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Abstracts

Activity: Herbicide (unclassified)
Structure:

Adverse Effects:
Anemia
Blood
Body Weight Decrease
Bone
Brain
Cholesterol
Cytotoxic (results equivocal)
Endocrine: Adrenal
Endocrine: Testicular
Endocrine: Thymus
Endocrine: Thyroid
Heart
Kidney
Liver
Lymph Node
Teratogen
Environmental

Anemia (click on for all fluorinated pesticides)

-- Subchronic toxicity. Subchronic toxicity studies conducted with flumioxazin technical in the rat (oral and dermal), mouse and dog indicate a low level of toxicity. Effects observed at high dose levels consisted primarily of anemia and histological changes in the spleen, liver and bone marrow related to the anemia.
-- Rats. A 90-day subchronic toxicity study was conducted in rats, with dietary intake levels of 0, 30, 300, 1,000 and 3,000 ppm flumioxazin technical (98.4% purity). The NOAEL of 300 ppm was based on decreased bwts; anemia; increases in absolute and/or relative liver, kidney, brain, heart, and thyroid weights, and histological changes in the spleen, liver, and bone marrow related to the anemia.
-- A second 90-day subchronic toxicity study was conducted with a sample of flumioxazin technical of typical purity (94.8%) at dietary concentrations of 0, 30, 300, 1,000, and 3,000 ppm. The NOAEL was 30 ppm based on anemia and related hematological changes; increases in liver, heart, kidney, and thyroid weights; and histological changes in the spleen, liver, and bone marrow related to the anemia.
Ref: Federal Register: February 14, 2001 [Notices] [Page 10292-10301]. Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food. http://www.fluoridealert.org/pesticides/Flumioxazin.FR.Feb.14.2001.htm

Blood (click on for all fluorinated pesticides)

Subchronic, Chronic, and Other Toxicity
-- 870.3100 90-Day oral toxicity -rat NOAEL = mg/kg/day: 69.7 (M), 71.5 (F) LOAEL = mg/kg/day: 243.5 (M), 229.6 (F) based on a decrease in MCV [mean corpuscular volume] both sexes; increase in platelets F only
-- 870.3100 90-Day oral toxicity -rat NOAEL = mg/kg/day: 65.0 (M), 72.9 (F) LOAEL = mg/kg/day: 196.7 (M), 218.4 (F) based on hematology changes
-- 870.4300 Combined chronic carcinogenicity - rat NOAEL = mg/kg/day: males = 1.8, females = 2.2 LOAEL = mg/kg/day: males = 18.0, females = 21.8 based on increased chronic nephropathy in males and decreased hematological parameters in females (Hgb, MCV, MCH and MCHC) No evidence of carcinogenicity 870.5100 Gene mutation in S. typhimurium and E. coli Neither cytotoxic nor mutagenic up to 2000 g/plate. There were reproducible increases in revertant colonies of S. typhimurium strains TA1538 and TA98 in S9 activated phases of the preliminary cytotoxicity and both mutation assays. [Results considered to be equivocal.]
Ref: US EPA Pesticide Fact Sheet. April 12, 2001.
http://www.epa.gov/opprd001/factsheets/flumioxazin.pdf

Abstract: On single oral administration of (14)C-S-53482 [7-fluoro-6-(3,4,5, 6-tetrahydrophthalimido)-4-(2-propynyl)-2H-1,4-benzoxazin-3( 4H)-one, Flumioxazin] labeled at the 1- and 2-positions of tetrahydrophthaloyl group to rats at 1 (low dose) or 100 (high dose) mg/kg, the radiocarbon was almost completely eliminated within 7 days after administration in both groups with generally very low residual (14)C tissue levels. The predominant excretion route was via the feces. The major fecal and urinary metabolites involved reduction or sulfonic acid addition reactions at the 1,2-double bond of the 3,4,5,6-tetrahydrophthalimide moiety and hydroxylation of the cyclohexene or cyclohexane ring. One urinary and four fecal metabolites were identified using chromatographic techniques and spectroanalyses (NMR and MS). Three of five identified metabolites were unique forms, reduced at the 1,2-double bond of the 3,4,5, 6-tetrahydrophthalimide moiety. On the basis of the metabolites identified in this study, the metabolic pathways of S-53482 in rats are proposed. To specify tissues forming reduced metabolites, an in vitro study was conducted. Reduction was found to take place in red blood cells.
Ref: Tomigahara Y et al. (1999). Metabolism of 7-fluoro-6-(3,4,5,6-tetrahydrophthalimido)-4- (2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (S-53482, flumioxazin) in the rat: II. Identification of reduced metabolites. J Agric Food Chem. Jun;47(6):2429-38.
http://www.fluorideaction.org/pesticides/flumioxazin.abstracts.htm

