EPA Registration Division contact: Laura Nollen,<PHONE_NUMBER>

{<HD1>} Interregional Research Project Number 4 (IR-4)

Petition Number (PP#) 2E8029{</HD1>}

	{
}EPA has received a pesticide petition, PP# 2E8029, from
Interregional Research Project Number 4 (IR-4), IR-4 Project
Headquarters, Rutgers, The State University of New Jersey, 500 College
Road East, Suite 201 W, Princeton, NJ  08450 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 180.564 {
} by establishing a
tolerance for residues of the combined residues of Indoxacarb,
(S)-methyl
7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)phenyl]am
ino]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-(trifluoromethox
y)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 bean, dry, seed at 0.07 parts per million
(ppm); bean, succulent at 0.64 ppm; bean, forage (foliage of leguminous
vegetables/cow pea foliage) at 37 ppm; small fruit, vine climbing,
except fuzzy kiwifruit, subgroup 13-07F at 2.0 ppm; and berry, low
growing, except strawberry, subgroup 13-07H at 0.9 ppm. Upon approval of
the aforementioned tolerances, the petition additionally requests to
remove the established tolerances in or on grape at 2.0 ppm and
cranberry at 0.90 ppm. in 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.

{<HD2>} A. Residue Chemistry{</HD2>}

The active ingredient in the end-use formulation DuPont Avaunt®
Insecticide 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.  The active ingredient in the end-use
formulation, DuPont™ Steward® EC Insecticide is indoxacarb; no
IN-KN127 is present.  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. {<E T=(03'>} Plant metabolism{</E>} . 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. {<E T=(03'>} Analytical method{</E>} . 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.  Nine field trials were conducted on
snap beans. Each field trial site consisted of one untreated control
plot and one treated plot. At all the trials the test substance was
applied as a foliar application.  Four applications, six to eight days
apart, were made at the maximum use rate of 0.119 lb of indoxacarb
active ingredient per acre (0.457 lb of active ingredient maximum
seasonal use rate).  Harvesting was done 2-3, 7 and 13 days after the
last application.  For the pods with seeds samples (at the 2 – 3 day
PHI), the residue levels ranged from 0.04 to 0.59 ppm and for the plant
samples (at the 2 – 3 day PHI), the residue levels range from 1.3 to
32.1 ppm.

{
}

					Thirteen field trials were conducted on dry beans.  Each field
trial site consisted of one untreated control plot and one treated plot.
At all the trials the test substance was applied as a foliar
application.  Four applications, six to eight days apart, were made at
0.106 to 0.118 lb of indoxacarb active ingredient per acre (0.438 to
0.463 lb of active ingredient maximum seasonal use rate).  Harvesting
was done 6-8 days after the last application.  The residue levels in the
harvested beans ranged from < 0.01 ppm to 0.093 ppm.

{<HD2>} B. Toxicological Profile{</HD2>}

	{
} 	1. {<E T=(03'>} Acute toxicity{</E>} .  Based on EPA criteria,
indoxacarb is classified as follows for Toxicity Categories

Guideline	Title	Results	Category

870.1100

870.1200

870.1300

870.2400

870.2500

870.2600	Acute Oral Toxicity

Acute Dermal Toxicity

 Acute Inhalation Toxicity

Primary Eye Irritation

Primary Dermal Irritation

Skin Sensitization	LD50:1730 mg/kg (M  Rat)

LD50: 268 mg/kg/(F  Rat)

LD50: >5000 mg/kg  (Rat)

LC50: >5.5 mg/L (M  Rat)

(70% MUP)

Effects reversed within 72 hours (Rabbit)

No irritation (Rabbit)

Sensitizer (Guinea Pig)	Category II

Category IV

Category IV

Category III

Category IV

---------------

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. {<E T=(03'>} Genotoxicty{</E>} .  [Indoxacarb has shown no
genotoxic activity in the following listed in-vitro and in-vivo tests:

Ames-- Negative

In-vitro mammalian gene mutation (CHO/HGPRT)-- Negative

In-vitro unscheduled DNA synthesis-- Negative

In-vitro chromosomal aberration-- Negative

In-vivo mouse micronucleus-- Negative]{
}

	{
} 	3.{<E T=(03'>}  Reproductive and developmental toxicity{</E>} .
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 1000 mg/kg/day.

