Document ID: EPA-HQ-OPP-2005-0149-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-07-11T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF                  

PREVENTION, PESTICIDES AND 

TOXIC SUBSTANCES       

MEMORANDUM

DATE:		23-MAY-2007

SUBJECT:	     PP#s: 2E6482, 3F6576, 5E6911, 5E6926, and 5E6991. 
Indoxacarb.  Health Effects Division (HED) Risk Assessment for Grapes;
Vegetable, Brassica, Leafy, Group 5; Turnip Greens; Vegetable, Leafy,
Except Brassica (Group 4); Pome Fruits (Group 11, except pear); Tuberous
and Corm Vegetables (Subgroup 1C); Cucurbit Vegetables (Group 9); Stone
Fruits (Group 12); Cranberry; Mint; Okra; Southern Pea; and Fire Ant
Bait.  

PC Code: 067710.  DP#s: 324855, 324862, 324893, 339668, and 339669. 
Decision#s: 355154, 356203, 360904, 306007, and 332867.

	

FROM:		Sarah J. Levy, Chemist

Guruva B. Reddy, D.V.M., Ph.D., Veterinary Medical Officer 

Mohsen Sahafeyan, Chemist

Kelly M. Lowe, Environmental Scientist

Yudith Tesfaye, Biologist

Registration Action Branch 1 (RAB1)/HED (7509P)

THRU:	    P.V. Shah, Ph.D., Acting Branch Chief

    RAB1/HED (7509P)

TO:			Dan Rosenblatt/Maria Rodriguez, PM Team 05

Registration Division (RD) (7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with
estimating the risk to human health from exposure to pesticides.  The
OPP RD has requested that HED evaluate hazard and exposure data and
conduct dietary, occupational/residential, and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result from the proposed and registered uses of indoxacarb.

A summary of the findings and an assessment of human risk resulting
from the proposed uses of indoxacarb is provided in this document.  The
risk assessment and residue chemistry data review were provided by Sarah
Levy of RAB1, the dietary exposure risk assessment was provided by
Mohsen Sahafeyan and Sarah Levy of RAB1; the hazard characterization by
Guruva Reddy of RAB1, the occupational and residential exposure and risk
assessment by Kelly Lowe and Yudith Tesfaye of RAB1, and the water
exposure assessment by Jim Hetrick of the Environmental Fate & Effects
Division (EFED).

NOTE:  The most recent Section 3 indoxacarb risk assessment that HED
completed was for new uses on alfalfa, lettuce, peanut, potato, and
soybean (Memo, S. Levy, et al., 23-MAY-2002; DP#: 276567).  The current
risk assessment document contains those aspects of the risk assessment
which are affected by the new toxicological studies and the addition of
proposed uses of indoxacarb on grapes, Brassica leafy vegetables, turnip
greens, vegetable, leafy, except Brassica (group 4), pome fruits (group
11, except pear), tuberous and corm vegetables (subgroup 1C), cucurbit
vegetables (group 9), stone fruits (group 12), cranberry, mint, okra,
and southern pea, as well as a residential use as a fire ant bait.

TABLE OF CONENTS

  TOC \o "1-6" \u  1.0.  EXECUTIVE SUMMARY	  PAGEREF _Toc167704759 \h  4

2.0.  PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION	  PAGEREF
_Toc167704760 \h  13 

2.1.  Identification of Active Ingredient	  PAGEREF _Toc167704761 \h  13

2.2.  Physical and Chemical Properties	  PAGEREF _Toc167704762 \h  14 

3.0.  HAZARD CHARACTERIZATION	  PAGEREF _Toc167704763 \h  14 

3.1.  Hazard Profile	  PAGEREF _Toc167704764 \h  14 

3.2.  FQPA Considerations	  PAGEREF _Toc167704765 \h  25 

3.2.1.  Pre-and/or Postnatal Toxicity	  PAGEREF _Toc167704766 \h  25 

3.2.1.1.  Determination of Susceptibility	  PAGEREF _Toc167704767 \h  25

3.2.1.2.  Degree of Concern Analysis and Residual Uncertainties	 
PAGEREF _Toc167704768 \h  25 

3.2.2.  Recommendation for a DNT Study	  PAGEREF _Toc167704769 \h  25 

3.3.  FQPA SF	  PAGEREF _Toc167704770 \h  25 

3.3.1.  Adequacy of the Exposure Database	  PAGEREF _Toc167704771 \h  25

3.3.2.  FQPA SF Conclusion	  PAGEREF _Toc167704772 \h  25 

3.4.  Endocrine Disruption	  PAGEREF _Toc167704773 \h  26 

4.0.  EXPOSURE ASSESSMENT	  PAGEREF _Toc167704774 \h  26 

4.1.  Summary of Proposed Food Uses	  PAGEREF _Toc167704775 \h  26 

4.2.  Dietary Exposure	  PAGEREF _Toc167704776 \h  28 

4.2.1.  Residue Profile	  PAGEREF _Toc167704777 \h  29 

4.2.2.  Dietary Exposure Analyses	  PAGEREF _Toc167704778 \h  37 

4.2.2.1.  Acute Dietary Exposure Analysis	  PAGEREF _Toc167704779 \h  38

4.2.2.2.  Chronic Dietary Exposure Analysis	  PAGEREF _Toc167704780 \h 
39 

4.2.2.3.  Cancer Dietary Exposure Analysis	  PAGEREF _Toc167704781 \h 
40 

4.3.  Water Exposure/Risk Pathway	  PAGEREF _Toc167704782 \h  40 

4.4.  Residential Exposure/Risk Pathway	  PAGEREF _Toc167704783 \h  41 

5.0.  AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION	  PAGEREF
_Toc167704784 \h  44 

5.1.  Short- and Intermediate-Term Aggregate Risk (food + drinking water
+ residential exposure)	  PAGEREF _Toc167704785 \h  44 

6.0.  CUMULATIVE RISK	  PAGEREF _Toc167704786 \h  45 

7.0.  OCCUPATIONAL EXPOSURE	  PAGEREF _Toc167704787 \h  46 

7.1.  Occupational Handler Exposure	  PAGEREF _Toc167704788 \h  46 

7.2.  Post-Application	  PAGEREF _Toc167704789 \h  49 

7.3.  Incidents	  PAGEREF _Toc167704790 \h  53 

8.0.  DATA NEEDS/LABEL REQUIREMENTS	  PAGEREF _Toc167704791 \h  54 

8.1.  Toxicology	  PAGEREF _Toc167704792 \h  54 

8.2.  Chemistry	  PAGEREF _Toc167704793 \h  54 

8.3.  Occupational/Residential Exposure	  PAGEREF _Toc167704794 \h  54 

 

1.0.  EXECUTIVE SUMMARY tc \l1 "1.0.	EXECUTIVE SUMMARY 

DuPontTM and Interregional Research Project No. 4 (IR-4) have submitted
petitions (PP#s: 2E6482, 3F6576, 5E6911, 5E6926, and 5E6991) proposing
to amend the label for DuPontTM’s 30% water-dispersible granule (WDG)
to include new uses on grapes, Brassica leafy vegetables, turnip greens,
cranberry, cucurbit vegetables (group 9), leafy vegetables except
Brassica, mint, okra, pome fruits (group 11, except pear), southern
peas, stone fruits (group 12), and tuberous and corm vegetables
(subgroup 1C).  Furthermore, the occupational/residential use of
indoxacarb as a fire ant bait (DuPontTM, Advion®; 0.045% (granular
formulation, EPA Reg. No. 352-627)) is assessed as well.  In conjunction
with these new uses, the petitioners proposed the following indoxacarb
tolerances:

Grape	2.0	ppm

Raisin	6.0	ppm

Vegetable, brassica, leafy, group 5	12	ppm

Turnip greens	12	ppm

Cranberry	1	ppm

Fruit, pome, except pear, group 11	1.0	ppm

Fruit, stone, group 12	1	ppm

Leafy vegetables except Brassica	14	ppm

Mint	10	ppm

Okra	0.5	ppm

Pea (southern)	0.1	ppm

Vegetable, cucurbit, group 9	0.5	ppm

Vegetable, tuberous and corm, subgroup 1C	0.01	ppm

An alternative to organophosphate (OP) insecticides, indoxacarb is an
oxadiazine class insecticide that is used primarily for the control of
lepidopteran pests in the larval stages on a variety of fruit, vegetable
and field crops.  Insecticidal activity occurs via blockage of the
sodium channels in the insect nervous system and mode of entry is via
stomach and contact routes.  Indoxacarb is a reduced-risk insecticide. 
There are currently two end-use products of indoxacarb with food/feed
uses registered to DuPontTM:  a 30% WDG formulation (DuPontTM Avaunt®
Insecticide, EPA Reg. No. 352-597) and a 1.25 lb/gal (15%)
suspension-concentrate (SC) formulation (DuPontTM Steward® Insecticide,
EPA Reg. No. 352-598).  Also, as stated above, there is one indoxacarb
product for use as a fire ant bait (DuPontTM, Advion®; 0.045% (granular
formulation, EPA Reg. No. 352-627)).  These formulations contain an
isometric mixture of indoxacarb (insecticidally active S-enantiomer;
DPX-KN128) and the R-enantiomer (insecticidally inactive; IN-KN127). 
The percentage of active ingredient (a.i.) listed on each label and the
labeled use rates for each crop are based only on the amount of
indoxacarb.

Permanent tolerances are established for the combined residues of
indoxacarb, (S)-methyl
7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoro
methoxy)phenyl]amino] carbonyl]
indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate, and its inactive
R-enantiomer in/on various plant commodities at levels ranging from 0.01
ppm in/on peanuts and potatoes to 50 ppm in/on alfalfa hay [40 CFR
§180.564(a)].  Tolerances are established for the combined residues of
indoxacarb + its R-enantiomer in livestock commodities at levels ranging
from 0.03 ppm in livestock meat byproducts to 4.0 ppm in milk fat. 
Time-limited tolerances are also established for the combined residues
of indoxacarb + its R-enantiomer, in connection with use under FIFRA
Section 5 experimental-use permit (EUP) on sweet and tart cherries (set
to expire 21-MAY-2007) and peaches (expired 15-MAY-2006).  Lastly,
time-limited tolerances are established for the combined residues of
indoxacarb + its R-enantiomer, in connection with use under Section 18
Emergency Exemptions on collards (expired 30-JUN-2006) and cranberries
(set to expire 31-DEC-2007).

Hazard Assessment

DPX-MP062 is an enantiomeric mixture containing indoxacarb, the
S-enantiomer (DPX-KN128, the insecticidally active component) and its
R-enantiomer (DPX-KN127, the insecticidally inactive component,) at
approximately a 75:25 ratio.  However, many of the toxicity studies for
this registration request were conducted with DPX-JW062, the racemic
mixture of the enantiomers at a 50:50 ratio.  HED’s Hazard
Identification Assessment Review Committee (HIARC; HED Doc No. 013528)
determined that it is appropriate to use data from DPX-JW062 to satisfy
the requirements for dietary subchronic, chronic, oncogenicity and
reproductive studies.  Based on previous conclusions by the HIARC, HED
also accepted the same rationale for bridging the data from DPX-JW062
and DPX-MP062 to register DPX-KN128 (100% insecticidally active isomer).

DPX-KN128, DPX-MP062 and DPX-JW062 appear to be of similar toxicity
acutely.  DPX-KN128 and DPX-MP062 were moderately acutely toxic by the
oral route (toxicity category II) while DPX-JW062 was practically
non-toxic (toxicity category IV) due to its poor solubility in the corn
oil vehicle.  However, it was as toxic as indoxacarb orally, when tested
using a solvent where it had a higher solubility, such as polyethylene
glycol (PEG).  By the dermal route, they had low toxicity (toxicity
category III and IV).  No acute inhalation toxicity study is available
for DPX-KN128; however, a waiver was requested for this study based on
the data from other two entantiomers.  DPX-MP062 and DPX-JW062 had low
acute inhalation toxicity (IV).  DPX-MP062 and DPX-JW062 had moderate to
low ocular irritant properties (III and IV), while DPX-KN128 was
practically non-irritant to the rabbit’s eyes.  By the maximization
test, DPX-KN128 and DPX-MP062 were considered dermal sensitizers, while
DPX-JW062 was not a sensitizer.

There was possible evidence of lung damage in the acute inhalation
studies with both DPX-MP062 and DPX-JW062. “Lung noise,” observed
with JW062 may indicate the development of acute lung injury and high
permeability pulmonary edema.  This was not unexpected since an oxidant
was generated during indoxacarb metabolism.  “Hunched over back and
gasping” were also present and suggested arterial hypoxemia that
accompanies alveolar flooding.  The acute inhalation study report with
indoxacarb 70% manufacturing use product, noted that a “red nasal
discharge” was detected for 2 days after exposure.  This may be
indicative of a lung exudate, a sign of lung injury.  Subchronic (28
days) inhalation toxicity on indoxacarb in rats was characterized by
increased spleen weights, increased pigmentation and hematopoiesis in
the spleen, and hematological changes.

The toxicity profiles for DPX-KN128, DPX-MP062 and DPX-JW062 in rats,
mice and dogs with both subchronic and chronic oral exposures were
similar.  Dermal subchronic exposure in the rat also resulted in a
similar profile.  The toxic signs occurred at similar doses and with a
similar magnitude of response, with females generally being more
sensitive than males.  The endpoints that most frequently defined the
lowest-observed-adverse-effect-level (LOAEL) were non-specific, and
included decreased body weight, weight gain, food consumption and food
efficiency.  These compounds also affected the hematopoietic system by
decreasing the red blood cell count, hemoglobin and hematocrit in rats,
dogs and mice.  It was frequently accompanied by an increase in
reticulocytes in all three species and an increase in Heinz bodies (dogs
and mice only).  None of these signs of toxicity appeared to get worse
over time.  In one subchronic rat study, the parameters appeared to
return to normal levels following a four-week recovery period. High
doses in the rats and mice also sometimes caused mortality.

There was no evidence of susceptibility from either in utero or neonatal
exposure to both rat and rabbit young with either DPX-MP062 or
DPX-JW062.  There was no evidence of susceptibility from in utero
exposure in rats with DPX-KN128.  There was no evidence of increased
susceptibility in the developmental neurotoxicity study in rats with
DPX-KN128.  No evidence of teratogenicity was observed in rats and
rabbits with DPX-MP062 or DPX-JW062.  No evidence of teratogenicity was
observed in rats with DPX-KN128.  There was no evidence of reproductive
effects in the 2-generation reproduction study in rats.

Neurotoxicity was present in both rats and mice; however, it did not
occur in the absence of other signs of toxicity.  Neurotoxicity was
characterized by one or more of the following symptoms in both male and
female rats and mice:  weakness, head tilting, and abnormal gait or
mobility with inability to stand, ataxia.  Acute and subchronic
neurotoxicity screening batteries were performed using DPX-MP062 in
rats.  Neurotoxicity was characterized by clinical signs (depression,
abnormal gait, head shake, salivation) and functional-observation
battery (FOB) (circling behavior, incoordination, slow righting reflex,
decreased forelimb grip strength, decreased foot splay, decreased motor
activity).  However, there was no evidence of neurohistopathology in any
study.  Learning and memory parameters were affected in the pups in the
developmental neurotoxicity study in rats with DPX-KN128.

There was no evidence of carcinogenicity in either the rat or mouse in
acceptable studies (using DPX-JW062).  DPX-JW062 was not mutagenic in a
complete battery of mutagenicity studies. There was also no evidence of
mutagenicity with either DPX-KN128, or DPX-MP062.  Therefore, DPX-KN128,
DPX-MP062 were classified as “not likely” to be carcinogenic in
humans by all relevant routes of exposure.

Both DPX-JW062 and DPX-MP062 were rapidly absorbed and eliminated
following oral administration. The absorption of DPX-JW062 was dose
dependent and appeared be saturated at the high dose.  Overall
absorption of [indanone-1-14C]DPX-JW062 was approximately 69-81% in the
low dose group and 8-14% in the high-dose group.  Plasma t1/2 values
were notably shorter for male rats than for female rats.  Both urine and
feces represented major routes of excretion (35-45% and 33-47%,
respectively).  The distribution pattern did not vary with dosing
regimen and overall tissue burden was limited to only 3.4-12.9% of the
administered dose.  The red blood cells of rats dosed with the
trifluoromethoxyphenyl label consistently contained much greater levels
of radioactivity than did plasma.  Fat tissue contained the greatest
level of radioactivity (1.76-8.76% of the administered dose) and, for
both compounds, was greater in female rats.  The finding also
demonstrates a greater propensity for accumulation by female rats than
by male rats. Both DPX-MP062 and DPX-JW062 were extensively metabolized
and that the metabolites were eliminated in the urine, feces, and bile. 
With the exception of parent compound (DPX-JW062, which accounted for
19.2% of a single low dose in the feces of female rats), none of the
metabolites from any source represented more than 12.3% of the
administered dose.  The metabolite profile for DPX-JW062 was dose
dependent and varied quantitatively between males and females. 
Differences in metabolite profiles were also observed for the different
label positions.  All of the biliary metabolites appear to undergo
further biotransformation in the gut.

Dose Response Assessment

On 06-JUN-2000, HIARC reviewed the recommendations of the toxicology
reviewer for DPX-MP062 with regard to the acute and chronic reference
doses (RfDs) and the toxicological endpoint selection for use, as
appropriate, in occupational/residential exposure risk assessments. 
HIARC also determined that toxicity data from DPX-JW062 (the racemic
mixture) could be used to support DPX-MP062 (HED Doc. No. 014241,
17-JUL-2000).  On 02-MAR-2004, the HED HIARC met to re-evaluate the
potential for increased susceptibility of infants and children from
exposure to indoxacarb as required by the Food Quality Protection Act
(FQPA) of 1996 according to the FEB-2002 OPP 10x Guidance Document and
to re-evaluate the inhalation endpoints based on the submission of a
28-day inhalation toxicity study (HED Doc. 0052478).  HED concluded that
the endpoints previously selected by the HIARC should be adjusted to
100% insecticidally active isomer (DPX-KN128), since the registrant
requested the registration of DPX-KN128 (25-AUG-2004; DP#:  307220). 
RAB1 toxicologists re-evaluated the endpoints due to submission of a
developmental neurotoxicity study (DNT).  RAB1 toxicologists concluded
that the database uncertainty factor (UF) due to lack of the DNT study
should be removed and the results of the DNT study did not impact
previously selected endpoints by the HIARC (HED Doc. No. 0052478).  The
FQPA Safety Factor (SF) Committee met on 19-JUN-2000 to evaluate the
hazard and exposure data for DPX-MP062 and recommended that the 10x
safety factor to account for enhanced sensitivity of infants and
children be reduced (1x) for the general U.S. population and all
population subgroups and scenarios (HED Document Number 014226, B.
Tarplee, 03-JUL-2000).  RAB1 toxicologists re-evaluated FQPA assessment
in light of the DNT study and concluded that the hazard-based FQPA
factor be reduced.

