Document ID: EPA-HQ-OPP-2008-0271-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-07-14T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION  AGENCY

WASHINGTON, D.C.  20460

OFFICE OF           

PREVENTION, PESTICIDES

AND TOXIC SUBSTANCES

MEMORANDUM

Date:		May 18, 2009

Subject:		Indoxacarb.  Health Effects Division (HED) Human Health Risk
Assessment for Bushberry Crop Subgroup 13-07B and Beets (Garden).   

PC Code:  067710	DP Barcode No.: D351087 

Decision No.: 390597	Registration No.: 352-597

Petition No.:  8E7324	Regulatory Action: Amended Section 3 Registration

Risk Assessment Type: Single Chemical /Aggregate	Case No.: NA

TXR No.:  NA	CAS No.: 173584-44-6

MRID No.:  NA	40 CFR:  180.564

		              									

	From:	Danette Drew, Chemist

		Peter Savoia, Chemist

	                    Seyed Tadayon, Chemist

		Risk Assessment Branch V

		Health Effects Division (7509P)

	

         And:	Nancy J. Tsaur, Chemist

		Risk Assessment Branch III

		Health Effects Division (7509P)

	Through:	Jack Arthur, Acting Branch Chief

		Risk Assessment Branch V

		Health Effects Division (7509P)

		

	To:	Barbara Madden, RM Team5

		Susan Stanton, RM Team5

		Risk Integration, Minor Use & Emergency Response Branch

		Registration Division (7505P)

EXECUTIVE SUMMARY

Indoxacarb, (S)-methyl
7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy)phenyl]
amino]carbonyl]indeno[1,2-e][1,3,4]oxadiazine-4a(3H)-carboxylate, a
reduced risk pesticide, is an oxadiazine class insecticide active
ingredient (ai) developed by E.I. du Pont de Nemours and Company (herein
referred to as DuPont)  for the control of lepidopteran pests on fruit,
vegetable, and field crops [water-dispersible granule (WDG) and
suspension-concentrate (SC) formulations]. Indoxacarb is also registered
as a fire ant bait and as a mole cricket bait [granular (G)
formulations], and for control of lepidopteran larvae (SC) on turf
and/or ornamentals. These formulations contain a mixture of indoxacarb
(insecticidally active S-enantiomer; DPX-KN128) and the R-enantiomer
(insecticidally inactive; IN-KN127; (R)-methyl
7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)[4-(trifluoromethoxy) phenyl]
amino] carbonyl]indeno[1,2-e][1,3,4][oxadiazine-4a(3H)-carboxylate). 
The percentage of active ingredient listed on each label and the labeled
use rates for each crop are based only on the amount of insecticidally
active indoxacarb (S-enantiomer; DPX-KN128). This document also refers
to the DPX-KN128 as KN128 and the IN-KN127 as KN127. Permanent
tolerances are established under 40 CFR 180.564(a) for the combined
residues of indoxacarb and its inactive R-enantiomer on a number of
plant as well as livestock commodities.  

DuPont and Interregional Research Project No. 4 (IR-4) have submitted a
petition (PP#   8E7324) proposing to amend the label for DuPont’s 30%
water-dispersible granule (WDG) to include new uses on garden beets and
bushberries (crop subgroup 13-07B). In conjunction with these new uses,
the petitioners proposed that permanent tolerances for residues of
indoxacarb be established in/on the following raw agricultural
commodities (RACs):   

Beet, garden, roots	0.30 ppm

Beets, garden, tops	6.0 ppm

Bushberry subgroup 13-07B	1.5 ppm

Hazard Characterization

Indoxacarb products are generally enantiomeric compounds containing
indoxacarb (S-enantiomer; DPX-KN1280) and its R-enantiomer (IN-KN127). 
DPX-MP062 (also referred to as MP062) is a mixture containing the
S-enantiomer and its R-enantiomer at approximately a 75:25 ratio. 
DPX-JW062 (also referred to as JW062) is the racemic mixture of the
enantiomers at a 50:50 ratio. Many of the toxicity studies for this
registration request were conducted with JW062 (50:50).  HED’s Hazard
Identification Assessment Review Committee (HIARC; HED Doc No. 013528)
determined that it is appropriate to use data from DPX-JW062 (50:50) 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 enantiomer for which registration is requested).

KN128 (100:0), MP062 (75:25) and JW062 (50:50) appear to be of similar
toxicity acutely.  KN128 and MP062 were moderately acutely toxic by the
oral route while JW062 was practically non-toxic due to its poor
solubility in the corn oil vehicle.  However, it was equally toxic
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. MP062 and JW062 had low acute inhalation toxicity. MP062 and
JW062 had moderate to low ocular irritant properties, while KN128 was
practically non-irritating to the rabbit’s eyes.  By the maximization
test, KN128 and MP062 were considered dermal sensitizers, while JW062
was not a sensitizer.

The toxicity profiles for KN128, MP062 and JW062 in rats, mice and dogs
with both subchronic and chronic oral exposures were qualitatively
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 decreases in 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 possible evidence of lung damage in the acute inhalation
studies with both MP062 and JW062. 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.

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

Neurotoxicity was seen in animal studies in rats and mice but at higher
doses (>100 mg/kg/day) than the hematologic effects (3.3. mg/kg/day) on
which EPA’s risk assessments are based.   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 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.  
There was no evidence of increased sensitivity of offspring in the
developmental neurotoxicity (DNT) study (KN128).  Clinical observations,
motor activity, acoustic startle habituation, and learning and memory
testing were all comparable between the control and treated groups. 
Mean brain weight, gross and microscopic examinations and morphometric
measurements of the brain were also comparable between the controls and
treated groups.

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

Both JW062 and MP062 were rapidly absorbed and eliminated following oral
administration. 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. Fat tissue contained the greatest level of radioactivity and,
for both compounds, was greater in female rats. Both MP062 and JW062
were extensively metabolized and that the metabolites were eliminated in
the urine, feces, and bile.  All of the biliary metabolites appear to
undergo further biotransformation in the gut.

With the exception of an immunotoxicity study, now mandatory under the
updated 40 CFR Part 158 data requirements (see Appendix 2), the
toxicological database for indoxacarb is complete. The available data do
not appear to indicate that indoxacarb is immunotoxic. In the 28 day
inhalation study (rats) increased spleen weights, pigmentation and
hematopoiesis in the spleen, and hematological changes were observed at
the highest dose tested (75.6 mg/kg/day). Increased spleen weights were
also observed in the 28 day dermal rat study (500 mg/kg/day). The
increase in spleen weights are not considered immunological in origin
but can be considered a result of the hemolytic effects, which is the
mode of action of indoxacarb. Indoxacarb is currently regulated based on
a NOAEL of 1.5 mg/kg/day for chronic dietary exposure (protective of
hemolytic effects) and 9 mg/kg/day for acute dietary exposure.  HED does
not believe that conducting a special series 870.7800 immunotoxicity
study will result in NOAELs lower than those currently identified for
indoxacarb, and an additional uncertainty factor (UFDB) for database
uncertainties does not need to be applied for the lack of an
immunotoxicity study. 

FQPA Safety Factor

After evaluating the toxicological database, the indoxacarb risk
assessment team has identified the following factors supporting
reduction of the FQPA safety factor (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.

Dose Response Assessment

Acute Dietary Endpoint:  An acute reference dose (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
using MP062.  A 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
KN128 (100% active).  The standard 100 UF was applied to account for
interspecies extrapolation and intraspecies variation.  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 MP062; 2)
rat subchronic neurotoxicity study with MP062; and 3) rat chronic/
carcinogenicity study with  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.    The NOAEL of 2 mg/kg was adjusted to 1.5
mg/kg based on KN128 (100% active).  This NOAEL was also supported by
the developmental neurotoxicity (DNT) study conducted with 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.  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 indoxacarb be classified as
“not likely” 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 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 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 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- , Intermediate- and Long-Term Inhalation Endpoints:  The short-,
intermediate-, and long-term inhalation endpoints were selected from a
28-day inhalation toxicity study in rats with MP062.  The NOAEL 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 MP062
study, it was adjusted to 4.5 mg/kg/day based on 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.

Occupational Exposure and Risk Estimates

A MOE  >100 is not of concern for HED’s dermal or inhalation
occupational exposure risk assessment.  The HED has assessed short-term
and intermediate- term occupational exposure risks for the proposed
bushberry and garden beet uses. Based on the use patterns, there are no
anticipated long-term occupational exposures to indoxacarb. Exposure
estimates in this assessment reflect both the insecticidally active
enantiomer (KN128) and the insecticidally inactive, but toxicologically
significant, enantiomer (KN127) since the proposed use product is an
enantiomeric mixture at about a 75:25 ratio. Application rates cited on
the product label (which reflect only KN128) were adjusted in this
assessment to account for application of both enantiomers present in the
product. Similarly, the toxicological doses used for this assessment
reflect the toxicity of the combined enantiomers. Occupational scenarios
assessed include mixer/loader/applicator scenarios and post-application
activities such as scouting, weeding, and harvesting.  For all of these,
the dermal and inhalation short-term and intermediate-term risk
estimates are below HED’s level of concern (MOEs>100). A re-entry
interval (REI) of 12 hours is adequate. 

