Return
to Indoxacarb Index Page
Activity:
Insecticide
(oxadiazine)
Structure:
Adverse
Effects:
Anemia
Ataxia
Blood
Body
Weight Decrease
Bone
Brain
CNS
Cytotoxic
Developmental
Endocrine: Thymus
Heart
Kidney
Liver
Lung
Spleen
Tremors
Environmental
As
of February 15, 2005, this insecticide is permitted in
or on 67 food commodities
in the United States - see list at http://www.fluorideaction.org/pesticides/mrl.indoxacarb.htm
Indoxacarb
is a new insecticide produced by DuPont
and marketed in the U.S. as Steward TM , Avaunt TM and Technical
Indoxacarb TM... Indoxacarb is designated
by the EPA to be a "reduced-risk" 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... 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... Several levels of
concern resulted, in marginal exceedences that, with further
refinements, would fall within the Agency's levels of concern.
In addition, these risk values are very low when compared
to those of the alternative chemicals.
Ref:
US EPA Pesticide Fact Sheet. Indoxacarb. Reason for Issuance:
Conditional Registration. Date Issued: October 30, 2000.
http://www.fluorideaction.org/pesticides/indoxacarb.epa.oct.2000.pdf
|
Metabolites
and other names for Indoxacarb |
Metabolite |
CAS
No. |
Scientific
Name(s) |
USEPA
/OPP PC Code: |
R-
enantiomer |
173584-44-6 |
[(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] |
067710 |
DPX-MP062
(Steward¨30%WG) |
173584-44-6 |
75:25
mixture of Indoxacarb and its R-enantiomer |
- |
DPX-KN
128 |
173584-44-6 |
Indoxacarb
METHYL 7-CHLORO-2,5-DIHYDRO-2-
{{(METHOXYCARBONYL){4-
(TRIFLUOROMETHOXY)PHENYL}AMINO}CARBONYL}-
INDENO{1,2-E}{1,3,4}OXADIAZINE-4A(3H)-CARBOXYLATE
California
Index Name:
INDENO{1,2-E}{1,3,4}OXADIAZINE-4A(3H)-CARBOXYLIC
ACID, 7-CHLORO-2,5-DIHYDRO-2-
{{(METHOXYCARBONYL){4-
(TRIFLUOROMETHOXY)PHENYL}AMINO}CARBONYL}-,
METHYL ESTER, (S)- (9CI) |
067710 |
DPX-JW062
(Steward¨30%WG) |
- |
Contains
50% Indoxacarb
- Ref: DuPont MSDS |
- |
IN-MK638 |
82971-90-2 |
UREA,
[4-(TRIFLUOROMETHOXY)PHENYL]-
(CAS NAME) (METABOLITE OF INDOXACARB) |
667710 |
IN-MK643
|
None
available as of April 2003 |
DIHYDRO-5-(TRIFLUOROMETHOXY)-2H-BENZIMIDAZOL-2-
ONE
(METABOLITE OF INDOXACARB) |
667711 |
Anemia
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A mammalian chronic
feeding Lowest Observable Effect Concentration (LOEC) Ms. was
exceeded at the highest predicted vegetation residue level. Residue
levels under field conditions will be lower as no foliar precipitation
wash-off or dilution due to growth was factored into the screening
modeling. Furthermore, the most sensitive reported end points
are used for the Department's risk assessments. In this case the
threshold exceeded was for hemolytic
effects, specifically anemia. While
these effects would reduce an individual animal's fitness should
they feed exclusively on treated vegetation, lethal or reproductive
effect thresholds are not reached and population level effects
are unlikely.
Ref: March 21, 2002 letter from N.Y. State
Department of Conservation, Division of Solid & Hazardous Materials,
Bureau of Pesticides Management Pesticide, Product Registration
Section to E.I. du Pont de Nemours and Company, Inc. Re: Registration
of DuPontTM Avaunt® Insecticide (EPA Reg. No. 352-597) Containing
the New Active Ingredient Indoxacarb.
http://www.fluoridealert.org/pesticides/Indoxacarb.NY.Mar.21.2002.htm
-- **52425-047 162215 "Chronic
Toxicity Study of DPX-JW062-106 (50% DPX-KN128, 50% DPX-KN127)
One Year Feeding Study in Dogs" (Mertens, J. 831-WIL Research
Laboratories, Inc. Ashland, Ohio. Study HLO 885-96, 11/19/97).
DPX-JW062-106 technical (Batch DPX-JW062- 106, 47.5% DPX-KN128)
was administered orally (via the feed) to 5 Beagle dogs/sex/dose
at levels of 0, 40, 80, 640 and 1280 ppm for 52 weeks. There was
a treatment-related decrease in body weight, body weight gain
and food consumption in 1280 ppm dogs during the first three months
of the study. Reduced mean hemoglobin, RBC count and hematocrit
was noted in the 80, 640 and 1280 ppm groups during all periods
tested; increased Heinz bodies in these groups indicated hemolysis.
Increased mean reticulocyte counts and MCV and decreased corpuscular
hemoglobin concentration, erythrocyte morphologic changes and
increased mean platelet counts indicated responses to hemolytic
anemia. Significantly decreased RBC counts were also reported
in 40 ppm males at week 25 and 51. Females at 40 ppm also showed
reductions in RBC, but the differences were not statistically
significant. Mean liver weights were increased in males (640 and
1280 ppm groups) and females (1280 ppm only). Microscopic changes
in groups 40 ppm and above included increased pigment (hemosiderin)
in liver Kupffer cells, kidney tubule epithelium, spleen and bone
marrow and increased extramedullary hematopoiesis in the spleen
and bone marrow hyperplasia. NOEL (M/F)=40 ppm (males: 1.1 mg/kg/day;
females: 1.3 mg/kg/day based on biologically
significant hemolytic anemia at 80 ppm and above). Acceptable.
Kellner, 1/12/99.
Ref: March 11, 1999: Summary
of Toxicology Data - Indoxycarb.
California EPA Department of Pesticide Regulation, Medical Toxicology
Branch.
http://www.fluorideaction.org/pesticides/indoxacarb.ca.epa.1999.pdf
Ataxia
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In a subchronic neurotoxicity
study in rats, there was no evidence of neurotoxicity at 11.9
and 6.09 mg/kg/day, the highest dose tested for males and females,
respectively. The standard subchronic rat study showed equivocal
evidence of neurotoxicity (i.e., ataxia
and tremors) but only in moribund
animals.
Ref: Federal Register: April 16, 1998 [Page
18912-18919]. Notice of Filing of Pesticide Petitions.
http://www.fluoridealert.org/pesticides/DPX-MP062.FR.Apr16.1998.htm
Blood
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-- The
substance causes damage to haemoglobin, resulting in an increased
turn over of red blood cells. At low exposure levels, some
fluctuations in isolated red blood cell parameters were observed,
which are of unclear biological significance and may be incidental.
Based on a weight of evidence consideration of all available short
and long term studies an overall NOEL of 10 ppm or 0.6 mg/kg was
proposed for the effects on blood parameters in rats. The U.S.
EPA has recently reached a similar conclusion and selected 40
ppm as a NOEL.
-- The haemosiderin deposits in spleen and liver, and spleen and
bone marrow hyperplastic response should be considered to be secondary
physiological responses to the increased RBC turn over.