In a developmental neurotoxicity study, dams administered 3 mg/kg/day
from gestation day 6 through lactation day 10 had decreased body weight,
weight gain, and food consumption; increased incidences of clinical
signs of toxicity; and test substance-related mortality.  At maternally
toxic doses of 3 mg/kg/day, there was also an increase in offspring
effects including lower body weight.    In addition, beginning on
lactation day 11, offspring  were directly administered the test
substance daily by oral gavage through lactation day 21.  There were no
effects in offspring on learning and memory, sexual maturation, motor
activity, acoustic startle habituation, terminal body weights, brain
weights, selected hematology parameters, neuromorphometric parameters,
or neurohistopathology.  There were no biologically significant effects
on dams or offspring administered dosages of 1.5, 1, or 0.5 mg/kg/day.

	{
} 	4. {<E T=(03'>} Subchronic toxicity. {</E>} 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.{<E T=(03'>}  Chronic toxicity{</E>} . 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. {<E T=(03'>} Animal metabolism{</E>} . 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.

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. Concentrations of residues in eggs were low,
0.3-0.4 of the total dose, as were the concentrations 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).

Poultry Feeding study.  Four groups of laying hens (10/ group) were
dosed orally once a day for 28 consecutive days-with capsules containing
indoxacarb at levels equivalent to target concentrations of 1.75, 7.0,
21.0, and 70.0 ppm in the feed on a dry weight basis.  Residues of each
analyte plateaued in whole eggs within 14-21 days of dosing.  Residues
in fat, skin, and liver were dose dependent, particularly for the top
three dose levels.

The maximum combined residues in fat were 0.11, 0.54, 1.5, and 5.0 ppm
from the 1.75, 7, 21, and 70 ppm dose groups, respectively; and combined
residues in fat averaged 0.10, 0.44, 1.4, and 4.13 ppm from the
respective dose groups. The maximum combined residues inskin were
<0.07,0.17,0.60, and 1.20 ppm from the 1.75,7,21, and 70 ppm dose
groups, respectively; and combined residues in skin averaged
<0.07,0.12,0.51, and 1.06 ppm from the respective dose groups. In liver,
the maximum combined residues were <0.06, <0.09, 6.21, and 0.67 ppm from
the 1.75,7,21, and 70 ppm dose groups, respectively; and combined
residues in liver averaged 0.03, 0.08, 0.18, and 0.52 ppm from the
respective dose groups In composited muscle, the maximum combined
residues were <0.06 ppm from the 1.75 and 7 ppm dose groups, <0.07 ppm
from the 21 ppm dose group, and 0.15 ppm from the 70 ppm dose group.
Combined residues in muscle averaged 0.03, 0.03, 0.06, and 0.12 ppm from
the 1.75, 7, 21, and 70 ppm dose groups, respectively.

Following a 28-day recovery period for hens dosed at 70 ppm, residues of
each analyte were non-detectable «0.003 ppm) in skin, liver, and
muscle. Residues of each analyte were also <0.003 ppm in fat with the
exception of IN-JT333, which had detectable residues (0.004-0.009 ppm)
below the method LOQ. following the cessation of dosing average combined
residues in eggs declined from 0.65 ppm at 2 days post-dose to 0.07 ppm
by 9 days post-dose. By 12 days postdose, residues of each analyte,
except IN-JT333, were <0.003 ppm in eggs, and residues of IN-JT333
declined to <0.003 ppm by 23 days post-dose.

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.