Residential Exposure and Risk Estimates

There are several indoxacarb products registered for use in or around
the home or in public recreational areas to control fire ants, mole
crickets, roaches, and lepidopterous larvae. The following products,
applied to turf, are assessed for residential handler and/or
post-application exposures as they represent the worse-case exposure
scenarios. Indoxacarb is registered for use as a fire ant bait (Advion
0.045% G), which may be applied as a mound treatment or as a broadcast
application. It may be applied to lawns, golf courses and other
recreational areas. The broadcast treatment results in a higher exposure
than the mound treatment and, therefore, is the residential scenario
assessed.  This product is restricted to application by commercial
handlers such as PCOs. Indoxacarb is also registered as a mole cricket
bait (Advion, 0.22% G), applied as a broadcast to lawns, golf courses,
parks, recreational areas and athletic fields. Indoxacarb is also
registered to control lepidopterous larvae on landscape and recreational
(including golf courses) turfgrass and ornamentals (Provaunt 1.25 SC)
which can be applied as a foliar or broadcast spray. While there is
provision for application to residential lawns and turf, according to Du
Pont (but not restricted on the label), applications are intended to be
made by commercial applicators.and not by private, i.e.,
homeowner/residential applicators). 

Based on the proposed use patterns, commercial and private (i.e.,
grower/homeowner) pesticide handlers are expected to have short-term
(1-30 days) exposures. It is possible for commercial handlers to
experience intermediate-term exposures (1-6 months) as well. The short-
and intermediate-term toxicological points of departure are the same
therefore the risk estimates for intermediate-term exposures are the
same as those for short-term exposures.

The short-term and intermediate- term risk estimates (dermal,
inhalation) for residential (private or commercial) handlers applying
the currently registered indoxacarb residential use products are not of
concern to HED (MOEs >100).

Post-application exposures (dermal and oral) to adults and children from
entering turf areas previously treated with indoxacarb (i.e., turf
treated for fire ants, mole crickets or lepidopterous larvae) were also
assessed. Inhalation exposures are expected to be negligible.
Post-application exposures on treated lawns are expected to be
short-term in duration. Post- application exposures to golfers on
treated golf courses may be short-term or intermediate term. The short-
and intermediate-term toxicological points of departure are the same
therefore the risk estimates for intermediate-term exposures are the
same as those for short-term exposures. Short-term and intermediate-term
risk estimates (dermal, oral) for residential post-application exposures
are not of concern (MOEs>100) for adults and children. 

Dietary (Food + Drinking Water) Assessment

The HED has assessed dietary (food + drinking water) as well as various
non-dietary residential exposures. Exposure estimates reflect both the
insecticidally active enantiomer (KN128) and the insecticidally
inactive, but toxicologically significant, enantiomer (KN127). The
toxicological doses used for this assessment reflect the toxicity of the
combined enantiomers.

The dietary exposure estimates are based on conservative,
health-protective assumptions regarding residue levels in food and water
as well as the extent to which crops are treated with indoxacarb.  Risk
estimates associated with dietary (food + drinking water) exposure are
below HED’s level of concern for all population subgroups, including
those of infants and children (the population subgroup with the highest
estimated acute dietary exposure to indoxacarb is children, 3 to 5 years
old, at 63% of the aPAD. The population subgroup with the highest
estimated chronic dietary exposure to indoxacarb is children, 1 to 2
years old, at 39% of the cPAD). 

Anticipated residues (ARs) for all registered and proposed food
commodities were based on reliable field trial data.  ARs for all
current uses were further refined using percent crop treated (%CT) data.
100% CT was assumed for the proposed bushberry and garden beet 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, default processing
factors (PFs) were assumed.

Estimated drinking water concentrations (EDWCs) were provided by the
Environmental Fate and Effects Division and were incorporated directly
into the DEEM-FCID( analyses. The surface water EDWCs for the
Mississippi cotton scenario were generated using the Pesticide Root
Zone/Exposure Analysis Modeling System and resulted in the highest
indoxacarb concentrations of the scenarios modeled. Both the acute and
chronic dietary analyses were conducted using the EDWCs from this
scenario. 

Aggregate Risk Assessment

Aggregate risk assessments were performed for the following: acute
aggregate exposure (food + drinking water exposure), chronic aggregate
exposure (food + drinking water exposure), and short- and
intermediate-term aggregate exposure (food + drinking water +
residential exposure). Acute and chronic aggregate (food + drinking
water) risk estimates are not of concern. 

While the chronic dietary (food + water) risk estimate is not of
concern, the initial chronic analysis was further refined to provide
additional room in the aggregate ‘risk cup’ for potential
residential exposures. Milk, specifically milk fat, and grape were
significant contributors to the food exposure estimates. The chronic
dietary assessment was further refined by using 2005 PDP data for grape
and 2007 PDP heavy cream data (non-detectable residues) for milk. Field
trial residues (and %CT) were used for the remaining commodities.
Estimated chronic dietary risk to indoxacarb from food and drinking
water is below HED’s level of concern (4.4 % of the cPAD for children,
1 to 2 years old, the highest exposed subpopulation) with these
refinements.

Exposures in a residential setting may occur following application of
indoxacarb to turf.  HED has assessed dermal and incidental oral
(hand-to-mouth, object-to-mouth, and soil ingestion) exposures. The
residential turf uses assessed for indoxacarb aggregate risk include
application for fire ants (Advion 0.045%G), application for mole
crickets (Advion 0.22%G), and application for lepidopterous larvae
(Provaunt 1.25% SC). The refined chronic dietary exposures were used in
the aggregate assessment. Indoxacarb aggregate (food + water +
residential) risk estimates are not  of concern for children or adults
when assessing the Advion 0.045%G, Advion 0.22%G, or Provaunt 1.25SC
turf scenarios (aggregate MOEs>100). 

Characterization of Aggregate Risk

The chronic dietary (food + water) is fairly refined with food residues
derived from field trail data, % CT values and processing factors for
most commodities. For milk and grape, PDP monitoring data were used.
Drinking water residues were derived from models. The residential
post-application assessments are conservative in that they relied on
default assumptions. The exception is the application of turf
transferable residue (TTR) data in assessing indoxacarb post-application
activities.  The data from this study were used for dermal and
incidental ingestion assessment of the Provaunt 1.25 SC (liquid) turf
uses.  Default TTRs were used with the granular assessments as the turf
study is only applicable to liquid formulations.

Environmental Justice

Potential areas of environmental justice concerns, to the extent
possible, were considered in this human health risk assessment, in
accordance with U.S. Executive Order 12898, “Federal Actions to
Address Environmental Justice in Minority Populations and Low-Income
Populations”   HYPERLINK
"http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf" 
http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).  As a part of
every pesticide risk assessment, OPP considers a large variety of
consumer subgroups according to well-established procedures.  In line
with OPP policy, HED estimates risks to population subgroups from
pesticide exposures that are based on patterns of that subgroup’s food
and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under the Continuing
Survey of Food Intakes by Individuals (CSFII) and are used in pesticide
risk assessments for all registered food uses of a pesticide.  These
data are analyzed and categorized by subgroups based on age, season of
the year, ethnic group, and region of the country.  Whenever
appropriate, non-dietary exposures based on home use of pesticide
products and associated risks for adult applicators and for toddlers,
youths, and adults entering or playing on treated areas post-application
are evaluated.  Further considerations are currently in development as
OPP has committed resources and expertise to the development of
specialized software and models that consider exposure to bystanders and
farm workers as well as lifestyle and traditional dietary patterns among
specific subgroups.

Human Studies

This risk assessment relies in part on data from studies in which adult
human subjects were intentionally exposed to a pesticide or other
chemical.  These studies, which comprise the Pesticide Handlers Exposure
Database (PHED), have been determined to require a review of their
ethical conduct, and have received that review.  The studies in PHED are
considered appropriate (ethically conducted) for use in risk
assessments.

2.0  Ingredient Profile  TC \l1 "2.0  Ingredient Profile 

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). A risk assessment was also performed in
2007 to evaluate several proposed new uses of indoxacarb. This 2007
assessment incorporated new toxicological data (Memo, Levy et al.,
23-MAY-2007; DP#s: 324855, 324862, 324893, 339668, and 339669).  A brief
summary of health hazard characterization and dose response assessment
are presented 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 enantiomer DPX-KN128),
since the registrant requested the registration of DPX-KN128
(25-AUG-2004; DP#: 307220).  HED toxicologists re-evaluated the
endpoints due to submission of a DNT study.  HED toxicologists concluded
that the database UFs imposed because of the 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 Safety Factor Committee (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).  HED
toxicologists re-evaluated the FQPA assessment subsequent to the
submission of the DNT study and concluded that the reduced FQPA SF (1x)
is appropriate for indoxacarb risk assessment.

HED has also recently evaluated the implications of the steep dose
response in the rat DNT study i.e., NOAEL of 1.5 mg/kg/day and LOAEL of
3.0 mg/kg/day based on increased pup mortality. The increase in
incidence of stillbirth (14 stillbirths) in the DNT occurred at 3
mg/kg/day (highest dose group), and the increase was driven by a single
litter which had 13 stillborn pups. Although there was an increase in
the incidence of mortality from days 1-4 in the 3 mg/kg dose group, that
increase was only 10% above the control group. No effect was seen in the
three lower dose groups (1.5, 1.0, & 0.5 mg/kg). The lowest selected
NOAEL for indoxacarb risk assessment (chronic dietary and incidental
oral) is 1.5 mg/kg (LOAEL of 3.3 mg/kg based on decreased body weight,
body-weight gain, food consumption and hemolytic effects; two generation
rat reproductive study). This selected NOAEL, along with the standard
100x uncertainty factor for interspecies extrapolation and intraspecies
variation, yields a point of departure of 0.02 mg/kg/day which is more
than 100 times less than the dose (3 mg/kg) which produced an increased
incidence of mortality. Therefore, the severity of effects (pup
mortality) and the steepness of the dose response curve produced by
indoxacarb in the DNT do not support the application of an additional
FQPA safety factor. The selected point of departure for indoxacarb risk
assessment is protective of potential effects to infants and children.

