DPX-MP062 (DuPont). Jan 25, 2002. Pesticide tolerance petition. Federal Register.

FLUORIDE ACTION NETWORK PESTICIDE PROJECT

DPX-MP062 (DuPont). January 25, 2002. Pesticide Tolerance Petition. Federal Register.

http://www.epa.gov/fedrgstr/EPA-PEST/2002/January/Day-25/p1763.htm

[Federal Register: January 25, 2002 (Volume 67, Number 17)]
[Notices]
[Page 3700-3706]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr25ja02-63]

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ENVIRONMENTAL PROTECTION AGENCY
[PF-1066; FRL-6819-2]

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 control number PF-1066, must be
received on or before February 25, 2002.

ADDRESSES: Comments may be submitted by mail, electronically, or in
person. Please follow the detailed instructions for each method as
provided in Unit I.C. of the SUPPLEMENTARY INFORMATION. To ensure
proper receipt by EPA, it is imperative that you identify docket
control number PF-1066 in the subject line on the first page of your
response.

FOR FURTHER INFORMATION CONTACT:
By mail: Geri McCann, Insecticide/Rodenticide Branch, Registration
Division (7505W), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460;
telephone number: (703) 308-8375; e-mail address: mccann.geri@epa.gov.

SUPPLEMENTARY INFORMATION:

I. General Information

A. Does This Action Apply to Me?

You may be affected by this action if you are an agricultural
producer, food manufacturer or pesticide manufacturer. Potentially
affected categories and entities may include, but are not limited to:

------------------------------------------------------------------------
Examples of
Categories NAICS codes potentially
affected entities
------------------------------------------------------------------------
Industry 111 Crop production
112 Animal production
311 Food manufacturing
32532 Pesticide
manufacturing
------------------------------------------------------------------------

This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in the table could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether or not this action might apply to certain entities. If you have
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 Additional Information, Including Copies of This
Document and Other Related Documents?

1. Electronically. You may obtain electronic copies of this
document, and certain other related documents that might be available
electronically, from the EPA Internet Home Page at http://www.epa.gov/.
To access this document, on the Home Page select ``Laws and
Regulations'' and then look up the entry for this document under the
``Federal Register--Environmental Documents.'' You can also go directly
to the Federal Register listings at http://www.epa.gov/fedrgstr/.
2. In person. The Agency has established an official record for
this action under docket control number PF-1066. The official record
consists of the documents specifically referenced in this action, any
public comments received during an applicable comment period, and other
information related to this action, including any information claimed
as confidential business information (CBI). This official record
includes the documents that are physically located in the docket, as
well as the documents that are referenced in those documents. The
public version of the official record does not include any information
claimed as CBI. The public version of the official record, which
includes printed, paper versions of any electronic comments submitted
during an applicable comment period, is available for inspection in the
Public Information and Records Integrity Branch (PIRIB), Rm. 119,
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal

[[Page 3701]]

holidays. The PIRIB telephone number is (703) 305-5805.

C. How and To Whom Do I Submit Comments?

You may submit comments through the mail, in person, or
electronically. To ensure proper receipt by EPA, it is imperative that
you identify docket control number PF-1066 in the subject line on the
first page of your response.
1. By mail. Submit your comments to: Public Information and Records
Integrity Branch (PIRIB), Information Resources and Services Division
(7502C), Office of Pesticide Programs (OPP), Environmental Protection
Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460.
2. In person or by courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Information Resources
and Services Division (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, Rm. 119, Crystal Mall #2, 1921
Jefferson Davis Highway, Arlington, VA. The PIRIB is open from 8:30
a.m. to 4 p.m., Monday through Friday, excluding legal holidays. The
PIRIB telephone number is (703) 305-5805.
3. Electronically. You may submit your comments electronically by
e-mail to: opp-docket@epa.gov, or you can submit a computer disk as
described above. Do not submit any information electronically that you
consider to be CBI. Avoid the use of special characters and any form of
encryption. Electronic submissions will be accepted in Wordperfect 6.1/
8.0 or ASCII file format. All comments in electronic form must be
identified by docket control number PF-1066. Electronic comments may
also be filed online at many Federal Depository Libraries.

D. How Should I Handle CBI That I Want To Submit to the Agency?

Do not submit any information electronically that you consider to
be CBI. You may claim information that you submit to EPA in response to
this document as CBI by marking any part or all of that information as
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 version of the
official record. Information not marked confidential will be included
in the public version of the official record without prior notice. If
you have any questions about CBI or the procedures for claiming CBI,
please consult the person identified 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.
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
control 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 Comestic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that this petition contains data or information
regarding the elements set forth in 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: January 14, 2002.
Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.