Acute Dietary Endpoints:  An acute RfD (aRfD) of 0.09 mg/kg was
established for the general U.S. population (including infants and
children).  It was based on an acute oral neurotoxicity study in the rat
with DPX-MP062.  The no-observable-adverse-effect-level (NOAEL) of 12
mg/kg was based on decreased body weight, body-weight gain, and food
consumption in females observed at the LOAEL of 50 mg/kg.  The NOAEL of
12 mg/kg was adjusted to 9.0 mg/kg based on DPX-KN128.  The standard 100
UF was applied to account for interspecies extrapolation and
intraspecies variation.  The FQPA SFC determined that a FQPA SF of 1x is
applicable for acute dietary risk assessment.  Thus, the acute
population-adjusted dose (aPAD) is equivalent to the aRfD of 0.09 mg/kg.
 An endpoint of concern attributable to a single dose for females 13-49
was not identified in the database.

Chronic Dietary Endpoint:  The chronic RfD (cRfD) of 0.015 mg/kg/day was
based on the:  1) rat 90-day subchronic toxicity study with DPX-MP062;
2) rat subchronic neurotoxicity study with DPX-MP062; and 3) rat
chronic/ carcinogenicity study with DPX-JW062.  The selected NOAEL was
2.0 mg/kg/day.  The LOAELs for the 3 co-critical studies were:  1) 3.8
mg/kg/day; 2) 3.3 mg/kg/day; and; 3) 3.6 mg/kg/day.  These were based on
decreased body weight, alopecia, body-weight gain, food consumption and
food efficiency in females.  In addition, study #3 also had decreased
hematocrit, hemoglobin and red blood cells only at 6 months in females. 
Using a weight-of-evidence approach, the NOAEL for use in establishing
the cRfD was 2.0 mg/kg/day.  Studies #1, #2 and #3 are all co-critical. 
There appeared to be little difference in toxicity between DPX-MP062
(90-day studies, #1 and #2) and DPX-JW062 (2-year study, #3), regardless
of study duration.  In addition, the low NOAEL (0.57 mg/kg/day) for
study #2 was due solely to the dose selection and was not used to
establish the chronic RfD since the LOAEL was approximately the same as
for studies #1 and #3.  Studies #1 and #2 were first since they were
conducted on DPX-MP062, the formulation being registered.  The NOAEL of
2 mg/kg was adjusted to 1.5 mg/kg based on DPX-KN128.  This NOAEL was
also supported by the newly-submitted DNT study conducted with DPX-KN128
in which the systemic toxicity NOAEL was 1.5 mg/kg/day.  The standard
100 UF was applied to account for interspecies extrapolation and
intraspecies variation.  The FQPA SFC determined that a FQPA SF of 1x is
applicable for chronic dietary risk assessment.  Thus, the chronic
population-adjusted dose (cPAD) is equivalent to the cRfD of 0.015
mg/kg.

Carcinogenicity:  HIARC recommended that DPX-MP062 be classified as
“not likely” to be carcinogenic to humans via relevant routes of
exposure using the Guidelines for Carcinogen Risk Assessment.  This was
based on no evidence of carcinogenicity in either the rat or mouse in
acceptable studies for DPX-JW062 and no evidence of mutagenicity for
DPX-MP062 or DPX-JW062.  DPX-KN128 was also non-mutagenic in various
assays.  Therefore, DPX-KN128 is not expected to be carcinogenic to
humans via relevant routes of exposure.  Therefore, a cancer risk
assessment is not required.

Incidental Oral:  The short- and intermediate-term endpoints were
selected from the studies mentioned in the chronic dietary endpoint (see
above).  The NOAEL of 2 mg/kg was adjusted to 1.5 mg/kg based on
DPX-KN128.  A margin of exposure (MOE) of 100 is considered adequate for
incidental oral exposure risk assessment.

Short- and Intermediate-Term Dermal Endpoints:  The short-, and
intermediate-term dermal endpoints were selected from a rat 28-day
dermal toxicity study with DPX-MP062.  The NOAEL of 50 mg/kg/day was
based on decreased body weights, body-weight gains, food consumption,
and food efficiency in females, and changes in hematology parameters
(increased reticulocytes), the spleen (increased absolute and relative
weight–males only, gross discoloration), and clinical signs of
toxicity in both sexes occurring at the LOAEL of 500 mg/kg/day.  The
NOAEL of 50 mg/kg/day was adjusted to 38 mg/kg/day based on DPX-KN128. 
There was little evidence (based on comparing oral subchronic and
chronic NOAEL/LOAELs and toxicity profiles) to indicate that studies of
longer duration would have a significantly more severe response.  Since
dermal studies were used for estimating dermal risks, no adjustment for
dermal absorption is required.  MOEs of 100 are considered adequate for
dermal exposure risk assessment.

Short- and Intermediate-Term Inhalation Endpoints:  The short-,
intermediate-, and long-term inhalation endpoints were selected from a
28-day inhalation toxicity study in rats with DPX-MP062.  The systemic
toxicity no-observed-adverse-concentration (NOEC) of 23 µg/L/day
(equivalent to 6 mg/kg/day) was based on increased spleen weights,
pigmentation and hematopoiesis in the spleen, hematological changes and
mortality (females) seen at the LOAEL of 290 µg/L/day (equivalent to
75.69 mg/kg/day).  Since the NOAEL was from a DPX-MP062 study, it was
adjusted to 4.5 mg/kg/day based on DPX-KN128.  The effects do not seem
to be progressing as study duration increases from subchronic to chronic
since the NOAELs of oral subchronic and chronic studies are similar. 
Therefore, use of the 28-day inhalation study is also appropriate for
the long-term exposure scenario.  MOEs of 100 are considered adequate
for inhalation exposure risk assessment.

FQPA Decisions

The indoxacarb risk assessment team recommends that the FQPA SF be
reduced to 1X for dietary, occupational, and residential exposure
assessments.  This recommendation by the indoxacarb risk assessment team
is based on 1) the hazard and exposure databases are considered
complete, 2) there are no concerns for pre- and/or postnatal toxicity,
3) there are no residual uncertainties with regard to pre- and/or
postnatal toxicity, and 4) there are no neurotoxic concerns.  

MOE for Occupational/Residential Risk Assessments

A MOE of >100 is not of concern for HED’s dermal or inhalation
occupational exposure risk assessment.  Based on the use patterns, there
are no anticipated long-term exposures to indoxacarb.

Residential Exposure Estimates

Currently, there is one registered use of indoxacarb that would result
in residential exposures.  Indoxacarb is registered for use as a fire
ant bait (0.045%), which may be applied as a mound treatment or as a
broadcast application by “residential” (i.e., private persons)
applicators as well as by commercial handlers such as professional lawn
care operators (PCOs).

Occupational Exposure and Risk Estimates

Based on the proposed use patterns, commercial and private (i.e.,
grower) pesticide handlers are expected to have short-term (1-30 days)
exposures.  While it is possible for handlers to experience
intermediate-term exposures (1-6 months), HED believes it is highly
unlikely.  Since the short- and intermediate-term dermal and inhalation
toxicity endpoints are the same; however, the short-term assessment is
considered protective of intermediate-term exposures.

Several pesticide handler activities are likely, including
mixing/loading of water-dispersible granules, application by air and
ground (groundboom, airblast, tractor-drawn spreader), and commercial
and residential mixer/loader/applicators applying granular fire ant
bait.   The most highly exposed handlers are expected to be
mixer/loaders supporting aerial operations, applicators using airblast
equipment, applicators using tractor-drawn spreader equipment,
mixer/loader/applicators using a scoop/spoon, and
mixer/loader/applicators using a push-type spreader.  No
chemical-specific handler exposure data were available with which to
estimate handler exposure and risk; therefore, surrogate data from the
Pesticide Handler’s Exposure Database (PHED) Surrogate Guide
(AUG-1998) were used to estimate the exposures and risk to pesticide
handlers.  This assessment indicates there are no risks of concern to
pesticide handlers (i.e., MOEs >100) who use a single layer of work
clothing (long pants, long-sleeved shirt, shoes plus socks) and
protective gloves.

Agricultural workers may have post-application exposures that occur
during the course of normal agricultural activities.  For several of the
proposed crop uses, mechanical harvesting is utilized, thereby
minimizing post-application exposure.  However, there are activities
that occur prior to harvest that may result in post-application
exposure.  For those activities, exposures were calculated using dermal
transfer coefficients (TCs) from the Science Advisory Council for
Exposure (ExpoSAC) Policy Number 3.1: Agricultural TCs (AUG-2000).  For
all crops, except grapes, there were no risks of concern to
post-application workers (i.e., MOEs >100).  The restricted-entry
interval (REI) is 24-hours.

For grapes, the registrant provided compound-specific
dislodgeable-foliar residue (DFR) data for indoxacarb.  In this study,
two applications were made, 5 days apart.  Since the revised label
indicates a 21-day interval for grape application, HED utilizes the
study data taken after the first application.  The MOE calculated using
the maximum DFR is of concern.  Since the highest DFR value reported
results in a MOE of concern, HED used the study results for all three
study sites and the associated MOEs for the DFR values reported for each
day, post-application.

For table and raisin grapes, where the post-application activities are
cane tying and turning, the MOE is not of concern on the day of
application at the California and New York sites and on Day 1
post-application at the Washington site.  For wine and juice grapes, use
of the maximum reported DFR value and a TC of 5,000 cm²/hr results in a
MOE >100, which is not of concern.  

For the turf uses, TCs were taken from a post-application exposure study
on golf course maintenance (MRID 46734001).  For transplanting sod, the
TC (6800 cm2/hr) was taken from MRID 45432303.  HED assumes 5% of the
application rate is available as DFR on day zero after application for
turf.  The MOEs calculated for post-application to turf are >100;
therefore, the estimated risks do not exceed HED’s level of concern.  

Although the interim Worker Protection Standard (WPS) REI of 12 hours is
adequate to protect agricultural workers from most post-application
exposures to indoxacarb, a 24-hour REI is recommended to be protective
of post-application activities in table and raisin grapes.

Dietary Risk Estimates (Food + Water)

Partially-refined acute and chronic dietary risk assessments were
conducted using the   SEQ CHAPTER \h \r 1 Dietary Exposure Evaluation
Model software with the Food Commodity Intake Database (DEEM-FCID™,
Version 2.03), which uses food consumption data from the U.S. Department
of Agriculture’s (USDA’s) Continuing Surveys of Food Intakes by
Individuals (CSFII) from 1994-1996 and 1998.  The exposure assessments
were conducted for all existing and proposed new food uses of
indoxacarb.  Anticipated residues (ARs) for all registered and proposed
food commodities were based on field trial data.  ARs for all current
uses were further refined using percent crop treated (%CT) data (Memo,
A. Halvorson, 05-APR-2007; DP#: 338731, and electronic communication, A.
Halvorson to M. Sahafeyan, 12-APR-2007, and A. Halvorson to S. Levy,
10-MAY-2007), following the guidance provided in HED Standard Operating
Procedure (SOP) 99.6 (Classification of Food Forms with Respect to level
of Blending; 20-AUG-1999).  100% CT was assumed for the remaining new
uses.  Available processing data for indoxacarb were used to refine ARs
for apples/pears (juice), potato (dry, chips), cotton (oil), tomato
(paste and puree), peanut (oil), soybean (oil), grapes (raisin and
juice), prunes (dried), and mint (oil), and other commodities where
translation was applicable.  For all other processed commodities,
DEEM-FCID( (ver. 7.81) default processing factors were assumed.

Estimated drinking water concentrations (EDWCs) were provided by EFED
(Memo, J. Hetrick, 01-FEB-2007; DP#: 293793) and incorporated directly
into the acute and chronic DEEM-FCID( analyses.  Both the acute and
chronic analyses were conducted using estimated surface water residues
generated using the Pesticide Root Zone/Exposure Analysis Modeling
System (PRZM/EXAMS).  EFED provided modeling results for several crop
scenarios.  The scenarios resulting in the highest EDWCs (cotton in
Mississippi) were used in this assessment.  For the acute and chronic
assessment, the estimated 1-in-10 year annual peak and 1-in-10 year
annual mean residue in surface water respectively were used as point
estimates in the DEEM-FCID( analysis.

Estimated acute dietary exposure to indoxacarb from food and drinking
water are not of concern to HED for any population subgroup.  Combined
dietary exposure from food and drinking water at the 99.9th percentile
of exposure is estimated to be 0.034881 mg/kg/day for the overall U.S.
population, equivalent to 39% of the aPAD.  The population subgroup with
the highest estimated acute dietary exposure to indoxacarb is children,
3 to 5 years old, with an estimated exposure at the 99.9th percentile of
0.075914 mg/kg/day, equivalent to 84% of the aPAD.  Estimated chronic
dietary exposure to indoxacarb from food and drinking water are not of
concern to HED for any population subgroup.  Combined dietary exposure
from food and drinking water is estimated at 0.002411 mg/kg/day for the
general U.S. population (16% of the cPAD) and 0.007940 mg/kg/day (53% of
the cPAD) for children, 1 to 2 years old, the population subgroup with
the highest estimated chronic dietary exposure to
indoxacarb.Aggregate-Risk Estimates

Aggregate exposure risk assessments were performed for the following: 
acute aggregate exposure (food + drinking water exposure), short- and
intermediate-term aggregate exposure (food + drinking water +
residential exposure), and chronic aggregate exposure (food + drinking
water exposure).  The acute and chronic dietary exposure estimates
mentioned above are equivalent to the acute and chronic aggregate
exposures.  A cancer aggregate risk assessment was not performed because
HIARC determined that cancer dietary risk concerns due to long-term
consumption of indoxacarb residues are adequately addressed by the
chronic exposure assessment.  Short- and intermediate-term aggregate
exposures and risk estimates were calculated for toddlers and adults. 
The aggregate MOEs are ≥100; and, therefore are not of concern to HED.

Recommendations for Tolerances/Registration

Pending submission of revised Sections B and F, there are no residue
chemistry, toxicology, or occupational/residential issues that would
preclude granting an unconditional registration for the requested uses
of indoxacarb.  The proposed uses and the submitted data support the
following permanent tolerances for the combined residues of indoxacarb +
its R-enantiomer in/on the following raw agricultural commodities
(RACs):

Grape	2.0	ppm

Grape, raisin	5.0	ppm

Vegetable, Brassica, leafy, group 5	12	ppm

Turnip greens	12	ppm

Cranberry	0.90	ppm

Fruit, pome, except pear, group 11	1.0	ppm

Fruit, stone, group 12	0.90	ppm

Vegetable, leafy, except Brassica, group 4	14	ppm

Peppermint, tops	11	ppm

Spearmint, tops	11	ppm

Okra	0.50	ppm

Pea, southern, seed	0.10	ppm

Vegetable, cucurbit, group 9	0.60	ppm

Vegetable, tuberous and corm, subgroup 1C	0.01	ppm

Pear, oriental	0.20	ppm

 [Note to RD:  in the current 2006 40 CFR §180.564 tolerance
definition, the word “enantimomer” is misspelled, the correct
spelling is “enantiomer.”  Furthermore, in 2004, HED recommended for
poultry tolerances which have not been established (Memo, S. Levy,
22-SEP-2004; DP#: 297936).]

2.0.  PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION tc \l1 "2.0.
PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION 

2.1.  Identification of Active Ingredient tc \l2 "2.1.	Identification of
A.I. 

Table 2.1.1.  Indoxacarb Nomenclature.

Compound	

Common name	Indoxacarb

Company experimental name	DPX-KN128

IUPAC name	(S)-methyl
7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)phenyl]am
ino]carbonyl]indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate

CAS name	  SEQ CHAPTER \h \r 1 methyl
(4aS)-7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-

(trifluoromethoxy)phenyl]amino]carbonyl]indeno[1,2-e][1,3,4]oxadiazine-4
a(3H)-carboxylate

CAS registry number	173584-44-6

End-use product (EP)	30% WDG (DuPontTM Avaunt® Insecticide; EPA Reg.
No. 352-597)

Regulated Enantiomer	

Company experimental name 	IN-KN127 (inactive R-enantiomer)

2.2.  Physical and Chemical Properties

TABLE 2.2.1.   Physicochemical Properties of Technical Grade Indoxacarb.

Parameter	Value	Reference

Melting range	140-141ºC	Memo, S. Levy, 19-JAN-2000; DP#: 244253

pH	5.32 at 25ºC

	Relative Density	1.34 at 20ºC

	Water solubility (25°C)	15.4 ± 2.3 ppb in pH 5 buffer

	Solvent solubility(25°C)	1.72 g/L in n-heptane; 14.5 g/L in 1-octanol;
103 g/L in methanol; 117 g/L in o-xylene; 139 g/L in acetonitrile; 160
g/L in ethyl acetate; and >250 g/kg in methylene chloride, acetone, and
dimethyl-formamide

	Vapor pressure (25ºC)1	2.5 x 10-8 Pa

	Dissociation constant, pKa1	Does not dissociate at pHs of 2.42-11.36

	Octanol/water partition coefficient, Log(KOW)	4.65 at pH 5

	UV/visible absorption spectrum (λmax, nm)1	Molar absorptivities at 3
maxima were affected by pH, but not over wavelengths of environmental
significance.