Acute Dietary Endpoint:  An acute reference dose (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 (75:25 mixture of S- and R-enantiomers).  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 (active S-enantiomer).  The standard 100
UF was applied to account for interspecies extrapolation and
intraspecies variation.  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 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.  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- , Intermediate- and Long-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 NOAEL 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.

MOE for Occupational/Residential Risk Assessments

A MOE  >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 occupational 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% IN 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% IN
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

	

strains TA98, TA100, TA1535 and TA1537 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 2.5-5000 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)

acceptable/guideline	no evidence of mutagenic activity at the following
concentration range: 1.56-200 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

	

without S9 activation for the concentration range 10-5000 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 for Use in Risk Assessment,

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

	Study NOAEL

(KN128 +KN127)	Adjusted to KN128 only(100% active)

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. There was no evidence of
increased sensitivity of offspring in the submitted study.  Clinical
observations, motor activity, acoustic startle habituation, and learning
and memory testing were all comparable between the control and treated
groups.  Mean brain weight, gross and microscopic examinations and
morphometric measurements of the brain were also comparable between the
controls and treated groups.

3.3.  FQPA SF

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

EPA has determined that the FQPA safety factor (SF) be reduced to 1x for
dietary, occupational, and residential exposure assessments.  This
recommendation is based on the following findings:

1) The toxicity database for indoxacarb is substantially complete for
assessing human health risk. EPA does not believe that conducting a
special series 870.7800 immunotoxicity study will result in NOAELs lower
than those currently identified for indoxacarb, and a database
uncertainty factor for the lack of immunotoxicity data is not required
at this time.

2) There are no neurotoxic concerns. Neurotoxicity was seen in animal
studies in rats and mice but at higher doses (>100 mg/kg/day) than the
hematologic effects (3.3. mg/kg/day) on which EPA’s risk assessments
are based.  To evaluate the potential for increased sensitivity of
infants and children to neurotoxic effects, EPA required a rat
developmental neurotoxicity (DNT) study.  The study has been submitted
and reviewed.  There was no evidence of increased sensitivity of
offspring in the submitted study.  Clinical observations, motor
activity, acoustic startle habituation, and learning and memory testing
were all comparable between the control and treated groups.  Mean brain
weight, gross and microscopic examinations and morphometric measurements
of the brain were also comparable between the controls and treated
groups.

3) There is no evidence that indoxacarb results in increased
susceptibility in in utero rats or rabbits in the prenatal developmental
studies or in young rats in the two-generation reproduction study.

4) There are no residual uncertainties identified in the exposure
databases.  The acute and chronic dietary food exposure assessments
utilize anticipated residues for most commodities that are based on
reliable field trial data.  They also utilize percent crop treated (PCT)
data that have been verified by the Agency for most existing uses.   For
all new uses, 100 PCT is assumed. The acute and chronic assessments are
somewhat refined and based on reliable data and will not underestimate
exposure/risk.  Conservative ground and surface water modeling estimates
were used.  Similarly conservative Residential SOPs were used to assess
post-application exposure to children as well as incidental oral
exposure of toddlers.  These assessments will not underestimate the
exposure and risks posed by indoxacarb.

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 

Summary of Proposed Food Uses

 tc \l2 "4.1.	Summary of Proposed Uses 

Proposed Food Uses:  DuPont and IR-4 have proposed amending the label
for DuPont Avaunt® Insecticide (EPA Reg. No. 352-597) to include new
uses on bushberry crop subgroup 13-07B and garden beets. The petitioners
have submitted new field trial data on blueberries (representative crop
for bushberry crop subgroup 13-07B) and garden beets to support these
uses.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 Directions for Use of Indoxacarb.

Applic. Timing, Type, and Equip. 1	Formulation

[EPA Reg. No.]	Applic. Rate 

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

(lb ai/A)	PHI

(days)	Use Directions and 

Limitations 2

Bushberries 3

Broadcast foliar applications when insects reach economic thresholds;
ground or air equipment	30% WDG

[352-597]	0.11	4	0.44	7	A minimum 7-day RTI is specified.

Apply in a minimum of 10 or 20 gal/A for aerial and ground applications,
respectively.

Do not apply dilute applications of more than 200 gal/A.

Garden beet

Broadcast foliar applications when insects reach economic thresholds;
ground or air equipment	30% WDG

[352-597]	0.11	4	0.44	7	A minimum 3-day RTI is specified.

Apply in a minimum of 5 or 10 gal/A for ground and aerial applications,
respectively.

1	Do not apply through any type of irrigation system, expect for
application to cranberry, mint, potato, and sweet corn, and as allowed
on supplemental labels.

2	Applications may include the use of an adjuvant.  Rotational crop
restrictions:  crops with labeled uses and alfalfa, cotton, peanuts and
soybeans may be planted immediately following harvest of a treated crop.
 Do not plant any food or feed crops not registered for use with
indoxacarb for 30 days after last use. 

3	Includes aronia berry, high and low bush blueberries, Chilean guava,
currants (black, buffalo, native and red), European barberry,
elderberry, gooseberry, highbush cranberry, honeysuckle, huckleberry,
jostaberry, juneberry, lingonberry, salal, and sea buckthorn.

Conclusions.  The new label directions are adequate in allowing for an
evaluation of the residue data to be made relative to the proposed new
uses.  The available blueberry and garden beet field trial data are
sufficient to support treatments of the Avaunt® 30% WDG end-use product
of indoxacarb to be made at the proposed application rates.  Although
the proposed label allows for the use of adjuvants, the blueberry and
garden beet field trial data provided did not include any results for
treatments made with these additives in the spray mix.  Therefore, the
label directions should be amended to prohibit the use of adjuvants in
applications to bushberries and garden beets.  The petitioner should
also note that the bushberry commodities specified on the proposed label
directions for use did not list lingonberry, a member of the bushberry
crop subgroup 13-07B, under the crops available for treatment.

Dietary Exposure

 tc \l2 "4.2.	Dietary Exposure 

The residue chemistry data submitted in support of the proposed petition
were evaluated by HED on 28-NOV-2008 (Memo, P. Savoia; DP#356925).  The
drinking water assessment was completed by EFED (Memo, J. Hetrick et
al., 01-FEB-2007; DP# 293793 and Memo, J. Lin, 09-JUL-2008; DP#351088). 
The dietary exposure assessment was completed by HED (Memo, S. Tadayon,
28-NOV-2008; DP# 356924 and Memo, S. Tadayon, 13-MAY-2009; DP# D364939).

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. HED has determined that indoxacarb and its R-enantiomer
were the relevant residues of concern to be established for the
tolerance enforcement and risk assessment of crops (S. J.
Levy,10-JUL-2000, DP #263986). There are no livestock feedstuffs
associated with the proposed new indoxacarb uses on bushberries and
garden beets.  Therefore, residue data requirements for livestock are
not relevant to this tolerance petition and are not discussed in this
risk assessment.

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. A revised Section F remains
outstanding)

DuPont and IR-4 have submitted a petition (PP# 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
bushberry crop subgroup 13-07B and garden beets. For this petition, the
prescribed use will allow up to four broadcast foliar treatments to be
made at the maximum rate of 0.11 lb ai/A/application using ground or
aerial equipment, for a combined total of 0.44 lb ai/A/season.  A
specified minimum retreatment interval (RTI) of 3 days for garden beets
and 7 days for bushberries is put forward along with a minimum
preharvest interval (PHI) of 7 days for both types of crops.  In
situations where it can be difficult to achieve adequate coverage, the
proposed label specifies that an adjuvant may be used to improve
performance. ).  In conjunction with these uses, the petitioners have
proposed permanent tolerances for combined indoxacarb residues at the
following levels:

Beet, garden, roots	0.30 ppm

Beets, garden, tops	6.0 ppm

Bushberry crop subgroup 13-07B	1.5 ppm

Nature of the Residue – Plants

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.  HED determined that the
residue of concern in plants is indoxacarb + its R-enantiomer (Memo, S.
Levy, 10-JUL-2000; DP#: 263986).  

Analytical Methods 

Adequate enforcement methodology is available to enforce the tolerance
expression (high-performance liquid chromatography (HPLC)/column
switching/ultraviolet (UV) method AMR 2712-93 with
confirmation/specificity provided by gas chromatography
(GC)/mass-selective detector method AMR 3493-95, Supplement No. 4).
These methods may be requested from: Chief, Analytical Chemistry Branch,
Environmental Science Center, 701 Mapes Rd., Ft. Meade, MD 20755-5350;
telephone number: (410) 305-2905; e-mail address:   HYPERLINK
"mailto:residuemethods@epa.gov"  residuemethods@epa.gov .

For this petition, the blueberry and garden beet field trial studies
were carried out using different analytical procedures to determine the
combined residues of indoxacarb which were found.  An HPLC/UV procedure
derived from Dupont Report No. AMR 2712-93 was used to quantitate
blueberries.  Alternately, a Gas Chromatogrph/Nitrogen-Phosphorus
Detector (GC/NPD) technique derived from Dupont Report No. AMR 4271-96
was used to quantitate garden beets.  Both methods were adequately
validated in conjunction with the sample analyses which were performed. 
For these data submissions, the validated LOQs for residues of
indoxacarb were determined to be 0.02 ppm in blueberries along with 0.01
ppm for the garden beet roots and tops.

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.  

Meat, Milk, Poultry, and Eggs  

There are no livestock feedstuffs associated with the proposed use on
bushberries or garden beets.  Therefore, data requirements pertaining to
meat, milk, poultry, and eggs are not relevant to this current petition.

Magnitude of the Residue  

In cooperation with the registrant DuPont, IR-4 has submitted field
trial data on blueberries and garden beets for the insecticide
indoxacarb.  These data are provided to support petition 8E7324
requesting that permanent indoxacarb tolerances be established for use
on bushberry crop subgroup 13-07B and garden beets.  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 Crop Field Trials with
Indoxacarb.

