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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
As
of August
31, 2004,
this herbicide is permitted in or
on 38 food commodities
in the United States - see list at bottom of page.
Pesticide
tolerance for Emergency Exemption.
This regulation establishes a time-limited tolerance for
residues of flumioxazin in or on sweet
potato, roots at 0.02 ppm in connection with a crisis
exemption declared by the State of
Louisiana. This regulation establishes a maximum
permissible level for residues of flumioxazin in this food
commodity. The tolerance will expire and is revoked on June
30, 2006.
Ref: Federal Register: August 27,
2003. Final Rule.
http://www.fluorideaction.org/pesticides/flumioxazin.fr.aug.27.2003.htm
April
13, 2001 - "U.S. Rep. Saxby Chambliss (R-GA) today
praised the Bush Administration and the Environmental Protection
Agency for their decision to allow growers to use the herbicide
Flumioxazin on their crops during the 2001 growing season.
According to the EPA, the herbicide was registered Thursday...
Chambliss and Southeastern peanut farmers have been urging
the EPA to release the herbicide by April 15, 2001, in order
to allow time for the herbicide to be used late in the planting
season, beginning around May 1, 2001... Flumioxazin
will also be labeled for soybeans, therefore lowering competitive
price options for growers. Studies have shown that use of
Flumioxazin could result in reduction of production costs
upwards of $16.08 per acre. Chambliss is a member of the
House Agriculture Committee and Chairman of the General
Farm Commodities and Risk Management Subcommittee. He represents
the 8th Congressional District of Georgia in the U.S. House
of Representatives. "
Ref:
Press Release from Saxby Chambliss, Georgia's 8th Congressional
District.
http://www.fluorideaction.org/pesticides/flumioxazin.congress.lobby.htm
|
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
Environmental
(click on for all fluorinated
pesticides)
Phototoxic
Pesticide.
Light-dependent peroxidizing herbicides
(LDPHs). US EPA identified the organofluorine herbicides
Acifluorfen, Azafenidin, Carfentrazone-ethyl, Flumiclorac-penty,
Flumioxazin, Fluthiacet-methyl,
Fomesafen, Lactofen, Oxadiargyl, Oxadiazon, Oxyfluorfen,
Sulfentrazone, Thidiazimin as phototoxic
pesticides that act by inhibiting protoporphyringen
oxidase in the heme and chlorophyll biosynthetic pathway.
[10 out of the 13 pesticides that EPA identified are organofluorines].
SEE http://www.fluoridealert.org/pesticides/PHOTOTOXICITY.PAGE.htm
Ref: December 11, 2001 - US EPA. Revised
Environmental Fate and Effects Division Preliminary Risk
Assessment for the Oxyfluorfen Reregistration Eligibility
Decision Document also at: http://www.epa.gov/oppsrrd1/reregistration/oxyfluorfen/oxyefedchap.pdf
--
Plants. Flumioxazin is highly toxic
to terrestrial plants. Seedling emergence studies
identified the most sensitive species to flumioxazin being
lettuce (EC25 = 0.0008 pounds active ingredient/acre). Vegetative
vigor studies with flumioxazin identified the cucumber as
the most sensitive species (EC25 = 0.00008 pounds active
ingredient/acre).
-- Environmental Hazards. This product is toxic
to aquatic invertebrates.
-- Mechanism of Pesticidal Action. Flumioxazin is a
light-dependent peroxidizing herbicide (LDPH) which
acts by blocking heme and chlorophyll biosynthesis resulting
in an endogenous accumulation of photo-toxic porphyrins.
This class of herbicides are known
to have a photo-toxic mode of action in plants and possibly
in fish. Standard toxicity testing may not include
light with the same wavelength or intensity as natural sunlight.
LDPHs may be more toxic when exposed
to natural sunlight, such as exposure conditions in the
field.
Ref: US EPA Pesticide Fact
Sheet. April 12, 2001.
http://www.epa.gov/opprd001/factsheets/flumioxazin.pdf
|
August
31, 2004,
check at the Code
of Federal Regulations for Flumioxazin: this herbicide
is permitted in or on 38
food commodities
in the United States. The
following list identifies these crops for which EPA has set
pesticide tolerances. |
[Code
of Federal Regulations]
[Title 40, Volume 22]
[Revised as of July 1, 2004]
From the U.S. Government Printing Office via GPO Access
[CITE: 40CFR180.568]
[Page 508]
TITLE 40--PROTECTION OF ENVIRONMENT
CHAPTER I--ENVIRONMENTAL PROTECTION AGENCY (CONTINUED)
PART 180_TOLERANCES AND EXEMPTIONS FROM TOLERANCES FOR PESTICIDE
CHEMICALS
IN FOOD--Table of Contents
Subpart C_Specific Tolerances
Sec. 180.568 Flumioxazin; tolerances for residues.
(a) General. Tolerances are established for residues of flumioxazin,
2-[7-fluoro-3,4-dihydro-3-oxo-4-(2-propynyl)-2H-1,4-benzoxazin-6-yl]-
4,5,6,7-tetrahydro-1H-isoindole-1,3(2H)-dione, in or on the
following
raw agricultural commodities: |
Date
Approval published in Federal Register |
Commodity |
Parts
per Million
PPM |
CFR |
Aug
25, 2004 |
Almond
(hulls) |
0.70 |
180.568 |
Almond
(nutmeat) |
0.02 |
180.568 |
Mar
31, 2004 |
Cotton,
gin byproducts |
0.6 |
180.568 |
Cotton,
undelinted seed |
0.02 |
180.568 |
Aug
25, 2004 |
Garlic
(bulb) |
0.02 |
180.568 |
Grape |
0.02 |
180.568 |
Onion
(dry bulb) |
0.02 |
180.568 |
Apr
18, 2001 |
Peanut |
0.02 |
180.568 |
Aug
25, 2004 |
Peppermint
(tops) |
0.04 |
180.568 |
Pistachio |
0.02 |
180.568 |
Shallot
(bulb) |
0.02 |
180.568 |
Apr
18, 2001 |
Soybean,
seed |
0.02 |
180.568 |
Aug
25, 2004 |
Spearmint
(tops) |
0.04 |
180.568 |
Sugarcane
(cane) |
0.20 |
180.568 |
Aug
27, 2003 |
Sweet Potato,
Roots |
0.02 |
180.568 |
Aug
25, 2004 |
Tuberous/corm
vegetables (Subgroup 1C)
This
group includes 22 commodities - see Ref.
1 below.
|
0.02 |
180.568 |
(b)
Section 18 emergency exemptions. Time-limited tolerances are
established for residues of the herbicide flumioxazin in connection
with
the use of the pesticides under section 18 emergency exemptions
granted
by EPA. The tolerances will expire and are revoked on the
dates
specified in the following table. |
Date
Approved by US EPA |
Commodity |
Parts
per Million
PPM |
Expiration/
Revocation Date |
Aug
27, 2003 |
Sweet Potato,
Roots |
0.02 |
06/30/05 |
(c)
Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved] |
|