The very shallow dose-response curve also indicates that the compensatory
mechanism of the haemopoietic system was not overcome (except
at high doses in the dog) and the effect of indoxacarb in rats
and dogs can be described as a compensated
haemolytic effect.
July
18, 2002: Opinion of the Scientific Committee on Plants on specific
questions from the Commission concerning the evaluation of Indoxacarb.
European Commission. Health & Consumer Protection Directorate-General.
http://www.fluorideaction.org/pesticides/indoxacarb.eu.july.18.2002.pdf
-- 90-Day oral toxicity
in nonrodents. DPX-JW062 NOAEL = 5.0 mg/kg/day LOAEL = 19 mg/kg/
day based on hemolytic anemia, as
indicated by decrease in HGB, 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);
increase in splenic EMH; and RBC hyperplasia in
bone marrow
in dogs
-- 21/28-Day dermal toxicity. DPX-MP062 NOAEL = 2,000 mg/kg/ day
LOAEL = < 2,000 mg/ kg/day in rats DPX-MP062 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 (increased reticulocytes),
the spleen (increased absolute and relative
weight M only, gross discoloration), clinical
signs of toxicity in both sexes in rats.
-- Chronic toxicity rodents. DPX-JW062
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
-- Chronic toxicity dogs. DPX-JW062
NOAEL = M 2.3, F 2.4 mg/kg/day LOAEL = M 18, F 19 mg/kg/day based
on decreased HCT, HGB nd 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
Ref: Federal Register: July 18, 2002. Indoxacarb;
Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluoridealert.org/pesticides/Indoxacarb.FR.July.18.2002.htm
Body
Weight Decrease
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In an acute neurotoxicity study in rats, alteration of some FOB
(functional observational battery) parameters (males) and in motor
activity (females) were observed at the highest dose associated
with, and possibly due to, general toxicity (reduced
body weight and body weight gain, decreased food intake,
alopecia etc). Reduced body weight gain
in males, and reduced food consumption and alopecia in
females were also observed in the mid dose. The NOAEL in this
study was 25 mg/kg bw in males and 12.5 mg/kg bw in females.
July 18, 2002: Opinion of the Scientific
Committee on Plants on specific questions from the Commission
concerning the evaluation of Indoxacarb. European Commission.
Health & Consumer Protection Directorate-General.
http://www.fluorideaction.org/pesticides/indoxacarb.eu.july.18.2002.pdf
-- 90-Day oral toxicity
rodents. DPX-MP062 NOAEL = M 3.1 milligrams/ kilogram/day (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.
-- 21/28-Day dermal toxicity. DPX-MP062 NOAEL = 2,000 mg/kg/ day
LOAEL = < 2,000 mg/ kg/day in rats DPX-MP062 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 (increased reticulocytes), the spleen (increased absolute
and relative weight M only, gross discoloration), clinical signs
of toxicity in both sexes in rats.
-- Prenatal developmental in rodents. DPX-MP062 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 DPX-JW062 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 DPX-JW062
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 = 2.2 mg/kg/ day based on decreased
fetal body weights
-- Prenatal developmental
in nonrodents. DPX-JW062 -
rabbits Maternal NOAEL = 500 mg/kg/ day LOAEL = 1,000 mg/kg/ day
based on slight decreases in maternal body weight gain and food
consumption Developmental NOAEL = 500 mg/kg/ day LOAEL = 1,000
mg/kg/ day based on decreased fetal body
weights and reduced ossification of the sternebrae
-- Reproduction and fertility effects.
DPX-JW062 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 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 decrease in the
body weights of the F1 pups during lactation.
-- Chronic toxicity rodents.
DPX-JW062 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
-- Carcinogenicity mice.
DPX-JW062 NOAEL = M 2.6, F 4.0 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
-- DPX-MP062 No evidence of mutagenic activity at the following
concentration range: 1.56-200 [mu]g/mL; cytotoxicity
was seen at concentrations of >100 [mu]g/mL DPX-JW062 No
evidence of mutagenic activity at the following concentration
range: 0.1-50 [mu]g/mL, cytotoxicity observed
at >50 [mu]g/mL
-- Acute neurotoxicity
screening battery. DPX-MP062 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, body weight gain, and food
consumption DPX-JW062
NOAEL > M 2,000 mg/ kg = F > 500 mg/kg LOAEL > M 2,000 mg/ kg
= F > 500 mg/kg based on clinical signs, decreased
body weight gains and food consumption,
and FOB effects
-- Subchronic
neurotoxicity screening battery. DPX-MP062NOAEL
= 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
Ref: Federal Register: July 18, 2002. Indoxacarb;
Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluoridealert.org/pesticides/Indoxacarb.FR.July.18.2002.htm
28-Day dermal toxicity
-- rats: DPX--MP062 / 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 (increased reticulocytes), the spleen (increased absolute
and relative weight M only, gross discoloration), clinical signs
of toxicity in both sexes in rats.
Ref: Federal Register: September
29, 2000. Indoxacarb; Pesticide Tolerance. Final Rule.
http://www.epa.gov/EPA-PEST/2000/September/Day-29/p25052.htm
In a 2-generation rat
reproduction study, the parental NOEL was 1.3 and 1.5 mg/kg/day
for males and females, respectively. The parental NOEL was based
on observations of reduced weight gain and
food consumption for the higher concentration groups of the F0
generation and potential treatment-related changes in spleen
weights for the higher groups of the F1 generation.
Ref: Federal Register: April 16, 1998 [Page
18912-18919]. Notice of Filing of Pesticide Petitions.
http://www.fluoridealert.org/pesticides/DPX-MP062.FR.Apr16.1998.htm
Bone
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-- 90-Day oral toxicity
in dogs: NOAEL = 5.0 mg/kg/day nonrodents-- LOAEL = 19 mg/kg/
day based on hemolytic anemia, as indicated by decreased in HGB,
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.
-- Chronic toxicity- dogs. 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; increased
Heinz bodies and reticulocytes and associated secondary microscopic
changes in the liver, kidneys, spleen, and bone
marrow; increased absolute and relative liver weights.
-- Prenatal developmental in nonrodents--rabbitts. Developmental
NOAEL = 500 mg/kg/ day LOAEL = 1,000 mg/kg/day based on decr.
fetal body weights and reduced ossification
of the sternebrae.
Ref: Federal
Register. September 29, 2000. Indoxacarb; Pesticide Tolerance.
Final Rule.
http://www.fluoridealert.org/pesticides/Indoxacarb.FR.Sept.2000.htm
COMBINED, RAT **52425-054 162226
"Combined Chronic Toxicity/Oncogenicity Study with DPX-JW062-106
(50% DPX-KN128, 50% DPX-KN127) Two-Year Feeding Study in Rats"
(Frame, S. 835-E. I. du Pont de Nemours and Company, Haskell Laboratory,
Elkton Road, Newark, Delaware, Study HLR 1174-96, 11/19/97). DPX-JW062-106
technical (Batch DPX-JW062-106, 47.5% DPX-KN128) was given
in the diet daily to males at 0, 20, 40, 60, 125 or 250 ppm and
females at 0, 10, 20, 40, 60 or 125 ppm for 24 months. Deaths
of one female at 60 ppm and seven at 125 ppm during the first
year were associated with bone marrow atrophy,
splenic lymphoid depletion and thymic necrosis. Decreases in mean
body weight/weight gain in males at 125 and 250 ppm and females
at 60 and 125 ppm correlated with decreased food consumption.