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 represents the view of the
petitioners. 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.

PP 1F6301

EPA has received a pesticide petition (PP 1F6301) from E. I. du
Pont de Nemours and Company (DuPont), P.O. Box 30, Newark, DE 19714,
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 by
establishing a 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 commodities as follows:
Alfalfa forage at 12 parts per million (ppm), alfalfa hay at 50 ppm,
peanut at 0.01 ppm, peanut hay at 40 ppm, potato at 0.02 ppm, soybean
aspirated grain fractions at 70 ppm, soybean hulls at 6.5 ppm, head
lettuce at 5 ppm, meat (of cattle, goats, hogs, horses and sheep) at
0.05 ppm, fat (of cattle, goats, hogs, horses and sheep) at 1.5 ppm,
meat by-products (of cattle, goats, hogs, horses and sheep) at 0.03 ppm
and milk at 0.15 ppm. Two analytical enforcement methods are available
for determining these plant and animal residues. They are GC-MSD and
HPLC column-switching with UV detection. 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.

A. Residue Chemistry

The active ingredient in the end-use formulations,
Steward and AvauntTM, is a 75:25 mixture of two
isomers, indoxacarb (IN-KN128) and IN-KN127. Only one of the isomers,
indoxacarb (DPX-KN128), has insecticidal activity. Since the
insecticidal efficacy is based

[[Page 3702]]