Crop matrix	Total Applic. Rate (lb ai/A)	PHI (days)	Residue Levels (ppm)
1

	n	Min.	Max.	HAFT 2	Median	Mean	Std. Dev.

Blueberry (proposed use = 0.44 lb ai/A total application rate, 7-day
PHI)

Blueberry	0.431-0.459	6-8	26	0.20	1.04	1.04	0.56	0.57	0.23

Garden Beet (proposed use = 0.44 lb ai/A total application rate, 7-day
PHI)

Garden beet roots	0.434-0.451	7	10	0.11	0.22	0.22	0.18	0.16	0.04

Garden beet tops

	10	1.31	3.96	3.83	2.19	2.47	0.96

1	Residues of indoxacarb and its inactive R-enantiomer are detected as a
single component.  The LLMV is 0.01 ppm for beet roots and tops and 0.02
ppm for blueberries.  The calculated LOQs are 0.005 ppm for beet roots,
0.02 ppm for beet tops, and 0.026 ppm for blueberries.

2	HAFT = Highest average field trial result.

The blueberry and garden beet field trials are adequate, provided that
the label is amended to preclude the addition of adjuvants to the spray
mix.  A sufficient number of trials were conducted on each crop at 1x
the maximum proposed rate in the appropriate geographic regions with the
proper representative RACs being collected for analysis.  Samples were
analyzed using adequate analytical methods, and the sample storage
intervals are supported by the available storage stability data.

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, storage stability data were provided with the submitted
blueberry and garden beet field trials. The concurrent storage stability
studies are inadequate due to a lack of 0-day data for the fortified
samples stored for testing.  However, given the fact that corrected
recoveries were determined which averaged 98-104%, the data obtained,
along with the previous storage stability data, will support the storage
intervals incurred in the field trials for purposes of this petition.  

Processed Food/Feed 

HED does not require residue data for any processed commodities
associated with bushberries or garden beets.  Therefore, data
requirements for processed food and feed are not relevant to this
current petition.

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 ,
Canadian or Mexican maximum residue limits (MRLs) for indoxacarb on
bushberries or garden beets; therefore, there are no international
harmonization issues associated with this petition.

Proposed/Recommended Tolerances

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 petition were determined using recent Agency
Guidance (Guidance for Setting Pesticide Tolerances Based on Field Trial
Data SOP). Tolerance calculations were made with the
petitioner-submitted residue data using the tolerance calculating spread
sheet. Adequate field trial data are available to establish tolerances
for the combined  residues of of indoxacarb, (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, and its
R-enantiomer, (R)-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 or on
bushberry, subgroup 13-07B, beet, garden, roots and beet, garden, tops.

Table 4.2.1.2. 	Tolerance Summary for Indoxacarb.

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;
Correct Commodity Definition

Beet, garden, roots	0.30	0.30	Adequate data are available

Beet, garden, tops	6.0	6.0	Adequate data are available

Bushberry, subgroup 13-07B	1.5	1.5	Adequate data are available

D敩慴祲䔠灸獯牵⁥湁污獹獥ഠ

Evaluation Model (DEEM-FCID™, Version 2.03) which uses food
consumption data from the U.S. Department of Agriculture’s Continuing
Surveys of Food Intakes by Individuals (CSFII) from 1994-1996 and 1998. 
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.  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.”  

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) 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 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 (PFs)
were assumed.

Estimated drinking water concentrations (EDWCs), provided by the
Environmental Fate and Effects Division (EFED; Memo, J. Lin,
09-JUL-2008; DP# 351088) and were incorporated directly into the
DEEM-FCID( analyses. EFED previously provided surface water and ground
water modeling results for several crop scenarios (Memo, J. Hetrick et
al., 01-FEB-2007). The surface water EDWCs for the Mississippi cotton
scenario were generated using the Pesticide Root Zone/Exposure Analysis
Modeling System and resulted in the highest indoxacarb concentrations.
Both the acute and chronic analyses were conducted using the EDWCs from
this scenario. 

Risk estimates for acute and chronic dietary (food plus water) exposure
for all assessed population subgroups are below HED’s level of concern
(generally 100% of the aPAD).

Acute Dietary Exposure Results

Estimated acute dietary exposure to indoxacarb from food and drinking
water is below HED’s level of concern for all population subgroups. 
Combined dietary exposure from food and drinking water at the 99.9th
percentile of exposure is estimated to be 0.034659 mg/kg/day for the
overall U.S. population equivalent to 29% 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 0.07614 mg/kg/day, equivalent to 63% of the aPAD.  An
acute dietary endpoint was not identified for females 13-49.  As a
result HED did not determine acute exposure and risk estimates for this
population subgroup.

Table 4.2.2.1  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	0.12	0.007942	7	0.015191	13	0.034659	29

All Infants (< 1 year old)

0.01090	9	0.02179	18	0.03979	33

Children 1-2 years old

0.01813	15	0.02739	23	0.06974	58

Children 3-5 years old

0.01347	11	0.02201	18	0.07614	63

Children 6-12 years old

0.00877	7.3	0.01344	11	0.02943	25

Youth 13-19 years old

0.00565	5	0.01161	10	0.03955	33

Adults 20-49 years old

0.00504	4	0.00971	8	0.02726	23

Adults 50+ years old

0.004500	4	0.01304	11	0.03185	27

*toxicological doses used here reflect KN128 and KN127 combined, not
adjusted for 100%KN128, since analytical methods detect combined
residues.

The population subgroup with the highest estimated exposure/risk is
bolded.

Chronic Dietary Exposure Results

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 0.002465 mg/kg/day for the
general U.S. population (12 % of the chronic population-adjusted dose
(cPAD)) and 0.007884 mg/kg/day (39 % 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  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	0.02	0.002465	12

All Infants (< 1 year old)

0.002468	12

Children 1-2 years old

0.007884	39

Children 3-5 years old

0.006041	30

Children 6-12 years old

0.003684	18

Youth 13-19 years old

0.002195	11

Adults 20-49 years old

0.00184	9

Adults 50+ years old

0.001840	9

Females 13-49 years old

0.001775	9

*toxicological doses used here reflect KN128 + KN127, not adjusted for
100%KN128, since analytical methods detect combined enantiomer residues.

The population subgroup with the highest estimated exposure/risk is
bolded.

While the chronic dietary (food + water) risk estimate is not of
concern, the analysis was further refined to provide additional room in
the aggregate ‘risk cup’ for potential residential exposures. In the
above chronic assessment, field trial data (with available %CT) were
used as anticipated residues. Milk and grape were significant
contributors to the food exposure estimates. The chronic dietary
assessment was further refined by using 2005 PDP data for grape and 2007
PDP heavy cream data (non-detectable residues) for milk. Field trial
residues were used for the remaining commodities. Crop treated
information was incorporated. Results of the refined analysis are
presented below:

Estimated chronic dietary risk to indoxacarb from food and drinking
water is below HED’s level of concern with the above refinements. 
Combined dietary exposure from food and drinking water is estimated at
0.00088 mg/kg/day (4.4 % of the cPAD) for children, 1 to 2 years old,
the population subgroup with the highest estimated chronic dietary
exposure to indoxacarb.

Table 4.2.2.3	Summary of Refined Chronic Dietary (Food + Drinking Water)
Exposure and Risk for Indoxacarb.

Population Subgroup	cPAD (mg/kg/day)	Chronic

Exposure (mg/kg/day)	

%cPAD

General U.S. Population	0.02	0.000516	2.6

All Infants (< 1 year old)

0.000579	2.9

Children 1-2 years old

0.000880	4.4

Children 3-5 years old

0.000843	4.2

Children 6-12 years old

0.000485	2.4

Youth 13-19 years old

0.000435	2.2

Adults 20-49 years old

0.000419	2.1

Adults 50+ years old

0.000621	3.1

Females 13-49 years old

0.000432	2.2

*toxicological doses used here reflect KN128 + KN127, not adjusted for
100%KN128, since analytical methods detect combined enantiomer residues.

The population subgroup with the highest estimated exposure/risk is
bolded.

Water Exposure/Risk Pathway

 tc \l2 "4.3.	Water Exposure/Risk Pathway 

Reference:  Memos, J. Lin, 09-JUL-2008; DP#: 351088 and J. Lin,
07-JAN-2009; DP#: 360115.

The highest indoxacarb concentrations in surface and ground source water
are associated with cotton.  This use pattern has a maximum label rate
of 0.11 lbs ai/A (0.15 lbs KN128+KN127/A).  Similar use rates are
recommended for apples, potatoes, and grapes (Draft Label for DuPont(
Avaunt®).  Tier II surface water modeling for cotton using the index
reservoir with the default percent cropped area (PCA=0.87) predicts the
1- in -10 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 (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 (KN128+KN127)
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)	1.563	0.109	0.034

Turf (PA)	1.935	0.168	0.067

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

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

Residential Exposure/Risk Pathway

 tc \l2 "4.4.	Residential Exposure/Risk Pathway 

Residential exposure/risk assessments for indoxacarb were provided by S.
Tadayon (Memo, 4-May-2009, DP#363731; 1.25%SC); and M. Dow (Memo,
25-AUG-2004, DP#: 289892; Memo, 7-MAR-2005, DP#302788 and Memo,
15-MAR-2005, DP#312428).

Indoxacarb is registered for use as a fire ant bait (Advion 0.045% G),
which may be applied as a mound treatment or as a broadcast application.
It may be applied to lawns, golf courses and other recreational areas. 
This product may only be applied by commercial handlers such as PCOs. 
Handler exposure and residential post-application exposures are assessed
in this document. [Note: the broadcast treatment results in a higher
exposure than the mound treatment and, therefore, is the
post-application scenario assessed].