Hemolytic anemia at 60 ppm and above (males) and 40 ppm and above
(females): RBC mass, hemoglobin and hematocrit were decreased
and linked with increased reticulocyte counts and increased MCV.
Bone marrow regenerative response was increased
bone marrow hyperplasia in the one-year interim sacrifice
125 ppm females. Spleen weights were increased in both sexes at
the respective high-dose levels and other non-neoplastic changes
were secondary physiological responses to test substance-related
hemolysis; increased pigment observed within the Kupffer cells
of female livers (125 ppm) and the macrophages of the spleen (both
sexes at 60 ppm and above) indicated increased RBC turnover. Increased
hematopoiesis was reported in the spleen of interim sacrifice
males at 125 ppm and above and in the bone
marrow of high-dose males and females. After two years,
secondary changes were seen in the
liver, spleen, bone marrow, kidneys
and thymus in high dose groups. Increased pigment was observed
in the Kupffer cells of female livers at 40 ppm and above; in
males, increases were noted at 250 ppm only. Increased splenic
pigment was seen in all compound-treated male groups and in females
at 60 ppm and above; a slight increase in splenic congestion was
seen in 250 ppm males. No evidence of an oncogenic effect was
reported. NOEL(M)= 40 ppm; (F)=20 ppm (M: 1.59 mg/kg/day; F: 1.04
mg/kg/day based on hemolytic anemia). Acceptable. Kellner, 1/29/99.
-- -- **52425-047 162215 "Chronic
Toxicity Study of DPX-JW062-106 (50% DPX-KN128, 50% DPX-KN127)
One Year Feeding Study in Dogs"
(Mertens, J. 831-WIL Research Laboratories, Inc. Ashland, Ohio.
Study HLO 885-96, 11/19/97). DPX-JW062-106 technical (Batch DPX-JW062-
106, 47.5% DPX-KN128) was administered orally (via the feed) to
5 Beagle dogs/sex/dose at levels of 0, 40, 80, 640 and 1280 ppm
for 52 weeks. There was a treatment-related decrease in body weight,
body weight gain and food consumption in 1280 ppm dogs during
the first three months of the study. Reduced mean hemoglobin,
RBC count and hematocrit was noted in the 80, 640 and 1280 ppm
groups during all periods tested; increased Heinz bodies in these
groups indicated hemolysis. Increased mean reticulocyte counts
and MCV and decreased corpuscular hemoglobin concentration, erythrocyte
morphologic changes and increased mean platelet counts indicated
responses to hemolytic anemia. Significantly decreased RBC counts
were also reported in 40 ppm males at week 25 and 51. Females
at 40 ppm also showed reductions in RBC, but the differences were
not statistically significant. Mean liver weights were increased
in males (640 and 1280 ppm groups) and females (1280 ppm only).
Microscopic changes in groups 40 ppm and above included increased
pigment (hemosiderin) in liver Kupffer cells, kidney tubule epithelium,
spleen and bone marrow and increased
extramedullary hematopoiesis in the spleen and bone
marrow hyperplasia. NOEL (M/F)=40
ppm (males: 1.1 mg/kg/day; females: 1.3 mg/kg/day based on biologically
significant hemolytic anemia at 80 ppm and above). Acceptable.
Kellner, 1/12/99.
-- -- ** 036; 162201; "Subchronic Oral Toxicity:90-Day Study
with DPX-JW062-106 (Approximately 50% DPX-KN128, 50% DPX-KN127)
Feeding Study in Dogs" (Mertens, J.J.W.M., WIL Research Laboratories,
Inc., Ashland, OH, Haskell Laboratory Project ID: HLO 494-95,
Performing Laboratory Project ID: WIL-189016, 11/19/97). 821.
DPX-JW062 Technical (Batch No. DPX-JW062- 106, 47.5% DPX-KN128)
was admixed to the feed at concentrations of 0, 40, 80, 160, or
640 ppm (0, 1, 2, 5, or 18 mg/kg/day, respectively, for males,
and 0, 1, 3, 5, or 17 mg/kg/day, respectively, for females) and
fed to 4 outbred beagle dogs per sex per dose level for 13 weeks.
No animals died during the study interval. No treatment-related
clinical signs were observed. Statistically significant and treatment-related
decreases in mean red blood cell and hemoglobin levels in males
at 160 and 640 ppm, and females at 640 ppm and statistically significant
and dose-related increases in mean cell volume in males beginning
at 160 ppm and in females beginning at 80 ppm and percent reticulocytes
in males at 640 ppm and in females at 160 and 640 ppm were observed.
Treatment-related increases in Heinz bodies and mean total bilirubin
levels were observed in males and females at 160 and 640 ppm.
Microscopic examination revealed a treatment-related increase
in pigment in the spleen beginning in males at 40 ppm and in females
at 80 ppm, increased extramedullary hematopoiesis in the spleen
beginning in males and females at 160 ppm, treatment-related erythrocytic
hyperplasia and an increase in pigment in
the bone marrow in males beginning at 80 ppm and in females beginning
at 40 ppm, and a treatment-related increase in pigment
in the liver in males and females beginning at 80 ppm. No adverse
effects. NOEL (M/F)< 1 mg/kg/day (40 ppm) (based on a treatment-related
increase in pigment in the spleen in males, and on a treatment-related
increase in extramedullary
hematopoiesis in the spleen,
and treatment-related erythrocytic hyperplasia and a treatment-related
increase in pigment in the bone marrow in
females). Acceptable. (Corlett, 2/10/99)
Ref: March 11, 1999: Summary
of Toxicology Data - Indoxycarb.
California EPA Department of Pesticide Regulation, Medical Toxicology
Branch.
http://www.fluorideaction.org/pesticides/indoxacarb.ca.epa.1999.pdf
The haemosiderin deposits in spleen and
liver, and spleen and bone marrow
hyperplastic response should be considered to be secondary
physiological responses to the increased RBC turn over. The very
shallow dose-response curve also indicates that the compensatory
mechanism of the haemopoietic system was not overcome (except
at high doses in the dog) and the effect of indoxacarb in rats
and dogs can be described as a compensated haemolytic effect.
July 18, 2002: Opinion of the Scientific
Committee on Plants on specific questions from the Commission
concerning the evaluation of Indoxacarb. European Commission.
Health & Consumer Protection Directorate-General.
http://www.fluorideaction.org/pesticides/indoxacarb.eu.july.18.2002.pdf
Brain
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•
Pyrazoline-type insecticides (PTIs) are potent neurotoxicants
that cause cessation of feeding, abnormal movement, and paralysis
in arthropods. Indoxacarb,
the first insecticide in this class to achieve commercial registration,
is a proinsecticide that is selectively activated in insects to
form the insecticidal N-decarbomethoxyllated metabolite, DCJW
is another pyrazoline-type compound that is an effective insecticide
but was not registered for use due to its unacceptable mammalian
toxicity ([Meier et al., 1992], [Silver and Soderlund, 2005a]
and [Silver and Soderlund, 2005b]).