Abstract: An N-phenylimide herbicide, S-53482, inhibits protoporphyrinogen oxidase, an enzyme common to chlorophyll and heme biosynthesis, and produces embryolethality, teratogenicity [mainly ventricular septal defects (VSD) and wavy ribs], and growth retardation in rats. In order to elucidate the mechanism of the developmental toxicity, in particular VSD, effects of the herbicide on rat embryonic blood cells were investigated histologically at the light and electron microscopic levels at 6, 12, 24, 36, and 48 h after oral administration of the chemical to pregnant rats on day 12 of gestation, the most sensitive day for toxicity. Electron and light microscopy demonstrated mitochondrial lesions, including abnormal iron deposits that were probably due to inhibition of heme biosynthesis, in erythroblasts derived from the yolk sac. Subsequently, degeneration of these erythroblasts occurred followed by erythrophagocytosis. Histologically hearts from exposed embryos had a thin ventricular wall, which may reflect a compensatory reaction to a loss of embryonic blood cells. Thus, the herbicide may induce VSD due to hematological dysfunction caused by the inhibition of heme biosynthesis rather than by direct injurious effects on the heart.
Ref: Kawamura S et al (1996). Histological changes in rat embryonic blood cells as a possible mechanism for ventricular septal defects produced by an N-phenylimide herbicide. Teratology. Nov;54(5):237-44.
http://www.fluorideaction.org/pesticides/flumioxazin.abstracts.htm

Body Weight Decrease (click on for all fluorinated pesticides)

Subchronic, Chronic, and Other Toxicity
-- 870.3800 Reproduction and fertility effects - rat. Parental/Systemic NOAEL = mg/kg/day: males = 12.7, females = 15.1 LOAEL = mg/kg/day: males = 18.9, females = 22.7 based on increase in clinical signs (red substance in vagina) and increased female mortality as well as decreased body weight, body weight gain and food consumption Reproductive NOAEL = mg/kg/day: males = 18.9 (HDT), females = 22.7 (HDT) LOAEL = mg/kg/day: males = >18.9 (HDT), females = >22.7 (HDT) Offspring NOAEL = mg/kg/day: males = 6.3, females = 7.6 LOAEL = mg/kg/day: males = 12.7, females = 15.1 based on a decrease in the number of liveborn and a decrease in pup body weight
-- 870.3700b Prenatal developmental - rabbit (oral) Maternal NOAEL = 1000 mg/kg/day LOAEL = 3000 mg/kg/day (HDT) based on decrease in body weight and food consumption during dosing Developmental NOAEL = 3000 mg/kg/day (HDT) LOAEL = >3000 mg/kg/day
-- there is concern for the severity of the effects observed in fetuses and young animals when compared to those observed in the maternal and parental animals (dose- and treatment-related increase in the incidence of cardiovascular abnormalities, particularly ventricular septal defect, in the developmental studies; and decreases in the number of live born pups and pup body weights in the absence of parental toxicity in the reproduction study).
Ref: US EPA Pesticide Fact Sheet. April 12, 2001.
http://www.epa.gov/opprd001/factsheets/flumioxazin.pdf

*Pregnant females were admin 400 mg/kg by gavage on gestation day 11 or 12 or 13 or 14 or 15. Day 12 admin showed: largest incidence of embryonic death, lowest fetal body weights & greatest incidence of ventricular spetal defects.
Ref: US EPA Pesticide Fact Sheet. April 12, 2001.
http://www.epa.gov/opprd001/factsheets/flumioxazin.pdf

Bone (click on for all fluorinated pesticides)

Abstract: An N-phenylimide herbicide, S-53482, inhibits protoporphyrinogen oxidase, an enzyme common to chlorophyll and heme biosynthesis, and produces embryolethality, teratogenicity [mainly ventricular septal defects (VSD) and wavy ribs], and growth retardation in rats. In order to elucidate the mechanism of the developmental toxicity, in particular VSD, effects of the herbicide on rat embryonic blood cells were investigated histologically at the light and electron microscopic levels at 6, 12, 24, 36, and 48 h after oral administration of the chemical to pregnant rats on day 12 of gestation, the most sensitive day for toxicity. Electron and light microscopy demonstrated mitochondrial lesions, including abnormal iron deposits that were probably due to inhibition of heme biosynthesis, in erythroblasts derived from the yolk sac. Subsequently, degeneration of these erythroblasts occurred followed by erythrophagocytosis. Histologically hearts from exposed embryos had a thin ventricular wall, which may reflect a compensatory reaction to a loss of embryonic blood cells. Thus, the herbicide may induce VSD due to hematological dysfunction caused by the inhibition of heme biosynthesis rather than by direct injurious effects on the heart.
Ref: Kawamura S et al (1996). Histological changes in rat embryonic blood cells as a possible mechanism for ventricular septal defects produced by an N-phenylimide herbicide. Teratology. Nov;54(5):237-44.
http://www.fluorideaction.org/pesticides/flumioxazin.abstracts.htm