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, grapes and tomatoes showed no significant
metabolites. The only significant residue was parent compound.
2. Analytical method. One plant residue enforcement method detects
and quantitates indoxacarb in cotton and sweet corn matrices by HPLC
with UV detection. The other plant residue enforcement method detects
and quantitates indoxacarb in various matrices including lettuce,
tomato, pepper, cabbage, broccoli, cauliflower, apple, pear, grape,
cottonseed, tomato and apple processed commodity samples by GC-MSD. The
analytical method for detecting and quantitating indoxacarb in animal
matrices including whole and skim milk, cream, fat, muscle, liver and
kidney is an HPLC column-switching method using UV detection. The limit
of quantitation in each method allows monitoring of crops and animal
matrices with indoxacarb residues at or above the levels proposed in
these tolerances.
3. Magnitude of residues--i. Alfalfa. Residue studies were
conducted at a total of 12 field sites. All studies were done using
Steward Insecticide. One broadcast application of
Steward Insecticide was made for each alfalfa cutting at each
test site. Each application was made at a maximum rate of 0.11 lb. a.i.
DPX-KN128/A. After application, the plant was cut at a PHI of 7 days
and samples of forage were taken. Additional forage was allowed to dry
to proper moisture content to produce hay samples (cutting 1). Plants
were allowed to regrow and were retreated with 0.11 lb. a.i. DPX-KN128
seven days prior to the next cutting. Residues were measured as the
combination of DPX-KN128 and IN-KN127 (enantiomers not resolved by the
analytical method). Maximum residues of KN128/KN127 in individual
duplicate forage samples were 9.0 ppm at a PHI of 7 days (range 0.8-9.0
ppm). Maximum residues of KN128/KN127 in individual duplicate hay
samples were 39 ppm at a PHI of 7 days (range 3.2-39 ppm).
ii. Lettuce. Residue studies were conducted at a total of 18 field
sites. All studies were done using AvauntTM Insecticide.
AvauntTM contains 30% active ingredient (a.i.) (300 g DPX-
KN128 per kg, w/w). Four broadcast applications of Avaunt TM
Insecticide were made at each test site. Each application was made at a
maximum rate of 0.111 lb. a.i. DPX-KN128/A (maximum seasonal use rate
of 0.444 lb. a.i./A). Applications were made approximately 3 days
apart. The target PHI was 3 days. Residues were measured as the
combination of DPX-KN128 and IN-KN127 (enantiomers not resolved by the
analytical method). Maximum residues of KN128/KN127 in individual
duplicate head lettuce samples collected from the field with wrapper
leaves were 4.4 ppm at a PHI of 3 days (range < 0.40-4.4 ppm). Maximum
residues of KN128/KN127 in individual duplicate head lettuce samples
without wrapper leaves were 1.1 ppm at a PHI of 3 days (range < 0.02-
1.1 ppm). Maximum residues of KN128/KN127 in individual duplicate leaf
lettuce samples were 8.7 ppm at a PHI of 3 days (range 2.7-8.7 ppm).
Head lettuce and leaf lettuce were each grown at 9 field sites.
iii. Peanuts. Residue studies were conducted at a total of 12 field
sites. All studies were done using Steward Insecticide.
Steward contains 15% a.i (150 g DPX-KN128 per liter, w/v).
Four broadcast applications of Steward Insecticide were made at each
test site. Each application was made at a maximum rate of 0.110 lb.
a.i. DPX-KN128/A (maximum seasonal use rate of 0.440 lb. a.i./A).
Applications were made approximately 5 days apart. The target PHI was
14 days. Residues were measured as the combination of DPX-KN128 and IN-
KN127 (enantiomers not resolved by the analytical method). Maximum
residues of KN128/KN127 in peanut hay were 32 ppm at a PHI of 14 days
(range 2.1-32 ppm). No detectable residues of KN128/KN127 were found in
peanut nutmeat at a PHI of 14 days at any of the 12 test sites in the
study (residues < 0.003 ppm).
iv. Peanuts, process fractions. A processing study was conducted to
determine the magnitude of KN128/KN127 residues in peanut nutmeat and
their possible concentration in peanut processed fractions (refined oil
and meal). Residues were measured as the combination of DPX-KN128 and
IN-KN127 (enantiomers not resolved by the analytical method). Peanuts
were treated with Steward Insecticide (see description above). Four
broadcast applications were made each at a rate of 0.110 and 0.550 lb.
a.i./A (1X and 5X the proposed maximum seasonal use rate of 0.440 lb.
a.i./A). The application interval was 5 days and the pre-harvest
interval (PHI) was 14 days. At 5X the maximum seasonal use rate,
quantifiable residues of KN128/KN127 were found in peanut nutmeat
(0.013 ppm). Residues of KN128/KN127 in refined oil were 0.013 ppm.
Quantifiable residues were not found in meal (residues < 0.0075 ppm).
Residues of KN128/KN127 did not concentrate in refined oil or meal to
levels greater than those on the raw agricultural commodity
(concentration factors =1 or < 1, respectively).
v. Potatoes. Residue studies were conducted at a total of 16 field
sites. All studies were done using AvauntTM Insecticide.
AvauntTM contains 30% a.i. (300 g DPX-KN128 per kg, w/w).
Four broadcast applications of AvauntTM Insecticide were
made at each test site. Each application was made at a maximum rate of
0.065 lb. a.i. DPX-KN128/A (maximum seasonal use rate of 0.26 lb. a.i./
A). Applications were made approximately 5 days apart. The target PHI
was 7 days. Residues were measured as the combination of DPX-KN128 and
IN-KN127 (enantiomers not resolved by the analytical method). No
quantifiable residues of KN128/KN127 were found in potato tubers at a
PHI of 7 days at any of the 16 test sites in the study (residues <
0.010 ppm).
vi. Potatoes, process fractions. A processing study was conducted
state to determine the magnitude of KN128/KN127 residues in unwashed
and washed potato tubers and culls and their possible concentration in
potato tuber processed fractions (wet peel, chips and flakes). Residues
were measured as the combination of DPX-KN128 and IN-KN127 (enantiomers
not resolved by the analytical method). Potatoes were treated with
Avaunt Insecticide (see description above). Four broadcast applications
were made each at a rate of 0.065 and 0.325 lb. a.i./A (1X and 5X the
proposed maximum seasonal use rate of 0.26 lb. a.i./A). The application
interval was 5 days and the pre-harvest interval (PHI) was 7 days. At
5X, the maximum seasonal use rate, no quantifiable residues of KN128/
KN127 were found in unwashed or washed potatoes, culls or in wet peel,
chips or flakes (residues < 0.010 ppm). Residues of KN128/KN127 did not
concentrate in any potato processed fraction to levels greater than
those on the raw agricultural commodity.
vii. Soybeans. Residue studies were conducted at a total of 20
field sites. All

[[Page 3703]]