Ref: Silver KS, Soderlund DM (2007). Point
mutations at the local anesthetic receptor site modulate the state-dependent
block of rat Nav1.4 sodium channels by pyrazoline-type insecticides.
NeuroToxicology 28:3 655-663. (Available at ScienceDirect.)
•
See also: Action of pyrazoline-type insecticides at neuronal
target sites. Silver
KS, Soderlund DM (2007). Pesticide Biochemistry and Physiology
81:2 136-143. (Available at ScienceDirect.)
52425-040
162205 "Oncogenicity Study with DPX-JW062-106 (50% DPX-KN128,
50% DPX-KN127) Eighteen-Month Feeding Study in Mice" (Frame,
S. 832-E. I. du Pont de Nemours and Company, Haskell Laboratory,
Elkton Road, Newark, Delaware, Study HLR 799-96, 3/24/97). DPX-JW062-106
technical (Batch DPX-JW062-106, approximately 48% DPX-KN128)
was given in the diet daily to 70 Crl:CD ¨ -1(ICR)BR mice/sex/dose
at 0, 20, 100, or 125/150/200 ppm for 18 months (200 ppm level
reduced to 150 ppm on day 126 and to 125 ppm on day 287 due to
excessive mortality). The cause of death was either central nervous
system disorder (determined from clinical signs of abnormal gait/mobility
and head tilt) or heart inflammation/ necrosis (males only) ...
Non-neoplastic changes were noted in the brain
of both sexes and in the heart of males only of mice that died
or were sacrificed in extremis. Neuronal
necrosis was reported in two high-dose males and two females
and in one female at 100 ppm. Both high-dose males were sacrificed
in extremis, one while receiving the 150 ppm diet (day 133) and
the other while receiving the 125 ppm diet (test day 302). The
two affected females died or were killed in extremis (day 83 and
108, respectively) while receiving 200 ppm.
Residual vacuolation of the piriform cortex was observed in 2
female high-dose mice that survived to the 18-month scheduled
sacrifice.
Ref: March
11, 1999: Summary
of Toxicology Data - Indoxycarb.
California EPA Department of Pesticide Regulation, Medical Toxicology
Branch.
http://www.fluorideaction.org/pesticides/indoxacarb.ca.epa.1999.pdf
Based on animal data
from DPX-JW062 (50% KN128
[Indoxacard], Active Ingredient), the following chronic effects
may occur in animals with DPX-MP062.
Ingestion of DPX-JW062 by dogs for one-year caused hemolytic
anemia with secondary histopathological changes and decreased
body weights. The NOEL for both male and female dogs was 40 ppm.
Effects in male and female rats that were fed DPX-JW062 in their
diets for two-years include decreased body weight, in addition
females also had some hemolysis. The NOEL for the two-year rat
feeding study was 60 ppm for male rats and 40 ppm for female rats.
Male and female mice fed DPX-JW062 for eighteen months had decreased
body weight, in addition females showed signs of neurotoxicity,
some mortality, and a few incidences of histopathologic
changes in the brain (probably secondary to seizures).
The NOEL for the eighteen month mouse feeding study was 20 ppm
in male and female mice.
Ref: Dupont's Material Safety Data Sheet
for STEWARD insecticide. January 2001.
http://www.fluoridealert.org/pesticides/DPX-MP062.MSDS.STEWARD.htm
Abstract: Indoxacarb is a newly developed insecticide with high
insecticidal activity and low toxicity to non-target organisms.
Its metabolite, DCJW, is known to block compound action potentials
in insect nerves and to inhibit sodium currents in cultured insect
neurons. However, little is known about the effects of these compounds
on the sodium channels of mammalian neurons. We compared the effects
of indoxacarb and DCJW on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant
(TTX-R) sodium channels in rat dorsal root ganglion neurons by
using the whole-cell patch clamp technique. Indoxacarb and DCJW
at 1-10 microM slowly and irreversibly blocked both TTX-S and
TTX-R sodium channels in a voltage-dependent manner. The sodium
channel activation kinetics were not significantly modified by
1 microM indoxacarb or 1 microM DCJW. The steady-state fast and
slow inactivation curves were shifted in the hyperpolarization
direction by 1 microM indoxacarb or 1 microM DCJW indicating a
higher affinity of the inactivated sodium channels for these insecticides.
These shifts resulted in an enhanced block at more depolarized
potentials, thus explaining voltage-dependent block, and an apparent
difference in the sensitivity of TTX-R and TTX-S channels to indoxacarb
and DCJW near the resting potential. Indoxacarb
and its metabolite DCJW cause toxicity through their action on
the sodium channels.
Ref: Zhao X et al. (2003).
Voltage-dependent block of sodium channels in mammalian neurons
by the oxadiazine insecticide indoxacarb and its metabolite DCJW.
Neurotoxicology. Jan;24(1):83-96.
Abstract: The effects of the oxadiazine insecticide
indoxacarb and its N-decarbomethoxylated
metabolite (DCJW) on tetrodotoxin-resistant (TTX-R)
voltage-gated sodium channels in rat dorsal
ganglion neurons were studied using the whole-cell patch
clamp technique. Indoxacarb and DCJW suppressed
the peak amplitude of action potentials, and DCJW exhibited a
faster time course and higher potency than indoxacarb in the blocking
effects. In voltage-clamp experiments, indoxacarb and DCJW suppressed
TTX-R sodium currents in a time-dependent manner without a steady-state
level of suppression. IC50 values for indoxacarb and DCJW on TTX-R
sodium currents were estimated to be 10.7 and 0.8 microM after
25 min of bath application, respectively. DCJW was about 10 times
more potent than indoxacarb in blocking TTX-R sodium currents.
Although the suppressive effects of indoxacarb were partially
reversible after washout with drug-free external solution, no
recovery of sodium current was observed in DCJW treated neurons
after prolonged washout. In current-voltage relationships, both
indoxacarb and DCJW blocked the sodium currents to the same degree
in the entire range of membrane potentials. The sodium conductance-voltage
curve was not shifted along the voltage axis by indoxacarb and
DCJW at 10 microM. In contrast, the steady-state inactivation
curves were shifted in the hyperpolarizing direction by indoxacarb
as well as by DCJW. Based on these results, it was concluded that
indoxacarb and DCJW potently blocked the TTX-R sodium channel
in rat DRG neurons with hyperpolarizing shifts of the steady-state
inactivation curves, suggesting preferential association of the
insecticides to the inactivated state of sodium channels.
The small structural variation between indoxacarb
and DCJW resulted in clear differences in potency for blocking
sodium channels and reversibility after washout.
Ref: Tsurubuchi Y, Kono Y (2003).
Modulation of sodium channels by the oxadiazine insecticide indoxacarb
and its N-decarbomethoxylated metabolite in rat dorsal root ganglion
neurons. Pest Manag Sci. Sep;59(9):999-1006.