-- "Teratology Study of S-53482 Administered Dermally to Rats"; (S. Kawamura; Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., Osaka, Japan; Project ID 2018; 3/14/91); The skin of twenty four mated Slc:SD¨ female rats was treated with 0, 30 or 100 mg/kg/day of S-53482 (lot no. PYG-89021-M, purity: 94.8%) for 6 hours/day from day 6 through day 15 of gestation. An additional group of 25 females were treated in the same manner with 300 mg/kg/day of the test material... There was an increased incidence of a minor skeletal anomaly of wavy ribs for the 300 mg/kg group (0:0/23 vs. 10/17)... (Moore, 6/7/02)
Ref: January 31, 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

-- "Preliminary Teratology Study of SB-1297, SB-1335 or SB-1855 Administered Orally to Rats"; (S. Kawamura; Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd, Osaka, Japan; Project ID 599; 1/9/89); Six mated female SPF Slc:SD rats/group were dosed by oral gavage with 0, 30, 100, 200, or 500 mg/kg of SB-1855 (lot no. OK-86-01, purity: 98.2%, also identified as S-53482 in vol. 52894-082) from gestation day 6 through day 15... Teratologic abnormalities for the 30 mg/kg group included ventricular septal defects in the heart (0:0/38 vs. 30:11/25, p<0.01)), persistent left umbilical artery (0:0/38 vs. 30:3/25), and wavy ribs (0:0/42 vs. 30:9/28)... (Moore, 7/29/02)
Ref: January 31, 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

-- "Pathogenesis of Developmental Effects Produced by S-53482, an N-phenylimide Herbicide, in Rats"; (S. Kawamura; Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd, Osaka, Japan; Project ID DSB06; 2/20/97); Pregnant female Crj:CD rats were dosed by oral gavage with 0 (0.5% methylcellulose) or 400 mg/kg of S-53482 (lot no. PYG-89021- M, purity: 94.8%) on day 12 of gestation... Examination of the embryonic blood revealed massive deposits of iron in the treated embryos by 24 hours post-dose... 17. In the skeletal examination, delayed ossification of the ribs was noted for the treated fetuses on day 17 (0: 0 vs. 400: 5.6%). On day 20, the incidence of wavy ribs (23.9%) and bent scapula (8.5%) was noted for the treated group in comparison with 0 incidence for the control. Physiologically, the anemia suffered by the treated fetuses preceded the effects of enlarged heart and edema and likely contributed to these effects. Likewise, the author of the report surmised that the skeletal abnormalities may have been due to reduced serum protein levels with delayed development of osteoblast progenitors and low fetal serum alkaline phosphatase levels. Study supplemental (non-guideline study). (Moore, 7/3/02)
Ref: January 31, 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

-- "Three-Month Subacute Toxicity Study of S-53482 by Dietary Administration in Rats"; (Haruhiko Adachi; Sumitomo Chemical Co., Environmental Health Science Laboratory,, Ltd., Osaka, Japan; Study No. 1760; 4/26/91); Sixteen Crj:CD (SD) rats/sex/group were treated in the diet with 0, 30, 300, 1000 or 3000 ppm of S-53482 (lot no. PYG-89021-M, purity: 94.8%). Six of these animals/sex/group were treated for 5 weeks. The remaining 10 animals/sex/group were treated for 13 weeks ((M): 0, 1.94, 19.4, 65.2, 197.3 mg/kg/day, (F) 0, 2.22, 22.4, 72.8, 218.4 mg/kg/day)... Hypercellularity in the bone marrow was evident for the 1000 and 3000 ppm females at 13 weeks (0: 0/10, 1000: 6/10, 3000: 7/10). Other noted lesions for the 3000 ppm females were focal or generalized necrosis in the liver (0:0/10 vs. 3000: 4/10), extramedullary hematopoiesis in the liver (0: 0/10 vs. 3000: 5/10), myocardial fibrosis in the heart (0: 0/10 vs. 3000: 2/10), myelofibrosis and osteosis in the bone marrow (0: 0/10 vs. 3000: 3/10)...
Ref: January 31, 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