studies were done using Steward Insecticide.
Steward contains 15% a.i. (150 g DPX-KN128 per liter, w/v).
Four broadcast applications of Steward Insecticide were made
at each test site. Each application was made at a maximum rate of 0.111
lb. a.i. DPX-KN128/A (maximum seasonal use rate of 0.444 lb. a.i./A).
Applications were made approximately 5 days apart. The target PHI was
21 days. Residues were measured as the combination of DPX-KN128 and IN-
KN127 (enantiomers not resolved by the analytical method). Maximum
residues of KN128/KN127 in soybean seed were 0.59 ppm at a PHI of 21
days (range < 0.010-0.59 ppm). As part of this study, large samples of
soybean seed were collected and subsequently processed into aspirated
grain fraction (dust). Analysis of the seed showed a residue of 0.032
ppm. Analysis of the aspirated grain fraction (dust) showed a residue
of 2.8 ppm (concentration factor of 88:1).
viii. Soybean, process fractions. A processing study was conducted
to determine the magnitude of KN128/KN127 residues in soybean seed and
their possible concentration in processed fractions (hulls, meal and
refined oil). Residues were measured as the combination of DPX-KN128
and IN-KN127 (enantiomers not resolved by the analytical method).
Soybeans were treated with Steward Insecticide (see
description above). Four broadcast applications were made each at a
rate of 0.111 and 0.555 lb. a.i./A (1X and 5X the proposed maximum
seasonal use rate of 0.444-lb. a.i./A). The application interval was 5
days and the pre-harvest interval (PHI) was 21 days. At 5X the maximum
seasonal use rate, residues of KN128/KN127 in soybean seed were 0.077
ppm. Quantifiable residues were found in hulls (0.63 ppm) and refined
oil (0.049 ppm). Quantifiable residues were not found in meal (residues
< 0.010 ppm). Residues of KN128/KN127 concentrated in hulls
(concentration factor = 8.12) but did not concentrate in refined oil or
meal to levels greater than those on the raw agricultural commodity
(concentration factors < 1).

B. Toxicological Profile

1.Acute toxicity Based on EPA criteria, indoxacarb is classified as
follows for Toxicity Categories

----------------------------------------------------------------------------------------------------------------
Guideline Title Results Category
----------------------------------------------------------------------------------------------------------------
81-1 Acute oral txicity LD₅₀ 1,730 mg/kg (M Category II
Rat)
LD₅₀ 268 mg/kg/(F Rat).
----------------------------------------------------------------------------------------------------------------
81-2 Acute dermal toxicity LD₅₀ > 5,000 mg/kg Category IV
(Rat)
----------------------------------------------------------------------------------------------------------------
81-3 Acute inhalation LC₅₀ > 5.5 mg/L (M Rat) Category IV
toxicity (70% MUP)
----------------------------------------------------------------------------------------------------------------
81-4 Primary eye irritation Effects reversed within Category III
72 hours (Rabbit)
----------------------------------------------------------------------------------------------------------------
81-5 Primary Dermal No irritation (Rabbit) Category IV
Irritation
----------------------------------------------------------------------------------------------------------------
81-6 Skin Sensitization Sensitizer (Guinea Pig) ---------------
----------------------------------------------------------------------------------------------------------------

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 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 (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 or
teratogenic hazards associated with the use of indoxacarb. In a 2-
generationrat reproduction study, the parental no observed adverse
effect level (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 offspring 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, M/F) was
based on hemolytic anemia. Erythrocyte values for most dogs were within
a range that would be considered normal for dogs in

[[Page 3704]]

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 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. 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.
iv. Cattle feeding study. A cattle feeding study was conducted with
indoxacarb at doses of 7.5 ppm, 22.5 and 75 ppm. KN128/KN127
concentrations at the 22.5 ppm feeding level were 0.053 ppm for whole
milk, 0.018 ppm for skim milk and 0.58 ppm for cream. The mean KN128/
KN127 concentrations were proportional to the dosing level in whole
milk, skim milk and cream. IN-JT333 concentrations at the 22.5 ppm
feeding level were below the LOQ for whole milk and skim milk. The
concentration of IN-JT333 in cream was 0.022 ppm. The mean IN-JT333
concentrations were proportional to the dosing level in cream. KN128/
KN127 and IN-JT333 concentrations at the 22.5 ppm feeding level were
below the level of LOQ for all tissues, except fat (0.45 ppm, KN128/
KN127 and 0.03 ppm IN-JT333) and kidney (0.017 ppm KN128/KN127),
throughout 28 days of dosing. The mean KN128/ KN127 residues in muscle,
fat, liver, and kidney samples were proportional to the dosing level.
The mean IN-JT333 residues in fat were proportional to the dosing
level. Tolerances have been established at 0.75 ppm in fat (cattle,
goat, horse, sheep and hog), 0.03 ppm in meat, 0.02 ppm in meat by-
products, 0.10 ppm in milk and 3.0 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, 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

Tolerances for indoxacarb are proposed to support agricultural uses
on alfalfa, lettuce, peanuts, potatoes and soybean. There are no
residential uses of indoxacarb.
1. Dietary exposure. The chronic RfD of 0.02 mg/kg bw/day is based
on a NOAEL of 2.0 mg/kg bw/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.
Food. Chronic dietary exposure assessment. Chronic dietary exposure
resulting from the currently approved use of indoxacarb on apples,
broccoli, cabbage, cauliflower, cotton, pears, peppers, sweet corn,
tomatoes and the proposed uses on alfalfa, lettuce, peanuts, potatoes
and soybeans are well within acceptable limits for all sectors