CNS
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52425-040
162205 "Oncogenicity Study with DPX-JW062-106 (50% DPX-KN128,
50% DPX-KN127) Eighteen-Month Feeding Study in Mice" (Frame,
S. 832-E. I. du Pont de Nemours and Company, Haskell Laboratory,
Elkton Road, Newark, Delaware, Study HLR 799-96, 3/24/97). DPX-JW062-106
technical (Batch DPX-JW062-106, approximately 48% DPX-KN128)
was given in the diet daily to 70 Crl:CD ¨ -1(ICR)BR mice/sex/dose
at 0, 20, 100, or 125/150/200 ppm for 18 months (200 ppm level
reduced to 150 ppm on day 126 and to 125 ppm on day 287 due to
excessive mortality). The cause of death was either central
nervous system disorder (determined from clinical signs
of abnormal gait/mobility and head tilt) or heart inflammation/
necrosis (males only). Non-neoplastic changes were noted in the
brain of both sexes and in the heart of males only of mice that
died or were sacrificed in extremis. Neuronal necrosis was reported
in two high-dose males and two females and in one female at 100
ppm. Both high-dose males were sacrificed in extremis, one while
receiving the 150 ppm diet (day 133) and the other while receiving
the 125 ppm diet (test day 302). The two affected females died
or were killed in extremis (day 83 and 108, respectively) while
receiving 200 ppm. Residual vacuolation of the piriform cortex
was observed in 2 female high-dose mice that survived to the 18-month
scheduled sacrifice.
Ref: March
11, 1999: Summary
of Toxicology Data - Indoxycarb.
California EPA Department of Pesticide Regulation, Medical Toxicology
Branch.
http://www.fluorideaction.org/pesticides/indoxacarb.ca.epa.1999.pdf
Neurotoxicity was present in both rats
and mice; however, it did not occur in the absence of other
signs of toxicity. Neurotoxicity was characterized by one or more
of the following symptoms in both male and female rats and mice:
weakness, head tilting, and abnormal gait
or mobility with inability to stand, ataxia. Acute and
subchronic neurotoxicity screening batteries were performed using
DPX-MP062 in rats. Neurotoxicity was characterized by clinical
signs (depression, abnormal gait, head shake,
salivation) and functional-observation battery (FOB) (circling
behavior, incoordination, slow righting reflex, decreased forelimb
grip strength, decreased foot splay, decreased motor activity).
However, there was no evidence of neurohistopathology in any study.
Learning and memory parameters were affected
in the pups in the developmental neurotoxicity study in
rats with DPX-KN128.
Ref: USEPA. May 23,
2007. Indoxacarb. Health Effects Division (HED) Risk Assessment
for Grapes; Vegetable, Brassica, Leafy, Group 5; Turnip Greens;
Vegetable, Leafy, Except Brassica (Group 4); Pome Fruits (Group
11, except pear); Tuberous and Corm Vegetables (Subgroup 1C);
Cucurbit Vegetables (Group 9); Stone Fruits (Group 12); Cranberry;
Mint; Okra; Southern Pea; and Fire Ant Bait.
http://www.fluoridealert.org/pesticides/EPA-HQ-OPP-2005-0149-0005.pdf
Cytotoxic
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--
DPX-MP062 No evidence of mutagenic activity at the following concentration
range: 1.56-200 [mu]g/mL; cytotoxicity was
seen at concentrations of >100 [mu]g/mL DPX-JW062 No evidence
of mutagenic activity at the following concentration range: 0.1-50
[mu]g/mL, cytotoxicity observed at >50 [mu]g/mL
Ref: Federal Register: July 18, 2002. Indoxacarb;
Pesticide Tolerance. Final Rule. Federal Register. http://www.fluoridealert.org/pesticides/Indoxacarb.FR.July.18.2002.htm
Developmental
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-- Developmental neurotoxicity - rat. 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.
Ref: USEPA. May 23, 2007. Indoxacarb. Health
Effects Division (HED) Risk Assessment for Grapes; Vegetable,
Brassica, Leafy, Group 5; Turnip Greens; Vegetable, Leafy, Except
Brassica (Group 4); Pome Fruits (Group 11, except pear); Tuberous
and Corm Vegetables (Subgroup 1C); Cucurbit Vegetables (Group
9); Stone Fruits (Group 12); Cranberry; Mint; Okra; Southern Pea;
and Fire Ant Bait.
http://www.fluoridealert.org/pesticides/EPA-HQ-OPP-2005-0149-0005.pdf
Endocrine:
Thymus
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**52425-054 162226 "Combined Chronic Toxicity/Oncogenicity
Study with DPX-JW062-106 (50% DPX-KN128, 50% DPX-KN127) Two-Year
Feeding Study in Rats" (Frame, S. 835-E. I. du Pont de Nemours
and Company, Haskell Laboratory, Elkton Road, Newark, Delaware,
Study HLR 1174-96, 11/19/97). DPX-JW062-106 technical (Batch DPX-JW062-106,
47.5% DPX-KN128) was given in the diet daily to males at 0, 20,
40, 60, 125 or 250 ppm and females at 0, 10, 20, 40, 60 or 125
ppm for 24 months. Deaths of one female at 60 ppm and seven at
125 ppm during the first year were associated with bone marrow
atrophy, splenic lymphoid depletion and
thymic necrosis... After two years, secondary changes were
seen in the liver, spleen, bone marrow, kidneys and thymus
in high dose groups.
Ref: March 11, 1999: Summary
of Toxicology Data - Indoxycarb.
California EPA Department of Pesticide Regulation, Medical Toxicology
Branch.
http://www.fluorideaction.org/pesticides/indoxacarb.ca.epa.1999.pdf
Heart
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**52425-040 162205 "Oncogenicity Study with DPX-JW062-106
(50% DPX-KN128, 50% DPX-KN127) Eighteen-Month Feeding Study in
Mice" (Frame, S. 832-E. I. du Pont de Nemours and Company,
Haskell Laboratory, Elkton Road, Newark, Delaware, Study HLR 799-96,
3/24/97). DPX-JW062-106 technical (Batch DPX-JW062-106, approximately
48% DPX-KN128) was given in the diet daily to 70 Crl:CD ¨ -1(ICR)BR
mice/sex/dose at 0, 20, 100, or 125/150/200 ppm for 18 months
(200 ppm level reduced to 150 ppm on day 126 and to 125 ppm on
day 287 due to excessive mortality). The
cause of death was either central nervous system disorder
(determined from clinical signs of abnormal gait/mobility and
head tilt) or heart inflammation/ necrosis
(males only)... Red fluid in plural cavity
noted after gross necropsy corresponded with heart
lesions in high-dose males (e.g., necrosis, hemorrhage
and inflammation)... Non-neoplastic changes were noted in the
brain of both sexes and in the heart of
males only of mice that died or were sacrificed in extremis...
NOEL(M/F)=20 ppm (M: 2.63 mg/kg/day based on neurotoxicity, heart
lesions at 125 ppm and decreased body weight gain at 100
ppm; F: 3.99 mg/kg/day based on neurotoxicity at 100 and 125 ppm).
Ref: March 11, 1999: Summary
of Toxicology Data - Indoxycarb.