-- "Teratology Study of S-53482 Administered Orally to Rats (Amendment Included)"; (S. Kawamura; Sumitomo Chemical Co., Ltd., Biochemistry and Toxicology Laboratory, Osaka, Japan; Project ID 1759; 8/28/90, (addendum) 12/26/95); Twenty two mated Slc:SD¨ female rats were treated by oral gavage with 0, 1, 3, 10, or 30 mg/kg/day of S-53482 (lot no. PYG-89021-M, purity: 94.8%) from day 6 through day 15 of gestation... There was an increased incidence/litter of cardiac (0:2/22 vs. 10:6/22, 30:12/18 (p<0.01)) and skeletal (0:0/22 vs. 30:4/18) malformations. The predominant cardiac and skeletal malformations were ventricular septal defect and double aortic arch and curvature of the scapula and ulna. There was also an increased incidence/litter of the minor skeletal anomaly, wavy ribs, in the 30 mg/kg group (0: 1/22 vs. 30: 12/18, p<0.01). Adverse effect indicated: malformations in cardiac and skeletal development; Maternal NOEL: 30 mg/kg/day (based upon a lack of treatment-related effects at the highest dose tested); Developmental NOEL: 3 mg/kg/day (based upon the increased incidence of cardiac malformations in the fetuses of the 10 mg/kg treatment group); Study acceptable. (Moore, 6/5/02)
Ref: January 31, 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

-- Subchronic toxicity. Subchronic toxicity studies conducted with flumioxazin technical in the rat (oral and dermal), mouse and dog indicate a low level of toxicity. Effects observed at high dose levels consisted primarily of anemia and histological changes in the spleen, liver and bone marrow related to the anemia.
-- Rats. A 90-day subchronic toxicity study was conducted in rats, with dietary intake levels of 0, 30, 300, 1,000 and 3,000 ppm flumioxazin technical (98.4% purity). The NOAEL of 300 ppm was based on decreased bwts; anemia; increases in absolute and/or relative liver, kidney, brain, heart, and thyroid weights, and histological changes in the spleen, liver, and bone marrow related to the anemia.
-- A second 90-day subchronic toxicity study was conducted with a sample of flumioxazin technical of typical purity (94.8%) at dietary concentrations of 0, 30, 300, 1,000, and 3,000 ppm. The NOAEL was 30 ppm based on anemia and related hematological changes; increases in liver, heart, kidney, and thyroid weights; and histological changes in the spleen, liver, and bone marrow related to the anemia.
Ref: Federal Register: February 14, 2001 [Notices] [Page 10292-10301]. Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food. http://www.fluoridealert.org/pesticides/Flumioxazin.FR.Feb.14.2001.htm

Brain (click on for all fluorinated pesticides)

-- ONCOGENICITY, MOUSE ** 050; 184618; "Oncogenicity Study of S-53482 by Dietary Administration in Mice"; (T. Seki; Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., Osaka, Japan; Project ID 1928; 9/24/93); Fifty one Crj:CD-1 (ICR) mice/sex/group were treated in the diet with 0, 300, 3000 or 7000 ppm of S-53482 (lot no. PYG-89021-M, purity: 94.8%) for 78 weeks ((M): 0, 31.1, 314.9, 754.1 mg/kg/day, (F) 0, 36.6, 346.4, 859.1 mg/kg/day). An additional 15 animals/sex/group were treated for 52 weeks (satellite)... An increased incidence of calcification in the brain was noted for the 3000 and 7000 ppm males which survived to the conclusion of the study (0: 3/37 vs. 3000: 11/36 (p<0.05), 7000: 13/38 (p<0.01).
Ref: January 31, 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

-- "The Pharmacokinetics of [ 14 C]S-53482 in the Rat 1 , Biliary Excretion of [ 14 C]S-53482 in the Rat 2 , Tissue Distribution of [ 14 C]S-53482 in the Rat 3"; (Gibson, N.A., G.R. Krautter, K. Jalali, and L.O. Ruzo; PTRL East, Inc., Richmond, CA and PTRL West, Inc., Richmond, CA; Project IDs: 1034E 1 , 1035E/588W 2 , 1036E/589W 3 ; 2/19/97 1 , 3/6/97 2 , 3/17/97 3 ); In the pharmacokinetic study, 7 Sprague-Dawley (Crl:CD:BR) rats/sex were dosed by oral gavage with 1 or 100 mg/kg of [Tetrahydrophthaloyl-1,2-14 C]S-53482 (Flumioxazin Technical) (lot no. RIS96014, specific activity: 121 mCi/mmole, radiochemical purity: 98.9%, chemical purity: 99.0%) mixed with; unlabeled S-53482 (lot no. 60208AG, purity: 99.9%)... Only a minimal amount of the radiolabel appeared to penetrate the blood-brain barrier.
Ref: January 31, 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