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. {<E T=(03'>} Metabolite toxicology{</E>} . 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. {<E T=(03'>} Endocrine disruption{</E>} .  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.{
}

{<HD2>} C. Aggregate Exposure{</HD2>}

Tolerances for indoxacarb are proposed to support agricultural use on
succulent beans, dried beans, and the crops of subgroups 13-07 F and
13-07 H.

	{
} 	1. {<E T=(03'>} Dietary exposure{</E>} . 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.{
}

	{
} 	i. {<E T=(03'>} Food{</E>} .  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 uses on grapes, leafy
Brassica, leafy greens crop subgroup 4A (except spinach), spinach, leaf
petioles crop subgroup 4B, tuberous and corm vegetables crop subgroup
1C, pome fruits crop group 11 (except pear), okra, pea (Southern) and
mint 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 7.87)
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 0.000185
mg/kg/day, and utilizes 1% of the RfD for the overall U.S. population.
The exposure of the most highly exposed subgroup in the population,
children age 1-2 years, is 0.000347 mg/kg/day, and utilizes 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.

 PRIVATE  Subgroup tc  \l 1 "Subgroup" 	Maximum Dietary Exposure
(mg/kg/day)	% RfD

U.S Population

All infants

Males 13-19

Males 20+

Seniors 55+

Children 1-2

Children 3-5

Children 6-12

Youth 13-19

Adults 20-49

Adults 50+

Females 13-19

(not preg or nursing)

Females 20+

(not preg or nursing)	0.000185

0.000126

0.000183

0.000165

0.000186

0.000347

0.000315

0.000191

0.000171

0.000163

0.000186

0.000157

0.000179	1

1

1

1

1

2

2

1

1

1

1

1

1

		Acute dietary exposure. Acute dietary exposure resulting from the
proposed uses and 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 uses on
grapes, leafy Brassica, leafy greens crop subgroup 4A (except spinach),
spinach, leaf petioles crop subgroup 4B, tuberous and corm vegetables
crop subgroup 1C, pome fruits crop group 11 (except pear), okra, pea
(Southern) and mint are well within acceptable limits for all sectors of
the population.  The Dietary Exposure Evaluation Model (DEEM, Exponent,
Inc., formerly Novigen Sciences, Inc., Version 7.87) was used to conduct
the assessment.  Margins of exposure (MOE) were calculated based on a
NOAEL of 12 mg/kg/day for children and the general population (Pesticide
Fact Sheet for Indoxacarb).  An endpoint of concern attributable to a
single dose was not identified for women of childbearing age; therefore
an acute RfD was not established for this population.  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.

Subgroup	99.9th Percentile Of Exposure

	Exposure (mg/kg/day)	% Acute population adjusted dose (aPAD)

U.S. Population

All infants

Males 13-19

Males 20+

Seniors 55+

Children 1-2

Children 3-5

Children 6-12

Youth 13-19

Adults 20-49

Adults 50+

	0.020267

0.018458

0.029223

0.019257

0.020072

0.036020

0.005358

0.017498

0.022245

0.018887

0.019883	17

15

24

16

17

23

30

15

19

16

17

	{
} 	ii. {<E T=(03'>} Drinking water{</E>} . 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 comparison (DWLOCs),
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 to 697 ppb. The acute DWLOCs ranged from
440 to 3890 ppb. Thus, exposure via drinking water is acceptable.{
}

	{
} 	2. {<E T=(03'>} Non-dietary exposure{</E>} . Indoxacarb product
registrations for residential non-food uses have been approved.
Non-occupational, non-dietary exposure for DPX- MP062 has been estimated
to be extremely small. Therefore, the potential for non-dietary exposure
is insignificant.{
}