California EPA Department of Pesticide Regulation, Medical Toxicology
Branch.
http://www.fluorideaction.org/pesticides/indoxacarb.ca.epa.1999.pdf
Kidney
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-- **52425-047 162215 "Chronic
Toxicity Study of DPX-JW062-106 (50% DPX-KN128, 50% DPX-KN127)
One Year Feeding Study in Dogs"
(Mertens, J. 831-WIL Research Laboratories,
Inc. Ashland, Ohio. Study HLO 885-96, 11/19/97). DPX-JW062-106
technical (Batch DPX-JW062- 106, 47.5% DPX-KN128) was administered
orally (via the feed) to 5 Beagle dogs/sex/dose at levels of 0,
40, 80, 640 and 1280 ppm for 52 weeks. There was a treatment-related
decrease in body weight, body weight gain and food consumption
in 1280 ppm dogs during the first three months of the study. Reduced
mean hemoglobin, RBC count and hematocrit was noted in the 80,
640 and 1280 ppm groups during all periods tested; increased Heinz
bodies in these groups indicated hemolysis. Increased mean reticulocyte
counts and MCV and decreased corpuscular hemoglobin concentration,
erythrocyte morphologic changes and increased mean platelet counts
indicated responses to hemolytic anemia. Significantly decreased
RBC counts were also reported in 40 ppm males at week 25 and 51.
Females at 40 ppm also showed reductions in RBC, but the differences
were not statistically significant. Mean liver weights were increased
in males (640 and 1280 ppm groups) and females (1280 ppm only).
Microscopic changes in groups 40 ppm and above included increased
pigment (hemosiderin) in liver Kupffer cells,
kidney tubule epithelium, spleen and bone marrow and increased
extramedullary hematopoiesis in the spleen and bone marrow hyperplasia.
NOEL (M/F)=40 ppm (males: 1.1 mg/kg/day; females: 1.3 mg/kg/day
based on biologically significant hemolytic anemia at 80 ppm and
above). Acceptable. Kellner, 1/12/99.
Ref: March 11, 1999: Summary
of Toxicology Data - Indoxycarb.
California EPA Department of Pesticide Regulation, Medical Toxicology
Branch.
http://www.fluorideaction.org/pesticides/indoxacarb.ca.epa.1999.pdf
Liver
(click
on for all fluorinated pesticides)
COMBINED, RAT **52425-054 162226
"Combined Chronic Toxicity/Oncogenicity Study with DPX-JW062-106
(50% DPX-KN128, 50% DPX-KN127) Two-Year Feeding Study in Rats"
(Frame, S. 835-E. I. du Pont de Nemours and Company, Haskell Laboratory,
Elkton Road, Newark, Delaware, Study HLR 1174-96,
11/19/97). DPX-JW062-106 technical (Batch DPX-JW062-106, 47.5%
DPX-KN128) was given in the diet daily to males at 0, 20, 40,
60, 125 or 250 ppm and females at 0, 10, 20, 40, 60 or 125 ppm
for 24 months. Deaths of one female at 60 ppm and seven at 125
ppm during the first year were associated with bone marrow atrophy,
splenic lymphoid depletion and thymic necrosis. Decreases in mean
body weight/weight gain in males at 125 and 250 ppm and females
at 60 and 125 ppm correlated with decreased food consumption.
Hemolytic anemia at 60 ppm and above (males) and 40 ppm and above
(females): RBC mass, hemoglobin and hematocrit were decreased
and linked with increased reticulocyte counts and increased MCV.
Bone marrow regenerative response was increased bone marrow hyperplasia
in the one-year interim sacrifice 125 ppm females. Spleen weights
were increased in both sexes at the respective high-dose levels
and other non-neoplastic changes were secondary physiological
responses to test substance-related hemolysis; increased
pigment observed within the Kupffer cells of female livers (125
ppm) and the macrophages of the spleen (both sexes at 60
ppm and above) indicated increased RBC turnover. Increased hematopoiesis
was reported in the spleen of interim sacrifice males at 125 ppm
and above and in the bone marrow of high-dose males and females.
After two years, secondary changes were seen in the
liver, spleen, bone marrow, kidneys and thymus in high
dose groups. Increased pigment was observed
in the Kupffer cells of female livers at 40 ppm and above;
in males, increases were noted at 250 ppm only. Increased
splenic pigment was seen in all compound-treated male groups and
in females at 60 ppm and above; a slight increase in splenic congestion
was seen in 250 ppm males. No evidence of an oncogenic effect
was reported. NOEL(M)= 40 ppm; (F)=20 ppm (M: 1.59 mg/kg/day;
F: 1.04 mg/kg/day based on hemolytic anemia). Acceptable. Kellner,
1/29/99.
Ref: March 11, 1999: Summary
of Toxicology Data - Indoxycarb.
California EPA Department of Pesticide Regulation, Medical Toxicology
Branch.
http://www.fluorideaction.org/pesticides/indoxacarb.ca.epa.1999.pdf
The haemosiderin deposits in spleen and liver,
and spleen and bone marrow hyperplastic response should be considered
to be secondary physiological responses to the increased RBC turn
over. The very shallow dose-response curve also indicates that
the compensatory mechanism of the haemopoietic system was not
overcome (except at high doses in the dog) and the effect of indoxacarb
in rats and dogs can be described as a compensated haemolytic
effect.
July 18, 2002: Opinion of the Scientific
Committee on Plants on specific questions from the Commission
concerning the evaluation of Indoxacarb. European Commission.
Health & Consumer Protection Directorate-General.
http://www.fluorideaction.org/pesticides/indoxacarb.eu.july.18.2002.pdf
Lung
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--
There was possible evidence of lung damage in the acute inhalation
studies with both DPXMP062 and DPX-JW062. “Lung noise,”
observed with JW062 may indicate the development
of acute lung injury and high permeability pulmonary edema.
This was not unexpected since an oxidant was generated during
indoxacarb metabolism. “Hunched over back and gasping”
were also present and suggested arterial hypoxemia that accompanies
alveolar flooding. The acute inhalation study report with indoxacarb
70% manufacturing use product, noted that a “red nasal discharge”
was detected for 2 days after exposure. This may be indicative
of a lung exudate, a sign of lung injury.
Ref: USEPA.
May 23, 2007. Indoxacarb. Health Effects Division (HED) Risk Assessment
for Grapes; Vegetable, Brassica, Leafy, Group 5; Turnip Greens;
Vegetable, Leafy, Except Brassica (Group 4); Pome Fruits (Group
11, except pear); Tuberous and Corm Vegetables (Subgroup 1C);
Cucurbit Vegetables (Group 9); Stone Fruits (Group 12); Cranberry;
Mint; Okra; Southern Pea; and Fire Ant Bait.
http://www.fluoridealert.org/pesticides/EPA-HQ-OPP-2005-0149-0005.pdf
Spleen
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on for all fluorinated pesticides)
COMBINED, RAT **52425-054 162226
"Combined Chronic Toxicity/Oncogenicity Study with DPX-JW062-106
(50% DPX-KN128, 50% DPX-KN127) Two-Year Feeding Study in Rats"
(Frame, S. 835-E. I. du Pont de Nemours and Company, Haskell Laboratory,
Elkton Road, Newark, Delaware, Study HLR 1174-96, 11/19/97). DPX-JW062-106
technical (Batch DPX-JW062-106, 47.5% DPX-KN128) was given in
the diet daily to males at 0, 20, 40, 60, 125 or 250 ppm and females
at 0, 10, 20, 40, 60 or 125 ppm for 24 months. Deaths of one female
at 60 ppm and seven at 125 ppm during the first year were associated
with bone marrow atrophy, splenic lymphoid
depletion and thymic necrosis.