-- Rats. A 90-day subchronic toxicity study was conducted in rats, with dietary intake levels of 0, 30, 300, 1,000 and 3,000 ppm flumioxazin technical (98.4% purity). The NOAEL of 300 ppm was based on decreased bwts; anemia; increases in absolute and/or relative liver, kidney, brain, heart, and thyroid weights, and histological changes in the spleen, liver, and bone marrow related to the anemia.
Ref: Federal Register: February 14, 2001 [Notices] [Page 10292-10301]. Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Flumioxazin.FR.Feb.14.2001.htm

Cholesterol (click on for all fluorinated pesticides)

-- 870.3150 90-Day capsule - dog NOAEL = mg/kg/day: 10 (M & F) LOAEL = mg/kg/day: 100 (M & F) based on dose dependent increase in total cholesterol, phospholipid & alkaline phosphatase
Ref: US EPA Pesticide Fact Sheet. April 12, 2001.
http://www.epa.gov/opprd001/factsheets/flumioxazin.pdf

Cytotoxic (results equivocal) (click on for all fluorinated pesticides)

Study # 870.4300. Combined chronic carcinogenicity - rat. NOAEL = mg/kg/day: males = 1.8, females = 2.2 LOAEL = mg/kg/day: males = 18.0, females = 21.8 based on increased chronic nephropathy in males and decreased hematological parameters in females (Hgb, MCV, MCH and MCHC) No evidence of carcinogenicity 870.5100 Gene mutation in S. typhimurium and E. coli Neither cytotoxic nor mutagenic up to 2000 g/plate. There were reproducible increases in revertant colonies of S. typhimurium strains TA1538 and TA98 in S9 activated phases of the preliminary cytotoxicity and both mutation assays. [Results considered to be equivocal.]
Ref: US EPA Pesticide Fact Sheet. April 12, 2001.
http://www.epa.gov/opprd001/factsheets/flumioxazin.pdf

Endocrine: Adrenal (click on for all fluorinated pesticides)

-- "Three-Month Subacute Toxicity Study of S-53482 by Dietary Administration in Rats"; (Haruhiko Adachi; Sumitomo Chemical Co., Environmental Health Science Laboratory,, Ltd., Osaka, Japan; Study No. 1760; 4/26/91); Sixteen Crj:CD (SD) rats/sex/group were treated in the diet with 0, 30, 300, 1000 or 3000 ppm of S-53482 (lot no. PYG-89021-M, purity: 94.8%). Six of these animals/sex/group were treated for 5 weeks. The remaining 10 animals/sex/group were treated for 13 weeks ((M): 0, 1.94, 19.4, 65.2, 197.3 mg/kg/day, (F) 0, 2.22, 22.4, 72.8, 218.4 mg/kg/day)... Other noted lesions for the 3000 ppm females were... atrophy of the thymus and the presence of thymal foam cells (0:0/10 vs. 3000: 3/10), sinus histiocytosis in the mesenteric lymph node (0:0/10 vs. 3000: 3/10), and cytoplasmic vacuolation in the adrenal cortex (0:0/10 vs. 3000: 3/10)...
Ref: January 31, 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

Endocrine: Testicular (click on for all fluorinated pesticides)

-- Reproduction. Two pilot range-finding rat reproduction studies were conducted with flumioxazin technical at dosages from 100 to 5,000 ppm in the diet. In the definitive 2-generation reproduction study in the rat dietary levels of 0, 50, 100, 200, and 300 ppm established a systemic NOAEL of 200 ppm based on increased clinical signs (both sexes and generations); mortality, gross, and histopathology findings in the liver (F1 females); decreased body weight/weight w/w gain (F0 and F1 females during gestation, F1 males during premating) and decreased food consumption (F0 and F1 females during lactation). The reproductive NOAEL of 100 ppm was mainly based on developmental toxicity at 200 ppm. Observed at 200 ppm were a decreased number of liveborn pups and reduced pup bwts. At 300 ppm the following effects were observed: decreased pup bwt (both generations); decreased number of live pups/litter and viability index (both generations); increased incidence of abnormalities of the reproductive organs (predominately atrophied or hypoplastic testes and/or epididymides in F1 males); decreased gestation index (F0 females); decreased mating and fertility indices (F1 males) and increased clinical signs (F1 pups).
Ref: Federal Register: February 14, 2001 [Notices] [Page 10292-10301]. Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Flumioxazin.FR.Feb.14.2001.htm

Endocrine: Thymus (click on for all fluorinated pesticides)

