Cattle. For the cow study, the cattle were fed at 10 ppm/day
for 5-days; approximately 20% of the total administered dose was
excreted in urine and 53-60% was excreted in feces in 5-days. Four
tenths to 1.2% of the total dose in urine was parent indicating
extensive metabolism; parent represented 46-68% of the fecal activity.
Thus, most residues were not absorbed; those residues that were
absorbed were extensively metabolized. Less than 1% of the total
administered dose was in milk, most of which was parent compound. The
insecticidally active metabolite IN-JT333 was not found in milk.
Residues in muscle represented less than 0.01% of the total
administered dose most of which was parent. IN-JT333 was not detected
in muscle. No other metabolites were seen above 10% of the dose, thus
only parent and IN-JT333 were monitored in the cattle feeding study.

v. Cattle feeding study. A cattle feeding study was conducted with
indoxacarb at doses of 7.5 ppm, 22.5 ppm and 75 ppm. The mean KN128/
KN127 concentrations were proportional to the dosing level in whole
milk, skim milk, cream, muscle, fat, liver and kidney. Based on final
residue values for the respective commodities contributing to the
cattle diet, the anticipated dietary burden in dairy cattle is 51.7 ppm
and the anticipated dietary burden in beef cattle is 49.1 ppm. The
proposed grape use will not increase the animal dietary burden. Based
on standard curves constructed from data in the cattle feeding study,
KN128/KN127 concentrations at the 51.7 ppm feeding level are 0.123 ppm
for whole milk, 0.033 ppm for skim milk and 1.46 ppm for cream. The
KN128/KN127 concentrations at the 49.1 ppm feeding level are 0.046 ppm
for muscle, 1.37 ppm for fat, 0.012 ppm for liver and 0.026 ppm for
kidney. Tolerances have been established at 1.5 ppm in fat (cattle,
goat, horse, sheep and hog), 0.05 ppm in meat, 0.03 ppm in meat by-
products, 0.15 ppm in milk and 4.0 ppm in milk fat.

7. Metabolite toxicology. In rats, indoxacarb was readily absorbed
at low dose (5 mg/kg), but saturated at the high dose (150 mg/kg).
Indoxacarb was metabolized extensively, based on very low excretion of
parent compound in bile and extensive excretion of metabolized dose in
the urine and feces. Some parent compound remained unabsorbed and was
excreted in the feces. No parent compound was excreted in the urine.
The retention and elimination of the metabolite IN-JT333 from fat
appeared to be the overall rate determining process for elimination of
radioactive residues from the body. Metabolites in urine were cleaved
products (containing only one radiolabel), while the major metabolites
in the feces retained both radiolabels. Major metabolic reactions
included hydroxylation of the indanone ring, hydrolysis of the
carboxylmethyl group from the amino nitrogen and the opening of the
oxadiazine ring, which gave rise to cleaved products. Metabolites were
identified by mass spectral analysis, NMR, ultraviolet (UV) and/or by
comparison to standards chemically synthesized or produced by
microsomal enzymes

8. Endocrine disruption. Lifespan, and multigenerational bioassays
in mammals and acute and subchronic studies on aquatic organisms and
wildlife did not reveal endocrine effects. Any endocrine-related
effects would have been detected in this definitive array of required
tests. The probability of any such effect due to agricultural uses of
indoxacarb is negligible.

C. Aggregate Exposure
Temporary tolerances for indoxacarb are proposed to support
agricultural use on cherries. Tolerances for indoxacarb are pending to
support agricultural use on grapes. There are residential uses of
indoxacarb pending (fire ant bait), however, the risk from that use has
been found to be negligible. The amount of acreage for cherry use
proposed in this Experimental Use Permit program is not significant
enough to alter the recent chronic dietary exposure, acute dietary
exposure, and aggregate exposure risk assessments previously submitted
to the Agency in March 2003, with the submission of the grape petition.
In those exposure analyses, there was adequate chronic, acute and
aggregate safety to all sub-populations. Therefore, the proposed new
experimental use of Avaunt on cherries does not pose any additional
risk beyond that of the currently registered and pending crop uses.