Decreases in mean body weight/weight gain in males at 125 and
250 ppm and females at 60 and 125 ppm correlated with decreased
food consumption. Hemolytic anemia at 60 ppm and above (males)
and 40 ppm and above (females): RBC mass, hemoglobin and hematocrit
were decreased and linked with increased reticulocyte counts and
increased MCV. Bone marrow regenerative response was increased
bone marrow hyperplasia in the one-year interim sacrifice 125
ppm females. Spleen weights were increased
in both sexes at the respective high-dose levels and other
non-neoplastic changes were secondary physiological responses
to test substance-related hemolysis; increased pigment observed
within the Kupffer cells of female livers (125 ppm) and the macrophages
of the spleen (both sexes at 60 ppm and above) indicated
increased RBC turnover. Increased hematopoiesis was reported in
the spleen of interim sacrifice males at 125 ppm and above and
in the bone marrow of high-dose males and females. After
two years, secondary changes were seen in the liver, spleen, bone
marrow, kidneys and thymus in high dose groups. Increased
pigment was observed in the Kupffer cells of female livers at
40 ppm and above; in males, increases were noted at 250 ppm only.
Increased splenic pigment was seen in all compound-treated male
groups and in females at 60 ppm and above; a slight increase
in splenic congestion was seen in
250 ppm males. No evidence of an oncogenic effect was reported.
NOEL(M)= 40 ppm; (F)=20 ppm (M: 1.59 mg/kg/day; F: 1.04 mg/kg/day
based on hemolytic anemia). Acceptable. Kellner, 1/29/99.
-- **52425-047 162215 "Chronic
Toxicity Study of DPX-JW062-106 (50% DPX-KN128, 50% DPX-KN127)
One Year Feeding Study in Dogs"
(Mertens, J. 831-WIL Research Laboratories, Inc. Ashland, Ohio.
Study HLO 885-96, 11/19/97). DPX-JW062-106 technical (Batch DPX-JW062-
106, 47.5% DPX-KN128) was administered orally (via the feed) to
5 Beagle dogs/sex/dose at levels of 0, 40, 80, 640 and 1280 ppm
for 52 weeks... Microscopic changes in groups
40 ppm and above included increased pigment (hemosiderin) in liver
Kupffer cells, kidney tubule epithelium, spleen and bone marrow
and increased extramedullary hematopoiesis in the spleen and bone
marrow hyperplasia. NOEL (M/F)=40 ppm (males: 1.1 mg/kg/day;
females: 1.3 mg/kg/day based on biologically significant hemolytic
anemia at 80 ppm and above). Acceptable. Kellner, 1/12/99.
-- REPRODUCTION, RAT **52425-046
162214 "Two Generation Reproduction/Fertility Study
with DPX-JW062-106 in Rats" (Breslin, W. 834-MPI Research,
Mattawan, MI, Report# HLO 115-96, 11/3/97). DPX-JW062- 106 (Batch
no. DPX-JW062-106, 47.7% DPX-KN128, dissolved in acetone) was
administered orally via the feed to 26 Crl:CD ¨ VAF/Plus ¨ rats/sex/dose
at levels of 0, 20, 60, 100 ppm beginning 70 days prior to mating
and continuing until euthanasia for 2 generations... Necropsy
findings included increased spleen weights
in the F0 and F1 males at 100 ppm and in the F0 and F1 females
at 60 and 100 ppm. Maternal NOEL=
20 ppm (0.856-4.141 mg/kg/day, based on increased spleen weights
in females at 60 and 100 ppm). There were no apparent compound-related
effects on gonad function, estrous cycling or mating behavior
in either the F0 or F1 animals. In F1 females at 100 ppm, slight
decreases in fecundity and fertility index were noted. While mean
F1 pup weights in the 60 and 100 ppm groups were statistically
reduced during the lactation period, corresponding weights in
the F2 generation showed no compound-related effect. Developmental
NOEL= 20 ppm (based on decreased F1 pup weights during lactation
at 60 and 100 ppm). No Adverse Effects; decrease in F1 fecundity
and fertility indices were not statistically significant, not
seen during F0 mating and not accompanied by effects in sperm
or estrous cycle evaluations. Reproductive NOEL= 60 ppm (1.734-11.610
mg/kg/day; based on slight reduction in F1 fertility index at
100 ppm). Acceptable. Kellner,
-- ** 034; 162199; "Subchronic
Oral Toxicity:90-Day Study with DPX-MP062 (Approximately 75% DPX-KN128,
25% DPX-KN127) Feeding Study in Rats"
(MacKenzie, S.A., Haskell Laboratory for Toxicology and Industrial
Medicine, E.I. du Pont de Nemours and Company, Newark, DE, Laboratory
Project ID DuPont HL-1997-00056, 3/24/97). 821. DPX-MP062 (Batch
No. DPX-MP062- 51A, 74.7% DPX-KN128) was admixed to the feed at
concentrations of 0, 10, 25 (females only), 50, 100, or 200 (males
only) ppm (0, 0.620, 3.09, 6.01, or 15.0 mg/kg/day, respectively,
for males and 0, 0.760, 2.13, 3.78, or 8.94 mg/kg/day, respectively,
for females) and fed to 10 Crl:CD ¨ (SD)BR rats per sex per dose
level for approximately 90 days. 5 females at 100 ppm died or
were sacrificed in extremis. No dose-related clinical signs were
observed in males; among females at 100 ppm, ataxia (in 2 of the
mortalities), weakness (in 4 animals), and tremors (in 1 of the
mortalities) were observed. Treatment-related decreased mean body
weight and decreased mean body weight gain in males at 200 ppm
and in females at 50 and 100 ppm were observed. Statistically
significant and dose-related decreases in mean red blood cell,
hemoglobin, and hematocrit levels in males beginning at 100 ppm,
50 ppm, and 100 ppm, respectively, and in females beginning at
25 ppm, 10 ppm, and 10 ppm, respectively, were observed. Microscopic
examination revealed treatment-related increased
pigment and increased extramedullary hematopoiesis in the spleen
in males at 50, 100, and 200 ppm, and in females at all dose levels.
No adverse effects. NOEL (M)=0.620 mg/kg/day (10 ppm) and (F)<
0.760 mg/kg/day (10 ppm) [based on treatment-related decreased
mean hemoglobin (males and females) and hematocrit (females) levels
and histologic effects in the spleen).
Acceptable. (Corlett, 1/19/99
-- ** 035; 162200; "Subchronic
Oral Toxicity:90-Day Study with DPX-JW062-34 (50% DPX-KN128, 50%
DPX-KN127) Feeding Study in Mice"
[Malek, D.E., Haskell Laboratory for Toxicology and Industrial
Medicine, E.I. du Pont de Nemours and Company, Newark, DE, Haskell
Laboratory Report No. 750-93 (Revision No. 1), 1/22/97]. 821.
