FLUORIDE ACTION NETWORK PESTICIDE PROJECT
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Indoxacarb (DuPont). July 2, 2003.
Pesticide petition for tolerances:
grape, 2 ppm and raisin, 6 ppm.
Federal Register.
http://www.epa.gov/fedrgstr/EPA-PEST/2003/July/Day-02/p16739.htm
[Federal Register: July 2, 2003 (Volume 68, Number 127)]
[Notices]
[Page 39541-39547]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr02jy03-65]
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ENVIRONMENTAL PROTECTION AGENCY
[OPP-2003-0212; FRL-7312-9]
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-2003-0212, must be
received on or before August 1, 2003.
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 provides
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. The North American Industrial Classification System (NAICS)
codes have 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. EPA Docket. EPA has established an official public docket for
this action under docket ID number OPP-2003-0212. 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
[[Page 39542]]
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 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 in 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,'' and then key in docket ID number
OPP-2003-0212. 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-2003-0212. 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-2003-0212.
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-2003-0212. 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
[[Page 39543]]
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.
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: June 19, 2003.
Peter Caulkins,
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. Du Pont de Nemours and Company, Du Pont
Crop Protection, 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. Du Pont de Nemours and Company
Du Pont Crop Protection
PP 3F6576
EPA has received a pesticide petition (PP 3F6576) from E. I. Du
Pont de Nemours and Company, Du Pont Crop Protection, Wilmington,
Delaware, 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 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: grape, 2 ppm and raisin, 6 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.
A. Residue Chemistry
The active ingredient in the end-use formulation, Avaunt[Ograve],
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 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--a. Grapes. Residue studies were conducted
at a total of 13 field sites. All studies were done using Avaunt[reg]
Insecticide containing 30% active ingredient (300 grams (g) DPX-KN128
per kilogram (kg), weight/weight (w/w). Four broadcast applications of
Avaunt[reg]. Insecticide were made at each test site at a maximum rate
of 0.11 lb. active ingredient (a.i.) DPX-KN128/acre/application
(maximum seasonal use rate of 0.44 lb DPX-KN128/acre). Applications
were made approximately 5 days apart. 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 samples were 1.72parts per million (ppm) at a pre-harvest
interval (PHI) of 7 days (range 0.066 to 1.72 ppm.
b. Grape processing. A grape processing study was also performed in
California. Grapes received four applications of an exaggerated rate of
[[Page 39544]]
0.555 lb. of indoxacarb per acre, 5X the labeled rate. Samples were
collected from control and treated plots 7 days after the last
application. The grape samples were then processed using standard grape
processing procedures. Samples collected at the processing facility
were whole fruit, raisins and grape juice. The mean KN128/KN127
residues in whole fruit, raisins and grape juice treated with the
exaggerated rate were 1.34 ppm, 3.66 ppm and <0.01 ppm, respectively.
B. Toxicological Profile
1. Acute toxicity. Based on EPA criteria, indoxacarb is classified
as follows for toxicity categories:
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Guideline Title Results Category
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81-1 Acute oral toxicity LD50:1,730 milligrams/ Category II
kilogram (mg/kg) (M
Rat)
LD50: 268 mg/kg/(F Rat)
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81-2 Acute dermal toxicity LD50: >5,000 mg/kg Category IV
(Rat)
-----------------------------------------------------------------------------------------
81-3 Acute inhalation LC50:>5.5 (milligrams/ Category IV
toxicity per Liter (mg/L) (M
Rat) (70% MUP)
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81-4 Primary eye irritation Effects reversed within Category III
72 hours (Rabbit)
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81-5 Primary dermal No irritation (Rabbit) Category IV
irritation
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81-6 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 adverse effects 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-vitroand in-vivotests:
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-
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 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 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.
[[Page 39545]]
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. 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
Tolerances for indoxacarb are proposed 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.
1. Dietary exposure. The chronic reference dose (RfD) of 0.02 mg/kg
bwt/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 (DEEMTM, 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, meat and poultry
products were also included in the analysis. The chronic dietary
exposure to indoxacarb is 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 probability of effects resulting
from chronic exposure to indoxacarb.
------------------------------------------------------------------------
Maximum
Dietary
Subgroup Exposure % RfD
(mg/kg/day)
------------------------------------------------------------------------
U.S Population 0.000089 0.4
------------------------------------------------------------------------
[[Page 39546]]
Non-Nursing Infants (<1 year old) 0.000063 0.3
------------------------------------------------------------------------
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
------------------------------------------------------------------------
ii. 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. The
Dietary Exposure Evaluation Model (DEEMTM, Exponent, Inc.,
formerly Novigen Sciences, Inc., Version 7.76) 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 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 Food Quality
Protection Act (FQPA) standard of reasonable certainty of no harm and
presents acceptable acute dietary risk.
------------------------------------------------------------------------
99.9th Percentile of
exposure
-------------------------
Subgroup % Acute
Exposure population
(mg/kg/day) adjusted
dose (aPAD)
------------------------------------------------------------------------
U.S. population 0.008795 7.3
------------------------------------------------------------------------
All infants 0.024729 20.6
------------------------------------------------------------------------
Non-nursing (<1 year) 0.026036 21.7
------------------------------------------------------------------------
Children (1-6 years) 0.013973 11.6
------------------------------------------------------------------------
Children (7-12 years) 0.006882 5.7
------------------------------------------------------------------------
Females (13-19 years) 0.005119 25.6
------------------------------------------------------------------------
Females (20+, not pregnant or nursing) 0.005358 26.8
------------------------------------------------------------------------
Females (13-50 years) 0.005307 26.5
------------------------------------------------------------------------
iii. Drinking water. Indoxacarb is highly unlikely to contaminate
groundwater 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 EECs for chronic exposures
are estimated to be 0.316 ppb for surface water and 0.0025 ppb for
ground water. Drinking water levels of comparisons (DWLOCs),
theoretical upper allowable limits on the pesticide's concentration in
drinking water, were calculated to be much higher than the EEC's. The
chronic DWLOC's ranged from 198 to 697 ppb. The acute DWLOC's ranged
from 440 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 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 (7.3% aPAD) for the
overall U.S. population shows that an adequate margin of safety exists.
Using only pesticide handlers exposure data base (PHED) data levels A
and B (those with a high level of confidence), margin of exposure
(MOEs) for occupational exposure are 650 for mixer/loaders and 1,351
for airblast 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, is
0.000238 mg/kg/day or 1.2% of the RfD. For infants (non-nursing, <1
yr.), 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% a PAD) for children 1-6 and 0.026036 mg/kg/
day (21.7% a PAD) for non-nursing infants. There are residential uses
of indoxa carb pending, but exposure is calculated to be extremely
minimal. The estimated levels of indoxa carb 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 indoxa carb, 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 indoxa carb,
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.
[[Page 39547]]
F. International Tolerances
To date, no international tolerances exist for indoxacarb.
[FR Doc. 03-16739 Filed 7-1-03; 8:45 am]
BILLING CODE 6560-50-S