1. Dietary exposure. The chronic RfD of 0.02 mg/kg bw/day is based
on a NOAEL of 2.0 mg/kg bwt/day from the subchronic rat feeding study,
the subchronic rat neurotoxicity study, and the chronic/carcinogenicity
study, using an uncertainty factor of 100. The acute RfD for the
general population is 0.12 mg/kg/day, based on the NOAEL of 12.5 mg/kg
in the acute neurotoxicity study and an uncertainty factor of 100. The
acute RfD for females 13-50 years of age is 0.02 mg/kg/day, based on
the NOAEL of 2 mg/kg/day observed in the developmental rat toxicity
study and using an uncertainty factor of 100.

i. Food. Chronic dietary exposure assessment. Chronic dietary
exposure resulting from the currently approved use of indoxacarb on
apples, Crop group 5 (brassica vegetables), cotton, pears, peppers,
sweet corn, tomatoes, eggplant, alfalfa, head and leaf lettuce,
peanuts, potatoes, soybeans, cranberries (current section 18 use) and
the proposed use on grapes are well within acceptable limits for all
sectors of the population. The Chronic Module of the Dietary Exposure
Evaluation Model (DEEM, Exponent, Inc., formerly Novigen Sciences,
Inc., Version 7.76) was used to conduct the assessment with the
reference dose (RfD) of 0.02 mg/kg/ day. The analysis used overall mean
field trial values, processing factors and projected peak percent crop
treated values. Secondary residues in milk, meatand poultry products
were also included in the analysis. The chronic dietary exposure to
indoxacarbis 0.000089 mg/kg/day, and utilizes 0.4% of the RfD for the
overall U.S. population. The exposure of the most highly exposed
subgroup in the population, children age 1-6 years, is 0.000238 mg/kg/
day, and utilizes 1.2% of the RfD. The table below lists the results of
this analysis, which indicate large margins of safety for each
population subgroup and very low
[[Page 12669]]
probability of effects resulting from chronic exposure to indoxacarb.
------------------------------------------------------------------------
Maximum Dietary
Subgroup Exposure (mg/kg/day) % RfD
------------------------------------------------------------------------
U.S. population 0.000089 0.4
-------------------------------------------------------
Non-nursing infants (<1 year 0.000063 0.3
old)
-------------------------------------------------------
Children (1-6 years) 0.000238 1.2
-------------------------------------------------------
Children (7-12 years) 0.000126 0.6
-------------------------------------------------------
Females (13+, nursing) 0.000073 0.4
-------------------------------------------------------
Males (13-19 years) 0.000090 0.5
------------------------------------------------------------------------
Acute dietary exposure. Acute dietary exposure resulting from the
currently approved use of indoxacarb on apples, Crop Group 5 (brassica
vegetables), cotton, pears, peppers, sweet corn, tomatoes, eggplant,
alfalfa, head and leaf lettuce, peanuts, soybeans, potatoes,
cranberries (current section 18 use) and the proposed use on grapes are
well within acceptable limits for all sectors of the population.
DEEMTM, was used to conduct the assessment. Margins of
exposure (MOE) were calculated based on an acute NOAEL of 2 mg/kg/day
for women of child-bearing age and a NOAEL of 12 mg/kg/day for children
and the general population (Pesticide Fact Sheet for Indoxacarb). The
Tier 3 analysis used distributions of field trial residue data adjusted
for projected peak percent crop treated. Secondary residues in milk,
meat and poultry products were also included in the analysis. The
results of this analysis are given in the table below. The percent of
the acute population adjusted dose (a PAD) for all population subgroups
shows that an adequate margin of safety exists in each case. Thus, the
acute dietary safety of indoxacarb for established and the follow-on
use clearly meets the FQPA standard of reasonable certainty of no harm
and presents acceptable acute dietary risk.
----------------------------------------------------------------------------------------------------------------
99.9th Percentile of Exposure
-------------------------------------------------
Subgroup % Acute population
Exposure (mg/kg/day) adjusted dose (aPAD)
----------------------------------------------------------------------------------------------------------------
U.S. population 0.008795 7.3
-----------------------------------------------------------------------------------------
All infants 0.024729 20.6
-----------------------------------------------------------------------------------------
Non-nursing (<1 year old) 0.026036 21.7
-----------------------------------------------------------------------------------------
Children (1-6 years old) 0.013973 11.6
-----------------------------------------------------------------------------------------
Children (7-12 years old) 0.006882 5.7
-----------------------------------------------------------------------------------------
Females (13-19 years old) 0.005119 25.6
-----------------------------------------------------------------------------------------
Females (20+, not pregnant or nursing) 0.005358 26.8
-----------------------------------------------------------------------------------------
Females (13-50 years old) 0.005307 26.5
----------------------------------------------------------------------------------------------------------------
ii. Drinking water. Indoxacarb is highly unlikely to contaminate
ground water resources due to its immobility in soil, low water
solubility, high soil sorption, and moderate soil half-life. Based on
the PRZM/EXAMS and SCI-GROW models, the estimated environmental
concentrations (EECs) of indoxacarb and its R-enantiomer for acute
exposures are estimated to be 6.84 parts per billion (ppb) for surface
water and 0.0025 ppb for ground water. The EEC for chronic exposures
are estimated to be 0.316 ppb for surface water and 0.0025 ppb for
ground water. Drinking water levels of comparison (DWLOC), theoretical
upper allowable limits on the pesticide's concentration in drinking
water, were calculated to be much higher than the EECs. The chronic
DWLOCs ranged from 198 ppb to 697 ppb. The acute DWLOCs ranged from 440
ppb to 3,890 ppb. Thus, exposure via drinking water is acceptable.

