United States Office of Prevention, Pesticides
Environmental Protection and Toxic Substances
Agency (7505C)
Pesticide
Fact Sheet
Name of Chemical: Indoxacarb
Reason for Issuance: Conditional Registration
Date Issued: October 30, 2000
I. DESCRIPTION OF CHEMICAL
Generic Name: (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
Common Name: Indoxacarb Structural Formula:
Other Name: DPX-KN128
Indoxacarb TechnicalTM Insecticide
Trade Name:
STEWARDTM Insecticide
AVAUNTTM Insecticide
EPA Pesticide
Chemical Code: 067710
Chemical Abstracts
Service (CAS) No.: 173584-44-6
Year of Initial
Registration: 2000
Pesticide Type: Insecticide
Chemical Family: oxadiazines
U.S. Producer: E. I. du Pont de Nemours and Company (DuPont), Wilmington, DE.
Page 2 of 17
II. OVERVIEW at the Time of Registration
Indoxacarb is a new insecticide produced by DuPont and marketed in the U.S. as StewardTM , AvauntTM and
Technical IndoxacarbTM. At the time of initial registration (10/2000) Indoxacarb was formulated as a 30% a.i.
water dispersible granule (WG) proposed for use on apples, pears, Brassica, sweet corn, lettuce and fruiting
vegetables at a maximum of 4 applications at 3 to 7 day intervals. It was also formulated as a 15% a.i. suspension
concentrate (SC) liquid for use on cotton only. Indoxacarb is used for the control of certain lepidopteran pests
including the beet armyworm. There were no international registrations at the time of initial registration.
Indoxacarb is designated by the EPA to be a 鈥渞educed-risk鈥? pesticide and is considered an organophosphate
(OP) replacement. It has moderate to low acute and chronic toxicity and does not cause mutagenic, carcinogenic,
developmental, or reproductive effects. Some neurotoxicity was present, but often at fatal doses. Based on the
lack of evidence of increased susceptibility of infants and children, the Agency reduced the FQPA safety factor to
1X.
At the time of registration based on the uses noted above, the acute dietary exposure from food to indoxacarb
and its R-enantiomer occupied 33% of the acute Population Adjusted Dose (aPAD) for the most sensitive
population subgroup, females 13-50 years of years. The acute dietary risk was fairly conservative in that 100%
crop treated was assumed as well as anticipated residues and processing factors. The chronic dietary exposure
occupied 73% of the chronic PAD for children (ages 1-6) which was a conservative estimate based on 100% crop
treated and tolerance level residues. In addition, there was a potential for acute and chronic dietary exposure to
indoxacarb and it R-enantiomer in drinking water. After calculating Drinking Water Levels of Concern
(DWLOCs) and comparing them to the Estimated Environmental Concentrations (EECs) for surface and ground
water, the aggregate exposure and risk did not exceed any of the Agency鈥檚 levels of concern for the U. S.
population and any of the population subgroups, in particular children and infants on a chronic or acute basis.
Occupational exposure as a result of mixer, loader, flagger and applicator activities were expected; however,
the scenarios at the time of registration did not exceed the EPA鈥檚 level of concern when characterized.
The environmental fate data to support the registration of indoxacarb and its R-enantiomer were complete and
adequately characterized indoxacarb, its R-enantiomer and a few of the degradates. Due to the exceptionally
complex degradation scheme, the registration is conditional upon receiving further elucidation and
characterization of some additional degradates. The environmental fate profile indicates no major issues in the
areas of soil persistence, mobility, and fish bioaccumulation for indoxacarb and its R-enantiomer. The risk posed
to non-target organisms, including endangered species, were based on the conservative Tier I terrestrial
assessment. Several levels of concern resulted, in marginal exceedences that, with further refinements, would fall
within the Agency鈥檚 levels of concern. In addition, these risk values are very low when compared to those of the
alternative chemicals.
III. USE PATTERNS, FORMULATIONS, AND MODE OF ACTION
Conditionally
1. Indoxacarb Technical TM (EPA Reg. No. 352-694)
Registered Products:
2. STEWARDTM Insecticide (EPA Reg. No. 352-598)
3. AVAUNTTM Insecticide (EPA Reg. No. 352-597)
Page 3 of 17
Table 1. Application Rates, Restrictions1 & Tolerances:
Maximum Application
Maximum
Rate (lb. a.i./A)
Tolerance Number PHI
Commodity REI
(ppm) 2 Applications (days)
per
per season
/Season application
Apple 1.0 3 0.11 0.44 12 12 hrs
Apple, wet pomace 3.0 NA
Pear 0.20 3 0.11 0.44 12 12 hrs
Brassica, head and stem,
5.0 4 0.0669 0.268 3 12 hrs
subgroup
Cotton, undelinted seed 2.0 4 0.11 0.44 14 12 hrs
Cotton gin byproducts 15 NA
Lettuce, leaf 10 4 0.0669 0.268 3 12 hrs
Lettuce, head 4.0 4 0.0669 0.268 3 12 hrs
Vegetables, fruiting, group
0.50 4 0.0669 0.268 3 12 hrs
(except Cucurbits)
Corn, sweet, kernel plus
0.02 4 0.0669 0.268 3 **
cob with husk removed
Corn, sweet, forage 10 4 0.0669 0.268 3 **
35
Corn, sweet, stover 15 4 0.0669 0.268 **
fodder,
stover
Meat 3 0.03
Fat 3 0.75
Mbyp 3 0.02 NA NA NA NA NA
Milk fat 3.0
Milk 0.10
NA = Not Applicable
** 12 hrs, 14 days for hand harvest.
1
Environmental Hazards: 鈥淭his pesticide is toxic to mammals, birds, fish, and aquatic invertebrates. Do not apply
directly to water or to areas where surface water is present or to intertidal areas below the
mean high water mark. Runoff from treated areas may be hazardous to aquatic organisms
in neighboring areas. Cover, incorporate, or clean up granules that are spilled. Do not
contaminate water when disposing of equipment wash water or rinsate.鈥?