	1   Properties are for pure active ingredient.  These properties were
not reported for technical grade indoxacarb.

3.0.  HAZARD CHARACTERIZATION tc \l1 "3.0.	HAZARD CHARACTERIZATION 

A complete hazard characterization is presented in the Section 3
indoxacarb risk assessment conducted in the year 2000 (Memo, Levy et
al., 22-AUG-2000; DP#: 267325).  Since this assessment, new
toxicological data were submitted.  The toxicological profile and
endpoints table are revised and incorporated in this risk assessment. 
For purposes of clarity, a brief summary of health hazard
characterization and dose response assessment are summarized below.

3.1.  Hazard Profile tc \l2 "3.1.	Hazard Profile 

On 06-JUN-2000, HIARC reviewed the recommendations of the toxicology
reviewer for DPX-MP062 with regard to the acute and chronic RfDs and the
toxicological endpoint selection for use, as appropriate, in
occupational/residential exposure risk assessments.  HIARC also
determined that toxicity data from DPX-JW062 (the racemic mixture) could
be used to support DPX-MP062 (HED Doc. No. 014241, 17-JUL-2000).  On
02-MAR-2004, the HED HIARC met to re-evaluate the potential for
increased susceptibility of infants and children from exposure to
indoxacarb as required by FQPA of 1996 according to the FEB-2002 OPP 10x
Guidance Document and to re-evaluate the inhalation endpoints based on
the submission of a 28-day inhalation toxicity study (HED Doc. 0052478).
 HED concluded that the endpoints previously selected by the HIARC
should be adjusted to 100% insecticidally active isomer DPX-KN128),
since the registrant requested the registration of DPX-KN128
(25-AUG-2004; DP#: 307220).  RAB1 toxicologists re-evaluated the
endpoints due to submission of a DNT study.  RAB1 toxicologists
concluded that the database UF due to lack of the DNT study should be
removed as the results of the DNT study did not impact previously
selected endpoints by the HIARC (HED Doc. No. 0052478).  The FQPA SFC
met on 19-JUN-2000 to evaluate the hazard and exposure data for
DPX-MP062 and recommended that the 10x SF to account for enhanced
sensitivity of infants and children be reduced (1x) for the general U.S.
population and all population subgroups and scenarios (HED Document
Number 014226, B. Tarplee, 03-JUL-2000).  RAB1 toxicologists
re-evaluated FQPA assessment in light of the DNT study and concluded
that the hazard-based FQPA SF should be reduced.

Acute Dietary Endpoints:  An aRfD of 0.09 mg/kg was established for the
general U.S. population (including infants and children).  It was based
on an acute oral neurotoxicity study in the rat with DPX-MP062.  The
NOAEL of 12 mg/kg was based on decreased body weight, body- weight gain,
and food consumption in females observed at the LOAEL of 50 mg/kg.  The
NOAEL of 12 mg/kg was adjusted to 9.0 mg/kg based on DPX-KN128.  The
standard 100 UF was applied to account for interspecies extrapolation
and intraspecies variation.  The FQPA SFC determined that a FQPA SF of
1x is applicable for acute dietary risk assessment.  Thus, the aPAD is
equivalent to the aRfD of 0.09 mg/kg.  An endpoint of concern
attributable to a single dose for females 13-49 was not identified in
the database.

Chronic Dietary Endpoint:  The cRfD of 0.015 mg/kg/day was based on the:
 1) rat 90-day subchronic toxicity study with DPX-MP062; 2) rat
subchronic neurotoxicity study with DPX-MP062; and 3) rat
chronic/carcinogenicity study with DPX-JW062.  The selected NOAEL was
2.0 mg/kg/day.  The LOAELs for the 3 co-critical studies were: 1) 3.8
mg/kg/day; 2) 3.3 mg/kg/day; and; 3) 3.6 mg/kg/day.  These were based on
decreased body weight, alopecia, body-weight gain, food consumption and
food efficiency in females.  In addition study #3 also had decreased
hematocrit, hemoglobin and red blood cells only at 6 months in females. 
Using a weight of evidence approach, the NOAEL for use in establishing
the cRfD was 2.0 mg/kg/day.  Studies #1, #2 and #3 are all co-critical. 
There appeared to be little difference in toxicity between DPX-MP062
(90-day studies, #1 and #2) and DPX-JW062 (2 year study, #3), regardless
of study duration.  In addition, the low NOAEL (0.57 mg/kg/day) for
study #2 was due solely to the dose selection and was not used to
establish the chronic RfD since the LOAEL was approximately the same as
for studies #1 and #3.  Studies #1 and #2 were first since they were
conducted on DPX-MP062, the formulation being registered.  The NOAEL of
2 mg/kg was adjusted to 1.5 mg/kg based on DPX-KN128.  The standard 100
UF was applied to account for interspecies extrapolation and
intraspecies variation.  The FQPA SFC determined that a FQPA SF of 1x is
applicable for chronic dietary risk assessment.  Thus, the cPAD is
equivalent to the cRfD of 0.015 mg/kg.

Carcinogenicity:  HIARC recommended that DPX-MP062 be classified as
“not likely” to be carcinogenic to humans via relevant routes of
exposure using the Guidelines for Carcinogen Risk Assessment.  This was
based on no evidence of carcinogenicity in either the rat or mouse in
acceptable studies for DPX-JW062 and no evidence of mutagenicity for
DPX-MP062 or DPX-JW062.  DPX-KN128 was also non-mutagenic in various
assays.  Therefore, DPX-KN128 is not expected to be carcinogenic to
humans via relevant routes of exposure.  Therefore, a cancer risk
assessment is not required.

Incidental Oral:  The short- and intermediate-term endpoints were
selected from the studies mentioned in the chronic dietary endpoint (see
above).  The NOAEL of 2 mg/kg was adjusted to 1.5 mg/kg based on
DPX-KN128.  The MOEs of 100 are considered adequate for incidental oral
exposure risk assessment.

Short- and Intermediate-Term Dermal Endpoints:  The short-, and
intermediate-term dermal endpoints were selected from a rat 28-day
dermal toxicity study with DPX-MP062.  The NOAEL of 50 mg/kg/day was
based on decreased body weights, body-weight gains, food consumption,
and food efficiency in females, and changes in hematology parameters
(increased reticulocytes), the spleen (increased absolute and relative
weight–males only, gross discoloration), and clinical signs of
toxicity in both sexes occurring at the LOAEL of 500 mg/kg/day.  The
NOAEL of 50 mg/kg/day was adjusted to 38 mg/kg/day based on DPX-KN128. 
There was little evidence (based on comparing oral subchronic and
chronic NOAEL/LOAELs and toxicity profiles) to indicate that studies of
longer duration would have a significantly more severe response.  Since
dermal studies were used for estimating dermal risks, no adjustment for
dermal absorption is required.  The MOEs of 100 are considered adequate
for dermal exposure risk assessment.

Short- and Intermediate-Term Inhalation Endpoints:  The short-,
intermediate-, and long-term inhalation endpoint were selected from a
28-day inhalation toxicity study in rats with DPX-MP062.  The systemic
toxicity NOEC of 23 µg/L/day (equivalent to 6 mg/kg/day) was based on
increased spleen weights, pigmentation and hematopoiesis in the spleen,
hematological changes and mortality (females) seen at the LOAEL of 290
µg/L/day (equivalent to 75.69 mg/kg/day).  Since the NOAEL was from
DPX-MP062 study, it was adjusted to 4.5 mg/kg/day based on DPX-KN128. 
The effects do not seem to be progressing as study duration increases
from subchronic to chronic since the NOAELs of oral subchronic and
chronic studies are similar.  Therefore, use of the 28-day inhalation
study is also appropriate for the long-term exposure scenario.  The MOEs
of 100 are considered adequate for inhalation exposure risk assessment.

MOE for Occupational/Residential Risk Assessments:  A MOE of >100 is not
of concern to HED for dermal or inhalation and occupational/residential
exposure risk assessment.  Based on the use patterns, there are no
anticipated long-term exposures to indoxacarb.



Table 3.1.1.  Acute Toxicity Data on Indoxacarb (DPX-KN128).

Guideline No./Study Type	MRID #	Results	Toxicity Category

870.1100 Acute oral toxicity	44477115	LD50 = 179 (F) and 843 (M) mg/kg
(rat)	II

870.1200 Acute dermal toxicity	46240001	LD50 > 5000 mg/kg (rat)	IV

870.1300 Acute inhalation toxicity	N/A	N/A	IV

870.2400 Primary eye irritation	46240002	Not a eye irritant (rabbit)	IV

870.2500 Primary dermal irritant	46240003	Not a dermal irritant (rabbit)
IV

870.2600 Skin sensitization	46240004	Is a dermal sensitizer (Guinea Pig)
NA

Table 3.1.2.  DPX-MP062 technical - Toxicity Categories.

Study

type	

DPX-MP062 Technical (94.5%;)

80% DPX KN128,  20% DPX KN127

81-1	

MRID 44477113	

LD50 = 	1730mg/kg males

268 mg/kg females , Toxicity Category II (in corn oil)

<1000 mg/kg combined (rat)

81-2	

MRID 44477118	

LD50 >5000mg/kg (limit test) (rat), Toxicity Category IV

81-3	

70%MUP MRID 44477120	

LC50 > 5.5 mg/L males, females and combined , Toxicity Category IV

81-4	

MRID 44477122	

Moderate eye irritant (rabbit), Toxicity Category III

81-5	

MRID 44477125	

Not a dermal irritant (rabbit), Toxicity Category IV

81-6	

MRID 44477126:	

Magnusson-Kligman Maximization test, Is a dermal sensitizer (Guinea Pig)

Table 3.1.3.  Acute Toxicity Data on DPX-JW062 (50% DPX KN128,50% DPX
KN127).

Guideline No./ Study Type	

MRID No.	

Results	

Toxicity Category

870.1100 Acute oral toxicity	

44701601

	

LD50 > 5000 mg/kg (males, females, combined) (in corn oil)	

IV

870.1200 Acute dermal toxicity	

44477119	

LD50 > 2000 mg/kg (males, females, combined) (rabbit)	

III

870.1300 Acute inhalation toxicity	

44477121	

LC50 > 5.4 mg/L males

LC50 = 4.2 mg/L females (rat)	

IV

870.2400 Primary eye irritation	

44701602	

Slight eye irritant (rabbit)	

IV

870.2500 Primary dermal irritation	

44701603	

Slight dermal irritation (rabbit)	

IV

870.2600 Skin sensitization	

44701604	

Is not a dermal sensitizer Magnusson-Kligman Maximization test, (Guinea
Pig)	

NA

Table 3.1.4.  Subchronic, Chronic, and Other Toxicity Data on Indoxacarb
(DPX-KN128). tc \l3 "9.1.2	Table 7. Subchronic, Chronic and Other
Toxicity Tables 

Guideline No./ Study Type	

MRID No. (year)/ Classification /Doses	

Results

870.3700a

Prenatal developmental in rodents - rat	46240005(2004)

Acceptable/guideline

0, 0.5, 1.0, 2.0, or 3.5 mg/kg/day	Maternal NOAEL = 2.0 mg/kg/day

LOAEL = 3.5 mg/kg/day, based on decrease in maternal overall body-weight
gain and adjusted body-weight gain.

Developmental NOAEL = 2.0 mg/kg/day

LOAEL = 3.5 mg/kg/day, based on decreased mean fetal weight.

Gene Mutation

870.5100

	46240006 (2004) Acceptable/guideline

	

5-5000 μg/plate

Gene Mutation

870.5300	46240007 (2003)

Acceptable/guideline

	negative for mutagenic activity for the following concentration range
5-50 μg/mL (±S9)

Cytogenetics 

870.5375	46240008 (2003)

Acceptable/guideline	no evidence of chromosomal aberrations induced by
the test article over background for the following concentration ranges:
1.25-100 μg/mL (+S9)

870.6300

Developmental neurotoxicity - rat	

46749002 (2006)

46749003 (2006)

Acceptable/non-guideline

0, 0.5, 1.0, 1.5, or 3.0 mg/kg/day	Maternal systemic/neurotoxicity NOAEL
= 1.5 mg/kg/day

LOAEL = 3.0 mg/kg/day, based on the adverse clinical signs observed,
decreased body-weight gain and food consumption and mortality.

Offspring systemic/neurotoxicity NOAEL= 1.5 mg/kg/day

LOAEL = 3.0 mg/kg/day, based on an increased incidence of stillbirths,
decreased mean pup body weight at birth and increased pup mortality
during PND 1-4 in males and females, and increase in number of learning
trials to reach criterion and increased latency in males.



Table 3.1.5.  Subchronic, Chronic, and Other Toxicity Data on Indoxacarb
(DPX-MP062). tc \l3 "9.1.2	Table 7. Subchronic, Chronic and Other
Toxicity Tables 

Guideline No./ Study Type	

MRID No. (year)/ Classification /Doses	

Results

870.3100

90-Day oral toxicity rodents	

44477129 (1997)

Acceptable/guideline

M 0, 10, 50, 100, 200 ppm

M 0, 0.6, 3.1, 6.0, 15 mg/kg/day

F 0, 10, 25, 50, 100 ppm F 0, 0.76, 2.1, 3.8, 8.9 mg/kg/day	

NOAEL = M 3.1 mg/kg/day

F 2.1 mg/kg/day

LOAEL = M 6.0 mg/kg/day, F 3.8 mg/kg/day based on decreased body weight,
body-weight gain, food consumption and food efficiency.



870.3200

28-Day dermal toxicity	

44477134 (1997)

acceptable (guideline)

0, 50, 500, 1000, 2000 mg/kg/day	

NOAEL = 2000 mg/kg/day

LOAEL = >2000 mg/kg/day in rats.



870.3200

28-Day dermal toxicity	

44983901 (1999)

acceptable/guideline

0, 50, 500, 1000, 2000 mg/kg/day	

NOAEL = 50 mg/kg/day

LOAEL = 500 mg/kg/day based on decreased body weights, body-weight
gains, food consumption, and food efficiency in F, and changes in
hematology parameters (incr. reticulocytes), the spleen (incr. abs. and
rel. weight–M only, gross discoloration), clinical signs of toxicity
in both sexes in rats.

870.3465

28-Day inhalation toxicity	45870001 (2003)

Acceptable/non-guideline

0, 4.6, 23, 290 µg/L/day	NOAEL = 23 µg/L/day

LOAEL = 290 µg/L/day (75.69 mg/kg/day), based on increased absolute and
relative spleen weights, pigmentation and hematopoiesis in the spleen,
and hematological changes.

870.3700a

Prenatal developmental in rodents - rat	

44477138, 44477142 (1997)

Acceptable (guideline)

0.0, 0.5, 1.0, 2.0, or 4.0 mg/kg/day (in PEG)	Maternal NOAEL = 2.0
mg/kg/day

LOAEL = 4.0 mg/kg/day based on decreased mean body weights, body-weight
gains, food consumption.

Developmental NOAEL = 2.0 mg/kg/day

LOAEL = 4.0 mg/kg/day based on decreased fetal weights.

Gene Mutation

870.5100	

44477149 (1997)

acceptable/guideline

	

strains TA97a, TA98, TA100 and TA1535 of S. typhimurium and strain
WP2(uvrA) of E. coli were negative for mutagenic activity both with and
without S9 activation for the concentration range 10-5000 μg/plate

Gene Mutation

870.5300	

44477147 (1997)

acceptable/guideline	negative for mutagenic activitity for the following
concentration ranges: 3.1-250 μg/mL (-S9); 3.1-250 μg/mL (+S9)

Cytogenetics 

870.5375	

44477146 (1996)

acceptable/guideline	no evidence of chromosomal aberrations induced by
the test article over background for the following concentration ranges:
15.7-1000 μg/mL (+S9)

Cytogenetics 

870.5395	

44477148 (1997)

acceptable/guideline	no evidence of mutagenicity for the following dose
ranges: 3000-4000 mg/kg - males; 1000-2000 mg/kg - females

Other Effects 

870.5550	

44477151 (1997)

 μg/mL; cytotoxicity was seen at concentrations of >100 μg/mL

870.6200a

Acute neurotoxicity screening battery	

44477127 (1997)

acceptable/guideline

M 0, 25, 100, 200 mg/kg

F 0, 12.5, 50, 100 mg/kg	study NOAEL = M 100, F 12.5 mg/kg

LOAEL = M 200 mg/kg based on decreased body-weight gain, decreased food
consumption, decreased forelimb grip strength, and decreased foot splay.
F 50 mg/kg based on decreased body weight and body-weight gain

870.6200b

Subchronic neurotoxicity screening battery	

44477135 (1997)

acceptable/guideline

M 0, 10, 100, 200 ppm 0.57, 5.6, 12 mg/kg/d F 0, 10, 50, 100 ppm

0.68, 3.3, 6.1 mg/kg/d	

study NOAEL = M 0.57, F 0.68 mg/kg/day

LOAEL = M 5.6, F 3.3 mg/kg/day based on decreased body weight and
alopecia.

870.7600

Dermal penetration	45911401 (2002) 45911402 (2002)

45911403 (2002)

Acceptable/guideline

0, 13.3, 2000 µg/cm2 for 6 hours

	Absorption ranged from 0.41% to 0.94% following 6 hours exposure. 
Following a 162 hours post dosing, the absorption ranged from 0.88% to
4.91% depending upon the dose/dilution. 

 Table 3.1.6.  Subchronic, Chronic, and Other Toxicity Data on
Indoxacarb (DPX-JW062).

Guideline No./ Study Type	

MRID No. (year)/ Classification/Doses	

Results

870.3700a

Prenatal developmental in rodents - rat	

44477140, 44477143 (1997)

acceptable/guideline

0, 10, 100, 500, 1000 mg/kg/day (in methyl cellulose)	

Maternal NOAEL = 10 mg/kg/day

LOAEL = 100 mg/kg/day based on mortality, clinical signs, and decreased
mean body weights, body-weight gains, and food consumption.

Developmental NOAEL = 10 mg/kg/day

LOAEL = 100 mg/kg/day based on decreased numbers of live fetuses/litter.