DPX-JW062-34 Technical (Batch No. DPX-JW062-34, 47.4% DPX-KN128)
was admixed to the feed at concentrations of 0, 10/300 (started
at 10 ppm and increased to 300 ppm on Day 42 of feeding), 35,
75, or 150 ppm (0, 1.7/44, 5.5, 12, or 23 mg/kg/day, respectively,
for males and 0, 2.1/51, 7.0, 16, or 30 mg/kg/day, respectively,
for females) and fed to 10 Crl:CD-1 ¨ (ICR)BR mice per sex per
dose level for approximately 90 days. One male at 300 ppm was
found dead on day 85. Treatment-related clinical signs included
animals leaning to one side (in males at 300 ppm and in females
at 150 and 300 ppm), abnormal gait or mobility (in females at
300 ppm), and tremors (in one male at 300 ppm). Treatment-related
decreases in mean body weight (in males at 300 ppm), mean body
weight gain (in males at 300 ppm), and mean daily food consumed
per mouse (in males at 300 ppm and in females at 150 and 300 ppm)
were observed. Treatment-related increases in mean reticulocyte
(in males and females at 300 ppm), mean cell volume (in males
at 300 ppm and in females at 150 and 300 ppm), and mean white
blood cell (in males and females at 300 ppm) levels, and the treatment-related
presence of Heinz bodies (in males and females at 150 and 300
ppm) were observed. Microscopic examination revealed treatment-related
increased pigment in the spleen in males
and females beginning at 75 ppm. No adverse effects. NOEL
(M)=5.5 mg/kg/day (35 ppm) and (F)=7.0 mg/kg/day (35 ppm) (based
on treatment-related increased pigment in the spleen).
Acceptable. (Corlett, 1/28/99)
-- ** 036; 162201; "Subchronic
Oral Toxicity:90-Day Study with DPX-JW062-106 (Approximately 50%
DPX-KN128, 50% DPX-KN127) Feeding Study
in Dogs" (Mertens, J.J.W.M., WIL Research Laboratories,
Inc., Ashland, OH, Haskell Laboratory Project ID: HLO 494-95,
Performing Laboratory Project ID: WIL-189016, 11/19/97). 821.
DPX-JW062 Technical (Batch No. DPX-JW062- 106, 47.5% DPX-KN128)
was admixed to the feed at concentrations of 0, 40, 80, 160, or
640 ppm (0, 1, 2, 5, or 18 mg/kg/day, respectively, for males,
and 0, 1, 3, 5, or 17 mg/kg/day, respectively, for females) and
fed to 4 outbred beagle dogs per sex per dose level for 13 weeks.
No animals died during the study interval. No treatment-related
clinical signs were observed. Statistically significant and treatment-related
decreases in mean red blood cell and hemoglobin levels in males
at 160 and 640 ppm, and females at 640 ppm and statistically significant
and dose-related increases in mean cell volume in males beginning
at 160 ppm and in females beginning at 80 ppm and percent reticulocytes
in males at 640 ppm and in females at 160 and 640 ppm were observed.
Treatment-related increases in Heinz bodies and mean total bilirubin
levels were observed in males and females at 160 and 640 ppm.
Microscopic examination revealed a treatment-related
increase in pigment in the spleen beginning in males at 40 ppm
and in females at 80 ppm, increased extramedullary hematopoiesis
in the spleen beginning in males and females at 160 ppm, treatment-related
erythrocytic hyperplasia and an increase in pigment in the bone
marrow in males beginning at 80 ppm and in females beginning at
40 ppm, and a treatment-related increase in pigment in the liver
in males and females beginning at 80 ppm. No adverse effects.
NOEL (M/F)< 1 mg/kg/day (40 ppm) (based on a
treatment-related increase in pigment in the spleen in males,
and on a treatment-related increase in
extramedullary hematopoiesis in the spleen, and treatment-related
erythrocytic hyperplasia and a treatment-related increase in pigment
in the bone marrow in females). Acceptable. (Corlett, 2/10/99)
Ref: March 11, 1999: Summary
of Toxicology Data - Indoxycarb.
California EPA Department of Pesticide Regulation, Medical Toxicology
Branch.
http://www.fluorideaction.org/pesticides/indoxacarb.ca.epa.1999.pdf
28-Day dermal toxicity
-- rats: DPX--MP062 / 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 (increased reticulocytes),
the spleen (increased
absolute and relative weight M only, gross discoloration),
clinical signs of toxicity in both sexes in rats.
Ref: Federal Register: September 29, 2000.
Indoxacarb; Pesticide Tolerance. Final Rule.
http://www.epa.gov/EPA-PEST/2000/September/Day-29/p25052.htm
In a 2-generation rat
reproduction study, the parental NOEL was 1.3 and 1.5 mg/kg/day
for males and females, respectively. The parental NOEL was based
on observations of reduced weight gain and food consumption for
the higher concentration groups of the F0 generation and potential
treatment-related changes in spleen weights
for the higher groups of the F1 generation.
Ref: Federal Register: April 16, 1998 [Page
18912-18919]. Notice of Filing of Pesticide Petitions.
http://www.fluoridealert.org/pesticides/DPX-MP062.FR.Apr16.1998.htm
The haemosiderin deposits in spleen and liver, and spleen and
bone marrow hyperplastic response should be considered to be secondary
physiological responses to the increased RBC turn over. The very
shallow dose-response curve also indicates that the compensatory
mechanism of the haemopoietic system was not overcome (except
at high doses in the dog) and the effect of indoxacarb in rats
and dogs can be described as a compensated haemolytic effect.
July 18, 2002: Opinion of the Scientific
Committee on Plants on specific questions from the Commission
concerning the evaluation of Indoxacarb. European Commission.
Health & Consumer Protection Directorate-General.
http://www.fluorideaction.org/pesticides/indoxacarb.eu.july.18.2002.pdf
Tremors
(click on for all fluorinated pesticides)
In a subchronic neurotoxicity
study in rats, there was no evidence of neurotoxicity at 11.9
and 6.09 mg/kg/day, the highest dose tested for males and females,
respectively. The standard subchronic rat study showed equivocal
evidence of neurotoxicity (i.e., ataxia
and tremors)
but only in moribund animals.
Ref: Federal Register: April 16, 1998 [Page
18912-18919]. Notice of Filing of Pesticide Petitions.
http://www.fluoridealert.org/pesticides/DPX-MP062.FR.Apr16.1998.htm
DPX-MP062
150SC in high single oral doses caused gait abnormalities, incoordination,
hypoactivity, convulsions,
tremors, hypothermia, hair loss, labored respiration, ocular
discharge, and vocalization in rats.
Ref: Dupont's Material Safety Data Sheet
for STEWARD insecticide. January 2001.
http://www.fluoridealert.org/pesticides/DPX-MP062.MSDS.STEWARD.htm
Environmental
(click on for all fluorinated pesticides)
--
Toxicity to Aquatic Animals - Indoxacarb,
its R-enantiomer and degradates are "moderately to
very highly toxic" to freshwater and estuarine/marine
fish on an acute basis with LC50 s ranging from 0.024 to
> 1.3 mg/L. These same compounds are
"moderately toxic" to "very highly toxic"
freshwater and estuarine/marine invertebrates on
an acute basis with EC50 s 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.
-- 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.
Ref: US EPA. Pesticide Fact
Sheet. Indoxacarb Reason for Issuance: Conditional Registration
Date Issued: October 30, 2000.
http://www.epa.gov/opprd001/factsheets/indoxacarb.pdf
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