Indoxacarb is also registered as a mole cricket bait (Advion 0.22% G),
applied as a broadcast to lawns, golf courses, parks, recreational areas
and athletic fields. Indoxacarb is also registered as a foliar or
broadcast spray (Provaunt 1.25 SC) to control lepidopterous larvae on
landscape and recreational turfgrass (including golf courses) and
ornamentals. While there is provision for application to residential
lawns and turf, according to Du Pont (but not restricted on the label),
applications of these products are intended to be made by commercial
applicators and not by private, i.e., homeowner/residential applicators.
Handler exposures and residential post-application exposures are
assessed. 

A turf transferable residue (TTR) study was submitted by the registrant
(MRID# 46798201) for use in assessing indoxacarb post-application
activities.   The data from this study were used for dermal and
incidental ingestion assessment of the Provaunt 1.25 SC (liquid) turf
uses.  Default TTRs were used with the granular assessments as the turf
study is only applicable to liquid formulations.

The results of the residential exposure assessments are presented below.

 

Residential Handlers

Based on the proposed use patterns, commercial and private (i.e.,
grower/homeowner) pesticide handlers are expected to have short-term
(1-30 days) exposures. It is possible for commercial handlers to
experience intermediate-term exposures (1-6 months) as well. The short-
and intermediate-term toxicological points of departure are the same
therefore the risk estimates for intermediate-term exposures are the
same as those for short-term exposures.

Short-term (and intermediate –term) risk estimates to handlers
(commercial or private) applying the 0.045%G, 0.22%G or 1.25 SC
indoxacarb formulations to turf are not of concern to HED (i.e., MOEs
>100). 

Table 4.4.1    Estimated Handler (Commercial only) Exposure and Risk
from the Use of 

Indoxacarb (Advion 0.045%;  Fire Ant Bait)  on Turfgrass

[Short-term and Intermediate–term Exposures]

Unit Exposure1

mg a.i./lb handled	

Applic. Rate2

lb a.i./A	

Units Treated3

Per Day	

Average Daily

Dose4

mg a.i./kg bw/day	

MOE5

Applicator - Solid Broadcast - Open Cab (Tractor Mounted Spreader)

Dermal:

No Glove     0.0099 LC

With Glove  0.0069 LC

Inhal             0.0012 LC	

0.000675	

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 ai/mound	

2.35 x 10-7 ai/mound

40 mounds/A @ 5A/day

200 mounds/day = 0.000047 lb ai/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 Version 1.1, August 1998.  Push  spreader Unit Exposure from
ORETF study OMA-001.   Dermal =  Single Layer Work Clothing No Gloves; 
Single Layer  Work Clothing With Gloves;  Inhal. = Inhalation.  Units =
mg a.i./pound of active ingredient handled.  Data Confidence: LC = Low
Confidence, MC = Medium Confidence, HC = High Confidence.

2.  Applic. Rate. = Taken from Avaunt insecticide label, proposed
Indoxacarb fire ant bait label

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”; SOP  No. 9.1.   Science Advisory Council for
Exposure;  Revised 5 July 2000; MRID No. 459028-10 for commercial
tractor drawn broadcast treatment, fire ant mound treatment and push
type spreader treatment.

4.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated  (
70 kg Body Weight

5.  MOE = Margin of Exposure = No Observable  Adverse Effect Level
(NOAEL)  ( ADD.   Short- and intermediate-term dermal  NOAEL = 38 mg
a.i./kg bw/day; short- and intermediate-term inhalation NOAEL = 4.5  mg
a.i./kg bw/day.  The dermal NOAELs were taken from a 28 day dermal study
therefore there is no correction for dermal absorption.   The inhalation
NOAELs were identified from a 28-day inhalation toxicity study in the
rat.  

Table 4.4.2    Estimated Handler (Commercial and Private) Exposure and
Risk from the Use of 

Indoxacarb (Advion  0.22% G;  Mole Cricket  Bait )  on Turfgrass 

 [Short-term and Intermediate–term Exposures]

Unit Exposure1

mg a.i./lb handled	Applic. Rate2

lb a.i./A	Units Treated3

Per Day	Average Daily

Dose4

mg a.i./kg bw/day	MOE5

Mixer/Loader - Open Pour - Granule

Dermal:

No Glove     0.0084 LC

With Glove  0.0069 MC

Inhal             0.0017 HC	0.587

total isomer/A	40 A	Dermal:

No Glove     0.00282

With Glove  0.00231

Inhal            0.00057	Dermal:

No Glove     17,730

With Glove  21,650

Inhal            10,500

Applicator - Solid Broadcast - Open Cab (Tractor Mounted Spreader)

Dermal:

No Glove     0.0099 LC

With Glove  0.0069 LC

Inhal             0.0012 LC	0.587

total isomer/A	40	Dermal:

No Glove     0.0033

With Glove  0.0023

Inhal            0.0004	Dermal:

No Glove      15,150

With Glove   21,700

Inhal              15,000

Mixer/Loader/Applicator - Commercial Rotary Broadcast

Dermal:

No Glove     0.35 HC

With Glove  0.22 HC

Inhal             0.0075 HC 	0.587

total isomer/A	5 A	Dermal:

No Glove      0.015

With Glove   0.0092

Inhal             0.00031	Dermal:

No Glove      3,330

With Glove   5,400

Inhal              19,350

Mixer/Loader/Applicator - Push  spreader

Dermal:

No Glove     10.0 MC

With Glove    9.3 LC

Inhal               0.062 HC	0.587

total isomer/A	1 A	Dermal:

No Glove      0.084

With Glove   0.078

Inhal             0.00052	Dermal:

No Glove         600

With Glove      640

Inhal            11,500

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.  Commercial rotary push  spreader
Unit Exposure from ORETF study OMA-001.   Dermal =  Single Layer Work
Clothing No Gloves;  Single Layer  Work Clothing With Gloves;  Inhal. =
Inhalation.  Units = mg a.i./pound of active ingredient handled.  Data
Confidence: LC = Low Confidence, MC = Medium Confidence, HC = High
Confidence.

2.  Applic. Rate. = Taken from DuPontTM AdvionTM Mole Cricket Bait label

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”;  SOP  No. 9.1.   Science Advisory Council for
Exposure;  Revised 5 July 2000 and from duPont MRID 464416-09.

4.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated 
÷ 70 kg Body Weight

5.  MOE = Margin of Exposure = No Observable  Adverse Effect Level
(NOAEL)  ÷ ADD.   Short- and intermediate-term dermal  NOAEL = 50 mg
a.i./kg bw/day; short- and intermediate-term inhalation NOAEL = 6.0  mg
a.i./kg bw/day.  The dermal NOAELs were taken from a 28 day dermal study
therefore there is no correction for dermal absorption.   The inhalation
NOAELs were identified from a 28-day inhalation toxicity study in the
rat.  

Table 4.4.3    Estimated Handler (Commercial and Private) Exposure and
Risk from the Use of  Indoxacarb (Provaunt 1.25 SC) on Landscape
Ornamental Plants and Turfgrass   

  [Short-term and Intermediate–term Exposures]

Unit Exposure1

mg a.i./lb handled	Applic. Rate2

lb a.i./A or

lb a.i./gal	Units Treated3

Per Day	Average Daily

Dose4

mg a.i./kg bw/day	MOE5

Mixer/Loader Using Open Pour Liquid

Dermal:

No Glove        2.9 HC

With Glove     0.023 HC

Inhal               0.0012 HC	0.293 lb a.i./A	40 A	Dermal:

No Glove     0.49

With Glove  0.0039

Inhal            0.0002	Dermal:

No Glove            102

With Glove    12,800

Inhal              30,000

Applicator - Ground-boom - Open Cab    

Dermal:

No Glove      0.014 HC

With Glove   0.014 MC

Inhal             0.00074 HC	0.293 lb 

a.i./ A	40 A	Dermal:

No Glove    0.0023

With Glove 0.0023

Inhal           0.00012	Dermal:

No Glove       22,000

With Glove    22,000

Inhal              50,000

Applicator - High pressure Handwand    

Dermal:

No Glove      1.8 LC

With Glove   0.64 LC

Inhal             0.079 LC	0.0065 lb a.i./gal	1,000 gal	Dermal:

No Glove    0.17

With Glove 0.06

Inhal           0.0073	Dermal:

No Glove           300

With Glove        800

Inhal                  800

Mixer/Loader/Applicator Using Low pressure Handwand and Liquid Open Pour
   

Dermal:

No Glove      100 LC

With Glove   0.43 LC

Inhal              0.03 MC	0.0065 lb a.i./gal	40 gal	Dermal:

No Glove    0.37

With Glove 0.0016

Inhal           0.00011	Dermal:

No Glove           135

With Glove   31,000

Inhal             55,000

Mixer/Loader/Applicator Using Backpack and Liquid Open Pour    

Dermal:

No Glove       no data

With Glove   2.5 LC

Inhal             0.03 LC	0.0065 lb a.i./gal	 40 gal	Dermal:

No Glove    no data

With Glove 0.0093

Inhal           0.00011	Dermal:

No Glove   no data

With Glove     5,400

Inhal             55,000

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE”,
Estimates of Worker Exposure from The Pesticide Handler Exposure
Database Version 1.1, August 1998.  Push spreader Unit Exposure from
ORETF study OMA-001.   Dermal = Single Layer Work Clothing No Gloves;
Single Layer Work Clothing With Gloves; Inhal. = Inhalation.  Units = mg
a.i./pound of active ingredient handled.  Data Confidence: LC = Low
Confidence, MC = Medium Confidence, HC = High Confidence.