870.3700a

Prenatal developmental in rodents - rat	

44477139 (1997)

acceptable/guideline

0, 20, 40, 80, or 120 ppm

1.11, 2.2, 4.1, 5.7 mg/kg/day (rounded to 2 sig. fig.)	

Maternal NOAEL = 1.1 mg/kg/day

LOAEL = 2.2 mg/kg/day based on decreased mean body weights, body-weight
gains, food consumption, and food efficiency.

Developmental NOAEL = 1.1 mg/kg/day

LOAEL = 4.1 mg/kg/day based on decreased fetal body weights.

870.3700b

Prenatal developmental in nonrodents - rabbit	

44477141 (1995)

acceptable/guideline

0, 250, 500, or 1000 mg/kg/day in methyl cellulose	

Maternal NOAEL = 500 mg/kg/day

LOAEL = 1000 mg/kg/day based on slight decreases in maternal body-weight
gain and food consumption.

Developmental NOAEL = 500 mg/kg/day

LOAEL = 1000 mg/kg/day based on decreased fetal body-weights and reduced
ossification of the sternebrae.



870.3800

Reproduction and fertility effects	

44477144 (1997)

acceptable/guideline

0, 20, 60, 100 ppm

M 0, 1.3, 3.9, 6.4 mg/kg/d

F 0, 1.5, 4.4, 6.9 mg/kg/d	

Parental/Systemic NOAEL = 1.5 mg/kg/day

LOAEL = 4.4 mg/kg/day based on decreased body weights, body-weight
gains, and food consumption of F0 females, and incr. spleen weights in
the F0 and F1 females.

Reproductive NOAEL = 6.4 mg/kg/day

LOAEL > 6.4 mg/kg/day.

Offspring NOAEL = 1.5 mg/kg/day

LOAEL = 4.4 mg/kg/day based on decrease in the body weights of the F1
pups during lactation.



870.4100a

Chronic toxicity rodents - rat	

44477145 (1997)

acceptable/guideline

0, 20, 40, 60, 125, 250 ppm 

M 0, 0.80, 1.6, 2.4, 5.0, 10 mg/kg/day

F 0, 10, 20, 40, 60, 125 ppm 

0, 0.55, 1.0, 2.1, 3.6, 7.8 mg/kg/day	

NOAEL = M 5, F 2.1 mg/kg/day

LOAEL = M 10, F 3.6 mg/kg/day based on decreased body weight,
body-weight gain, and food consumption and food efficiency; decreased
HCT, HGB and RBC at 6 months in F only.

No evidence of carcinogenic potential.

870.4100b

Chronic toxicity dogs	

44477136 (1997)

acceptable/guideline

0, 40, 80, 640, 280 ppm

M 0, 1.1, 2.3, 18, 34 mg/kg/day

F 0, 1.3, 2.4, 19, 36 mg/kg/day	

NOAEL = M 2.3, F 2.4 mg/kg/day

LOAEL = M 18, F 19 mg/kg/day based on decreased HCT, HGB and RBC; incr.
Heinz bodies and reticulocytes and assoc. secondary microscopic changes
in the liver, kidneys, spleen, and bone marrow; incr. abs. and rel.
liver weights.

870.4200

Carcinogenicity rats	

see 870.4100a	

see 870.4100a

No evidence of carcinogenicity.

870.4300

Carcinogenicity mice	

44477137 (1997)

0, 20, 100, 200/150/125 ppm

M 2.6, 14, 22 mg/kg/day

F 4.0, 20, 31 mg/kg/day

(rounded to 2 sig. fig.)	

NOAEL = M 2.6, F4.0 mg/kg/day

LOAEL = M 14, F 20 mg/kg/day based on decreased body weight, body-weight
gain, and food efficiency and clinical signs indicative of
neurotoxicity.

No evidence of carcinogenicity.

Gene Mutation

870.5100	

44701606 (1995)

acceptable/guideline

	

0-5000 μg/plate.

Gene Mutation

870.5300	

44701607 (1995)

acceptable/guideline	

Negative for mutagenic activity for the following concentration ranges: 
Negative;100-1000 μg/mL (-S9); 100-1000 μg/mL (+S9), precipitate >1000
μg/mL

Cytogenetics 

870.5375	

44701608 (1995)

acceptable/guideline	No evidence of chromosomal aberrations induced by
the test article over background for the following concentration ranges:
19-300 μg/mL (-S9), 19-150 μg/mL (+S9); partial insoluble &
cytotoxicity > 150 μg/mL



Cytogenetics 

870.5395	

44701610 (1995)	No evidence of mutagenicity at 2500 or 5000 mg/kg

Other Effects 

870.5550	

44701609 (1995)

acceptable/guideline	

No evidence of mutagenic activity at the following concentration range:
0.1-50 μg/mL, cytotoxicity observed at >50 μg/mL

870.6200a

Acute neurotoxicity screening battery	

44477128 (1996)

acceptable/guideline

0, 500, 1000, 2000 mg/kg	

study NOAEL >= M 2000 mg/kg

= F < 500 mg/kg

LOAEL > M 2000 mg/kg

F < 500 mg/kg based on clinical signs, decreased body-weight gains and
food consumption, and FOB effects

870.7485

Metabolism and pharmacokinetic	

44477152, 44477153 (1997)

acceptable/guideline

	

Both indoxacarb and JW062 were extensively metabolized and the
metabolites were eliminated in urine, feces, and bile. The metabolite
profile for JW062 was dose dependent and varied quantitatively between
males and females. Differences in metabolite profiles were also observed
for the different label positions (indanone and trifluoromethoxyphenyl
rings). All biliary metabolites undergo further biotransformation in the
gut. The proposed metabolic pathway for both indoxacarb and JW062 has
multiple metabolites bearing one of the two ring structures.

SUMMARY OF TOXICOLOGY ENDPOINT SELECTION

Table 3.1.7.  Doses and Toxicological Endpoints Selected for INDOXACARB
for Various Exposure Scenarios.

Exposure

Scenario	Dose Used in Risk Assessment,

UF	FQPA SF* and Level of Concern for Risk Assessment	Study and
Toxicological Effects

	Study NOAEL	Adjusted to KN128

Acute Dietary

females 13-49 years of age	An endpoint of concern attributable to a
single dose was not identified.  An acute RfD was not  established.

Acute Dietary

general population including infants and children	NOAEL= 12 mg/kg

UF = 100

Acute RfD = 0.12 mg/kg	NOAEL= 9 mg/kg

UF = 100

Acute RfD = 0.09 mg/kg	FQPA SF = 1x

aPAD = 0.09 mg/kg

              (aRfD)        

         1x (FQPA SF)

= 0.09 mg/kg	acute oral rat neurotoxicity study.

LOAEL = 50 mg/kg based on decreased body weight and body-weight gain in
females.

Chronic Dietary

all populations	NOAEL= 2.0 mg/kg/day

UF = 100

Chronic RfD = 0.02 mg/kg/day	NOAEL= 1.5 mg/kg/day

UF = 100

Chronic RfD = 0.015 mg/kg/day	FQPA SF = 1x 

cPAD = 0.015mg/kg

                (cRfD)       

          1x (FQPA SF)

= 0.015 mg/kg/day	Weight of evidence approach was used from four
studies: 

1) Subchronic toxicity study- rat (INDOXACARB)

2) Subchronic neurotoxicity study - rat (INDOXACARB)	

3) Chronic/carcinogenicity study - rat (JW062)

4) Two generation rat reproduction study (JW062).

LOAEL = 3.3 mg/kg/day based on decreased body weight, body-weight gain,
food consumption and food efficiency; decreased hematocrit, hemoglobin
and red blood cells only at 6 months.

Short-Term Incidental Oral

(1 to 30 days)

	Oral NOAEL= 2.0 mg/kg/day	Oral NOAEL= 1.5 mg/kg/day	Residential LOC for
MOE = 100

Occupational LOC for MOE = 100	Weight of evidence approach was used from
four studies: 

1) Subchronic toxicity study- rat (INDOXACARB)

2) Subchronic neurotoxicity study - rat (INDOXACARB)	

3) Chronic/carcinogenicity study - rat (JW062)

4) Two generation rat reproduction study (JW062).

LOAEL = 3.3 mg/kg/day based on decreased body weight, body-weight gain,
food consumption and food efficiency; decreased hematocrit, hemoglobin
and red blood cells only at 6 months.

Intermediate-Term Incidental Oral (1- 6 months)	oral NOAEL= 2.0
mg/kg/day	oral NOAEL= 1.5 mg/kg/day	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	Weight of evidence approach was used from
four studies:

1) Subchronic toxicity study- rat (INDOXACARB)

2) Subchronic neurotoxicity study - rat (INDOXACARB)	

3) Chronic/carcinogenicity study - rat (JW062)

4) Two generation rat reproduction study (JW062).

LOAEL = 3.3 mg/kg/day based on decreased body weight, body-weight gain,
food consumption and food efficiency; decreased hematocrit, hemoglobin
and red blood cells only at 6 months.

Short-Term Dermal (1 to 30 days)

Intermediate-Term

Dermal (1 - 6 months)

Long-Term Dermal (> 6 Months)	Dermal NOAEL= 50 mg/kg/day	Dermal NOAEL=
38 mg/kg/day	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	28-day rat dermal toxicity study.

LOAEL = 500 mg/kg/day based on decreased body weights, body-weight
gains, food consumption, and food efficiency in females, and changes in
hematology parameters (increased reticulocytes), the spleen (increased
absolute and relative weight–males only, gross discoloration), and
clinical signs of toxicity in both sexes.

Short-Term Inhalation (1 to 30 days)

Intermediate-Term Inhalation (1 - 6 months)

Long-Term Inhalation (> 6 Months)	Inhalation NOAEL= 23 µg/L/day (6
mg/kg/day)	Inhalation NOAEL= 17 µg/L/day (4.5 mg/kg/day)	Residential
LOC for MOE = 100

Occupational LOC for MOE = 100	28-day rat inhalation toxicity study. The
LOAEL of 290 µg/L/day (75.69 mg/kg/day). is based on increased spleen
weights, pigmentation and hematopoiesis in the spleen, hematological
changes and mortality (females).  

Cancer (oral, dermal, inhalation)	“Not likely” to be carcinogenic to
humans since no evidence of carcinogenicity in either the rat or mouse
studies, and no evidence of mutagenicity.

1 UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL =
no-observable-adverse-effect-level, LOAEL =
lowest-observable-adverse-effect-level, PAD = population-adjusted dose
(a = acute, c = chronic) RfD = reference dose, LOC = level of concern,
MOE = margin of exposure.

3.2.  FQPA Considerations

3.2.1.  Pre-and/or Postnatal Toxicity

3.2.1.1.  Determination of Susceptibility

There was no evidence of increased susceptibility in the two
developmental toxicity studies in rats with DPX-JW062, one developmental
toxicity study in rats with DPX-MP062 and DPX-KN128, one developmental
toxicity study in rabbits with DPX-JW062, one 2-generation reproduction
studies in rats with DPX-JW062 and a DNT study in rats with DPX-KN128. 
In these studies, developmental toxicity was observed in the presence of
maternal toxicity.

3.2.1.2.  Degree of Concern Analysis and Residual Uncertainties

HED concluded that there is no increased susceptibility following
pre-natal or post-natal exposure to indoxacarb.  In these studies there
are well defined NOAELs/LOAELs; therefore, there are no residual
uncertainties with regard to pre- and/or post-natal susceptibility. 

3.2.2.  Recommendation for a DNT Study

The DNT study is available with DPX-KN128.

3.3.  FQPA SF

After evaluating the toxicological database, the indoxacarb risk
assessment team has identified the following factors supporting
reduction of the FQPA SF to 1X:  1) the hazard and exposure databases
are complete; 2) there are no concerns for pre- and/or postnatal
toxicity; 3) there are no residual uncertainties with regard to pre-
and/or postnatal toxicity; and 4) there are no neurotoxic concerns.

3.3.1.  Adequacy of the Exposure Database

Exposure pathways resulting from the use of indoxacarb are dietary (food
and drinking water), occupational, and residential.  The chronic dietary
analysis incorporated field trial data, %CT estimates provided by
OPP’s Biological and Economic Analysis Division (BEAD), and processing
factors.  The database is considered adequate to characterize the risks
(including aggregate) associated with potential exposure to indoxacarb
in all three exposure pathways.

3.3.2.  FQPA SF Conclusion

Based on above discussion, the indoxacarb risk assessment team
recommends that the FQPA SF be reduced to 1X for dietary, occupational
and residential exposure risk assessments.

3.4.  Endocrine Disruption tc \l2 "3.2.	Endocrine Disruption 

EPA is required under the Federal Food Drug and Cosmetic Act (FFDCA), as
amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) "may have an effect in humans that is similar to an effect
produced by a naturally occurring estrogen, or other such endocrine
effects as the Administrator may designate."  Following the
recommendations of its Endocrine Disruptor Screening and Testing
Advisory Committee (EDSTAC), EPA determined that there was scientific
bases for including, as part of the program, the androgen and thyroid
hormone systems, in addition to the estrogen hormone system.  EPA also
adopted EDSTAC’s recommendation that the Program include evaluations
of potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA has authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP).

When the appropriate screening and/or testing protocols being considered
under the Agency’s EDSP have been developed, indoxacarb may be
subjected to additional screening and/or testing to better characterize
effects related to endocrine disruption.

4.0.  EXPOSURE ASSESSMENT tc \l1 "4.0.	EXPOSURE ASSESSMENT 

4.1.  Summary of Proposed Food Uses tc \l2 "4.1.	Summary of Proposed
Uses 

Proposed Food Uses:  DuPontTM and IR-4 have proposed amending the label
for DuPontTM Avaunt® Insecticide (EPA Reg. No. 352-597) to include new
uses on grapes, Brassica leafy vegetables, turnip greens, cranberry,
cucurbit vegetables (group 9), leafy vegetables except Brassica (group
4), pome fruits (group 11, except pear), tuberous and corm vegetables
(subgroup 1C), mint, okra, southern peas, and stone fruits (group 12). 
The petitioners have submitted new field trial data to support these
uses and/or they have proposed using existing field trial data on
apples, lettuce, peppers, and potatoes to support expanding the uses on
the 30% WDG to cover pome fruits (expect pear), leafy vegetables except
Brassica, okra, and tuberous and corm vegetables.  The petitioners
provided both a summary of the proposed uses and example labels
containing the use directions.  The proposed use directions are
summarized below in Table 4.1.1. 

Table 4.1.1.  Summary of Proposed Food Use Directions for Indoxacarb.

Applic. Timing, Type, and Equip.1	Formulation

[EPA Reg. No.]	Applic. Rate 

(lb a.i./A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb a.i./A)	Pre-harvest interval (PHI)

(days)	Use Directions and Limitations2

Grape

Broadcast foliar applications using ground or aerial equipment	30% WDG

[352-597]	0.065-0.11	NS = not specified	0.44	7	The proposed label
specifies a minimum retreatment interval (RTI) of 5 days and a maximum
seasonal use rate of 0.44 lb a.i./A.  Mix with water for application to
obtain thorough, uniform coverage.  For aerial application, a minimum of
5 GPA are required.

Brassica Leafy Vegetables and Turnip Greens

Broadcast foliar applications using ground or aerial equipment	30% WDG

[352-597]	0.045-0.065	NS	0.26	3	The proposed label specifies a minimum
RTI of 3 days and a maximum seasonal use rate of 0.26 lb a.i./A.  Mix
with water for application to obtain thorough, uniform coverage.  For
aerial application, a minimum of 5 GPA are required.

Cranberry

Broadcast foliar applications using ground or aerial equipment	30% WDG

[352-597]	0.11	4	0.44	30	Minimum RTI is 7 days.

Do not apply to flow through bogs or allow release of irrigation water
from bogs for at least 1 day following application.

Cucurbit Vegetables

Broadcast foliar applications using ground or aerial equipment	30% WDG

[352-597]	0.045-0.11	4	0.44	3	Minimum RTI is 5 days.  Make uniform
application of insecticide in 10-50 GPA of water.  For ground
application, apply using a minimum of 10 GPA of water.

Leafy Green Vegetables, except spinach

Broadcast foliar applications using ground or aerial equipment	30% WDG

[352-597]	0.045-0.11	4	0.44	3	Minimum RTI is 3 days.

Leaf Petiole Vegetables

Broadcast foliar applications using ground or aerial equipment	30% WDG

[352-597]	0.065	4	0.26	3	Minimum RTI is 3 days.

Mint

Broadcast foliar applications using ground or aerial equipment	30% WDG

[352-597]	0.065	4	0.26	7	Minimum RTI is 3 days.  Use a minimum of 20 GPA
of water for ground applications.

Okra

Broadcast foliar applications using ground or aerial equipment	30% WDG

[352-597]	0.065	4	0.26	3	Minimum RTI is 5 days.



Pome Fruits, except pears

Foliar applications using Ground or aerial equipment	30% WDG

[352-597]	0.056-

0.11	4	0.44	14	Minimum RTI is 7 days.  For best results, apply a uniform
application of insecticide in 50-150 GPA of water.  Do not apply in a
dilute application of more than 200 GPA of water.

Southern Pea

Broadcast foliar applications using ground or aerial equipment	30% WDG

[352-597]	0.065	4	0.26	7	Minimum RTI is 3 days.  Make a uniform
application in approximately 20-100 GPA of water.

Spinach

Broadcast foliar applications using ground or aerial equipment	30% WDG

[352-597]	0.065	4	0.26	3	Minimum RTI is 3 days.

Stone Fruits

Foliar applications using ground or aerial equipment	30% WDG

[352-597]	0.09-

0.11	4	0.44	14	Minimum RTI is 7 days.  For best results, apply a uniform
application of insecticide in 50-150 GPA of water.  Do not apply in a
dilute application of more than 200 GPA of water.

Tuberous and Corm Vegetables

Broadcast foliar applications using ground or aerial equipment	30% WDG

[352-597]	0.045-0.11	4	0.44	7	Minimum RTI is 5 days.  For aerial
application, use a minimum of 5 GPA of water.