2. Non-dietary exposure. Indoxacarb product registrations for
residential non-food uses are pending. Non-occupational, non-dietary
exposure for DPX-MP062 has been estimated to be extremely small.
Therefore, the potential for non-dietary exposure is insignificant.

D. Cumulative Effects
EPA's consideration of a common mechanism of toxicity is not
necessary at this time because there is no indication that toxic
effects of indoxacarb would be cumulative with those of any other
chemical compounds. Oxadiazine chemistry is new, and indoxacarb has a
novel mode of action compared to currently registered active
ingredients.

E. Safety Determination
1. U.S. population. Dietary and occupational exposure will be the
major routes of exposure to the U.S. population, and ample margins of
safety have been demonstrated for both situations. The chronic dietary
exposure to indoxacarb is 0.000089 mg/kg/day, which utilizes 0.4% of
the RfD for the
[[Page 12670]]
overall U.S. population, using mean field trial values, processing
factors and projected peak percent crop treated values. The percent of
the acute population adjusted dose (aPAD) (7.3%) for the overall U.S.
population shows that an adequate margin of safety exists. Using only
PHED data levels A and B (those with a high level of confidence), MOEs
for occupational exposure are 650 for mixer/loaders and 1,351 for air
blast applicators (worst-case). Based on the completeness and
reliability of the toxicity data and the conservative exposure
assessments, there is a reasonable certainty that no harm will result
from the aggregate exposure of residues of indoxacarb including all
anticipated dietary exposure and all other non-occupational exposures.

2. Infants and children. Chronic dietary exposure of the most
highly exposed subgroup in the population, children age 1-6 years old,
is 0.000238 mg/kg/day or 1.2% of the RfD. For infants (non-nursing, 1
year old), the exposure accounts for 0.3% of the RfD. For acute
exposure at the 99.9th percentile (based on a Tier 3
assessment) the exposure was 0.013973 mg/kg/day (11.6% aPAD) for
children 1-6 years old and 0.026036 mg/kg/day (21.7% aPAD) for non-
nursing infants. There are residential uses of indoxacarb pending, but
exposure is calculated to be extremely minimal. The estimated levels of
indoxacarb in drinking water are well below the below the DWLOC. Based
on the completeness and reliability of the toxicity data, the lack of
toxicological endpoints of special concern, the lack of any indication
that children are more sensitive than adults to indoxacarb, and the
conservative exposure assessment, there is a reasonable certainty that
no harm will result to infants and children from the aggregate exposure
of residues of indoxacarb, including all anticipated dietary exposure
and all other non-occupational exposures. Accordingly, there is no need
to apply an additional safety factor for infants and children.
F. International Tolerances
To date, no international tolerances exist for indoxacarb.
[FR Doc. E4-550 Filed 3-16-04; 8:45 am]
BILLING CODE 6560-50-S