[[Page 3705]]

of the population. The Chronic Module of the Dietary Exposure
Evaluation Model (DEEM, Novigen Sciences, Inc., 1997 Version 7.075) 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 and
conservatively assumed that 100% of the crops on the proposed label
would be treated with indoxacarb. The chronic dietary exposure to
indoxacarb is 0.001428 mg/kg/day, and utilizes 7.1% 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 0.003929 mg/kg/
day, and utilizes 19.6% 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 probability of effects resulting from
chronic exposure to indoxacarb.

------------------------------------------------------------------------
Maximum Dietary
Subgroup Exposure (mg/kg/ %RfD
day)
------------------------------------------------------------------------
U.S population 0.001428 7.1
Non-nursing infants (< 1 year 0.001707 8.5
old)
Children (1-6 years) 0.003929 19.6
Children (7-12 years) 0.002233 11.2
Females (13+, pregnant/not 0.001353 6.8
nursing)
------------------------------------------------------------------------

2. Acute dietary exposure. Acute dietary exposure resulting from
the currently approved use of indoxacarb on apples, broccoli, cabbage,
cauliflower, cotton, pears, peppers, sweet corn, tomatoes and the
proposed uses on alfalfa, lettuce, peanuts, and soybeans are well
within acceptable limits for all sectors of the population. The Dietary
Exposure Evaluation Model (DEEM, Novigen Sciences, Inc., 1997 Version
7.075) 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
childbearing age and a NOAEL of 12 mg/kg/day for children and the
general population (Pesticide Fact Sheet for Indoxacarb). The Tier 2
analysis used anticipated residues and conservatively assumed that 100%
of the crops on the proposed label would be treated with indoxacarb.
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
follow-on uses clearly meets the FQPA standard of reasonable certainty
of no harm and presents much lower acute dietary risk than many of its
competitors.

------------------------------------------------------------------------
95th Percentile of Exposure
---------------------------------------
Subgroup % Acute Population
Exposure (mg/kg/ Adjusted Dose
day) (aPAD)
------------------------------------------------------------------------
U.S. population 0.009013 7.5
Non-Nursing (< 1 year) 0.013429 11.9
Children (1-6 years) 0.018211 15.8
Children (7-12 years) 0.010682 8.9
Females (13+, pregnant/not 0.006256 31.3
nursing)
------------------------------------------------------------------------

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 highly conservative, estimated
environmental concentrations (EECs) of indoxacarb and its R-enantiomer
for acute exposures are estimated to be 3.81 parts per billion (ppb)
for surface water and 0.02 ppb for ground water (Indoxacarb Final Rule,
65 FR 58421). The EECs for chronic exposures are estimated to be 0.56
ppb for surface water and 0.02 ppb for ground water. Drinking water
levels of comparison (DWLOCs), theoretical upper limits on the
pesticides concentration in drinking water, were calculated to be much
higher than the EEC's. Thus, exposures to drinking water are expected
to be negligible.
3. Non-dietary exposure. Indoxacarb products are not labeled for
residential non-food uses, thereby eliminating the potential for
residential exposure. Non-occupational, non-dietary exposure for DPX-
MP062 has not been estimated because the proposed products are limited
to commercial crop production. Therefore, the potential for non-
occupational 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 0.001428 mg/kg/day, which utilizes 7.1% of
the RfD for the overall U.S. population, assuming 100% of the crops are
treated and residues equivalent to overall mean field trial values. The
percent of the acute population adjusted dose (7.5% aPAD) for all
population subgroups 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 600 for mixer/loaders
and 2,500 for applicators. 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, is
0.003929 mg/kg/day or 19.6% of the RfD. For infants (non-nursing, >1
year), the exposure

[[Page 3706]]

accounts for 8.5% of the RfD. For acute exposure at the 95th
percentile (based on a conservative Tier 2 assessment) the exposure was
0.018211 mg/kg/day (15.8% aPAD),for children 1-6 and 0.013429 mg/kg/day
(11.9% aPAD) for non-nursing infants. There are no residential uses of
indoxacarb and contamination of drinking water is extremely unlikely.
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 andn
children.

F. International Tolerances

To date, no international tolerances exist for indoxacarb.
[FR Doc. 02-1763 Filed 1-24-02; 8:45 am]
BILLING CODE 6560-50-S