1	Do not apply through any type of irrigation equipment, except as
allowed by supplemental labels. 

2	The label currently specifies a minimum REI of 12 hours and a rotation
crop restriction of 30 days for food/feed crops not registered for use
with indoxacarb.  Unless otherwise specified, apply aerial applications
in a minimum of 5 gallons per acre (GPA) or 10 GPA for tree and orchard
crops.

RTI = retreatment interval.

Conclusions.  The proposed use directions adequately reflect the use
patterns used in the new or previously reviewed field trials, with the
exceptions of southern peas and turnip greens.  Based on the available
southern pea field trial data, it is unclear whether the petitioner is
pursuing a use on succulent or dry southern peas.  The proposed label
directions for southern peas should be amended to allow applications
only to varieties used to produce dry seed.  If the petitioner intends
to support a generalized use on southern peas, field trials will be
required for the succulent variety as well.  In addition, the use
directions for southern peas should prohibit applications to varieties
grown for livestock feed.  For turnip greens, a restriction should be
placed on the label to prohibit use on dual purpose turnip cultivars or
varieties which produce a harvestable root.  Revised Section B’s
should be submitted.

4.2.  Dietary Exposure tc \l2 "4.2.	Dietary Exposure 

The residue chemistry data submitted in support of the proposed
petitions were evaluated by HED on 18-FEB-2005 (Memo, S. Levy; DP#:
290126) and 09-MAR-2007 (Memo, S. Levy; DP#: 325479).  The drinking
water assessment was completed by EFED (Memo, J. Hetrick et al.,
01-FEB-2007; DP#: 293793).  The dietary exposure assessment was
completed by HED (Memo, M. Sahafeyan, et al., 23-MAY-2007; DP#: 339398).

4.2.1.  Residue Profile tc \l3 "4.2.1.	  Residue Profile 

Because the insecticidal efficacy of the end use products are based on
the concentration of indoxacarb, the petitioner normalized the
application rates for the submitted studies on an indoxacarb basis.  The
residue analytical methods proposed for enforcement, as well as those
used for data collection, do not distinguish between the enantiomers;
therefore, residues are reported as the sum of indoxacarb + its
R-enantiomer.

Background

Data for indoxacarb were originally reviewed by HED under a petition
(PP# 8F04948) for use on Brassica, sweet corn, cotton, fruiting
vegetables, lettuce (head and leaf), and pome fruit (Memo, S. Levy, et
al., 22-AUG-2000; DP#: 267325).  Tolerances for indoxacarb residues have
since been established in 40 CFR 180.564 in/on various RACs and meat and
milk products.  HED also recommended (Memo, S. Levy, 22-SEP-2004; DP#:
297936) that tolerances be established for the combined residues of
indoxacarb + its R-enantiomer, IN-JT333, IN-KT319, IN-JU873, IN-KG433,
and IN-KB687 in/on egg, and poultry meat, fat, and meat byproducts. 
(Note to RD:  these tolerances were recommended for by HED, but have not
been established in the 40 CFR 180.564.)

DuPontTM and IR-4 have submitted five petitions (PP#s: 2E6482, 3F6576
5E6911, 5E6926, and 5E6991) proposing new uses of indoxacarb, formulated
as a 30% WDG (DuPontTM Avaunt® Insecticide; EPA Reg. No. 352-597), on
the following crops or crop groups:  grapes, Brassica leafy vegetables
(group 5), turnip greens, cranberry, cucurbit vegetables (group 9),
mint, southern pea and stone fruits (group 12).  Under these petitions,
IR-4 has also proposed expanding existing uses and tolerances on apples,
lettuce, peppers and potatoes to cover pome fruits (except pear, group
11), leafy vegetables except Brassica (group 4), okra, and tuberous and
corm vegetables (subgroup 1C).

The proposed uses on Brassica leafy vegetables, turnip greens, leaf
petiole vegetables, mint, okra, and southern pea are for up to four
broadcast foliar applications at 0.065 lb a.i./A, at minimum RTIs of 3-5
days, for a total application rate of 0.26 lb a.i./A/crop.  The proposed
uses on grapes, cranberry, leafy green vegetables (except spinach), pome
fruits, stone fruits, and tuberous and corm vegetables are for up to
four broadcast foliar applications at 0.11 lb a.i./A, at minimum RTIs of
3-7 days, for a total application rate of 0.44 lb a.i./A/crop.  All uses
allow applications using either ground or aerial equipment, and the
proposed PHIs range from 3 days (for Brassica leafy vegetables, turnip
greens, cucurbits, okra, and leafy vegetables, except Brassica, group 4)
to 30 days (for cranberries).  In conjunction with these uses, the
petitioners have proposed permanent tolerances for combined indoxacarb
residues at the following levels:



Grape	2.0	ppm

Raisin	6.0	ppm

Vegetable, brassica, leafy, group 5	12	ppm

Turnip greens	12	ppm

Cranberry	0.90	ppm

Fruit, pome, except pear, group 11	1.0	ppm

Fruit, stone, group 12	0.90	ppm

Vegetable, leafy, except Brassica, group 4	14	ppm

Peppermint	11	ppm

Spearmint	11	ppm

Okra	0.50	ppm

Pea, southern, seed	0.10	ppm

Vegetable, cucurbit, group 9	0.60	ppm

Vegetable, tuberous and corm, subgroup 1C	0.01	ppm

Nature of the Residue – Plants/Livestock

Adequate metabolism studies on cotton, lettuce, and tomatoes were
reviewed in conjunction with an earlier petition (Memo, S. Levy,
19-JAN-2000; DP#: 244253).  The nature of the residue in plants is
adequately understood based on these studies.  The HED Metabolism
Assessment Review Committee (MARC) determined that the residue of
concern in plants is indoxacarb + its R-enantiomer (Memo, S. Levy,
10-JUL-2000; DP#: 263986).  

  SEQ CHAPTER \h \r 1 Adequate ruminant and poultry metabolism studies
were reviewed in conjunction with an earlier petition (Memo, S. Levy,
19-JAN-2000; DP#: 244253).  Based on these studies, the MARC has
determined that the tolerance expression for milk and ruminant
commodities will include indoxacarb + its R-enantiomer (Memo, S. Levy,
10-JUL-2000; DP#: 263986).  However, for purposes of risk assessment,
the metabolite IN-MP819 should also be considered in milk.  For poultry
commodities, HED has recommended that tolerances be established for the
combined residues of indoxacarb + its R-enantiomer, IN-JT333, IN-KT319,
IN-JU873, IN-KG433, and IN-KB687 (Memo, S. Levy, 22-SEP-2004; DP#:
297936).  For purposes of risk assessment, residues of concern in
poultry commodities also include 5-OH-IN-JT333 and Metabolite F (Memo,
S. Levy, 04-OCT-2001; DP#: 277922).

Analytical Methods 

For PP#s:  5E6911, 5E6926 and 5E6991:  Vegetable, Leafy, Except Brassica
(Group 4), Pome Fruits (Group 11, except pear), Tuberous and Corm
Vegetables (Subgroup 1C), Cucurbit Vegetables (Group 9), Stone Fruits
(Group 12), Cranberry, Mint, Okra, and Southern Pea:  Two
high-performance liquid chromatography (HPLC)/column
switching/ultraviolet (UV) methods (AMR 2712-93 and DuPont-11978) are
available for enforcing indoxacarb tolerances on plant commodities, and
a third gas chromatography (GC)/mass-selective detector (MSD) method
(AMR 3493-95, Supplement No. 4) is available for confirmation of
residues in plants.  The limits of quantitation (LOQs) for the HPLC
methods are 0.01-0.05 ppm for a variety of plant commodities, and the
limits of detection (LODs) are 0.0025-0.006 ppm.  For the GC/MSD method,
the LOQs range from 0.2 to 1.0 ppm depending on the matrix, and the LODs
are 0.0008-0.21 ppm.  Each of these methods determines both indoxacarb +
its R-enantiomer as a single component.  Another HPLC/column
switching/UV Method (AMR 3337-95) is also available for enforcing the
current tolerances on livestock commodities.  The LOQ for this method is
0.01 ppm and the LOD is 0.002-0.003 ppm.

For PP#s:    SEQ CHAPTER \h \r 1 3F6576 and 2E6482:    SEQ CHAPTER \h \r
1 Grapes, Brassica Leafy Vegetables, and Turnip Greens.   

  SEQ CHAPTER \h \r 1 The petitioner submitted a method that combines
the extraction procedure from one previously- validated method (Method
AMR 3493-95, Supplement No. 1) with the cleanup and analysis procedures
from another previously-validated method (Method AMR 2712-93). 
Therefore, only a limited verification of the combined method was made. 
An independent laboratory validation (ILV) of this method was conducted
(MRID 45900304) and observations from the ILV work concerning the method
were incorporated into this method revision.  A petition method
validation (PMV) is not necessary for this method; however, this method
will be sent to the U.S. Food and Drug Administration (FDA) for
inclusion in the Pesticide Analytical Manual, Volume II (PAM, Vol. II). 
There is adequate methodology for monitoring and confirming indoxacarb
tolerance-level residues.  Tolerances can be monitored by method AMR
2712-93 with confirmation/specificity provided by method AMR 3493-95,
Supplement 4.

Multiresidue Method  

Acceptable data are available depicting the recovery of indoxacarb + its
R-enantiomer using FDA multiresidue method protocols (PAM, Vol. I) C, D,
and E.  Indoxacarb + its R-enantiomer were not evaluated through
Protocol A because it does not possess an N-methylcarbamate structure. 
It was not tested through Protocol B because it does not possess a
carboxylic acid or phenolic moiety.  It was not tested through Protocol
F because indoxacarb + its R-enantiomer are not recoverable from
Florisil at a level ≥30%.  Indoxacarb + its R-enantiomer are
completely recovered through Protocol D; however, matrix enhancement
effects were seen in certain matrices.  The results of multiresidue
testing were forwarded to FDA for review (Memo, S. Levy, 03-NOV-1999;
DP#: 260955).

Meat, Milk, Poultry, and Eggs  

The only livestock feed items associated with the proposed uses are wet
apple pomace and potato culls and processed waste, which are covered
under the proposed uses for pome fruits and tuberous and corm
vegetables.  The effects of indoxacarb residues in these commodities on
livestock diets were previously addressed under earlier petitions
supporting uses on apples and potatoes (Memos, S. Levy, 19-JAN-2000;
DP#: 244253 and 30-MAY-2002; DP#: 276516).  As the proposed uses will
not alter the dietary exposure of livestock, data requirements
pertaining to meat, milk, poultry, and eggs will not be further
addressed under the current petitions.  Note that new poultry and
livestock diets were constructed based on current guidelines
(“reasonably-balanced diet” guidelines, J. Stokes, Revisions of
Livestock Diets Percents) for purposes of assessing dietary risk from
exposure to consuming livestock RACs (see Memo, M. Sahafeyan, et al.,
23-MAY-2007; DP#: 339398 for details).

Magnitude of the Residue  

To support the proposed new uses of indoxacarb (30% WDG), crop field
trials on grapes, cherries, plums, peaches, cucumbers, summer squash,
cantaloupes, mint, cranberry, and southern peas were submitted.  To
support the purposed uses on pome fruits (group 11, except pear), leafy
vegetables except Brassica (group 4), and tuberous and corm vegetables
(subgroup 1C), IR-4 cited the existing tolerances and field trial data
on apples, leaf and head lettuce, and potatoes.  IR-4 also submitted new
field trial data on mustard greens, and spinach and celery to support
the crop group tolerance on Brassica leafy vegetables (group 5), and
leafy vegetables except Brassica (group 4), respectively.  Furthermore,
IR-4 requested that the existing tolerance and residue data on peppers
be translated to support the proposed use on okra.    SEQ CHAPTER \h \r
1 The results from these studies are discussed below and summarized in
Table 4.2.1.1.

Table 4.2.1.1.  Summary of Residue Data from Field Trials on Grapes,
Mustard Greens, Spinach, Celery, Cucurbit Vegetables, Southern Pea,
Stone Fruits, Cranberry, and Mint Following Application of Indoxacarb
(30% WDG).

Commodity	Total Applic. Rate

(lb a.i./A)	PHI (days)	Residue Levels (ppm)1

	n	Min.	Max.	HAFT2	Median	Mean	Std. Dev.

Grapes (proposed maximum application rate:  0.44 lb a.i./A; PHI: 7 days)

Fruit	0.438-0.507	7	26	0.089	1.72	1.52

0.487	0.450

Brassica leafy vegetables, group 5 (proposed maximum application rate: 
0.26 lb a.i./A; PHI: 3 days)

Mustard Greens	0.265 - 0.268	3	10	1.2	10	9.8

5.63	3.61

Leafy Vegetables except Brassica, group 4 (proposed maximum application
rate:  0.26 lb a.i./A; PHI: 3 days)

Spinach	0.268	3	16	2.2	13.0	10.5	4.45	5.27	2.59

7	16	0.49	6.1	5.20	2.90	3.16	1.44

14	14	0.29	2.5	2.35	1.90	1.69	0.70

Celery

Untrimmed Stalks (RAC)	0.268	7	12	0.32	1.80	1.70	1.20	1.07	0.62

14	12	0.12	1.00	0.99	0.37	0.51	0.36

21	12	0.11	0.77	0.50	0.21	0.27	0.18

Celery Trimmed Stalks	0.268	3	12	0.31	1.90	1.75	0.54	0.82	0.55

7	12	0.21	0.65	0.62	0.37	0.38	0.13

14	12	0.12	0.53	0.38	0.19	0.24	0.13

Southern Peas (proposed maximum application rate:  0.26 lb a.i./A; PHI:
7 days)

Mature Seed3	0.255-0.266	6-7	14	<0.01	0.067	0.065	0.014	0.021	0.021

Cucurbit Vegetables (proposed maximum application rate:  0.44 lb a.i./A;
PHI: 3 days)

Cantaloupe	0.437-0.475	3-4	22	0.018	0.393	0.312	0.064	0.102	0.095

Cucumber	0.414-0.463	3	20	<0.01	0.069	0.055	0.020	0.022	0.014

Summer Squash	0.423-0.459	2-4	22	<0.01	0.120	0.102	0.024	0.032	0.033

Stone Fruits (proposed maximum application rate:  0.44 lb a.i./A; PHI:
14 days)

Cherry	0.437-0.468	12-144	32	0.07	0.64	0.63	0.20	0.25	0.16

Peach	0.420-0.449	13-144	30	0.03	0.59	0.59	0.10	0.16	0.14

Plum	0.431-0.448	13-15	22	<0.01	0.19	0.185	0.020	0.045	0.050

Cranberry (proposed maximum application rate:  0.44 lb a.i./A; PHI: 30
days)

Cranberry	0.438-0.451	13-15	12	0.11	0.39	0.32	0.22	0.23	0.09

28-30	12	0.086	0.69	0.63	0.15	0.22	0.20

Mint (proposed maximum application rate:  0.26 lb a.i./A; PHI: 7 days)

Mint Tops	0.260-0.270	7-8	12	2.10	6.84	6.37	3.06	3.87	1.83

1       The validated LOQ is 0.01 ppm for cantaloupes, cucumbers,
squash, southern peas, peaches and plums; 0.02 ppm for spinach, celery
and cherries; and 0.05 ppm for cranberries and mint.  For samples having
residues <LOQ, ½ LOQ was used for calculating of the median, mean and
standard deviation.

2	HAFT = Highest-Average Field Trial.

3	Samples were only identified as “mature seed” and did not specify
whether samples were dry seed or succulent seed.

4	Includes samples from one cherry trial collected at 5 days after the
last application (DALA) and one peach trial at 7 DALA.  Residues in/on
samples from these earlier intervals were similar to residues in/on
samples collected at ~14 DALA.

The submitted field trial data on spinach, cantaloupes, cucumbers,
summer squash, cherries, peaches, plums, cranberries, mint, grape, and
mustard greens are adequate and support the proposed use patterns for
indoxacarb (30% WDG) on these crops or crop groups.  The number and
geographic distribution of the field trials are adequate, and the
appropriate samples were collected at the proposed PHIs.  The samples
were analyzed using adequate analytical methods and the sample storage
intervals are supported by the available storage stability data.

The available field trial data on celery (the representative crop for
subgroup 4B) would not be adequate to support a subgroup tolerance, as
only six field trials were conducted using the WDG formulation, rather
than the required eight field trials, but are adequate to support a crop
group tolerance for the crop group vegetable, leafy, except Brassica
(group 4).

The southern pea field trial data are also adequate; however, the
petitioner did not specify if they wanted succulent or dry.  The field
trial data submitted were for dry peas.  The proposed label directions
for southern peas should be amended to allow for applications only to
varieties used to produce dry seed.  If the petitioner intends to
support a generalized use on southern peas, then field trials will be
required for succulent varieties as well.  Furthermore, the use
directions for southern peas should prohibit applications to varieties
grown for livestock feed. 

Storage Stability

Adequate storage stability data have been previously reviewed   SEQ
CHAPTER \h \r 1 indicating that indoxacarb residues are stable in frozen
storage for up to 6-23 months in a wide variety of plant commodities. 
In addition, adequate storage stability data were provided with the new
field trials and processing studies.  These data also indicate that
indoxacarb is stable in frozen storage for at least 1.5 months in
cranberries, 5-8 months in peaches, plums, prunes, and mint tops and
oil, 10-12 months in peas, celery, spinach, cantaloupes, and squash, 15
months in cherries, and 24 months in cucumbers.  These data support the
sample storage intervals and conditions used in the submitted field
trials and processing studies.    SEQ CHAPTER \h \r 1 The submitted
grape and mustard green field trials and grape processing study are
supported by the previously-submitted storage stability data.

Processed Food/Feed 

To support the proposed new uses of indoxacarb (30% WDG), adequate
processing studies were conducted on grapes, mint and plums.   SEQ
CHAPTER \h \r 1  For grapes, a separate tolerance is not required for
juice as residues were reduced on average by 0.007x for grape juice. 
However, residue concentrations were observed in raisins (2.7x).  Based
on the observed 2.7x processing factor for raisins and HAFT residues of
1.52 ppm from the grape field trials, the maximum expected indoxacarb
residues in raisins would be 4.1 ppm.  These data support a tolerance of
5.0 ppm for residues in/on “grape, raisin.”  A revised Section F
should be submitted.  

