Document ID: EPA-HQ-OPP-2008-0271-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-05-16T04:00Z

Notice of Filing of Pesticide Petition PP#8E7324

EPA Registration Division contact: Susan Stanton, 703-305-5218	

The Interregional Research Project #4 (IR-4)

PP# 8E7324

EPA has received a pesticide petition (PP# 8E7324) from The
Interregional Research Project #4 (IR-4), 500 College Rd. East, Suite
201 W, Princeton, NJ 08540, 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 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-(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 Bushberry subgroup 13-07B at 1.5 parts per
million (ppm); Beet, garden, roots at 0.3 ppm; and Beet, garden, tops at
6.0 ppm. EPA has determined that the petition contains data or
information regarding the elements set forth in section 408(d)(2) of the
FFDCA; however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of the
petition.  Additional data may be needed before EPA rules on the
petition.

A. Residue Chemistry                                      

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.  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.	Blueberries Thirteen field trials were conducted on blueberries. 
Four foliar applications were made at the maximum use rate of 0.11 lb.
of active ingredient per acre (0.44 lb. of active ingredient maximum
seasonal use rate).  Harvesting was conducted 6 - 8 days after the last
application (PHI- Post Harvest Interval).  The mean field residue value
for blueberries was 0.57 ppm and the maximum at 1.04 ppm.   

b.	Garden beets: Five field trials were conducted on garden beets.  Four
applications were made at the maximum use rate of 0.11 lb. of active
ingredient per acre (0.44 lb. of active ingredient maximum seasonal use
rate).  The trials were harvested at 7 days after the final application.
 In addition, one trial was harvested at 3, 10 and 14 days post
application.  The mean field residue value for garden beet roots was
0.164 ppm with a maximum residue level of 0.22 ppm.  The mean field
residue value for garden beet tops was 2.47 ppm with a maximum residue
level of 3.96 ppm.

B. Toxicological Profile

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

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

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. 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 use on
garden beets and blueberries.  

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.

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, grapes, leafy Brassica, leafy vegetables crop group 4,
tuberous and corm vegetables crop subgroup 1C, pome fruits crop group 11
(except pear), okra, pea (Southern), mint, Cucurbits (Crop Group 9),
Stone Fruit (Crop Group 12), cranberries, and the proposed uses on
garden beets, and bushberries (Crop SubGroup 13-07B) is well within
acceptable limits for all sectors of the population. The chronic module
of the Dietary Exposure Evaluation Model with Food Commodity Intake
Database (DEEM-FCIDTM, version 2.00, Exponent, Inc.) was used to conduct
the assessment with the chronic reference dose (cRfD) of 0.02mg/kg/ day.
This model incorporates nationwide food consumption data as reported by
respondents in the U.S. Department of Agriculture (USDA) 1994-1996, 1998
Continuing Surveys of Food Intake by Individuals (CSFII).  The analysis
used overall mean field trial values, processing factors and actual and
projected five-year average 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 0.000294
mg/kg/day, and utilizes 2% of the cRfD for the overall U.S. population.
The exposure of the most highly exposed subgroup in the population,
children age 1-2 years, is 0.000751 mg/kg/day, which is 4% of the cRfD. 
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)	% cRfD

U.S Population

All infants

Children 1-2

Children 3-5

Children 6-12

Youth 13-19

Adults 20-49

Adults 50+	0.000294

0.000256

0.000751

0.000592

0.000343

0.000257

0.000229

0.000293	2

1

4

3

2

1

1

2

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, potatoes, soybeans, grapes,
leafy Brassica, leafy vegetables crop group 4, tuberous and corm
vegetables crop subgroup 1C, pome fruits crop group 11 (except pear),
okra, pea (Southern), mint, Cucurbits (Crop Group 9), Stone Fruit (Crop
Group 12), cranberries, and the proposed uses on garden beets, and
bushberries (Crop SubGroup 13-07B) is well within acceptable limits for
all sectors of the population.  The acute module of the Dietary Exposure
Evaluation Model with Food Commodity Intake Database (DEEM-FCIDTM,
version 2.15, Exponent, Inc.) was used to conduct the assessment with
the acute reference dose (aRfD) of 0.12mg/kg/ day. This model
incorporates nationwide food consumption data as reported by respondents
in the U.S. Department of Agriculture (USDA) 1994-1996, 1998 Continuing
Surveys of Food Intake by Individuals (CSFII).  The Tier 3 analysis used
distributions of field trial residue data adjusted for actual and
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
reference dose (aRfD) 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 proposed uses clearly meets the
FQPA standard of reasonable certainty of no harm.

Subgroup	99.9th Percentile Of Exposure

	Exposure (mg/kg/day)	% Acute reference dose

(aRfD)

U.S. Population

All infants

Children 1-2

Children 3-5

Children 6-12

Youth 13-19

Adults 20-49

Adults 50+	0.025644

0.067568

0.055866

0.048160

0.022815

0.025837

0.022442

0.026808	21

56

47

40

19

22

19

22

ii. 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 FIRST Tier 1 surface water and SCI GROW Tier 1 groundwater models
under worst-case conditions the acute estimated environmental
concentrations (EECs) of indoxacarb and its R enantiomer are 15.614
parts per billion (ppb) for surface water and 0.02 ppb for ground water.
The chronic EECs are 1.655 ppb for surface water and 0.02 ppb for ground
water.  

When the higher surface water concentrations were included in the acute
and chronic dietary risk assessments, there was little change from the
food-only dietary risk assessments.  For the acute assessment which
included drinking water as a point estimate the predicted exposure at
the 99.9th percentile for the general U.S. population was 0.025710
mg/kg/day which corresponds to 21% of the aRfD; the most sensitive
subpopulation, infants, had an estimated exposure of 0.066107 mg/kg/day,
55% of the aRfD.  For the chronic assessment which included drinking
water the predicted exposure for the general population was 0.000330
mg/kg/day, 2% of the cRfD; the most sensitive subpopulation, children
1-2 years, had an estimated exposure of 0.000804 mg/kg/day, 4% of the
cRfD.  Thus, the acute and chronic dietary exposure of indoxacarb,
including the contribution of drinking water, clearly meets the standard
of reasonable certainty of no harm.  

 

2. Non-dietary exposure. Indoxacarb product registrations for
residential non food uses have been approved. Non-occupational,
non-dietary exposure for indoxacarb has been estimated to be low.

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. Indoxacarb has a novel mode of action compared to currently
registered active ingredients.

E. Safety Determination

1. U.S. population. 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. Based on the completeness and reliability of
the toxicity data, the lack of toxicological endpoints of special
concern, the lack of any indication that children are more sensitive
than adults to indoxacarb, and the conservative exposure assessment,
there is a reasonable certainty that no harm will result to infants and
children from the aggregate exposure of residues of indoxacarb,
including all anticipated dietary exposure and all other
non-occupational exposures. Accordingly, there is no need to apply an
additional safety factor for infants and children.

F. International Tolerances

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