2.  Applic. Rate = Taken from labels

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture”; SOP No. 9.1.   Science Advisory Council for
Exposure; Revised 5 July 2000

4.  Average Daily Dose (ADD) = Unit Exposure * Applic. Rate * Units
Treated ÷ 70 kg Body Weight

5.  MOE = Margin of Exposure = No Observable Adverse Effect Level
(NOAEL) ÷ ADD.   Short- and intermediate-term dermal NOAEL = 50 mg
a.i./kg bw/day; short- and intermediate-term inhalation NOAEL = 6.0  mg
a.i./kg bw/day.  The dermal NOAELs were taken from a 28 day dermal study
therefore there is no correction for dermal absorption.   

Residential Post-application Exposure

There is the potential for short-term post-application exposure to
adults and children from entering areas previously treated with
indoxacarb (i.e., turf treated for fire ants, mole crickets or
lepidopterous larvae). Post-application exposures to golfers on treated
golf courses may be short-term or intermediate- term. The short- and
intermediate-term toxicological points of departure are the same
therefore the risk estimates for intermediate-term exposures are the
same as those for short-term exposures. 

 The post-application 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).

Incidental oral object to mouth (toddler).

Inhalation exposures are expected to be negligible and are not included
in this assessment.

For children, there are a number of post-application non-dietary
ingestion exposure scenarios (listed above) that could potentially be
combined with the dermal exposure scenario.  These non-dietary ingestion
scenarios should be considered inter-related and it is likely that they
occur interspersed amongst each other across time.  For example a child
may place his hand in his mouth X number of times as well as place an
object in his mouth Y number of times during a certain period of time. 
Each of these events could result in a potential transfer of residue but
could also result in a soil ingestion event as soil may be present on
the hand or object during mouthing.  The potential combinations of
co-occurrence of the hand-to-mouth/object-to-mouth/soil ingestion
scenarios across a particular period of time are limitless.  Combining
all three of these scenarios with the dermal exposure scenario would be
overly-conservative because of the conservative nature of each
individual assessment.  Therefore, it is recommended that the dermal and
hand-to-mouth scenarios be combined short-term (and acute) exposure
durations and this combination should be considered a protective
estimate of children’s exposure to pesticides used on turf. Due to its
episodic nature, the granular ingestion scenario should never be
combined with any other exposure scenario.      

For indoxacarb, short-term oral and dermal exposures to a toddler are
combined since the oral and dermal toxicological effects are similar.
HED summed exposures from 1) oral hand-to-mouth from treated turf and 2)
dermal post-application exposure.  

A summary of the residential post-application exposures and risks are
provided in the tables below. Short-term (and intermediate-term) risk
estimates (dermal, oral) for residential post-application exposures are
not of concern (MOEs>100) for adults and children. 

Table 4.4.4.  Summary Residential Post-Application Exposures and Risks.
(Advion 0.045% G)

Activity	

Exposure (Dose)

mg a.i./kg bw/day	

MOE3

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

Adult dermal post application  turf contact	

0.000156	

240,000

Toddler dermal post applic turf contact	

0.00026	

150,000

Adult golfer post app turf contact	

0.0000108	

3,500,000

Child golfer post app turf contact	

0.0000184	

2,100,000

Toddler combined exposure2	

oral hand-to-mouth treated turf      1 x 10-5

dermal post application                  2.6 x 10-4        

	

75,0004

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 (highest oral exposure), and  2) dermal
post-application exposure.

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

Dermal NOAEL = 38 mg a.i./kg bw/day (KN128)

Short-term incidental oral NOAEL = 1.5 mg a.i./kg bw/day (KN128)

Label application rate of 0.000675 lb ai/A (KN128) not adjusted for
total application of KN127 and KN128 as toxicological doses used in this
assessment reflect toxicity of 100%KN128.

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/MOEd post-applic))                 
          

MOET =          1 / ((1/150,000) + (1/150,000)) = 75,000

Table 4.4.5 Summary Residential Post-Application Exposures and Risks
(Advion 0.22%G)

Activity	

Exposure (Dose)

mg a.i./kg bw/day	

MOE1

Toddler oral hand-to-mouth from contacting treated turf	

0.0088	

230

Toddler incidental oral ingestion of treated soil	

0.000029	

69,000

Toddler oral object to mouth 	

0.00055	

3,600

Toddler oral object to mouth granules	

0.000000044	

> 45 million

Adult dermal post applic turf contact	

0.137	

370

Toddler dermal post applic turf contact	

0.239	

210

Adult golfer post app turf contact	

0.012	

5,300

Child golfer post app turf contact	

0.016	

3,100

Toddler combined exposure2	

oral hand-to-mouth from treated turf  0.0088

dermal post application                      0.239        

                                                      	

107

1.  MOE = Margin of Exposure = No Observable Adverse Effect Level (mg
a.i./kg bw/day) ( Average Daily Dose (mg a.i./kg bw/day).  Dermal NOAEL
= 50 mg a.i./kg bw/day (KN127 + KN128)

Short-term incidental oral NOAEL = 2.0 mg a.i./kg bw/day (KN127 + KN128)

Label application rate of 0.11 lb/A adjusted to 0.146 lb/A to account
for both KN127 and KN128.

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 (highest oral exposure), and 2) dermal
post-application.

Table 4.4.6 Summary Residential Post-Application Exposures and Risks
(Provaunt 1.25SC)

Activity	

Exposure (Dose)

mg a.i./kg bw/day	

MOE1

Toddler oral hand-to-mouth from contacting treated turf	0.0044	460

Toddler incidental oral ingestion of treated soil	0.000015	140,000

Toddler oral object to mouth 	0.0011	1,800

Adult dermal post applic turf contact	0.013	3,800

Toddler dermal post applic turf contact	0.022	2,300

Adult golfer post app turf contact	0.0063	8,000

Toddler combined exposure2	

oral hand-to-mouth from treated turf  

0.0044

dermal post application    

0.022          

                                                     	

380

1. MOE = Margin of Exposure = No Observable Adverse Effect Level (
Average Daily Dose

Dermal NOAEL = 50 mg a.i./kg bw/day (KN127 + KN128)

Short-term incidental oral NOAEL = 2.0 mg a.i./kg bw/day (KN127 + KN128)

Label application rate of 0.22 lb/A adjusted to 0.293 lb/A to account
for both KN127 and KN128.

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 (highest oral exposure), and 2) dermal
post-application exposure.

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 of this document represent acute and chronic
aggregate assessments. Acute and chronic aggregate (food + drinking
water) risk estimates are not of concern. 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 Risk (food + drinking water +
residential exposure)

Potential short- and intermediate-term exposures exist for adults and
children from the registered turf application uses.  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.

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 are
both short- and intermediate-term post-application, (non-dietary) oral
and dermal exposure potentials for children, it is appropriate to
aggregate these exposures with dietary (food) and water.  Children may
be exposed to the following four 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); 3) post-
application incidental exposure object-to mouth; and 4) post-application
dermal exposure from contact with treated turf. For indoxacarb,
hand-to-mouth from contacting treated turf is the scenario resulting in
the highest anticipated oral exposure for children, and is the exposure
scenario combined with the dermal and dietary exposures in the aggregate
assessment. 

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.

The residential turf uses assessed for aggregate risk include indoxacarb
application for fire ants (Advion 0.045%G), application for mole
crickets (Advion 0.22%G), and application for lepidopterous larvae
(Provaunt 1.25% SC). The refined chronic dietary exposures (Table
4.2.2.3) were used in the aggregate assessment. Tables 5.1.1 through
5.1.6 are summaries of the short- and intermediate-term aggregate
exposures and risk estimates for toddlers and adults. Indoxacarb
aggregate (food + water + residential) risk estimates are not  of
concern for children or adults when assessing the Advion 0.045%G, Advion
0.22%G, or Provaunt 1.25SC turf scenarios (aggregate MOEs>100). 

Advion 0.045%G

Table 5.1.1.  Short/Intermediate-Term Aggregate Risk Calculations for
Toddlers:  Advion 0.045%G

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	0.00088	2300	0.00001	150,000	0.00026
150,000	2200

1   MOE = NOAEL (2.0 mg/kg/day; KN127+ KN128)) ÷ (chronic food + water
exposure)

2   Residential oral = hand-to-mouth from contacting treated turf, the
highest oral exposure scenario (ingestion of treated soil and mouthing
grass exposures are not significant exposure contributors compared to
hand-to-mouth activities)

3   MOE = NOAEL (1.5 mg/kg/day; KN128) ÷ (sum of residential oral
exposure)

4   Residential dermal = post-application turf contact5   MOE = NOAEL
(38 mg/kg/day; KN128) ÷ (residential dermal exposure)

6   Aggregate MOE = 1/[(1/2300) + (1/150,000) + (1/150,000)]

Table 5.1.2.  Short/Intermediate-Term Aggregate Risk Calculations for
Adults:  Advion 0.045%G

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	0.000516	3900	0.000156	240,000	3800

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

2   MOE = NOAEL (2.0 mg/kg/day; KN127+KN128) ÷ (chronic food + water
exposure)

3   Residential dermal = post-application exposure; application exposure
not a significant contributor compared to post-application.