For mint, a separate tolerance is not required for oil as residues were
reduced on average by 0.028x in mint oil.  For plums, although residues
were shown to concentrate by 4x in prunes, a separate tolerance is not
required for prunes.  Based on the highest-average field trial (HAFT)
residues for plums (0.185 ppm) and the above processing factor, the
maximum expected residues in prunes would be 0.74 ppm, which is below
the recommended tolerance for stone fruits (0.90 ppm).  Processing
studies on apples and potatoes were previously considered under earlier
petitions.  Based on these petitions, no tolerances were required for
potato processed products and a 3.0 ppm tolerance was established for
wet apple pomace.

Confined/Field Accumulation in Rotational Crops  

  SEQ CHAPTER \h \r 1 An adequate confined rotational crop study,
conducted at a rate of 0.268 lb a.i./A (1x the proposed application rate
for proposed crops), was reviewed in conjunction with an earlier
petition (Memo, S. Levy, 19-JAN-2000; D244253).  The residues of concern
in rotated crops include indoxacarb + its R-enantiomer (Memo, S. Levy,
10-JUL-2000; D263986).  HED has also concluded that the available data
support a 30-day plant-back interval (PBI) for all non-labeled crops
(Memo, S. Levy, 07-SEP-2000; D256351).  As the maximum rate conducted in
the confined accumulation study does not exceed the proposed application
rate for the proposed crops, the study conclusions support the proposed
uses in the subject petition.  

Other Considerations  

  SEQ CHAPTER \h \r 1 There are no established or proposed Codex or
Canadian maximum residue limits (MRLs) for indoxacarb.  However, Mexico
has established MRLs for indoxacarb on several crops at levels ranging
from 0.5 mg/kg on tomatoes and pepper to 10 mg/kg on corn.  None of the
proposed crops currently have equivalent Mexican MRLs; therefore, there
are no international harmonization issues associated with these
petitions.

Proposed/Recommended Tolerances

For PP#s:  5E6911, 5E6926 and 5E6991:  Vegetable, Leafy, Except Brassica
(Group 4), Pome Fruits (Group 11, except pear), Tuberous and Corm
Vegetables (Subgroup 1C), Cucurbit Vegetables (Group 9), Stone Fruits
(Group 12), Cranberry, Mint, Okra, and Southern Pea:  The tolerances
proposed by the petitioners are listed below in Table 4.2.1.2, along
with the HED’s recommended tolerance levels.    SEQ CHAPTER \h \r 1
The recommended tolerance levels for each RAC or crop group in the
current petitions were determined using recent Agency Guidance (Guidance
for Setting Pesticide Tolerances Based on Field Trial Data SOP).  For
southern peas, the recommended tolerance was based on the observed
maximum residue value.

For purposes of determining tolerances, adequate field trial data are
available to set individual tolerances on southern peas, cranberries,
and mint.  In addition, the available data on cantaloupes, cucumbers,
and squash will support a crop group tolerance on cucurbit vegetables,
and the available data on cherries, peaches and plums will support a
crop group tolerance on stone fruits.  As residues were highest in
cantaloupes and cherries, these data were used to set tolerances for
their respective crop groups.

Based on previously reviewed field trial data supporting the existing
tolerances on leaf and head lettuce (10 and 5.0 ppm, respectively) and
the currently-submitted spinach and celery data, a new crop group
tolerance can be established at 14 ppm for “vegetable, leafy, except
Brassica, group 4.”  As residues were highest in spinach, these data
were used to set the crop group tolerance.

Based on previously reviewed field trial data supporting the existing
tolerances on potatoes and apples, new tolerances can be established at
the same levels on tuberous and corm vegetables (subgroup 1C) and pome
fruit (group 11, except pear).  The existing pear tolerance (0.20 ppm)
can be translated to pear, oriental.  In addition, the residue data on
fruiting vegetables can be translated to support the same use pattern
for indoxacarb (WDG) on okra, as okra is now considered part of the
“vegetable, fruiting, group 8” crop group.

Based on the mint and plum processing studies, separate tolerances are
not required for either mint oil or prunes.

For PP#s:    SEQ CHAPTER \h \r 1 3F6576 and 2E6482:    SEQ CHAPTER \h \r
1 Grapes, Brassica Leafy Vegetables, and Turnip Greens.   

  SEQ CHAPTER \h \r 1 DuPontTM and IR-4 proposed tolerances for
indoxacarb of 2.0 ppm in/on grape and 6.0 ppm in/on raisins and 12 ppm
in/on Vegetable, brassica, leafy, group 5 and turnip greens,
respectively.  Furthermore, IR-4 requests that the established 5.0 ppm
tolerance for residues in/on Brassica, head and stem, subgroup be
revoked.  HED concludes that the proposed tolerances for grape,
vegetable, Brassica, leafy, group 5, and turnip greens are adequate. 
However, the proposed raisin tolerance should be lowered to 5.0 ppm and
the correct commodity definition is “grape, raisin.”  

  SEQ CHAPTER \h \r 1 The petitioner has requested a tolerance be set
for residues in/on turnip greens at 12 ppm.  Turnip greens is not
officially classified under 40 CFR 180.41 as a part of group 5; however,
a turnip green tolerance can be requested when submitting mustard greens
data for a tolerance (Memo, B. Schneider, 10-FEB-2000).  Thus, the
residue chemistry database also supports a 12 ppm tolerance for turnip
greens.

Table 4.2.1.2.  Tolerance Summary for Indoxacarb.

Crop Commodity	Proposed or Existing Tolerance (ppm)	Recommended
Tolerance

 (ppm)	Comments

(Corrected commodity definition)

Cranberry	1	0.901	Adequate residue data are available.

Fruit, pome, except pear, group 11	1.0	1.02	The existing residue data on
apples are adequate and will support an expanded use and a tolerance on
Fruit, pome, group 11, except pear.

Pear, oriental	--	0.202	The existing pear tolerance is adequate to cover
a separate Pear, oriental tolerance.

Apple	1.0	Delete	Once the tolerance is established on group 11, the
separate tolerance on apple should be deleted.

Fruit, stone group 12	1	0.901	Adequate residue data are available on
cherries, plums and peaches.  The group tolerance is based on residue
data from cherries.  Fruit, stone, group 12

Leafy vegetables except Brassica	14	141	The existing residue data on
leaf and head lettuce are adequate, as well as the currently- submitted
spinach and celery data will support a crop group tolerance for
Vegetable, Leafy, Except Brassica, Group 4.

Lettuce, head	5.0	Delete	Once the tolerance is established on Vegetable,
Leafy, except Brassica, Group 4, the separate tolerances on leaf and
head lettuce should be deleted.

Lettuce, Leaf	10.0

Mint 	10	111	Adequate residue data are available.

Separate tolerances should be established for Peppermint, tops and
Spearmint, tops.

Okra	0.5	0.502	The existing residue data on tomatoes and  peppers will
be translated to support the same use pattern and tolerance on okra, as
okra is now considered part of the “vegetable, fruiting, group 8”
crop group.

Pea (southern)	0.1	0.101	Adequate residue data are available for dried
pea only.

Pea, southern, seed

Vegetable, cucurbit, group 9	0.5	0.601	Adequate residue data are
available on cucumbers, squash, and cantaloupes.  The tolerance is based
on residue data from cantaloupes.

Vegetable, tuberous and corm, subgroup 1C	0.01	0.012	The existing
residue data on potatoes are adequate and will support an expanded use
and a tolerance on Vegetable, tuberous and corm, subgroup 1C.

Potato	0.01	Delete	Once the tolerance is established on subgroup 1C, the
separate tolerance on potato should be deleted.

  SEQ CHAPTER \h \r 1 Grape	2.0	2.0	Adequate residue data are available.

  SEQ CHAPTER \h \r 1 Raisin	6.0	5.0	  SEQ CHAPTER \h \r 1 Grape, raisin

  SEQ CHAPTER \h \r 1 Vegetable, brassica, leafy, group 5	12	12	Adequate
residue data are available.   SEQ CHAPTER \h \r 1 

Brassica, head and stem, subgroup 5A  SEQ CHAPTER \h \r 1 	5.0	Delete
Once the tolerance is established on crop group 5, the separate
“Brassica, head and stem, subgroup 5A” should be revoked.

Turnip Greens	12	12	Adequate residue data are available.

1	Tolerance was determined using tolerance calculating spread sheet. 

2	Tolerance is based on translation of existing residue data.

4.2.2.  Dietary Exposure Analyses tc \l3 "4.2.2.	 Dietary Exposure
Analyses 

Indoxacarb acute and chronic dietary exposure assessments were conducted
using the DEEM-FCID™, Version 2.03, which incorporates consumption
data from USDA’s CSFII, 1994-1996 and 1998.  The 1994-96, 98 data are
based on the reported consumption of more than 20,000 individuals over
two non-consecutive survey days.  Foods “as consumed” (e.g., apple
pie) are linked to EPA-defined food commodities (e.g. apples, peeled
fruit - cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or
N/S, baked) using publicly available recipe translation files developed
jointly by USDA/ARS and EPA.  For chronic exposure assessment,
consumption data are averaged for the entire U.S. population and within
population subgroups, but for acute exposure assessment are retained as
individual consumption events.  Based on analysis of the 1994-96, 98
CSFII consumption data, which took into account dietary patterns and
survey respondents, HED concluded that it is most appropriate to report
risk for the following population subgroups: the general U.S.
population, all infants (<1 year old), children 1-2, children 3-5,
children 6-12, youth 13-19, adults 20-49, females 13-49, and adults 50+
years old.

For chronic dietary exposure assessments, an estimate of the residue
level in each food or food-form (e.g., orange or orange juice) on the
food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form to produce a residue intake
estimate.  The resulting residue intake estimate for each food/food form
is summed with the residue intake estimates for all other food/food
forms on the commodity residue list to arrive at the total average
estimated exposure.  Exposure is expressed in mg/kg body weight/day and
as a percent of the cPAD.  This procedure is performed for each
population subgroup.

For acute exposure assessments, individual one-day food consumption data
are used on an individual-by-individual basis.  The reported consumption
amounts of each food item can be multiplied by a residue point estimate
and summed to obtain a total daily pesticide exposure for a
deterministic exposure assessment, or “matched” in multiple random
pairings with residue values and then summed in a probabilistic
assessment.  The resulting distribution of exposures is expressed as a
percentage of the aPAD on both a user (i.e., only those who reported
eating relevant commodities/food forms) and a per-capita (i.e., those
who reported eating the relevant commodities as well as those who did
not) basis.  In accordance with HED policy, per capita exposure and risk
are reported for all tiers of analysis.  However, for Tiers 1 and 2, any
significant differences in user vs. per capita exposure and risk are
specifically identified and noted in the risk assessment.

Partially-refined acute probabilistic and chronic dietary exposure
assessments were conducted for all existing and proposed new food uses
of indoxacarb.  A cancer dietary exposure assessment was not conducted
for indoxacarb, because indoxacarb has been classified as “not likely
to be carcinogenic.”  ARs for all registered and proposed food
commodities were based on field trial data.  ARs for all current uses
were further refined using %CT data (Memo, A. Halvorson, 05-APR-2007;
DP#: 338731, and electronic communication, A. Halvorson to M. Sahafeyan,
12-APR-2007, and A. Halvorson to S. Levy, 10-MAY-2007), following the
guidance provided in HED SOP 99.6 (Classification of Food Forms with
Respect to level of Blending; 20-AUG-1999). 100% CT was assumed for the
remaining new uses.  Available processing data for indoxacarb were used
to refine ARs for apples/pears (juice), potato (dry, chips), cotton
(oil), tomato (paste and puree), peanut (oil), soybean (oil), grapes
(raisin and juice), prunes (dried), and mint (oil), and other
commodities where translation was applicable.  For all other processed
commodities, DEEM-FCID( (ver. 7.81) default processing factors were
assumed.

EDWCs were provided by EFED (Memo, J. Hetrick, 01-FEB-2007; DP#: 293793)
and incorporated directly into the DEEM-FCID( analyses.  Both the acute
and chronic analyses were conducted using estimated surface water
residues generated using PRZM/EXAMS.  EFED provided modeling results for
several crop scenarios.  The scenarios resulting in the highest EDWCs
(cotton in Mississippi) were used.  For the acute and chronic
assessments, the estimated 1-in-10 year annual peak and 1-in-10 year
annual mean residue in surface water, respectively, were used as point
estimates in the DEEM-FCID( analysis.

4.2.2.1.  Acute Dietary Exposure Analysis tc \l4 "4.2.2.1.	Acute Dietary
Exposure Analysis 

™ software are below HED’s level of concern for the U.S. population
and each of the population subgroups.  Combined dietary exposure from
food and drinking water at the 99.9th percentile of exposure is
estimated to be 0.034881 mg/kg/day for the overall U.S. population,
equivalent to 39% of the aPAD.  The population subgroup with the highest
estimated acute dietary exposure to indoxacarb is children, 3 to 5 years
old, with an estimated exposure at the 99.9th percentile of 0.075914
mg/kg/day, equivalent to 84% of the aPAD.  The estimated exposures/risks
from food and water are summarized in Table 4.2.2.1.1 for all
populations.

Table 4.2.2.1.1.  Summary of Acute Dietary (Food + Drinking Water)
Exposure and Risk for Indoxacarb.

Population Subgroup	aPAD (mg/kg/day)	95th Percentile	99th Percentile
99.9th Percentile

Exposure (mg/kg/day)	% aPAD	Exposure (mg/kg/day)	% aPAD	Exposure
(mg/kg/day)	% aPAD

General U.S. Population	0.09	0.007763	8.6	0.015056	17	0.034881	39

All Infants (< 1 year old)

0.011092	12	0.021882	24	0.039554	44

Children 1-2 years old

0.018245	20	0.027641	31	0.070299	78

Children 3-5 years old1

0.013500	15	0.021957	24	0.075914	84

Children 6-12 years old

0.008839	9.8	0.013521	15	0.029817	33

Youth 13-19 years old

0.005670	6.3	0.011517	13	0.039626	44

Adults 20-49 years old

0.004719	5.2	0.008655	9.6	0.027228	30

Adults 50+ years old

0.004489	5.0	0.012210	14	0.031662	35

1  The population subgroup with the highest estimated acute dietary
(food + drinking water) exposure and risk is indicated by bold text.

4.2.2.2.  Chronic Dietary Exposure Analysis tc \l4 "4.2.2.2.	Chronic
Dietary Exposure Analysis 

™ software are below HED’s level of concern for the U.S. population
and each of the population subgroups.  Estimated chronic dietary
exposure to indoxacarb from food and drinking water is below HED’s
level of concern.  Combined dietary exposure from food and drinking
water is estimated at 0.002411 mg/kg/day for the general U.S. population
(16% of the cPAD) and 0.007940 mg/kg/day (53% of the cPAD) for children,
1 to 2 years old, the population subgroup with the highest estimated
chronic dietary exposure to indoxacarb.

Table 4.2.2.2.1.  Summary of Chronic Dietary (Food + Drinking Water)
Exposure and Risk for Indoxacarb.

Population Subgroup	cPAD (mg/kg/day)	Exposure (mg/kg/day)	% cPAD

General U.S. Population	0.015	0.002411	16

All Infants (< 1 year old)

0.002574	17

Children 1-2 years old1

0.007940	53

Children 3-5 years old

0.006068	41

Children 6-12 years old

0.003701	25

Youth 13-19 years old

0.002197	15

Adults 20-49 years old

0.001764	12

Adults 50+ years old

0.001747	12

Females 13-49 years old

0.001693	11

1The population subgroup with the highest estimated chronic dietary
(food + drinking water) exposure and risk is indicated by bold text.

4.2.2.3.  Cancer Dietary Exposure Analysis tc \l4 "4.2.2.3.	Cancer
Dietary Exposure Analysis 

Indoxacarb has been classified as “not likely to be carcinogenic in
humans” by HIARC; therefore, no carcinogenic dietary risk analysis was
performed.

4.3.  Water Exposure/Risk Pathway tc \l2 "4.3.	Water Exposure/Risk
Pathway 

year peak (acute) concentration of DPX-JW062 residues of 25.1 μg/L. 
The 1-in-10 year annual average concentration (non-cancer chronic) and
30-year annual average concentration (cancer) of DPX-JW062 residues are
not likely to exceed 5.37 and 2.78 μg/L, respectively.  SCI-GROW
modeling indicates concentrations of DPX-JW062 are not expected to
exceed 0.21 μg/L.  The highest indoxacarb residue concentrations are
associated with the Mississippi cotton scenario (Table 4.3.1).  

For acute and chronic dietary risk assessments, the 1-in-10 year peak
(25.1 ppb) and the 1-in-10 year annual average, (5.37 ppb) indoxacarb
residues of concern in water from cotton scenario were used.

Table 4.3.1.  Default PCA Corrected PRZM/EXAMS Indoxacarb Residue
Concentrations (µg/L).

Scenario	

1-in-10 year peak	

1-in-10 year annual average	

30-year annual average

Cotton (MS)	25.068	5.373	2.782

Turf (FL)1	0.05	0.014	0.008

Apples (NC)	18.093	4.738	2.560

Cabbage (FL)	8.275	1.940	1.185

Potato (ME)	11.083	5.346	3.961

Swiss Chard (CA)

Aerial Application	9.220	3.788	2.643

Swiss Chard (CA)

Ground  Application	9.173	3.564	2.379

1- The default PCA correction (0.87) was not used for turf because this
use pattern was not considered in development of  PCAs.

4.4.  Residential Exposure/Risk Pathway tc \l2 "4.4.	Residential
Exposure/Risk Pathway 

Residential exposure/risk assessments for indoxacarb were provided by M.
Dow (Memo, 25-AUG-2004; DP#: 289892).

Residential Handlers

Indoxacarb is registered for use as a fire ant bait (DuPontTM Indoxacarb
0.045% fire ant bait), which may be applied as a mound treatment or as a
broadcast application by “residential” (i.e., private persons)
applicators as well as by commercial handlers such as PCOs.  The
broadcast treatment results in a higher exposure than the mound
treatment and, therefore, is the scenario assessed here.

