Adverse Effects
Indoxacarb
CAS No. 173584-44-6

 
 

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 (click on for all fluorinated pesticides)

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 (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

Blood (click on for all fluorinated pesticides)

-- 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 (click on for all fluorinated pesticides)

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 (click on for all fluorinated pesticides)

-- 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 (click on for all fluorinated pesticides)

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 (click on for all fluorinated pesticides)

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 (click on for all fluorinated pesticides)

-- 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 (click on for all fluorinated pesticides)

-- 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 (click on for all fluorinated pesticides)

**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 (click on for all fluorinated pesticides)

**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 (click on for all fluorinated pesticides)

-- **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 (click on for all fluorinated pesticides)

-- 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 (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.
-- **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


 
Fluoride Action Network | Pesticide Project | 315-379-9200 | pesticides@fluoridealert.org