1
Crop Rotation Restrictions: 鈥淐rops that are on this label and cotton may be planted immediately following
harvest. Do not plant for food or feed any other crops not registered for use with
indoxacarb for 30 days after last use.鈥?
2
For crops, meat, and milk, the tolerance expression is indoxacarb + its R-enantiomer.
3
of cattle, goats, hogs, horses, and sheep.
FACT SHEET (New Chemical) Indoxacarb
Page 4 of 17
Mechanism of Pesticidal Action
The insecticide belongs to the oxadiazine chemical family and is being registered for the control of
lepidopterous pests in the larval stages. Insecticidal activity occurs via blockage of the sodium channels in the
insect nervous system and the mode of entry is via the stomach and contact routes.
IV. SCIENCE FINDINGS
A. Chemical Characteristics
Empirical Formula: C22H17ClF3N3O7
Molecular Weight: 527.8 g/mole
Melting Point: 88.1 C (99% indoxacarb PAI)
7.3 x 10-11 torr at 20o C (9.8 x 10-9 Pa)
Vapor Pressure:
1.9 x 10-10 torr at 25o C (2.5 x 10-8 Pa)
Henry's Law Constant at 25o C = 6 x 10-5 Pa m3/mol
(99% indoxacarb PAI; Knudsen-Effusion apparatus)
99% Indoxacarb TGAI at 25o C
Solubility:
1.72 mg/mL in n-heptane
14.5 mg/mL in 1-octanol
103 mg/mL in methanol
117 mg/mL in o-xylene
139 mg/mL in acetonitrile
160 mg/mL in ethyl acetate
>250 g/kg in dichloromethane, acetone, and dimethyl-formamide
99% indoxacarb PAI (25o C)
0.20 ppm in distilled water (generator column)
9.49 mg/mL in n-octanol (shake-flask method)
Partition Coefficient: log Kow = 4.65
B. Toxicology Characteristics
The nature of the toxic effects caused by indoxacarb and its R-enantiomer are discussed in the following
Tables 2-5 as well as the no observed adverse effect level (NOAEL) and the lowest observed adverse effect level
(LOAEL) from the toxicity studies reviewed. DPX-MP062 is a 75:25 mixture of the two enantiomers: indoxacarb
which is insecticidally active, and its R-enantiomer, which is insecticidally inactive, respectively. DPX-JW062 is
a mixture of these same two enantiomers; however, they are in a 50:50 ratio. Toxicology data submitted on DPX-
JW062 were considered relevant and included in the evaluation.
FACT SHEET (New Chemical) Indoxacarb
Page 5 of 17
1. Acute Toxicity
Table 2. Acute Toxicity Data on Technical DPX-MP062 TM Insecticide (EPA Reg No. 352-597)).
Guideline No./ Study Type MRID No. Results Toxicity
Category
870.1100 Acute oral toxicity 44477113 LD50=1730 mg/kg (male) II
= 268 mg/kg (females)
<1000 mg/kg (combined) (rat)
870.1200 Acute dermal toxicity 44477118 LD50 > 5000 mg/kg (rat) IV
870.1300 Acute inhalation toxicity 44477120 LC50 > 5.5mg/L IV
(70% MUP) (males, females, combined) (rat)
870.2400 Primary eye irritation 44477122 Moderate eye irritant (rabbit) III
870.2500 Primary dermal irrit. 44477125 Not a dermal irritant (rabbit) IV
870.2600 Skin sensitization 44477126 Is a dermal sensitizer (Guinea Pig) NA
Table 3. Acute Toxicity Data on DPX-MP062 MUP (67.8%;) (50.6% indoxacarb, 17.2% R-enantiomer).
Guideline No./ Study Type MRID No. Results Toxicity
Category
870.1100 Acute oral toxicity 44477114 LD50 = 1070mg/kg males II
407 mg/kg females
<750 mg/kg combined (rat)
870.1200 Acute dermal toxicity no test
870.1300 Acute inhalation toxicity 44477120 LC50 > 5.5 mg/L males, females and IV
combined (rat)
870.2400 Primary eye irritation 44477123 Mild eye irritant (rabbit) III
870.2500 Primary dermal irritat. no test
870.2600 Skin sensitization no test
FACT SHEET (New Chemical) Indoxacarb
Page 6 of 17
Table 4. Acute Toxicity Data on STEWARDTM Insecticide (EPA File Symbol 352-598) (14.7% indoxacarb,
4.3% R-enantiomer).