4   MOE = NOAEL (38 mg/kg/day; KN128) ÷ (residential dermal exposure)

5   Aggregate MOE = 1/[(1/3900) + (1/240,000)]

Advion 0.22%G

Table 5.1.3.  Short/Intermediate-Term Aggregate Risk Calculations for
Toddlers:  Advion 0.22%G

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	0.00088	2300	0.0088	230	0.239	210	105

1   MOE = NOAEL (2.0 mg/kg/day; KN127+ KN128)) ÷ (chronic food + water
exposure)

2   Residential oral = hand-to-mouth from contacting treated turf, the
highest oral exposure scenario (ingestion of treated soil and mouthing
grass exposures are not significant exposure contributors compared to
hand-to-mouth activities)

3   MOE = NOAEL (2.0 mg/kg/day; KN127+KN128) ÷ (sum of residential oral
exposure)

4   Residential dermal = post-application turf contact5   MOE = NOAEL
(50 mg/kg/day;KN127+ KN128) ÷ (residential dermal exposure)6  
Aggregate MOE = 1/[(1/2300) + (1/230) + (1/210)]

Table 5.1.4.  Short/Intermediate-Term Aggregate Risk Calculations for
Adults: Advion 0.22%G

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	0.000516	3900	0.137	360	330

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

2   MOE = NOAEL (2.0 mg/kg/day; KN127+KN128) ÷ (chronic food + water
exposure)

3   Residential dermal = post-application; application exposure not a
significant contributor compared to post-application.

4   MOE = NOAEL (50 mg/kg/day; KN127+KN128) ÷ (residential dermal
exposure)

5   Aggregate MOE = 1/[(1/3900) + (1/360)]

Provaunt 1.25%SC

Table 5.1.5.  Short/Intermediate-Term Aggregate Risk Calculations for
Toddlers:  Provaunt 1.25%SC

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	0.00088	2300	0.0044	460	0.022	2300	330

1   MOE = NOAEL (2.0 mg/kg/day; KN127+ KN128)) ÷ (chronic food + water
exposure)

2   Residential oral = hand-to-mouth from contacting treated turf, the
highest oral exposure scenario (ingestion of treated soil and mouthing
grass exposures are not significant exposure contributors compared to
hand-to-mouth activities)

3   MOE = NOAEL (2.0 mg/kg/day; KN127+KN128) ÷ (sum of residential oral
exposure)

4   Residential dermal = post-application turf contact

5   MOE = NOAEL (50 mg/kg/day;KN127+ KN128) ÷ (residential dermal
exposure)

6   Aggregate MOE = 1/[(1/2300) + (1/460) + (1/2300)]

Table 5.1.6.  Short/Intermediate-Term Aggregate Risk Calculations for
Adults: Provaunt 1.25%SC

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	0.000516	3900	0.013	3800	1900

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

2   MOE = NOAEL (2.0 mg/kg/day; KN127+KN128) ÷ (chronic food + water
exposure)

3   Residential dermal = post-application; application exposure not a
significant contributor compared to post-application.

4   MOE = NOAEL (50 mg/kg/day; KN127+KN128) ÷ (residential dermal
exposure)

5   Aggregate MOE = 1/[(13900) + (1/3800)]

 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/ .

OCCUPATIONAL EXPOSURE 

Occupational exposure/risk assessments for indoxacarb were previously
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) for currently registered uses of
indoxacarb. An occupational risk assessment for the proposed bushberry
and garden beet uses was performed to estimate  exposure and risk to
pesticide handlers from mixing, loading and applying the material and to
agricultural workers from post-application re-entry exposures (Memo,
24-FEB-2009, N. Tsaur, DP# 360560). That assessment is summarized in the
sections below.

The proposed section 3 use for DuPontTM Avaunt® Insecticide indicates
that it contains 30% indoxacarb active ingredient (ai) formulated as a
water dispersible granule (WDG).  Table 7.0 summarizes the proposed use
pattern and formulation specified in the end-use product containing
indoxacarb.

Table 7.0   Summary of Proposed New Use of Indoxacarb in End-Product
Formulation: DuPontTM Avaunt®;  30% water dispersible granule (WG)

	Garden Beets	Crop Subgroup 13B: Bushberry

Method of Application	Groundboom, aerial spray	Groundboom, aerial spray

Pests	Beet armyworm, Garden webworm	Cranberry fruitworm, Cherry
fruitworm, Winter moth, Bruce spanworm

Rate of Application†	Range: 0.065-0.11 lb ai/A	Range: 0.065-0.11 lb
ai/A

Maximum Rate	0.44 lb ai/A (4 applications)	0.44 lb ai/A (4 applications)

Frequency of Application	3 day intervals	7 day intervals

Restricted Entry Interval	12 hrs	12 hrs

Pre-harvest Interval (PHI)	7 days	7 days

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.”

Occupational Handler Exposure

	HED expects the most highly exposed occupational pesticide handlers are
likely to be involved in:  

1) mixing/loading dry flowables for groundboom applications, 

2) mixing/loading dry flowables for aerial applications, 

3) applying sprays via groundboom equipment,

4) applying sprays via aircraft equipment, and

5) flagging for liquid aerial sprays.

HED believes most exposure durations will be short-term (1 - 30 days).  
However, the Science Advisory Council for Exposure maintains it is
possible for commercial applicators to be exposed to intermediate-term
exposure durations (1 - 6 months).   Therefore, estimates for short- and
intermediate-term durations are presented.  The short- and
intermediate-term toxicological endpoints are the same, therefore, the
estimates of risk for intermediate-term duration exposures are the same
as are estimated for short-term duration exposures.

No chemical specific data were available with which to assess potential
exposure to occupational pesticide handlers.  The estimates of exposure
to pesticide handlers are based upon surrogate study data available in
the Pesticide Handler’s Exposure Database (PHED) (v. 1.1, 1998).   For
pesticide handlers, it is HED standard practice to present estimates of
dermal exposure for “baseline” that is, for workers wearing a single
layer of work clothing consisting of a long sleeved shirt, long pants,
shoes plus socks and no protective gloves as well as for “baseline”
and the use of protective gloves with other Personal Protective
Equipment (PPE) as might be necessary.  The proposed product label
involved in this assessment directs applicators and other handlers to
wear long-sleeved shirt, long pants, chemical resistant gloves and shoes
plus socks. 

Table 7.1.1 presents the exposure/risks for short and intermediate-term
dermal and inhalation exposures at baseline with additional personal
protective equipment.  The NOAELs used for MOE calculations are taken
from the endpoints which include the assessment of both enantiomers of
indoxacarb, not the readjusted endpoints for 100% KN128 (S-enantiomer)
ai.  The label indicates that the formulation consists of 30% ai which
only accounts for KN128 (S-enantiomer).  However, both KN128
(S-enantiomer) and KN127 (R-enantiomoer) have toxic effects.  Thus, in
calculating hazards of exposure, the application rate must be adjusted
by a factor of 4/3.  Translated, this means that in a 75:25 KN128:KN127
mixture, there are 4 parts of toxic indoxacarb for every 3 parts of
active indoxacarb.  An MOE of 100 is adequate to protect occupational
handlers.  Estimated MOEs are > 100, therefore, the proposed use pattern
does not exceed HED’s level of concern.  

	

Table 7.1.1    Short- and Intermediate-term Exposures and Risks for
Occupational Handlers of Indoxacarb

Exposure Scenario	Crop	Mitigation Level	Application Rate

(lb ai/ acre)	Daily Area Treated (acres)	Dermal Unit Exposure (mg/ lb
ai)	Inhalation Unit Exposure (mg/ lb ai)	Dermal Dose (mg/kg/day)
Inhalation Dose (mg/kg/day)	Dermal MOE	Inhalation MOE

Mixer/Loader

Mixing/ Loading Dry Flowables (open pour) for Groundboom Application
Garden Beets

Bushberries (Blueberry, Currant, Elderberry, Gooseberry, and
Huckleberry)	Baseline, Single Layer Gloves

 	0.147*	80	0.066

High Confidence

 	0.00077	0.011

 	0.00013	4,500	46,000

Mixing/ Loading Dry Flowables (open pour) for Airblast Application
Bushberries (Blueberry, Currant, Elderberry, Gooseberry, and
Huckleberry)	Baseline, Single Layer Gloves

 	0.147*	40	0.066

High Confidence

 	0.00077	0.0055

 	0.000065	9,000	93,000

Mixing/ Loading Dry Flowables (open pour) for Aerial Application	Garden
Beets

Bushberries (Blueberry, Currant, Elderberry, Gooseberry, and
Huckleberry)	Baseline, Single Layer Gloves	0.147*	350	0.066

High Confidence

 	0.00077	0.048

 	0.00056	1,000	11,000

Applicator

Applying Sprays by Groundboom (Open Cab)	Garden Beets

Bushberries (Blueberry, Currant, Elderberry, Gooseberry, and
Huckleberry)	Baseline, Single Layer 

No Gloves	0.147*	80	 0.014

 	0.00074	0.0023

 	0.00012	21,000	48,000

Applying Sprays by Airblast (Open Cab)	Bushberries (Blueberry, Currant,
Elderberry, Gooseberry, and Huckleberry)	Baseline, Single Layer 

No Gloves	0.147*	40	0.24

High Confidence

 	0.0045	0.020	0.00038	2,500	16,000

Applying Sprays by Aircraft (Closed Cockpit)	Garden Beets

Bushberries (Blueberry, Currant, Elderberry, Gooseberry, and
Huckleberry)	Baseline, Single Layer 

No Gloves	0.147*	350	0.0050	0.000068	0.0037	0.000050	13,600	120,000

Mixer/Loader/Applicator

Handgun Sprayer	Bushberries (Blueberry, Currant, Elderberry, Gooseberry,
and Huckleberry)	Baseline, Single Layer 

Gloves	0.147*	5	0.58	0.00022	0.0061	0.0000023	8,000	2,600,000

Flagger

Flagging for Spray Applications	Garden Beets

Bushberries (Blueberry, Currant, Elderberry, Gooseberry, and
Huckleberry)	Baseline, Single Layer 

No Gloves

 	0.147*	350	0.011	0.00035	0.0081	0.00026

	6,000	23,000

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

Since no postapplication data were submitted in support of this
registration action, exposures during post-application activities were
estimated using dermal transfer coefficients from the Science Advisory
Council (SAC) for Exposure Policy Number 3.1: Agricultural Transfer
Coefficients, August 2000, summarized in Table 7.2.1 below, and the
following assumptions:

					

Assumptions:

Application Rate	= 	0.147 lb ai/A*

* application rate used to calculate MOEs has been adjusted by a 4/3
factor to account for 4 parts of toxic indoxacarb for every 3 parts of
active indoxacarb.