-- "Three-Month Subacute Toxicity Study of S-53482 by Dietary Administration in Rats"; (Haruhiko Adachi; Sumitomo Chemical Co., Environmental Health Science Laboratory,, Ltd., Osaka, Japan; Study No. 1760; 4/26/91); Sixteen Crj:CD (SD) rats/sex/group were treated in the diet with 0, 30, 300, 1000 or 3000 ppm of S-53482 (lot no. PYG-89021-M, purity: 94.8%). Six of these animals/sex/group were treated for 5 weeks. The remaining 10 animals/sex/group were treated for 13 weeks ((M): 0, 1.94, 19.4, 65.2, 197.3 mg/kg/day, (F) 0, 2.22, 22.4, 72.8, 218.4 mg/kg/day)... Other noted lesions for the 3000 ppm females were... atrophy of the thymus and the presence of thymal foam cells (0:0/10 vs. 3000: 3/10), sinus histiocytosis in the mesenteric lymph node (0:0/10 vs. 3000: 3/10), and cytoplasmic vacuolation in the adrenal cortex (0:0/10 vs. 3000: 3/10)...
Ref: January 31, 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

Endocrine: Thyroid (click on for all fluorinated pesticides)

-- Rats. A 90-day subchronic toxicity study was conducted in rats, with dietary intake levels of 0, 30, 300, 1,000 and 3,000 ppm flumioxazin technical (98.4% purity). The NOAEL of 300 ppm was based on decreased bwts; anemia; increases in absolute and/or relative liver, kidney, brain, heart, and thyroid weights, and histological changes in the spleen, liver, and bone marrow related to the anemia.
-- A second 90-day subchronic toxicity study was conducted with a sample of flumioxazin technical of typical purity (94.8%) at dietary concentrations of 0, 30, 300, 1,000, and 3,000 ppm. The NOAEL was 30 ppm based on anemia and related hematological changes; increases in liver, heart, kidney, and thyroid weights; and histological changes in the spleen, liver, and bone marrow related to the anemia.
Ref: Federal Register: February 14, 2001 [Notices] [Page 10292-10301]. Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Flumioxazin.FR.Feb.14.2001.htm

Heart (click on for all fluorinated pesticides)

-- "Teratology Study of S-53482 Administered Dermally to Rats"; (S. Kawamura; Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd., Osaka, Japan; Project ID 2018; 3/14/91); The skin of twenty four mated Slc:SD¨ female rats was treated with 0, 30 or 100 mg/kg/day of S-53482 (lot no. PYG-89021-M, purity: 94.8%) for 6 hours/day from day 6 through day 15 of gestation. An additional group of 25 females were treated in the same manner with 300 mg/kg/day of the test material... There was an increased incidence/litter of cardiac malformations (0:1/23 vs. 300:9/17). The predominant cardiac malformation was a ventricular septal defect... Among the visceral variations noted for the 300 mg/kg group, there was an increased incidence/litter of persistent right azygous vein (0: 1/23 vs. 300: 7/17) and supernumerary coronary orifice in the heart (0:0/23 vs. 300: 3/17). Indicated adverse effect: increased incidence of a ventricular septal defect in the heart; Maternal NOEL: 100 mg/kg/day (based upon decreased weight gain noted for the 300 mg/kg treatment group); Developmental NOEL: 30 mg/kg/day (based upon the increased incidence of cardiovascular variations experienced by the 100 mg/kg treatment group); Study acceptable. (Moore, 6/7/02)
Ref: January 31, 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

-- "Preliminary Teratology Study of SB-1297, SB-1335 or SB-1855 Administered Orally to Rats"; (S. Kawamura; Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd, Osaka, Japan; Project ID 599; 1/9/89); Six mated female SPF Slc:SD rats/group were dosed by oral gavage with 0, 30, 100, 200, or 500 mg/kg of SB-1855 (lot no. OK-86-01, purity: 98.2%, also identified as S-53482 in vol. 52894-082) from gestation day 6 through day 15... The developing fetuses were adversely affected at all of the treatment levels. There were no surviving fetuses in the 200 and 500 mg/kg treatment groups. Excessive death was noted for both the 30 and 100 mg/kg groups. The mean fetal body weights of the 30 mg/kg group were less than those of the control (p<0.05). Teratologic abnormalities for the 30 mg/kg group included ventricular septal defects in the heart (0:0/38 vs. 30:11/25, p<0.01)), persistent left umbilical artery (0:0/38 vs. 30:3/25), and wavy ribs (0:0/42 vs. 30:9/28). These data indicate that, even at the 30 mg/kg treatment level, significant developmental defects occurred. Possible adverse effect: ventricular septal defects in the heart. Maternal NOEL: not determinable. Developmental NOEL: < 30 mg/kg/day (based upon the incidence of developmental defects in the 30 mg/kg treatment group). Study supplemental (non-guideline study). (Moore, 7/29/02)
Ref: January 31, 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