Guideline No./ Study Type MRID No. Results Toxicity
Category
870.1100 Acute oral toxicity 44482003 LD50 = 3619 mg/kg males III
in corn oil 751 mg/kg females
1818 mg/kg combined (rat)
870.1200 Acute dermal toxicity 44482004 LD50 > 5000 mg/kg males, females, IV
combined (rat)
870.1300 Acute inhalation toxicity 44482005 LC50 > 2.7 mg/L males, females and IV
combined (rat)
870.2400 Primary eye irritation 44482006 Mild eye irritant (rabbit) III
870.2500 Primary dermal irritation 44482007 Moderate dermal irritant (rabbit) III
870.2600 Skin sensitization 44482008 Is a dermal sensitizer (Guinea Pig) with NA
the Magnusson-Kligman Maximization
test
2. Subchronic, Chronic, Carcinogenicity, Developmental, Reproductive, and Mutagenic Toxicity
Indoxacarb has been classified as a 鈥渘ot likely鈥? human carcinogen. Neurotoxicity was observed in several
studies in both rats and mice. It is characterized by weakness, head tilting, and abnormal gait or mobility with
inability to stand. Some of these signs occurred at fatal doses. There was no evidence of susceptibility from
either in utero or neonatal exposure to both rat and rabbit young. A developmental study was used to determined
the acute dietary endpoint for females 13 - 50 years of age based on decreased fetal body weight. The compound
is negative for mutagenicity. The compound(s) was extensively metabolized and the metabolites were eliminated
in the urine, feces and bile in rats. The metabolite profile was dose dependent and varied quantitatively between
males and females. The metabolic pathway proposed yielded multiple metabolites bearing one of the two ring
structures, the indeno or trifluoromethoxyphenyl groups. Additional details are provided in Table 5. A summary
of the toxicological endpoints used for risk assessment are provided in Table 6.
Table 5.--Subchronic, Chronic and Other Toxicity
Guideline No./ Study Type Test material / Results
870.3100 DPX-MP062 (75% indoxacarb / 25% enantiomer)
90-Day oral toxicity rodents - NOAEL = Male (M) 3.1 mg/kg/day, Female (F) 2.1 mg/kg/day
rats 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.
870.3100 DPX-JW062 (50% indoxacarb / 50% enantiomer) / NOAEL = M 8.0, F 4.6 mg/kg/day
90-Day oral toxicity rodents - LOAEL = M 16, F 9.5 mg/kg/day based on mortality (F only), decreased. body weight,
rats body weight gain, food consumption and food efficiency in rats.
870.3100 DPX-JW062 / NOAEL = M 3.7, F 4.9 mg/kg/day
90-Day oral toxicity rodents - LOAEL = M 7.5, F 12 mg/kg/day based on decreased in absolute body weight, body
rats weight gain and food efficiency in rats.
FACT SHEET (New Chemical) Indoxacarb
Page 7 of 17
Guideline No./ Study Type Test material / Results
870.3100 DPX-JW062 / NOAEL = M23, F 16 mg/kg/day
90-Day oral toxicity rodents - LOAEL = M 44, F 30 mg/kg/day based on mortality (M only); increased reticulocytes
mice and Heinz bodies and decreased body weight, weight gain, food consumption, food
efficiency; and increased clinical signs (leaning to one side and/or with abnormal gait or
mobility) (F only) in mice.
870.3150 DPX-JW062 / NOAEL = 5.0 mg/kg/day
90-Day oral toxicity in LOAEL = 19 mg/kg/day based on hemolytic anemia, as indicated by decreased in HGB,
nonrodents - dogs RBCs; increases in platelets, increased reticulocytes; and secondary histopathologic
findings indicative of blood breakdown (pigment in Kupffer cells, renal tubular
epithelium, and spleen and bone marrow macrophages); increased in splenic EMH; and
RBC hyperplasia in bone marrow in dogs.
870.3200 DPX-MP062
28-Day dermal toxicity - rats NOAEL = 2000 mg/kg/day
LOAEL = >2000 mg/kg/day in rats.
870.3200 DPX-MP062 / NOAEL = 50 mg/kg/day
28-Day dermal toxicity - rats 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 (increased
reticulocytes), the spleen (increased absolute and relative weight鈥揗 only, gross
discoloration), clinical signs of toxicity in both sexes in rats.
870.3700a DPX-MP062
Prenatal developmental in Maternal NOAEL = 2.0 mg/kg/day, LOAEL = 4.0 mg/kg/day based on decreased mean
rodents - rats 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.
870.3700a DPX-JW062
Prenatal developmental in Maternal NOAEL = 10 mg/kg/day, LOAEL = 100 mg/kg/day based on mortality,
rodents - rats 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 DPX-JW062
Prenatal developmental in Maternal NOAEL = 1.1 mg/kg/day
rodents - rats 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 = 2.2 mg/kg/day based on decreased fetal body weights.
870.3700b DPX-JW062
Prenatal developmental in Maternal NOAEL = 500 mg/kg/day
nonrodents - rabbits 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 decr. fetal body weights and reduced ossification of
the sternebrae.
FACT SHEET (New Chemical) Indoxacarb
Page 8 of 17
Guideline No./ Study Type Test material / Results
870.3800 DPX-JW062
Reproduction and fertility Parental/Systemic NOAEL = 1.5 mg/kg/day
effects - rats LOAEL = 4.4 mg/kg/ day based on decreased. body weights, body-weight gains, and
food consumption of F0 females, and increased 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 decreased in the
body weights of the F1 pups during lactation.
870.4100a DPX-JW062 / NOAEL = M 5, F 2.1 mg/kg/day, LOAEL = M 10, F 3.6 mg/kg/day based
Chronic toxicity rodents - rats 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 DPX-JW062 / NOAEL = M 2.3, F 2.4 mg/kg/day
Chronic toxicity - dogs LOAEL = M 18, F 19 mg/kg/day based on decreased. HCT, HGB and RBC; increased
Heinz bodies and reticulocytes and associated secondary microscopic changes in the
liver, kidneys, spleen, and bone marrow; increased absolute and relative liver weights.