A residential (homeowner) applicator using a push-type spreader to apply
granules is assessed using HED’s SOPs for Residential Exposure
Assessments (DEC-1997) in conjunction with unit exposures developed by
the Outdoor Residential Exposure Task Force (ORETF) and cited as ExpoSAC
standard operating procedure in a memorandum by G. Bangs (Memo, G.
Bangs, 30-APRIL-2001; MRID 44972201).  The dermal unit exposure for an
applicator wearing short pants and short sleeved shirt plus shoes and
socks is 0.68 mg a.i./lb handled.  The inhalation unit exposure is
0.00091 mg a.i./lb handled.  The rate of application is taken from the
proposed label for indoxacarb fire ant bait 0.045%.

Dose (mg/kg/day) = Unit exposure (mg/lb a.i. handled) * Application rate
(lb a.i./A) * Amount handled (A/day) ( Body weight (kg)

Dermal dose = 0.68 mg a.i./lb handled * 0.000675 lb handled/A * 0.5
A/day  ( 70 kg bw = 0.0000033 mg a.i./kg/day 

Inhalation dose = 0.00091 mg a.i./lb handled * 0.000675 lb handled/A *
0.5 A/day ( 70 kg bw = 4.38 x 10-9 mg a.i./kg/day 

Dermal MOE = NOAEL/Dose = 38 mg a.i./kg/day ( 0.0000033 mg a.i./kg/day =
11,500,000.

Inhalation MOE = NOAEL/Dose = 4.5 mg a.i./kg/day ( 4.38 x 10-9 mg
a.i./kg/day = 1,030,000,000.  

Residential Post-application Exposure

There is the potential for postapplication exposure to adults and
children from entering areas previously treated with indoxacarb (i.e.,
turf treated for fire ants).  The postapplication scenarios assessed
from exposure to treated turf include:  

Dermal exposure from treated lawns due to high contact lawn activities
(adult and toddler); 

Dermal exposure from treated turf due to golfing (adults and youths); 

Hand-to-mouth transfer of pesticide residues on lawns (toddler); 

Incidental ingestion of granules from pesticide-treated residential
areas (toddler); and 

Incidental ingestion of soil from pesticide-treated residential areas
(toddler).

Exposures were calculated by considering the potential sources of
exposure, then calculating dermal and incidental oral exposures.

A summary of the residential exposures and risks are provided in Table
4.4.1.  Residential post-application MOEs ranged from 1,000 for a
toddler ingesting pesticide granules to 45 million for toddler
incidental oral ingestion of treated soil.  Therefore, the fire ant bait
residential use is not of concern to HED (i.e., MOEs >100).



Table 4.4.1.  Summary Residential Post-Application Exposures and Risks.

Activity	Exposure (Dose)

mg a.i./kg bw/day	MOE3

Adult dermal post application  turf contact	0.000156	244,000

Toddler dermal post app turf contact	0.00026	146,000

Adult golfer post app turf contact	0.0000108	3,520,000

Child golfer post app turf contact	0.0000184	2,070,000

Toddler oral hand to mouth from contacting treated turf	0.00001	150,000

Toddler oral - ingestion of granules	0.009	1,000

Toddler incidental oral ingestion of treated soil	3.33 x 10-8	45,000,000

Combined Exposures

Adult combined dermal exposure = application + post-application1	dermal
application -- 0.000003

dermal post-application -- 0.000156

total adult dermal exposure -- 0.000159	239,000

Toddler combined exposure2	oral hand to mouth treated turf -- 1 x 10-5

oral ingestion treated soil -- 3.33 x 10-8

dermal post application -- 2.6 x 10-4

total toddler dermal + oral exposure -- 2.7 x 10-4	

74,0004

1.  For the combined adult exposure (i.e., from application and from
post-application exposure) HED only sums the dermal fractions. 
Post-application inhalation exposure is considered negligible since the
material is a granule and is not volatile.  As can be seen above (under
“Resident Applicator”), the inhalation fraction of exposure to the
resident applicator is so small (4.38 x 10-9 mg a.i./kg bw/day) it would
not materially change the summed dermal exposures (application +
post-application).  The resulting inhalation MOE is > 1.0 x 109  for the
resident applicator.

2.  For combined exposure to a toddler, since the oral and dermal
toxicological effects are similar, HED sums exposures from 1) oral hand
to mouth from treated turf, 2) oral ingestion of treated soil and 3)
dermal post-application exposure.  Ingestion of treated granules is
considered to be an episodic, “one-time” occurrence and is therefore
not summed (combined) with other toddler exposures.  

3.  MOE = Margin of Exposure = NOAEL (mg a.i./kg bw/day) ( Dose (mg
a.i./kg bw/day).

4.  MOEs for two or more routes of exposure can be combined (Memo, J.
Whalen & H. Pettigrew, “Inhalation Risk Characterization and the
Aggregate Risk Index [ARI]”, 25 NOV. 1998) to derive an MOET provided
the MOEs are based on studies of similar duration and exhibit the same
toxicological effects and are compared against the same UF (100 in this
case).   The MOEs are combined with the following convention:

MOET =         1 / ((1/MOEo turf) + (1/MOEo soil) + (1/MOEd
post-applic))                            

MOET =          1 / ((1/150,000) + (1/45,000,000) + (1/146,000) = 74,000

Spray Drift

Spray drift is always a potential source of exposure to residents nearby
to spraying operations.  This is particularly the case with aerial
application, but, to a lesser extent, could also be a potential source
of exposure from groundboom application methods.  The Agency has been
working with the Spray Drift Task Force, EPA Regional Offices and State
Lead Agencies for pesticide regulation and other parties to develop the
best spray drift management practices.  The Agency is now requiring
interim mitigation measures for aerial applications that must be placed
on product labels/labeling.  The Agency has completed its evaluation of
the new database submitted by the Spray Drift Task Force, a membership
of U.S. pesticide registrants, and is developing a policy on how to
appropriately apply the data and the AgDRIFT® computer model to its
risk assessments for pesticides applied by air, orchard airblast, and
ground hydraulic methods.  After the policy is in place, the Agency may
impose further refinements in spray drift management practices to reduce
off-target drift and risks associated with aerial as well as other
application types where appropriate.

5.0.  AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION tc \l1 "5.0.
AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION 

Aggregate exposure risk assessments were performed for the following: 
acute aggregate exposure (food + drinking water exposure), short- and
intermediate-term aggregate exposure (food + drinking water +
residential exposure), and chronic aggregate exposure (food + drinking
water exposure).  The acute and chronic dietary exposure estimates
provided in Sections 4.2.2.2 and 4.2.2.3, respectively, of this document
represent acute and chronic aggregate exposure. A cancer aggregate risk
assessment was not performed because HIARC determined that cancer
dietary risk concerns due to long-term consumption of indoxacarb
residues are adequately addressed by the chronic exposure assessment.

5.1.  Short- and Intermediate-Term Aggregate Risk (food + drinking water
+ residential exposure)

 tc \l2 "5.2.  Short- and Intermediate-Term Aggregate Risk (food +
drinking water + residential exposure) 

Short- and intermediate-term exposures exist for adults and children
from the registered turf (fire ant bait) application use.  For both
short- and intermediate-term exposures, incidental oral and dermal
exposure risk assessments are appropriate to aggregate due to the same
target organ toxicity (endpoints of concern) identified in both oral and
dermal studies used for risk assessment.  The short- and
intermediate-term incidental oral and dermal exposures are combined with
chronic dietary (food and water) exposure for determination of aggregate
short- and intermediate-term exposures.  HED uses chronic dietary
exposure when conducting short- and intermediate-term aggregate
assessments as they have been determined that these will more accurately
reflect exposure from food over the HED defined short-term interval
(1-30 days) than will acute exposure.  When different endpoints and dose
levels have been identified for dermal, incidental oral, dietary and
inhalation routes of exposure, but the LOCs are the same, the
“1/MOE” approach is used to aggregate exposure.  

For adults, there is no significant incidental oral exposure; therefore,
only dermal exposure (application + post-application) was appropriate to
aggregate with dietary (food) and water.  For young children, due
primarily to their hand-to-mouth activities, potential for
post-application exposure to children was assessed.  Since there is both
short- and intermediate-term post-application, (non-dietary) oral and
dermal exposures, for children, it is appropriate to aggregate these
exposures with dietary (food) and water.  Children can be exposed to the
following three post-application scenarios: 1) post-application exposure
from the incidental ingestion (hand-to-mouth) from contacting treated
turf; 2) post-application exposure from incidental ingestion of treated
soil (soil ingestion); and 3) post-application dermal exposure from
contact with treated turf.  Ingestion of granules is considered an
episodic event and not a routine behavior.  Because HED does not believe
that this would occur on a regular basis, HED’s concern for human
health is related to acute poisoning rather than short or
intermediate-term residue exposure and therefore was not aggregated into
the total oral exposure in determining aggregate risk.

Since the aggregate MOEs are ≥100, short- and intermediate-term
aggregate exposures to indoxacarb is not of concern to HED.

Table 5.1.1.  Short/Intermediate-Term Aggregate Risk Calculations for
Toddlers.

Population	Target

MOE	Chronic Food + Water	Residential Oral	Residential Dermal	Aggregate
MOE6

(food + water + residential)

Exposure

(mg/kg/day)	MOE1	Exposure2

(mg/kg/day)	MOE3	Exposure4

(mg/kg/day)	MOE5

	Children (1-2 years old)	100	0.007940	190	0.00001+3.3x10-8	150,000
0.00026	146,000	190

1   MOE = NOAEL (1.5 mg/kg/day) ÷ (chronic food + water exposure)

2   Residential oral = sum of oral (hand-to-mouth from contacting
treated turf and ingestion of treated soil).

3   MOE = NOAEL (1.5 mg/kg/day) ÷ (sum of residential oral exposure)

4   Residential dermal = post-application turf contact

5   MOE = NOAEL (38 mg/kg/day) ÷ (residential dermal exposure)

6   Aggregate MOE = 1/[(1/191) + (1/150,000) + (1/146,000)]

Table 5.1.2.  Short/Intermediate-Term Aggregate Risk Calculations for
Adults.

Population1	Target

MOE	Chronic Food + Water	Residential Dermal	Aggregate MOE5

(food + water + residential)

Exposure

(mg/kg/day)	MOE2	Exposure3

(mg/kg/day)	MOE4

	U.S. Population	100	0.002411	620	0.000159	239,000	620

1   Adult population with highest chronic food and water exposure value
was used.

2   MOE = NOAEL (1.5 mg/kg/day) ÷ (chronic food + water exposure)

3   Residential dermal = combined application (0.000003) +
post-application (0.000156)

4   MOE = NOAEL (38 mg/kg/day) ÷ (residential dermal exposure)

5   Aggregate MOE = 1/[(1/620) + (1/239,000)]

6.0.  CUMULATIVE RISK tc \l1 "6.0.	CUMULATIVE RISK 

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency consider
"available information” concerning the cumulative effects of a
particular pesticide's residues and "other substances that have a common
mechanism of toxicity.” 

EPA does not have, at this time, available data to determine whether
indoxacarb has a common mechanism of toxicity with other substances. 
Unlike other pesticides for which EPA has followed a cumulative risk
approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to indoxacarb and any other
substances and indoxacarb does not appear to produce a toxic metabolite
produced by other substances. For the purposes of this tolerance action,
therefore, EPA has not assumed that indoxacarb has a common mechanism of
toxicity with other substances.  For information regarding EPA’s
efforts to determine which chemicals have a common mechanism of toxicity
and to evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA’s Office of Pesticide Programs concerning
common mechanism determinations and procedures for cumulating effects
from substances found to have a common mechanism on EPA’s website at  
HYPERLINK "http://www.epa.gov/pesticides/cumulative/" 
http://www.epa.gov/pesticides/cumulative/ .

7.0.  OCCUPATIONAL EXPOSURE tc \l1 "7.0.	OCCUPATIONAL EXPOSURE 

7.1.  Occupational Handler Exposure tc \l2 "7.1.	Occupational Exposure 

		

Occupational exposure/risk assessments for indoxacarb were provided by
M. Dow (Memo, 22-FEB-2002; DP#: 325480; Memo, 26-MAR-2006; DP#:326515;
Memo, 25-AUG-2004, DP#: 289892) and K. Lowe/Y. Tesfaye (Memo,
15-FEB-2007; DP#: 335921).

DuPontTM has submitted an application to register the compound
indoxacarb for new uses on leafy green vegetables, leaf petiole
vegetables, okra, pome fruit (except pear), spinach, tuberous and corm
vegetables, southern pea, mint, stone fruit, cucurbit vegetable crop
group, cranberry, swiss chard, Brassica leafy vegetables, turnip greens,
grape, and as a fire ant bait.  HED has conducted an estimate of
exposure and risk to pesticide handlers from mixing, loading and
applying the material and to agricultural workers from post-application
re-entry exposures.

The products proposed for use are DuPontTM Avaunt® insecticide (EPA
Reg. No. 352-597) and DuPontTM Advion®; 0.045% fire ant bait (EPA Reg.
No. 352-627).  Avaunt® is a 30% by weight, a.i., WDG formulation. 
DuPontTM Indoxacarb 0.045% fire ant bait is a granular formulation. 
Table 7.1.1 provides a summary of the proposed use patterns.

Table 7.1.1.  Summary of Proposed New Uses of Indoxacarb.

Formulation	DuPontTM Avaunt® insecticide; 30% a.i. WDG; EPA Reg. No.
352-597

DuPontTM Advion®; 0.045% fire ant bait, EPA Reg. No. 352-627

Methods of Application	aerial, groundboom, airblast

as broadcast or mound treatment for fire ants using drop or broadcast
spreaders or “scoop”/spoon for mound treatment

Use Sites	Leafy green vegetables, leafy petiole vegetables, okra, pome
fruit (except pear), spinach, tuberous & corm vegetables

Southern pea, mint, stone fruit, cucurbit vegetables and cranberry

Swiss chard

Brassica leafy vegetables, turnip greens, grapes, fire ant bait

Maximum Rates of Application 	Leafy greens: 0.11 lb a.i./A;  0.44 lb
a.i./A/crop

Leafy petioles: 0.065 lb a.i./A; 0.26 lb a.i./A/crop

Okra: 0.065 lb a.i./A; 0.26 lb a.i./A/crop

Pome fruit: 0.11 lb a.i./A; 0.44 lb a.i./A/crop

Spinach: 0.065 lb a.i./A; 0.26 lb a.i./A/crop

Tubers & corms: 0.11 lb a.i./A; 0.44 lb a.i./A/crop	

Southern pea  & mint:   0.065 lb a.i./A; 0.26 lb a.i./A/yr

Cucurbit vegetables, stone fruit, cranberry: 0.11 lb a.i./A; 0.44 lb
a.i./A/crop

Swiss chard: 0.11 lb a.i./A; 0.263 lb a.i./A/crop

Brassica leafy vegetables: 0.065 lb a.i./A; 0.26 lb a.i./A/crop

Turnip greens: 0.065 lb a.i./A; 0.26 lb a.i./A/crop

Grapes: 0.11 lb a.i./A;  0.44 lb a.i./A/crop

Fire ant bait: 0.000675 lb a.i./A;  0.00135 lb a.i./A/year

Frequency of Application	4 per crop at the highest rates, except for
swiss chard: 2 per crop at the highest rate

PHI	Leafy greens and Okra - 3 days

Tubers & corms - 7 days

Leafy petioles, pome fruit and spinach  - 14 days

Southern pea and mint - 7 days

Stone fruit - 14 days

Cucurbit vegetable - 3 days

Cranberry - 30 days

Swiss chard - 3 days

Brassica leafy vegetables – 3 days

Turnip greens – 3 days

Grapes – 7 days

REI	12 hours

Manufacturer	E. I. du Pont de Nemours and Company (DuPontTM)

The proposed Avaunt® product may be applied by air, groundboom, or
airblast.  The label directs applicators and other handlers to wear the
following personal-protective equipment (PPE): long-sleeved shirt, long
pants, shoes plus socks and chemical resistant gloves.

The 0.045% fire ant bait may be applied as a mound treatment or as a
broadcast application.  It may be applied by “residential” (i.e.,
homeowner) applicators as well as by commercial handlers such as PCOs. 
The fire ant bait use does not fall under the purview of the WPS because
it is a nonagricultural use and, therefore, there is no restricted REI. 
However, the label does direct: “Do not allow unprotected workers or
other persons or pets in treated area during application.”  The label
also directs applicators and other handlers “must wear:  Long-sleeved
shirt and long pants.  Shoes plus socks.”

7.1.  Handler

Based on the proposed use patterns, commercial and private (i.e.,
grower) pesticide handlers are expected to have short-term (1-30 days)
exposures.  While it is possible for handlers to experience
intermediate-term exposures (1-6 months), HED believes it is highly
unlikely.  Since the short- and intermediate-term dermal and inhalation
toxicity endpoints are the same, however, the short-term assessment is
considered protective of intermediate-term exposures.  

The labels indicate several probable pesticide handler activities,
including mixing/loading of water dispersible granules, application by
air and ground (groundboom, airblast, and tractor-drawn spreader), and
commercial and residential mixer/loader/applicators applying granular
fire ant bait.  HED expects the most highly exposed occupational
pesticide handlers are likely to be involved in:  1) mixing/loading dry
flowables for aerial applications, 2) applying sprays via groundboom
equipment, 3) applying sprays via airblast equipment, 4) applying
granules via tractor-drawn spreader, 5) mixing/loading/applying granules
with a scoop/spoon, and 6) mixing/loading/applying granules with a
push-type spreader.

No chemical-specific data are available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure in this
document are based upon study data available in the PHED Surrogate Guide
(AUG-1998).  For pesticide handlers, it is HED policy to present
estimates of dermal exposure with a single layer of work clothing (i.e.,
long pants, long-sleeved shirt and shoes plus socks) and either with or
without gloves.  Table 7.1.1 provides a summary of estimates of
pesticide handler exposure and risk.

Table 7.1.1.  Estimated Handler Exposure and Risk from the Use of
Indoxacarb.