-- Prenatal developmental - Maternal NOAEL = 30 mg/kg/day (HDT) LOAEL = rat (oral) >30 mg/kg/day (HDT) Developmental NOAEL = 3 mg/kg/day LOAEL = 10 mg/kg/day based on cardiovascular effects (especially ventricular septal defects).
-- Prenatal developmental - Maternal NOAEL = 300 mg/kg/day (HDT) LOAEL rat (dermal) = >300 mg/kg/day (HDT) Developmental NOAEL = 30 mg/kg/day LOAEL = 100 mg/kg/day based on cardiovascular effects (especially ventricular septal defects).
-- Special Study - Rat Developmental: Critical Time for Defects: Pregnant females were administered 400 mg/ kg by gavage on gestation day 11 or 12 or 13 or 14 or 15. Day 12 administration showed: largest incidence of embryonic death, lowest fetal body weights and greatest incidence of ventricular spetal defects.
Ref: Federal Register: April 18, 2001. Flumioxazin; Pesticide Tolerances. Final Rule.
http://www.fluoridealert.org/pesticides/Flumioxazin.FR.Apr.18.2001.htm

-- Rats. A 90-day subchronic toxicity study was conducted in rats, with dietary intake levels of 0, 30, 300, 1,000 and 3,000 ppm flumioxazin technical (98.4% purity). The NOAEL of 300 ppm was based on decreased bwts; anemia; increases in absolute and/or relative liver, kidney, brain, heart, and thyroid weights, and histological changes in the spleen, liver, and bone marrow related to the anemia.
-- A second 90-day subchronic toxicity study was conducted with a sample of flumioxazin technical of typical purity (94.8%) at dietary concentrations of 0, 30, 300, 1,000, and 3,000 ppm. The NOAEL was 30 ppm based on anemia and related hematological changes; increases in liver, heart, kidney, and thyroid weights; and histological changes in the spleen, liver, and bone marrow related to the anemia.
Ref: Federal Register: February 14, 2001 [Notices] [Page 10292-10301]. Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Flumioxazin.FR.Feb.14.2001.htm

-- there is concern for the severity of the effects observed in fetuses and young animals when compared to those observed in the maternal and parental animals (dose- and treatment-related increase in the incidence of cardiovascular abnormalities, particularly ventricular septal defect, in the developmental studies; and decreases in the number of live born pups and pup body weights in the absence of parental toxicity in the reproduction study).
-- Pregnant females were admin 400 mg/kg by gavage on gestation day 11 or 12 or 13 or 14 or 15. Day 12 admin showed: largest incidence of embryonic death, lowest fetal body weights & greatest incidence of ventricular spetal defects.
Ref: US EPA Pesticide Fact Sheet. April 12, 2001.
http://www.epa.gov/opprd001/factsheets/flumioxazin.pdf

Kidney (click on for all fluorinated pesticides)

-- Combined chronic carcinogenicity - rat: NOAEL = mg/kg/day: males = 1.8, females = 2.2 LOAEL = mg/kg/day: males = 18.0, females = 21.8 based on increased chronic nephropathy [kidney] in males and decreased hematological parameters in females (Hgb, MCV, MCH and MCHC) No evidence of carcinogenicity
Ref: Federal Register: April 18, 2001. Flumioxazin; Pesticide Tolerances. Final Rule.
http://www.fluoridealert.org/pesticides/Flumioxazin.FR.Apr.18.2001.htm

-- Rats. A 90-day subchronic toxicity study was conducted in rats, with dietary intake levels of 0, 30, 300, 1,000 and 3,000 ppm flumioxazin technical (98.4% purity). The NOAEL of 300 ppm was based on decreased bwts; anemia; increases in absolute and/or relative liver, kidney, brain, heart, and thyroid weights, and histological changes in the spleen, liver, and bone marrow related to the anemia.
-- A second 90-day subchronic toxicity study was conducted with a sample of flumioxazin technical of typical purity (94.8%) at dietary concentrations of 0, 30, 300, 1,000, and 3,000 ppm. The NOAEL was 30 ppm based on anemia and related hematological changes; increases in liver, heart, kidney, and thyroid weights; and histological changes in the spleen, liver, and bone marrow related to the anemia.
Ref: Federal Register: February 14, 2001 [Notices] [Page 10292-10301]. Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Flumioxazin.FR.Feb.14.2001.htm

Liver (click on for all fluorinated pesticides)