870.4200 DPX-JW062 / see 870.4100a
Carcinogenicity - rats no evidence of carcinogenicity
870.4300 DPX-JW062 / NOAEL = M 2.6, F4.0 mg/kg/day, LOAEL = M 14, F 20 mg/kg/day
Carcinogenicity - mice based on decreased body weight, body weight gain, and food efficiency and clinical
signs indicative of neurotoxicity.
no evidence of carcinogenicity
870.5100 DPX-MP062 / strains TA97a, TA98, TA100 and TA1535 of S. typhimurium and strain
Gene Mutation WP2(uvrA) of E. coli were negative for mutagenic activity both with and without S9
activation for the concentration range 10-5000 碌g/plate
870.5100 DPX-JW062 / strains TA97a, TA98, TA100 and TA1535 of S. typhimurium and strain
Gene Mutation WP2(uvrA) of E. coli were negative for mutagenic activity both with and without S9
activation for the concentration range 10-5000 碌g/plate.
870.5300 DPX-MP062 / negative for mutagenic activity for the following concentration ranges:
Gene Mutation 3.1-250 碌g/mL (-S9); 3.1-250 碌g/mL (+S9)
870.5300 DPX-JW062 / negative for mutagenic activity for the following concentration ranges:
Gene Mutation Negative;100-1000 碌g/mL (-S9); 100-1000 碌g/mL (+S9), precipitate >1000 碌g/mL
870.5375 DPX-MP062 / no evidence of chromosomal aberrations induced by the test article over
Cytogenetics background for the following concentration ranges: 15.7-1000 碌g/mL (+S9)
870.5375 DPX-JW062 / no evidence of chromosomal aberrations induced by the test article over
Cytogenetics background for the following concentration ranges: 19-300 碌g/mL (-S9), 19-150 碌g/mL
(+S9); partial insoluble & cytotoxicity > 150 碌g/mL
870.5395 DPX-MP062 / no evidence of mutagenicity for the following dose ranges: 3000-4000
Cytogenetics mg/kg - males; 1000-2000 mg/kg - females
870.5395 DPX-JW062 / no evidence of mutagenicity at 2500 or 5000 mg/kg
Cytogenetics
FACT SHEET (New Chemical) Indoxacarb
Page 9 of 17
Guideline No./ Study Type Test material / Results
870.5550 DPX-MP062 / no evidence of mutagenic activity at the following concentration range:
Other Effects 1.56-200 碌g/mL; cytotoxicity was seen at concentrations of >100 碌g/mL
870.5550 DPX-JW062 / No evidence of mutagenic activity at the following concentration range:
Other Effects 0.1-50 碌g/mL, cytotoxicity observed at >50 碌g/mL
870.6200a DPX-MP062 / NOAEL = M 100, F 12.5 mg/kg
Acute neurotoxicity screening LOAEL = M 200 mg/kg based on decreased body weight gain, decreased food
battery - rat consumption, decreased forelimb grip strength, and decreased foot splay. F 50 mg/kg
based on decreased body weight, body weight gain, and food consumption
870.6200a DPX-JW062 / NOAEL >= M 2000 mg/kg, F < 500 mg/kg
Acute neurotoxicity screening LOAEL > M 2000 mg/kg, F < 500 mg/kg based on clinical signs, decreased body weight
battery -rats gains and food consumption, and FOB effects
870.6200b DPX-MP062 / NOAEL = M 0.57, F 0.68 mg/kg/day
Subchronic neurotoxicity LOAEL = M 5.6, F 3.3 mg/kg/day based on decreased body weight and alopecia.
screening battery - rats
870.7485 Both DPX-MP062 and DPX-JW062 were extensively metabolized and the metabolites
Metabolism and were eliminated in urine, feces, and bile. The metabolite profile for DPX-JW062 was
pharmacokinetic - rats 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 DPX-MP062 and DPX-JW062 has
multiple metabolites bearing one of the two ring structures.
C. Toxicological Endpoints and Exposure Doses
Based on the review of the toxicological data submitted and summarized in Table 5, the Agency selected
specific studies, end points (adverse biological effects), a Lowest Observed Adverse Effect Level (LOAEL), and
several No Observed Adverse Effect Levels (NOAELs), and modified by several safety (SF) or uncertainty factors
(UF), to derive acceptable exposure doses in mg/kg/day for use in acute and chronic risk assessments. Table 6
lists the studies, endpoints, exposure doses, uncertainty/safety factors, and exposure profiles that the Agency used
in these risk assessments.
The FQPA safety factor is 1x. EPA determined that the 10X safety factor to protect infants and children
should be removed because:
1) there is no indication of quantitative or qualitative increased susceptibility of rats or rabbits to in utero
and/or postnatal exposure;
2) the requirement of a developmental neurotoxicity study is not based on the criteria reflecting special
concern for the developing fetuses or young which are generally used for requiring a developmental
neurotoxicity study - and a safety factor (e.g.: neuropathy in adult animals; central nervous system
malformations following prenatal exposure; brain weight or sexual maturation changes in offspring; and/or
functional changes in offspring) - and therefore does not warrant an FQPA Safety Factor;
3) the dietary (food and drinking water) exposure assessments will not underestimate the potential exposures
for infants and children; and
4) there are no registered residential uses at the current time.