Exposure Duration	=	8 hours per day

Body Weight		=	70 kg			

Dermal Absorption	= 	not required; endpoint is from a dermal study 

Fraction of ai retained on foliage is assumed to be 20% (0.2) on day
zero which is equal to the % dislodgeable foliar residue (DFR) after
initial treatment.  This fraction is assumed to further dissipate at the
rate of 10% (0.1) per day on following days.  These are default values
established by HED’s Exposure SAC.

Table 7.2.1. Anticipated Post-application Activities and Dermal Transfer
Coefficients

Proposed Crops	Policy Crop Group Category	Transfer Coefficients (cm2/hr)
Activities

Garden Beets	Vegetable, leaves of root and tuber	2500† 	hand
harvesting, irrigation, scouting, hand weeding, hand pruning, and
thinning

 Bushberry Subgroup	Berry, bushberry	5000‡ 	hand harvesting,
irrigation, scouting, hand weeding, hand pruning, hedging, and thinning

† No specific transfer coefficient for Garden Beets; highest transfer
coefficient for crop grouping (based off Turnips) used for assessment.

‡ No specific transfer coefficient for Bushberry Subgroup; highest
transfer coefficient for crop grouping (based off Blueberries, highbush)
used for assessment.

-- The information in the table is based on proprietary and
non-proprietary data.

For garden beets and the bushberry subgroup applications, risks do not
exceed HED’s level of concern on day 0 (REI = 12 hours) for activities
associated with the highest transfer coefficient.  

Table 6 presents a summary of occupational post-application risks
associated with use of indoxacarb and the calculated MOEs are not of
concern.



Table 7.2.2  Summary of Occupational Post-application Risks for
Indoxacarb

Crops	

Application Rate

(lb ai/A)	

Post-application Day (t)	

Fraction of ai Retained on the Foliage	

Fraction of Residue That Dissipates Daily	

Dislodgeable 

Foliar Residue

(ug/cm2) 1	

Dermal Transfer 

Coefficient 2

(cm2/hr)	

Exposure Time 

(hrs/day)	

Dermal

Absorption Factor 3	

Body Weight (kg)	

 Daily Dose 4

(mg/kg/day)	

Short-/

Intermed.

Term Dermal

MOE 5

Garden Beets 	0.147*	0 (12 hours)	0.2 (20%)	0.1 (10%)	0.330	2500	8	1.0
70	0.094	530

Bushberry Subgroup	.0147*	0 (12 hours)	0.2 (20%)	0.1 (10%)	0.330	5000	8
1.0	70	0.188	260

μg/cm2) = Application rate (lb ai/A) x Fraction of ai Retained on the
Foliage x (1- Fraction of Residue that Dissipates Daily) Postapplication
day x  4.54E+8 μg/lb x 2.47E-8 A/cm2

* application rate used to calculate MOEs has been adjusted by a 4/3
factor to account for 4 parts of toxic indoxacarb for every 3 parts of
active indoxacarb.

2  Taken from Science Advisory Council (SAC) for Exposure Policy Number
3.1: Agricultural Transfer Coefficients, August 2000.

3  For short- and intermediate-term dermal risk assessment, the dermal
absorption factor of 100% was applied because the endpoint chosen for
this risk assessment was derived from an oral toxicity study.

μg  x Dermal Transfer Coefficient x Exposure Time)/Body weight 

5  MOE = NOAEL/Daily Dose, where Short-/Intermediate-Term Dermal NOAEL =
50 mg/kg/day       

REI

Indoxacarb is classified in Acute Toxicity Category IV for acute dermal
toxicity, and primary skin irritation.  It is classified in Category III
for primary eye irritation.  It is not a dermal sensitizer.  Therefore,
the interim worker protection standard (WPS) restricted entry interval
of 12 hours is adequate to protect agricultural workers from
post-application exposures from bushberry and garden beet uses.  The
Avaunt® label lists a REI of 12 hours.

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 

870.7800 Immunotoxicity Study

	•	The petitioner should submit, as a condition of registration, an
immunotoxicity study.  This study is now required under the new 40 CFR
Part 158 data requirements (see Appendix 2).  The available data do not
appear to indicate that indoxacarb is immunotoxic. Indoxacarb is
currently regulated based on a NOAEL of 1.5 mg/kg/day for chronic
dietary exposure and 9 mg/kg/day for acute dietary exposure.  HED does
not believe that conducting a special series 870.7800 immunotoxicity
study will result in NOAELs less than the NOAELs of 1.5 and 9 mg//kg/day
currently identified for indoxacarb, and an additional uncertainty
factor (UFDB) for database uncertainties does not need to be applied for
the lack of an immunotoxicity study. 

8.2.  Chemistry

 tc \l2 "8.2.	Chemistry 

860.1200 Directions for Use

	•	The available blueberry and garden beet field trial data did not
provide results supporting the use of an adjuvant in the spray mix. 
Therefore, the Section B proposed label directions should be amended to
prohibit the use of adjuvants in applications made to bushberries and
garden beets.

[It is noted that the individual bushberry commodities specified on the
proposed label directions for use did not list lingonberry, a member of
the bushberry crop subgroup 13-07B, under the crops available for
treatment. It is unclear if the omission was intentional. If desired,
lingonberry may be added to the label.]

	

860.1550 Proposed Tolerances

	•	A revised Section F must be submitted which consistently denotes
the bushberry crop subgroup designation as being 13-07B in their
submission proposing tolerance levels. 

	•	While not germane to the petition 8E7324 (bushberry subgroup13-07B
and garden beet), a revised Section F proposing tolerances for residues
of indoxacarb in egg, and poultry meat, fat, and meat byproducts remains
outstanding.

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Appendices

Appendix 1:  Chemical Structures

Appendix 2: Rationale for Toxicology Data Requirements 

 tc \l2 "8.3.	Occupational/Residential Exposure 

Appendix 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	

 

Appendix 2:  Rationale for Toxicology Data Requirements  TC \l1
"Appendix II – Rationale for Toxicology Data Requirements 

Guideline Number:  870.7800

Study Title:  Immunotoxicity 

Rationale for Requiring the Data

The immunotoxicity study is a new data requirement under 40 CFR Part 158
as a part of the data requirements for registration of a pesticide (food
and non-food uses). 

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional
immunotoxicity testing and is designed to evaluate the potential of a
repeated chemical exposure to produce adverse effects (i.e.,
suppression) on the immune system. Immunosuppression is a deficit in the
ability of the immune system to respond to a challenge of bacterial or
viral infections such as tuberculosis (TB), Severe Acquired Respiratory
Syndrome (SARS), or neoplasia.  Because the immune system is highly
complex, studies not specifically conducted to assess immunotoxic
endpoints are inadequate to characterize a pesticide’s potential
immunotoxicity.  While data from hematology, lymphoid organ weights, and
histopathology in routine chronic or subchronic toxicity studies may
offer useful information on potential immunotoxic effects, these
endpoints alone are insufficient to predict immunotoxicity.  

Practical Utility of the Data

How will the data be used?

Immunotoxicity studies provide critical scientific information needed to
characterize potential hazard to the human population on the immune
system from pesticide exposure. Since epidemiologic data on the effects
of chemical exposures on immune parameters are limited and are
inadequate to characterize a pesticide’s potential immunotoxicity in
humans, animal studies are used as the most sensitive endpoint for risk
assessment.  These animal studies can be used to select endpoints and
doses for use in risk assessment of all exposure scenarios and are
considered a primary data source for reliable reference dose
calculation. For example, animal studies have demonstrated that
immunotoxicity in rodents is one of the more sensitive manifestations of
TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) among developmental,
reproductive, and endocrinologic toxicities.  Additionally, the EPA has
established an oral reference dose (RfD) for tributyltin oxide (TBTO)
based on observed immunotoxicity in animal studies (IRIS, 1997).

How could the data impact the Agency's future decision-making? 

If the immunotoxicity study shows that the test material poses either a
greater or a diminished risk than that given in the interim decision’s
conclusion, the risk assessments for the test material may need to be
revised to reflect the magnitude of potential risk derived from the new
data.

 

If the Agency does not have these data, a 10X database uncertainty
factor may be applied for conducting a risk assessment from the
available studies.

 Maximum Application Rate = 0.11 lb ai/acre  

*application rate used to calculate MOEs has been adjusted by a 4/3
factor to account for 4 parts of toxic indoxacarb for every 3 parts of
active indoxacarb.

 Units Treated taken from Science Advisory Council for Exposure,
Standard Operating Procedure 9.1, Standard Values for Daily Acres
Treated in Agriculture, Rev.  25 SEP 2001.

 Dermal Unit Exposure = mg ai/lb ai handled from the Pesticide Handler
Exposure Database (PHED), Version 1.1, August 1998. (100%)

 Inhalation Unit Exposure = mg ai/lb ai handled from the Pesticide
Handler Exposure Database (PHED), Version 1.1, August 1998. (100%)

 Dermal Dose = Dermal Unit Exposure * Application Rate * Units Treated *
Absorption Factor (dermal 100%)  Body Weight (70 kg).

 Inhalation Dose = Inhalation Unit Exposure * Application Rate * Units
Treated * Absorption Factor (inhalation 100%)  Body Weight (70 kg).

 Dermal Margin Of Exposure (MOE) = NOAEL (mg/kg/day)  ADD
(mg/kg/day); where the NOAEL = 50 mg/kg/day for all durations of  dermal
exposure

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