{<HD2>} D. Cumulative Effects{</HD2>}

	{
} 	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.{
}

{<HD2>} E. Safety Determination{</HD2>}

	{
} 	1. {<E T=(03'>} U.S. population{</E>} . 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 0.000185 mg/kg/day, which
utilizes 1% 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 (17% aPAD) 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 1351 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. {<E T=(03'>} Infants and children{</E>} . Chronic dietary
exposure of the most highly exposed subgroup in the population, children
age 1-2 years, is 0.000347 mg/kg/day or 2% of the RfD. For all infants,
the exposure accounts for 1% of the RfD.  For acute exposure at the
99.9th percentile (based on a Tier 3 assessment) the exposure was
0.005358 mg/kg/day (30% aPAD) for children 3-5 and 0.018458 mg/kg/day
(15% aPAD) for all infants. Residential uses of indoxacarb have been
approved and 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.{
}

{<HD2>} F. International Tolerances{</HD2>}

	{
} 	To date, numerous tolerances exist for indoxacarb residues in
various food and feed crops and foods of animal origin in at least 25
countries.{
}

	 page \* arabic 2


[Federal Register Volume 85, Number 221 (Monday, November 16, 2020)]
[Notices]
[Pages 73057-73060]
[FR Doc No: 2020-25239]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. FDA-2020-N-2030]

Agency Information Collection Activities; Proposed Collection;
Comment Request; Application for Food and Drug Administration Approval
To Market a New Drug

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is announcing
an opportunity for public comment on the proposed collection of certain
information by the Agency. Under the Paperwork Reduction Act of 1995
(PRA), Federal Agencies are required to publish notice in the Federal
Register concerning each proposed collection of information, including
each proposed extension of an existing collection of information, and
to allow 60 days for public comment in response to the notice. This
notice solicits comments on information collection associated with
applications for FDA approval to market a new drug.

DATES: Submit either electronic or written comments on the collection
of information by January 15, 2021.

ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before January 15, 2021. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of January 15, 2021. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are postmarked or the delivery
service acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2020-N-2030 for ``Agency Information Collection Activities;
Proposed Collection; Comment Request; Application for FDA Approval To

Market a New Drug.'' Received comments, those filed in a timely manner
(see ADDRESSES), will be placed in the docket and, except for those
submitted as ``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday,<PHONE_NUMBER>.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852,<PHONE_NUMBER>.

FOR FURTHER INFORMATION CONTACT: Domini Bean, Office of Operations,
Food and Drug Administration, Three White Flint North, 10A-12M, 11601
Landsdown St., North Bethesda, MD 20852,<PHONE_NUMBER>,
<EMAIL_ADDRESS>
SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3521), Federal
Agencies must obtain approval from the Office of Management and Budget
(OMB) for each collection of information they conduct or sponsor.
``Collection of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR
1320.3(c) and includes Agency requests or requirements that members of
the public submit reports, keep records, or provide information to a
third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A))
requires Federal Agencies to provide a 60-day notice in the Federal
Register concerning each proposed collection of information, including
each proposed extension of an existing collection of information,
before submitting the collection to OMB for approval. To comply with
this requirement, FDA is publishing notice of the proposed collection
of information set forth in this document.
    With respect to the following collection of information, FDA
invites comments on these topics: (1) Whether the proposed collection
of information is necessary for the proper performance of FDA's
functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.

Application for FDA Approval To Market a New Drug;