FACT SHEET (New Chemical) Indoxacarb
Page 10 of 17
Table 6.--Summary of Toxicological Dose and Endpoints for Indoxacarb and its R-enantiomer for Use in
Human Risk Assessment.*
Exposure Dose Used in Risk FQPA Safety Factor Study and Toxicological Effects
(SF)** and Endpoint for
Scenario Assessment,
Uncertainty Factor Risk Assessment
(UF)
Acute Dietary NOAEL = 2.0 FQPA SF = 1 developmental rat toxicity study.
females 13-50 mg/kg/day aPAD = acute RfD developmental LOAEL = 4.0 mg/kg/day
years of age UF = 100 FQPA SF based on decreased fetal body weight.
Acute RfD = 0.02
mg/kg = 0.02 mg/kg/day
Acute Dietary NOAEL= 12.5 mg/kg FQPA SF = 1 acute oral rat neurotoxicity study.
general population UF = 100 aPAD = acute RfD LOAEL = 50 mg/kg based on decreased
including infants Acute RfD = 0.12 FQPA SF body weight and body weight gain in
and children mg/kg females.
= 0.12 mg/kg/day
Chronic Dietary NOAEL= 2.0 FQPA SF = 1 90-day rat subchronic toxicity study,
all populations mg/kg/day cPAD = chr RfD 90-day rat neurotoxicity study,
UF = 100 FQPA SF chronic/carcinogenicity rat study.
Chronic RfD = 0.02 LOAEL = 3.3 mg/kg/day based on decreased
mg/kg/day = 0.02 mg/kg/day body weight, alopecia, body weight gain,
food consumption and food efficiency;
decreased hematocrit, hemoglobin and red
blood cells only at 6 months. 3.3 mg/kg/day
is the lowest NOAEL of the 3 studies.
Short-Term Oral oral study NOAEL= LOC for MOE = 100 developmental rat toxicity study.
(1-7 days) 2.0 mg/kg/day (Residential, includes the maternal LOAEL = 4.0 mg/kg/day based on
FQPA SF) decreased mean maternal body weights, body
(Residential) weight gains, and food consumption.
Intermediate-Term oral study NOAEL= LOC for MOE = 100 90-day rat subchronic toxicity study.
Oral (1 week - 2.0 mg/kg/day (Residential, includes the LOAEL = 3.8 mg/kg/day based on decreased
several months) FQPA SF) body weight, body weight gain, food
consumption and food efficiency.
(Residential)
Short- (1-7 days), dermal study LOC for MOE = 100 28-day rat dermal toxicity study.
Intermediate- (1 NOAEL= 50 (Occupational) LOAEL = 500 mg/kg/day based on
week - several mg/kg/day decreased body weights, body weight gains,
months), and Long- LOC for MOE = 100 food consumption, and food efficiency in
(several months - (Residential, includes the females, and changes in hematology
lifetime) Term FQPA SF) parameters (increased reticulocytes), the
Dermal spleen (increased absolute and relative
weight鈥搈ales only, gross discoloration), and
(Occupational/ clinical signs of toxicity in both sexes.
Residential)
FACT SHEET (New Chemical) Indoxacarb
Page 11 of 17
Table 6.--Summary of Toxicological Dose and Endpoints for Indoxacarb and its R-enantiomer for Use in
Human Risk Assessment.*
Exposure Dose Used in Risk FQPA Safety Factor Study and Toxicological Effects
(SF)** and Endpoint for
Scenario Assessment,
Uncertainty Factor Risk Assessment
(UF)
Short-Term oral study NOAEL= LOC for MOE = 100 rat developmental toxicity study.
Inhalation (1-7 2.0 mg/kg/day (Occupational) maternal LOAEL = 4.0 mg/kg/day based on
days) (inhalation absorption decreased mean maternal body weights, body
rate = 100%) LOC for MOE = 100 weight gains, and food consumption.
(Occupational/ (Residential, includes the
Residential) FQPA SF)
Intermediate-Term oral study NOAEL= LOC for MOE = 100 90-day rat subchronic toxicity study.
Inhalation (1 week 2.0 mg/kg/day (Occupational) LOAEL = 3.8 mg/kg/day based on decreased
- several months) (inhalation absorption body weight, body weight gain, food
rate = 100%) LOC for MOE = 100 consumption and food efficiency.
(Occupational/ (Residential, includes the
Residential) FQPA SF)
Long-Term oral study LOC for MOE = 100 90-day rat subchronic toxicity study,
Inhalation (several NOAEL= 2.0 (Occupational) 90-day rat neurotoxicity study,
months - lifetime) mg/kg/day chronic/carcinogenicity rat study.
(inhalation absorption LOC for MOE = 100 LOAEL = 3.3 mg/kg/day based on decreased
(Occupational/ rate =100%) (Residential, includes the body weight, body weight gain, food
Residential) FQPA SF) consumption and food efficiency; decreased
hematocrit, hemoglobin and red blood cells
only at 6 months.
Cancer (oral, 鈥渘ot likely鈥? to be N/A no evidence of carcinogenicity in either the
dermal, inhalation) carcinogenic to rat or mouse in acceptable carcinogenicity
humans studies and no evidence of mutagenicity.
*
UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL =
lowest observed adverse effect level, PAD = population adjusted dose (a = acute, c = chronic) RfD = reference
dose, LOC = level of concern, MOE = margin of exposure
** The reference to the FQPA Safety Factor refers to any additional safety factor retained due to concerns unique
to the FQPA.