Subchronic, Chronic, and Other Toxicity
-- 870.3100 90-Day oral toxicity -mouse NOAEL = mg/kg/day: 429 (M & F) LOAEL = mg/kg/day: 1429 (M & F) based on increased liver weight in males
-- 870. 3100 4-Week oral toxicity -mouse NOAEL = mg/kg/day: 151.5 (M), 164.5 (F) LOAEL = mg/kg/day: 419.9 (M), 481.6 (F) based on increased absolute &/or relative liver weights in M & F
-- 870.4100 12-Month capsule -dog NOAEL = 100 mg/kg/day (M & F) LOAEL = 1000 mg/kg/day (M &F), (LIMIT DOSE) based on the following for males and females: increased absolute and relative liver weights; 300% increase in alkaline phosphatase values
Ref: US EPA Pesticide Fact Sheet. April 12, 2001.
http://www.epa.gov/opprd001/factsheets/flumioxazin.pdf

Lymph Node (click on for all fluorinated pesticides)

SUBCHRONIC STUDIES 52894-046; 184614; "Three-Month Subacute Toxicity Study of S-53482 by Dietary Administration in Rats"; (Haruhiko Adachi; Sumitomo Chemical Co., Environmental Health Science Laboratory,, Ltd., Osaka, Japan; Study No. 1760; 4/26/91); Sixteen Crj:CD (SD) rats/sex/group were treated in the diet with 0, 30, 300, 1000 or 3000 ppm of S-53482 (lot no. PYG-89021-M, purity: 94.8%). Six of these animals/sex/group were treated for 5 weeks. The remaining 10 animals/sex/group were treated for 13 weeks ((M): 0, 1.94, 19.4, 65.2, 197.3 mg/kg/day, (F) 0, 2.22, 22.4, 72.8, 218.4 mg/kg/day). One female in the 3000 ppm group died during week 12. The mean body weights for the 3000 ppm males and females were 95.3 and 90.2% of the mean values for the control animals, respectively at the termination of the study. ... Other noted lesions for the 3000 ppm females were focal or generalized necrosis in the liver (0:0/10 vs. 3000: 4/10), extramedullary hematopoiesis in the liver (0: 0/10 vs. 3000: 5/10), myocardial fibrosis in the heart (0: 0/10 vs. 3000: 2/10), myelofibrosis and osteosis in the bone marrow (0: 0/10 vs. 3000: 3/10), atrophy of the thymus and the presence of thymal foam cells (0:0/10 vs. 3000: 3/10), sinus histiocytosis in the mesenteric lymph node (0:0/10 vs. 3000: 3/10), and cytoplasmic vacuolation in the adrenal cortex (0:0/10 vs. 3000: 3/10). Adverse effects indicated: anemia and hepatic necrosis. Subchronic NOEL (M/F): 300 ppm ((M) 19.4 mg/kg/day, (F) 22.4 mg/kg/day) (based upon hematologic effects noted for the 1000 ppm treated animals); Study acceptable. (Moore, 5/20/02)
Ref: January 31, 2003 (revised) - Summary of Toxicological Data. California EPA, Department of Pesticides Regulation, Medical Toxicology Branch.

Teratogen (click on for all fluorinated pesticides)

Abstract: An N-phenylimide herbicide, S-53482, inhibits protoporphyrinogen oxidase, an enzyme common to chlorophyll and heme biosynthesis, and produces embryolethality, teratogenicity [mainly ventricular septal defects (VSD) and wavy ribs], and growth retardation in rats. In order to elucidate the mechanism of the developmental toxicity, in particular VSD, effects of the herbicide on rat embryonic blood cells were investigated histologically at the light and electron microscopic levels at 6, 12, 24, 36, and 48 h after oral administration of the chemical to pregnant rats on day 12 of gestation, the most sensitive day for toxicity. Electron and light microscopy demonstrated mitochondrial lesions, including abnormal iron deposits that were probably due to inhibition of heme biosynthesis, in erythroblasts derived from the yolk sac. Subsequently, degeneration of these erythroblasts occurred followed by erythrophagocytosis. Histologically hearts from exposed embryos had a thin ventricular wall, which may reflect a compensatory reaction to a loss of embryonic blood cells. Thus, the herbicide may induce VSD due to hematological dysfunction caused by the inhibition of heme biosynthesis rather than by direct injurious effects on the heart.
Ref: Kawamura S et al (1996). Histological changes in rat embryonic blood cells as a possible mechanism for ventricular septal defects produced by an N-phenylimide herbicide. Teratology. Nov;54(5):237-44.
http://www.fluorideaction.org/pesticides/flumioxazin.abstracts.htm