OMB Control No. 0910-0001--Revision

    This information collection supports FDA regulations. Under Sec.
505(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21
U.S.C. 355(a)), a new drug may not be commercially marketed in the
United States unless an approval of an application filed with FDA under
Sec.  505(b) or (j) of the FD&C Act is effective with respect to such
drug. We have issued regulations in part 314 (21 CFR part 314) to
govern procedures and requirements for applications submitted in
accordance with section 505. The regulations in subpart A (Sec. Sec.
314.1 through 314.3) set forth general provisions, while regulations in
subparts B and C (Sec. Sec.  314.50 through 314.99) set forth content
and format requirements for new drug applications (NDAs) and
abbreviated new drug applications (ANDAs) respectively. The regulations
include requirements for the submission of specific data elements along
with patent information, pediatric use information, supplements and
amendments, proposed labeling, and specific postmarketing reports.
Respondents to the information collection are sponsors of these
applications.
    To assist respondents to the information collection we have
developed the following forms:
     Form FDA 0356h (and instructions): Application to Market a
New or Abbreviated New Drug or Biologic for Human Use;
     Form FDA 2252 (and instructions): Transmittal of Annual
Reports for Drugs and Biologics For Human Use (Sec.  314.81);
     Form FDA 2253 (and instructions): Transmittal of
Advertisements and Promotional Labeling For Drugs and Biologics For
Human Use; and
     Forms FDA 3331/3331a: Field Alert Report and Instruction;
     Forms FDA 3542 and 3542a and Instructions: Patent
Information Submitted Upon and After Approval of an NDA Supplement;
Patent Information Submitted With the Filing of an NDA, Amendment, or
Supplement;
     New Draft Form FDA 3898 and Instruction: Drug Master File.
    Individuals requesting printed forms are instructed to contact the
FDA Forms Manager by email at<EMAIL_ADDRESS>Certain fees may
be applicable.
    Regulations in subpart D (Sec. Sec.  314.100 through 314.170)
explain Agency actions on applications and set forth timeframes for FDA
review. We are revising the information collection to include
provisions established through our Agency user fee programs, most
recently authorized under the FDA Reauthorization Act of 2017. These
provisions pertain to review transparency, communications with FDA,
dispute resolution, drug safety enhancements, and the allocation of
Agency resources to align with these program objectives as agreed to
with our stakeholders and set forth in our ``Performance Goals for
Fiscal Years 2018-2022'' Commitment Letters, which are available from
our website at https://www.fda.gov along with more information about
FDA user fee programs.
    Information collection pertaining to hearing and other
administrative proceedings covered in 21 CFR subpart E are approved
under OMB control no. 0910-0191. Unless otherwise noted, information
collection pertaining to postmarket safety reporting and associated
recordkeeping is approved under OMB control nos. 0910-0230, 0910-0291,
and 0910-0645.

    Included among the miscellaneous provisions in subpart G
(Sec. Sec.  314.410-314.445), Sec.  314.420 covers information to
include in drug master files (DMFs). To assist respondents to this
information collection we have prepared templates and resources
available from our website at www.fda.gov/drugs/forms-submission-requirements/drug-master-files-dmfs. As noted above, we have developed
new Form FDA 3898 and accompanying instructions on submitting DMFs in
accordance with the applicable regulations. In accordance with Sec.
314.445, we also develop Agency guidance documents to assist
respondents in complying with provisions in part 314. These guidance
documents are issued consistent with our good guidance practice
regulations at Sec.  10.115. To search available FDA guidance
documents, visit our website at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. Finally, applications
submitted in accordance with subpart H (Sec. Sec.  314.500 through
314.560) pertain to accelerated approval of new drugs for serious or
life-threatening illness, and submissions in subpart I (Sec. Sec.
314.600 through 314.650) pertain to approval of new drugs when human
efficacy studies are not ethical or feasible. The regulations provide
for the submission of specific data elements along with promotional
material.
    We use the information collection to approve drugs shown to be safe
and effective and to implement effective public health monitoring
systems. We also use product approval and related patent and
exclusivity information to publish the ``Approved Drug Products with
Therapeutic Equivalence Evaluations'' list (the Orange Book). More
information regarding the Orange book is available from our website at
www.fda.gov/drugs/drug-approvals-and-databases/approved-drug-products-therapeutic-equivalence-evaluations-orange-book.
    We estimate the burden for this collection of information as
follows:

                                                       Table 1--Estimated Annual Reporting Burden
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                                                                   Number of
                21 CFR section                     Number of     responses per   Total annual   Average burden  per response  (in hours)    Total hours
                                                  respondents     respondent       responses
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                                                                        SUBPART B
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314.50(a)-(l)--Content and format of a                     121            1.15             139  1,921...................................         267,019
 505(b)(1) or 505(b)(2) application.
314.50(i)(1)--patent certifications Form FDA               281           2.875             808  10......................................           8,080
 3542.
Form FDA 3542a................................             310           2.084             646  15......................................           9,690
314.50(i)(6) amended patent certifications....              17               1              17  2.......................................              34
314.52(a), (b), and (e)--NDAs--notice of                    15               3              45  15......................................             675
 noninfringement of patent certification.
314.52(c)--Noninfringement of patent                        22               3              66  0.33 (20 minutes).......................              22
 certification notice content.
314.53(f)(1)--Correction of patent information              24               1              24  10......................................             240
 errors by persons other than the NDA holder.
314.53(f)(2)--Correction of patent information              28             1.4              39  1.......................................              39
 errors by the NDA holder.
314.60--Amendments to unapproved NDA,                      256            8.23           2,106  80......................................         168,480
 supplement or resubmission.
314.60(f)--patent certifications for                         6               1               6  2.......................................              12
 unapproved applications.
314.65--Withdrawal of unapproved applications.              14            1.21              17  2.......................................              34
314.70 and 314.71--Supplements and other                   492            6.57           3,232  150.....................................         484,800
 changes to approved application.
314.72--Changes of ownership of NDAs..........              67            1.45              97  2.......................................             194
314.81--Other postmarketing reports                        484            20.3           9,834  8.......................................          78,672
 314.81(b)(1) [3331 and 3331a field alert
 reports and followups].
314.81(b)(2)[2252]--Annual reports............             626             4.9           3,066  40......................................         122,640
314.81(b)(2)[2253]--Promotional labeling......             331           141.3          46,782  2.......................................          93,564
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                                                                        SUBPART C
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314.94(a)and(d)--ANDA content.................             229             4.3             987  480.....................................         473,760
314.94(a)(12)(viii) amended patent                         153               1             153  2.......................................             306
 certifications before approval of ANDA.
314.95(c)--Non-infringement of patents (ANDAs)             400               3           1,200  0.33 (20 minutes).......................             400
314.96(a)(1)--Amendments to unapproved ANDAs..             451            36.2          16,311  80......................................       1,304,880
314.96(c) amendment for pharmaceutical                       1               1               1  300.....................................             300
 equivalent to a listed drug other than RLD.
314.96(d)--patent certification requirements..             100               1             100  2.......................................             200
314.97--Supplements and other changes to ANDAs             361            22.8           8,237  80......................................         658,960
314.97(b) Supplements to ANDA for                            1               1               1  300.....................................             300
 pharmaceutical equivalent to a listed drug
 other than RLD.
314.99(a)--ANDA Applicants: Withdrawal of                   77             2.3             177  2.......................................             354
 unapproved ANDAs.
314.99(a)--ANDA Transfer of ownership.........             135            1.24             167  2.......................................             334
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                                                                        SUBPART D
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314.101(a)--NDA or ANDA filing over protest...               1               1               1  0.5 (30 minutes)........................             0.5

314.107(e)--notification of court actions or               247               2             494  0.5 (30 minutes)........................             247
 written consent to approval.
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                                                                     SUBPART G, H, I
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314.420--drug master files [FDA 3938]--                     36            27.2             981  61......................................          59,841
 original amendments.
DMFs--technical, administrative, REMS)........           2,946            11.4          33,590  8.......................................         268,720
DMFs--annual reports..........................           2,946            3.33           9,834  4.......................................          39,336
314.550--Promotional material and subpart H                 55            11.6             640  120.....................................          76,800
 applications.
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    Total.....................................  ..............  ..............  ..............  ........................................     4,118,933.5
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    Our estimated burden for the information collection reflects a
decrease. We attribute this adjustment to improved operational
efficiencies with regard to Agency data systems and digital submission
processes.

    Dated: November 10, 2020.
Lauren K. Roth,
Acting Principal Associate Commissioner for Policy.
[FR Doc. 2020-25239 Filed 11-13-20; 8:45 am]
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