E. Residue Chemistry
Tolerances are established for the combined residues of the insecticide indoxacarb [(S)-methyl
7-chloro-2,5-dihydro-2-[(methoxycarbonyl)[4-(trifluoromethoxy)phenyl]amino]carbonyl]indeno[1,2-e][1,3,4]oxad
iazine-4a(3H)-carboxylate] and its R-enantimomer[(R)-methyl7-chloro-2,5-dihydro-2-[[(methoxycarbonyl)
[4-(trifluoromethoxy)phenyl]amino]carbonyl]indeno[1,2-e] [1,3,4]oxadiazine-4a(3H)-carboxylate] in or on the
following raw agricultural commodities:
apple 1.0 ppm
apple, wet pomace 3.0 ppm
Brassica, head and stem, subgroup 5.0 ppm
FACT SHEET (New Chemical) Indoxacarb
Page 12 of 17
cattle, goat, horse, sheep and hog fat 0.75 ppm
cattle, goat, horse, sheep and hog meat 0.03 ppm
cattle, goat, horse, sheep and hog meat byproducts 0.02 ppm
corn, sweet, forage 10 ppm
corn, sweet, kernel plus cob with husk removed 0.02 ppm
corn, sweet, stover 15 ppm
cotton gin byproducts 15 ppm
cotton, undelinted seed 2.0 ppm
lettuce, head 4.0 ppm
lettuce, leaf 10 ppm
milk 0.10 ppm
milk fat 3.0 ppm
pear 0.20 ppm
vegetables, fruiting, group 0.50 ppm
鈥? The metabolism of indoxacarb in plants and animals is understood.
鈥? The enforcement methodologies for indoxacarb residues are adequate.
F. Occupational and Residential Exposure and Risk:
1. Handlers. The worker exposure and risk assessment presented in this document are based on the
Pesticide Handler Exposure Database Version 1.1 (PHED, Surrogate Exposure Guide, August 1998) unit
exposure estimates for workers wearing long pants, long sleeves, gloves, and using open cab ground
equipment. The worker exposure and risk assessment was conducted using the maximum application
rate, the crop with the highest average farm size (cotton), and the unit exposure estimates for liquid
formulations representing the worst case scenario among the proposed uses.
Based on the use patterns, only short- and intermediate- term exposures resulting from the proposed
uses are expected. Short-term exposures are expected for the private applicator (farmers treating their
own fields). Both short- and intermediate-term exposures are expected for the commercial handler
(mixer/loaders and applicators for groundboom and aerial applications). Since the maximum
application rate, the crop with the highest average farm size (cotton), and the unit exposure estimates for
liquid formulations were used to assess exposures from dry flowable and suspension concentrate
formulations, the estimates of risk are considered conservative. The potential risks for occupational
workers from short- and intermediate- term exposures from the proposed uses of indoxacarb do not
exceed HED鈥檚 level of concern.
2. Post application. The post-application exposure and risk assessments are based on chemical specific
data on apples, tomatoes, and broccoli. Since lettuce, sweet corn, and cotton were not included in the
FACT SHEET (New Chemical) Indoxacarb
Page 13 of 17
studies, the highest average residue of the submitted data were used to determine the potential risks
from post-application activities associated with the proposed Section 3 uses of indoxacarb for these
crops. There is potential for post-application exposures to workers entering treated areas for routine
crop maintenance tasks and harvesting of the subject crops. The risk estimate for post-application
exposures for the use of indoxacarb on broccoli, cabbage, cauliflower, and lettuce do not exceed
Agency鈥檚 level of concern after four applications of DPX-MP062. The risk estimates for post-
application exposures from the uses of indoxacarb do not exceed Agency鈥檚 level of concern for hand
harvesting sweet corn with a 14 day restricted entry interval. Because of the post-application exposures
and risk estimates for thinning/hand harvesting of apples and pears, the applications were reduced from
4 to 3 resulting in a marginal exceedence. Further refinements would likely lower the risk estimate to
the point there is no exceedence of the Agency鈥檚 level of concern.
3. Residential. There are no registered residential uses for indoxacarb at this time.
G. Human Risk Assessments
1. Acute Dietary and Aggregate Risk. There is a reasonable certainty of no harm resulting from
aggregate acute dietary exposure to indoxacarb and its R-enantiomer. The Acute Population Adjusted
Dose (aPAD) is less than 100% for all population groups including infants and children based on
conservative assumptions (100% crop treated, anticipated residues, processing factors). The EECs in
surface (3.81 ppb) and ground (0.02 ppb) water are less than the Drinking Water Levels of Concern
(DWLOCs). No residential non-food exposures are expected.
Acute Dietary Risk: Females 13-50 years old = 33% aPAD
Children 1-6 years old = 10% aPAD
All other groups = < 10 % aPAD
Acute DWLOC: Females 13-50 years old = 3400 ppb
Children 1-6 years old = 1100 ppb
All other groups = > 3400 ppb
2. Chronic Dietary and Aggregate Risk. There is reasonable certainty of no harm resulting from
aggregate chronic dietary exposure to indoxacarb and its R-enantiomer. The chronic population
adjusted dose (cPAD) is less than 100% for all population groups including infants and children based
on very conservative assumptions (tolerance level residues and 100% crop treated). The EECs in
surface (0.56 ppb) and ground (0.02 ppb) water are less than the drinking water levels of concern
(DWLOCs).