Unit Exposure1

mg a.i./lb handled	Application Rate2

lb a.i./A	Units Treated3

Per Day	Average Daily

Dose4

mg a.i./kg bw/day	MOE5

Mixing/Loading Dry Flowables for Aerial Application

Dermal:

No Glove     0.066 LC

With Glove  0.066 HC

Inhal             0.00077 HC	0.11 1b a.i./A	350A	Dermal:  

No Glove     0.036    

With Glove  0.036

Inhal            0.00049	Dermal:

No Glove      1,000

With Glove    1,000

Inhal              9,100

Applying Sprays via Groundboom Equipment

Dermal:

No Glove     0.014 HC

With Glove  0.014 MC

Inhal             0.00074 HC	0.11 lb a.i./A	200A	Dermal:

No Glove     0.0044

With Glove  0.0044

Inhal            0.00027	Dermal:

No Glove      8,600

With Glove    8,600

Inhal              17,000

Applying Sprays via Airblast Equipment

Dermal:

No Glove       0.36 HC

With Glove    0.24 HC

Inhal              0.0045 HC	0.11 lb a.i./A	40 A	Dermal:

No Glove     0.023

With Glove   0.015

Inhal            0.00033	Dermal:

No Glove       1,700

With Glove    2,500

Inhal              14,000

Applying Granules via Tractor-drawn Broadcast Spreader

Dermal:

No Glove     0.0099 LC

With Glove  0.0069 LC

Inhal             0.0012 LC	0.000675 lb a.i./A	80	Dermal:

No Glove   7.6 x 10-6

With Glove5.3 x 10-6

Inhal          9.3 x 10-7	Dermal:

No Glove    5 x 106

With Glove 7.2 x 106

Inhal           4.8 x 106

Mixer/Loader/Applicator - Scoop/Spoon (Granular bait dispersed by hand)

Dermal:

No Glove      no data 

With Glove   71.0    MC

Inhal               0.47   MC	2.35 x 10-7 lb a.i./mound	2.35 x 10-7
a.i./mound

40 mounds/A @ 5A/day

200 mounds/day = 0.000047 lb a.i./day	Dermal:

No Glove    no data

With Glove 4.8 x 10-5

Inhal          3.2 x 10-7	Dermal:

No Glove     no data

With Glove 792,000

Inhal            1.4 x 107

Mixer/Loader/Applicator - Push  spreader

Dermal:

No Glove     0.35 HC

With Glove  0.22 HC

Inhal             0.0075 HC	0.000675	5 A	Dermal:

No Glove   1.7 x 10-5

With Glove1.1 x 10-5

Inhal           3.6 x 10-7	Dermal:

No Glove    2.2 x 106

With Glove 3.5 x 106

Inhal           1.3 x 107

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database, August 1998.   Dermal No Glove = Dermal Unit Exposure with a
Single Layer Work Clothing and No Gloves; Dermal With Glove = Dermal
Unit Exposure with a Single Layer Work Clothing With Gloves; Inhal. =
Inhalation.  Units = mg a.i./pound of a.i. handled.  Data Confidence: LC
= Low Confidence, MC = Medium Confidence, HC = High Confidence.

2.  Application Rate. = Maximum rate of application listed on the
proposed label.

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”; Policy No. 9. Expo SAC; Revised 05-JUL-2000.

4.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated (
Body Weight (70 kg for short- and intermediate-term dermal and 60 kg for
short and intermediate inhalation).  Inhalation absorption assumes 100%
absorption.  Dermal exposures not adjusted for percent dermal absorption
as NOAELs were derived from 28-day rat dermal toxicity study.

5.  MOE = Margin of Exposure = No-Observable-Adverse-Effect-Level
(NOAEL) ( ADD.  Short- and intermediate-term dermal NOAEL = 38 mg
a.i./kg/day.  Short- and intermediate-term inhalation NOAEL = 4.5 mg
a.i./kg/day.

HED’s level of concern is for MOEs <100.  HED did not identify any
risks of concern since the estimated MOEs >100.

7.2.  Post-Application tc \l2 "7.2.	Post-Application 

Estimates of re-entry exposure are based upon ExpoSAC No. 3.1
(AUG-2000) and conventional HED methodology for assessing re-entry
exposure.  

All Crops except Grapes

Agricultural workers may have post-application exposures that occur
during the course of normal agricultural activities.  For several of the
proposed crop uses, mechanical harvesting is utilized, thereby
minimizing post-application exposure.  However, there are activities
that occur prior to harvest that may result in post-application exposure
(e.g., irrigation, scouting, pruning, thinning).  For those activities,
exposures were calculated using dermal TCs from the ExpoSAC Policy
Number 3.1: Agricultural TCs (AUG-2000).  Among the crops considered
here with the highest application rates, the most conservative
(protective) TC is 3,000 cm²/hr for thinning pome fruit, and this value
was used in the assessment.

Post-application agricultural worker exposure is estimated using an HED
procedure that assumes 20% of the application rate is available as DFR
on the day of treatment.  HED does not expect post-application exposures
to exceed short-term exposure.  Therefore, only short-term exposures are
assessed.  However, since the toxicological endpoints are the same for
short-term and intermediate-term exposures, the risks from short- or
intermediate-term exposures would also be the same.  The following
convention is used to estimate post-application agricultural worker
exposure:

PDRt  =  DFRt * CF1 * TC * ET 

where:

PDRt	=	potential dose rate on day “t” (mg/day);

DFRt	=	DFR on day “t” (µg/cm2);

CF1	= 	weight unit conversion factor to convert µg units in DFR value
to mg for the daily

		dose (0.001 mg/µg);

TC	=	transfer coefficient (cm2/hr) (In this case 3,000 cm2/hr; ExpoSAC
Policy 003.1

		Rev. 07-AUG-2000); and

ET	=	Exposure Time (8 hrs).

and

DFRt = AR * F * (1-D)t * CF2 * CF3

where:

AR	=	application rate (0.11 lb a.i./A);

F	=	fraction of a.i. retained on foliage (20%); 

D	=	fraction of residue that dissipates daily (10%); 

t	=	post-application day on which exposure is being assessed;

CF2	=	weight unit conversion factor to convert the lbs a.i. in the
application rate to µg for the DFR value

		(4.54E8 µg/lb); and

CF3	=	area unit conversion factor to convert the surface area units in
the application rate to cm2 for

		the DFR value (2.47E-8 acre/cm2).

( DFR = 0.11 lb a.i./A * 0.20 * (1-0)0 * 4.54 x 108 µg/lb *  2.47 x10-8
A/cm² = 0.25 µg/cm2

PDR =  (0.25 µg/cm2  * 0.001 mg/µg * 5,000 cm2/hr * 8 hr/day) / 70 kg
= 0.143 mg/kg/day.

MOE = NOAEL ( PDR 

( 38 mg a.i./kg/day ( 0.086 mg a.i./kg/day = 450

HED’s level of concern is for MOEs <100.  In this case the estimated
MOE is >100 and, therefore, not of concern to HED.

Grapes

The registrant has presented compound specific DFR data for indoxacarb
on grapes (MRID 45900302; Memo, M. Dow, 10-MAR-2004; DP#: 299249).  In
this study, two applications were made, 5 days apart.  Since the revised
label indicates a 21-day interval for grape application, HED utilizes
the study data taken after the first application.  The maximum DFR
reported after the first application was from the Washington site (0.532
µg/cm²).  

TC = 10,000 cm2/hr Grapes (table/raisin)

0.532 µg/cm2 * 10,000 cm2/hr * 8 hr/day * 0.001 mg/µg *  1/70 kg bw =
0.608 mg/kg bw/day.

MOE = NOAEL ( ADD then 50 mg/kg bw/day ( 0.608 mg/kg bw/day = 82.

For grapes, the unadjusted NOAEL (50 mg/kg/day) has been used since the
formulation measured in the DFR study is the same as that measured in
the toxicity studies.  An MOE < 100 is of concern to HED.  Since the
highest DFR value reported results in a MOE of concern, HED presents the
summary study results for all three study sites and the associated
MOE’s for the DFR values reported for each day, post-application.

Table 7.2.1.  Indoxacarb DFR Data for Grape Vines in California.

Sampling Interval

(days after treatment)	Corrected DFR level1

(μg/cm2)

	Replicate 1	Replicate 2	Replicate 3	Arithmetic Mean

(μg/cm2)

0.083	0.174	0.179	0.186	0.180

1	0.180	0.177	0.151	0.169

3	0.116	0.196	0.136	0.150

5	0.097	0.120	0.139	0.118

1  Raw residue data corrected for overall average field fortification
recovery of 84.3%.

Table 7.2.2.  Indoxacarb DFR Data for Grape Vines in New York.

Sampling Interval

(days after treatment)	Corrected DFR level1

(μg/cm2)

	Replicate 1	Replicate 2	Replicate 3	Arithmetic Mean

(μg/cm2)

0.083	0.450	0.328	0.380	0.386

1	0.368	0.241	0.288	0.299

3	0.259	0.284	0.245	0.263

5	0.166	0.150	0.188	0.168

1  Raw residue data corrected for overall average field fortification
recovery of 87.3%

Table 7.2.3.  Indoxacarb DFR Data for Grape Vines in Washington.

Sampling Interval

(days after treatment)	Corrected DFR level1

(μg/cm2)

	Replicate 1	Replicate 2	Replicate 3	Arithmetic Mean

(μg/cm2)

0.083	0.466	0.543	0.585	0.532

1	0.436	0.415	0.464	0.438

3	0.426	0.432	0.413	0.424

5	0.348	0.382	0.426	0.385

1  Raw residue data corrected for overall average field fortification
recovery of 85.4%

To reiterate, ADD (mg a.i./kg bw/day) = DFR µg/cm2 * TC cm2/hr * hr/day
* 0.001 mg/µg * 1/70 kg bw where TC is 10,000 cm²/hr for 8 hr/day and

MOE = NOAEL (50 mg a.i./kg bw/day) ( ADD (mg a.i./kg bw/day)

Table 7.2.4.  Summary of MOEs Associated with DFR for Table/Raisin
Grapes with a TC of 10,000 cm²/hr for Three Treatment Sites (CA, NY and
WA).

Post-application day	DFR µg/cm²	ADD	MOE

California

Day 0 (12 hours)	0.180	0.210	240

Day 1	0.169	0.190	260

Day 3	0.150	0.170	290

Day 5	0.118	0.130	370

New York

Day 0 (12 hours)	0.386	0.440	110

Day 1	0.299	0.340	150

Day 3	0.263	0.300	170

Day 5	0.168	0.190	260

Washington

Day 0 (12 hours)	0.532	0.610	82

Day 1	0.438	0.500	100

Day 3	0.424	0.480	100

Day 5	0.385	0.440	110

Sample calculation:

0.180 µg/cm² * 10,000 cm2/hr * 8 hr/day * 0.001 mg/µg * 1/70 kg bw =
0.210 mg/kg bw/day.

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0.210 mg a.i./kg bw/day = 240

For table and raisin grapes, where the post-application activities are
cane tying and turning, the MOE is not of concern to HED on the day of
application at the California and New York sites and on Day 1
post-application at the Washington site.

For wine and juice grapes, use of the maximum reported DFR value and a
TC of 5,000 cm²/hr results in a MOE >100 on the day of application,
which is not of concern to HED.

TC = 5,000/Grapes (wine/juice)

0.532 µg/cm2 * 5,000 cm2/hr * 8 hr/day * 0.001 mg/µg * 1/70 kg bw =
0.304 mg/kg bw/day.

MOE = NOAEL ( ADD then 50 mg/kg bw/day ( 0.304 mg/kg bw/day = 164.  

Turf Uses

For the turf uses, TCs were taken from a post-application exposure study
on golf course maintenance (MRID 46734001).  It should be noted that a
previous study on golf course maintenance (MRID 45530101) had been
submitted, but had been determined to be unacceptable.  Data from MRID
46734001 are believed to be more appropriate for this use.  For
transplanting sod, the TC (6800 cm2/hr) was taken from MRID 45432303. 
The TCs used are conservative, and were used here per ExpoSAC
recommendation.

Compound-specific data were not available for the proposed new crop
uses.  Therefore, HED assumes 5% of the application rate is available as
turf transferable residue on day zero after application.  This is
adapted from the ExpoSAC SOP No. 003 (07-MAY-1998 - Revised
07-AUG-2000).  HED considers this practice to be conservative, that is
to say, protective. 



TC = 6,800/Turf harvest

0.000675 lb a.i./A * 0.05 * (1-0)0 * 4.54 x 108 µg/lb *  2.47 x10-8
A/cm² = 0.000378 µg/cm2 , therefore,

0.000378 µg/cm2 * 6,800 cm2/hr * 8 hr/day * 0.001 mg/µg * 1/70 kg bw =
0.00029 mg/kg bw/day.

MOE = NOAEL ( ADD then 38 mg/kg bw/day ( 0.00029 mg/kg bw/day = 130,000.

TC = 3,400/Turf Golf Course maintenance

0.000675 lb a.i./A * 0.05 * (1-0)0 * 4.54 x 108 µg/lb *  2.47 x10-8
A/cm² = 0.000378 µg/cm2 , therefore,

0.000378 µg/cm2 * 3,400 cm2/hr * 8 hr/day * 0.001 mg/µg * 1/70 kg bw =
0.00015 mg/kg bw/day.

MOE = NOAEL ( ADD then 38 mg/kg bw/day ( 0.00015 mg/kg bw/day = 260,000.

A MOE of 100 is adequate to protect agricultural workers from
post-application exposures to indoxacarb.  Except as reported earlier
for table and raisin grapes, the MOEs are > 100, and the estimated risks
are not of concern to HED.  

REI

Indoxacarb is in Acute Toxicity Category IV for acute dermal, III for
primary eye irritation, IV for primary skin irritation and it is not a
dermal sensitizer.  Although the interim WPS REI of 12 hours is adequate
to protect agricultural workers from most post-application exposures to
indoxacarb, a 24-hour REI is recommended to be protective of
post-application activities in table and raisin grapes.

7.3.  Incidents tc \l2 "7.3.	Incidents 

The OPP’s Incident Data System (25-MAR-2002) indicates there are no
incidents reported for the compound indoxacarb.



8.0.  DATA NEEDS/LABEL REQUIREMENTS tc \l1 "8.0.	DATA NEEDS/LABEL
REQUIREMENTS 

8.1.  Toxicology tc \l2 "8.1.	Toxicology 

None.

8.2.  Chemistry tc \l2 "8.2.	Chemistry 

Revised Section B.  Based on the available southern pea field trial
data, it is unclear whether the petitioner is pursuing a use on
succulent or dry southern peas.  The proposed label directions for
southern peas should be amended to allow applications only to varieties
used to produce dry seed.  If the petitioner intends to support a
generalized use on southern peas, field trials will be required for the
succulent variety as well.  In addition, the use directions for southern
peas should prohibit applications to varieties grown for livestock feed.
 For turnip greens, a restriction should be placed on the label to
prohibit use on dual purpose turnip cultivars or varieties which produce
a harvestable root.

Revised Section F.  The petitioner should submit a revised Section F
reflecting the HED-recommended tolerance levels and correct commodity
definitions as specified in Table 4.2.1.2.

8.3.  Occupational/Residential Exposure tc \l2 "8.3.
Occupational/Residential Exposure 

Revised Section B.  The label should be revised to indicate a 24-hour
REI for postapplication activities.

Attachments

Attachment 1:  Chemical Structures

cc: S. Levy (RAB1/HED-7509P)

RDI: PV Shah (16-MAY-2007); RAB1 (16-MAY-2007)

S. Levy:S-10953:PY1:(703)305-0783:7509P:RAB1

Attachment 1:  Chemical Structures

Common Name

Chemical Name	

Structure

Indoxacarb/R-indoxacarb

CAS Name:  (R,S)-Methyl
7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)phenyl]am
ino]-carbonyl]indeno[1,2-e] [1,3,4]-oxadiazine-4a(3H)-carboxylate	

IN-JT333

CAS Name:  Methyl
7-chloro-2,5-dihydro-2-[[[4-(trifluoromethoxy)-phenyl]amino]carbonyl]ind
eno-[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate

CAS Inverted Name:  Indeno-[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylic
acid, 7-chloro-2,5-dihydro-2-[[[4-(trifluoromethoxy)-
phenyl]amino]carbonyl]-, methyl ester	

 

5-HO-IN-JT333

CAS Name:  Methyl
7-chloro-2,5-dihydro-5-hydroxy-2-[[[4-(trifluoromethoxy)phenyl]-amino]ca
rbonyl]indeno[1,2-e]-[1,3,4]oxadiazine-4a(3H)-carboxylate	

 



IN-KG433

CAS Name:  Methyl
5-chloro-2,3-dihydro-2-hydroxy-1-[[[(methoxycarbonyl)[4-trifluoromethoxy
) phenyl]amino]carbonyl]hydrazono]-1H-indene-2-carboxylate

CAS Inverted Name:  1H-indene-2-carboxylic acid,
5-chloro-2,3-dihydro-2-hydroxy-1-[[[(methoxycarbonyl)[4-(trifluoromethox
y)phenyl]amino]-carbonyl] hydrazono]-, methyl ester (Z)

	

 

IN-KB687

CAS Inverted Name:  Methyl [4-(trifluoro-methoxy)phenyl]-carbamate

	

 

Metabolite F

Characterized as the product of dehydration and rehydration of IN-KG433.

	

 



IN-KT319

Note:  IN-KT319 is a geometrical isomer of IN-KG433.

CAS Name:  (E)-methyl
5-chloro-2,3-dihydro-2-hydroxy-1-[[[(methoxycarbonyl)[4-(trifluoromethox
y)phenyl]amino]-carbonyl]hydrazono]-IH-indene-2-carboxylate

	

 

IN-JU873

CAS Name:  Methyl
5-chloro-2,3-dihydro-2-hydroxy-1-[[[[4-(trifluoromethoxy)phenyl]amino]-c
arbonyl]hydrazono]-1H-indene-2-carboxylate	

 

 ai = active ingredient is defined as the S isomer of indoxacarb
(KN128).  The R isomer (KN127) is an inactive isomer.
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ക഍഍