Chronic Dietary Risk: Females 13-50 years old = 22% cPAD
Children 1-6 years old = 73% cPAD
All other groups = < 40 % cPAD
Chronic DWLOC: Females 13-50 years old = 540 ppb
Children 1-6 years old = 53 ppb
All other groups = >120 ppb
3. Short-term risk. Short-term aggregate exposure takes into account residential exposure plus chronic
exposure to food and water (considered to be a background exposure level). Indoxacarb and its
R-enantiomer is not registered for use on any sites that would result in residential exposure at this time.
Therefore, the aggregate risk is the sum of the risk from food and water which does not exceed the
Agency's level of concern.
FACT SHEET (New Chemical) Indoxacarb
Page 14 of 17
4. Intermediate-term risk. Intermediate-term aggregate exposure takes into account residential
exposure plus chronic exposure to food and water (considered to be a background exposure level).
Indoxacarb and its R-enantiomer are not registered for use on any sites that would result in residential
exposure. Therefore, the aggregate risk is the sum of the risk from food and water, which does not
exceed the Agency's level of concern.
5. Determination of safety. Based on these risk assessments, EPA concludes that there is a reasonable
certainty that no harm will result to the general population, and to infants and children from aggregate
exposure to indoxacarb and its R-enantiomer residues.
H. Ecological Effects
1. Hazard
Toxicity to Birds - Indoxacarb and its R-enantiomer are 鈥渕oderately toxic鈥? to avian species on an acute
oral basis and subacute dietary basis. The lowest LC50 is 808 mg/kg-diet for bobwhite quail. The metabolite
JT333 is 鈥渟lightly toxic鈥? to avian species on an acute oral basis (LC50 1618 mg/kg).
Toxicity to Bees - Indoxacarb and its R-enantiomer is 鈥減ractically non-toxic鈥? by dietary intake and 鈥渉ighly
toxic鈥? by contact.
Toxicity to Mammals - Mammalian toxicity studies were extrapolated from laboratory studies in rats. The
acute LD50 was determined to 179 mg/kg-bw. A chronic No Observable Effect Concentration (NOEC) of 40
mg/kg diet was determined for developmental and reproductive effects. Additionally, a subchronic/chronic
toxicity value was determined which yields a NOEC of 8 mg/kg diet. However, the importance of the
endpoint (hemolysis) to the effect on wildlife populations was not certain.
Toxicity to Aquatic Animals - Indoxacarb, its R-enantiomer and degradates are 鈥渕oderately to very highly
toxic鈥? to freshwater and estuarine/marine fish on an acute basis with LC50s ranging from 0.024 to > 1.3
mg/L. These same compounds are 鈥渕oderately toxic鈥? to 鈥渧ery highly toxic鈥? freshwater and
estuarine/marine invertebrates on an acute basis with EC50s ranging from 0.029 to 2.94 mg/L. Chronic
toxicities range from 0.0006 to 0.0184 mg/L for estuarine fish and invertebrates and from 0.004 to 0.15
mg/L for freshwater fish and invertebrates.
I. Environmental Fate Characteristics
The environmental fate data base submitted to support the registration of indoxacarb and its R-enantiomer is
complete and adequately characterizes indoxacarb, its R-enantiomer and a few of the degradates. However, due
to the exceptionally complex degradation scheme, the registration is conditional upon receiving further
elucidation and characterization of some additional degradates.
鈥? Indoxacarb is considered to be moderately persistent with aerobic half lives ranging from 3 to 693 days
and anaerobic range from 147 to 233 days. It is considered to be immobile with Kocs ranging from 3300
to 9600 ml/g.
鈥? The environmental fate profile indicates no major issues in the areas of soil persistence, mobility, and
fish bioaccumulation for the indoxacarb and its R-enantiomer.
鈥? Minimal environmental residues of this chemical in water resources are expected; only the risks
associated with indoxacarb and its R-enantiomer were included in the water assessment.
FACT SHEET (New Chemical) Indoxacarb
Page 15 of 17
J. Environmental Exposure
Terrestrial exposure was evaluated using estimated environmental concentrations generated from a
spreadsheet-based model that calculates the decay of a indoxacarb and its R-enantiomer applied to foliar
surfaces for a single or multiple applications. The Tier I terrestrial exposure assessment is based on the methods
of Hoerger and Kenaga as modified by Fletcher et al. Overall, the terrestrial exposure is considered low for
indoxacarb and its R-enantiomer. There was no compensation to the exposure assessment to include the
numerous degradates.
Using the Tier II PRZM/Exams index reservoir model, EFED estimated environmental concentrations
(EECs) in surface water resulting from the application of indoxacarb, its R-enantiomer and a limited number of
degradates to cotton over a 36 year period. The model predicted the peak and average concentrations using the
percent cropped area for cotton in surface water were not likely to exceed 3.81 ppb and 0.56 ppb on an acute and
chronic basis respectively. A Tier I SCI-GROW groundwater modeling predicted the acute and chronic
concentration of indoxacarb, its R-enantiomer and a limited number of degradates in shallow groundwater is not
likely to exceed 0.02 ppb. An uncertainty in these assessments is the lack of environmental fate data for the
unknown transformation products of indoxacarb.
Several levels of concern are exceeded for indoxacarb, its R-enantiomer and a limited number of
degradates. However, the risk determination was based on the Tier I terrestrial assessments and maximum
application rates resulting, in many cases, in only slight exceedences. Further refinements would likely lower the
value to the point where there is no exceedence. In addition, these risk values are very low when compared to
those of the alternative chemicals.
Aquatic Organisms - The acute restricted use level of concern (0.1) was only marginally exceeded for for
one scenario (estuarine/marine invertebrates) for indoxacarb, its R-enantiomer and one degradate (JT333).
Birds - The acute restricted risk levels of concern (0.1) were only marginally exceeded for two avian
scenarios and one avian food item (short grass) as a result of multiple applications of indoxacarb and it R-
enantiomer.
Mammals - Several subchronic/chronic levels of concern for small mammals (1.0) were exceeded for
several food items; however, these risks are based on conservative assumptions (potentially reversible
hemolytic effects) and the importance of these toxic effects on survival of wildlife is uncertain.
Bees - Risks to bees via the dietary route were considered minimal; however, high toxicities were noted by
the contact routes.
Endangered Species - The level of concerns for endangered species (0.05) were only marginally exceeded
for one scenario (estuarine/marine invertebrates) for indoxacarb, its R-enantiomer and one degradate
(JT333). The level of concerns for endangered species were exceed for two avian scenarios and one avian
food item as a result of multiple applications of indoxacarb and its R-enantiomer. The risk quotients (RQs)
are likely fall below the levels of concern upon refinement.
V. SUMMARY OF REGULATORY POSITION AND RATIONALE
The Agency has established permanent tolerances for use on apples, pears, cotton, sweet corn, Brassica,
lettuce and fruiting vegetables in a Final Rule published in the Federal Register on September 29, 2000 (65 FR
58415-24). As part of the labeling for crop uses, EPA, in some cases reduced the number of applications and
required a pre-harvest intervals (PHI), crop rotation restrictions, environmental hazard information, and various
restricted re-entry intervals for indoxacarb (see Table 1). Available data provided adequate information to
FACT SHEET (New Chemical) Indoxacarb
Page 16 of 17
support the conditional registrations of Indoxacarb technical, STEWARDTM Insecticide on cotton, and
AVAUNTTM Insecticide on fruiting vegetables, head and leaf lettuce, broccoli, cabbage, cauliflower, apples,
pears, and sweet corn
VI. SUMMARY OF DATA GAPS
Product Chemistry Data: The basic data requirements have been met; however, additional
clarification or supplementation data and/or information is required for these guideline studies.
鈥? 830.1550 - product identity and composition
鈥? 830.1600 - description of materials used to produce the product
鈥? 830.1620 - description of production process
鈥? 830.1650 - description of formulation process
鈥? 830.1670 - discussion of formation of impurities
鈥? 830.6313 - stability to normal, elevated temperatures, metal ions, metals
Residue Chemistry Data: The basic data requirements have been met; however, additional
clarification or supplementation data and/or information is required for these guidelines.
鈥? revised Section B's and Section F鈥檚
鈥? 860.1480 - poultry feeding study
鈥? 860.1340 - confirmatory method for plants
鈥? 860-1340 - specificity testing for analytical methods for plants
鈥? 860.1380 - storage stability data reflecting the maximum frozen storage intervals of cotton
processed samples.
鈥? receipt of analytical methodology standards to EPA repository (awaiting confirmation for
shipment of Sept. 13, 2000.)
Toxicology Data: These data are not part of the core requirements for registration.
鈥? 870.6300 - developmental neurotoxicity study in the rat (due to neurotoxicity concerns, not
developmental concerns)
鈥? 870.3465 - 90-day inhalation toxicity study in the rat
Specially recommended study conditions are:
(1) HED is in the process of determining whether it wants lungs for histopathology (from inhalation
studies) to be fixed by immersion in the fixative, or by intra-tracheal instillation of the fixation.
Lungs fixed by intra-tracheal instillation may show artifacts, such as pre-bronchial and peri-
vascular cuffing, and widening of interstitial spaces, making it difficult to diagnose actual toxicity
effects. Therefore, it is recommended that the Registrant contact OPP/HED prior to initiating the
study; (2) In addition to H&E staining of lung tissue, another set of slides should be stained with
fibrin-specific stain in order to be able to detect the possible presence of organized fibrin in the lung
following the multiple exposure (90-days).
Environmental Fate Data: The basic data requirements have been satisfied for these guideline
studies; however, additional elucidation of the degrates are necessary which are not part of the core
requirements.
鈥? hydrolysis
鈥? photodegradation in water
鈥? aerobic soil metabolism
鈥? anaerobic aquatic metabolism
鈥? aerobic aquatic metabolism
鈥? leaching-adsorption/desorption
鈥? terrestrial field dissipation
FACT SHEET (New Chemical) Indoxacarb
Page 17 of 17
鈥? accumulation in fish
VI. CONTACT PERSON AND MAILING ADDRESS AT EPA
Jane Smith
Insecticide-Rodenticide Branch
Registration Division (7504C)
Office of Pesticide Programs
Environmental Protection Agency
401 M Street, SW
Washington, DC 20460
Office Location, Telephone Number, Fax Number, and E-Mail
Room 207, Crystal Mall Building #2
1921 Jefferson Davis Highway
Arlington, VA 22202
Tel: (703) 305-7378
Fax: (703) 305-6596
E-Mail: Smith.Jane-Scott@epa.gov
DISCLAIMER: The information presented in this Pesticide Fact Sheet is for informational purposes only and
may not be used to fulfill data requirements for pesticide registration and reregistration.
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