Return to Clodinafop-propargyl
Index Page
Activity: Herbicide,
Plant Growth Regulator (Aryloxyphenoxy propionic acid)
Structure:
Adverse
Effects:
Anemia
Bladder (ureter)
Blood
Body Weight Decrease
Bone
Cancer: Likely
to be carcinogenic to humans - PROSTATE, OVARIAN, LIVER, BLOOD
Clastogenicity
Dermal
Endocrine: Ovary
Endocrine: Prostate
Endocrine: Thymus
Kidney
Liver
Tremors
Environmental
As
of February 2005: US EPA has maximum residue level tolerances
for 4 food commodities - see list at bottom of page
|
Anemia
(click
on for all fluorinated pesticides)
Clodinafop-propargyl induces anaemia in
all tested species, peroxisome proliferation in rodents
and increases in inflammation with indications of immunosuppression
and fat reduction in dogs. The dose levels at which severe effects
were seen in rats and mice in the longest studies do not warrant
classification. However, severe effects were seen in dogs at a
dose level requiring classification with R48/22.
Ref: Classification of clodinafop-propargyl
with R48/22. The Netherlands, May 2005.
http://www.fluorideaction.org/pesticides/clodinafop-prop.may.2005.html
Bladder
(ureter) (click on
for all fluorinated pesticides)
Study # 870.3700a.
Prenatal Developmental Toxicity in Rats. Maternal NOAEL = 160
mg/kg/day Maternal LOAEL > 160 mg/kg/day based on lack of effect.
Developmental NOAEL = 5 mg/kg/day Developmental LOAEL = 40 mg/kg/day
based on increased incidences of bilateral
distension and torsion of the ureters,
unilateral 14th ribs, and incomplete ossification
of the metacarpals and various cranial bones (parietals, interparietals,
occipital, and squamosal).
Ref: US EPA Pesticide Fact Sheet. Reason
for Issuance: Conditional Registration. June 6, 2000.
http://www.epa.gov/opprd001/factsheets/clodinafop.pdf
Blood
(click
on for all fluorinated pesticides)
-- Carcinogenicity.
In accordance with the EPA Proposed EPA Weight-of-the-Evidence
Categories, August 1999, the Agency's Cancer Assessment Review
Committee (CARC) classified clodinafop-propargyl as "likely
to be carcinogenic to humans" by the oral route based on
the occurrence of prostate tumors in male rats, ovarian tumors
in female rats, and liver tumors in both
sexes of mice, as well as blood vessel tumors
in female mice. For the quantification of human cancer
risk, the CARC recommended a linear low-dose extrapolation approach
based on the most potent of these tumor types. This approach is
supported by possible genotoxic potential and the lack of confirmation
of the mode of action of clodinafop-propargyl. The most potent
unit risk, Q1 * (mg/kg/day) -1 , of those calculated for clodinafop-propargyl
is that for male mouse liver benign hepatoma and/or carcinoma
combined tumor rates at 0.129 (mg/kg/day) -1 in human equivalents.
Ref:
US EPA Pesticide Fact Sheet. Reason for Issuance: Conditional
Registration. June 6, 2000.
http://www.epa.gov/opprd001/factsheets/clodinafop.pdf
Body
Weight Decrease (click
on for all fluorinated pesticides)
SUBCHRONIC AND CHRONIC
TOXICITY
-- 870.3100/ 13 Week Oral Toxicity in Rodent NOAEL = M: 0.9 mg/kg;
F: 8.2 mg/kg/day LOAEL = M: 120 ppm (8.2 mg/kg/day); F: 1000 ppm
(71.1 mg/kg/day) decreased body weight;
based on increased liver weights and enzymes
(AlPtase); decreased
thymus weight (atrophy). Reversed after 28 day recovery period.
-- 870.3700b Prenatal Developmental Toxicity in Rabbits Maternal
NOAEL = 25 mg/kg/day Maternal LOAEL = 125 mg/kg/day based on mortality,
clinical signs and body weight loss
Developmental NOAEL = 125 mg/kg/day Developmental LOAEL >125 mg/kg/day
-- 870.3800 Two Generation Rat Reproduction Study Parental/Systemic
NOAEL= 3.2 mg/kg/day. Parental/Systemic LOAEL = 31.7 mg/kg/day
based on decrease in body weight gain, reduced
food consumption, increased liver and kidney weights and histopathological
changes in the liver and renal tubules.
Offspring NOAEL
= 3.2 mg/kg/day Offspring LOAEL = 31.7 mg/kg/day based on reduced
viability, decreased pup body weight
and dilatation of renal pelvis. Reproductive NOAEL = 64.2 mg/kg/day.
Reproductive LOAEL 64.2 mg/kg/day
-- 870.4100b Chronic Toxicity -Nonrodent NOAEL = M: 3.38 mg/kg/day;
F: 3.37 mg/kg/day LOAEL = M: 15.2 mg/kg/day ; F: 16.7 mg/kg/day
based on occurrence of skin lesions, clinical
signs, and reduced body weight gain and
food consumption.
Ref: US EPA Pesticide Fact Sheet. Reason
for Issuance: Conditional Registration. June 6, 2000.
http://www.epa.gov/opprd001/factsheets/clodinafop.pdf
Chronic toxicity. In
a 12-month feeding study in dogs, 500 ppm resulted in transient
dermatitis and reduced body weight gain.
Two females were more severely affected and showed inappetence,
body weight loss, tremors and
severe dermatitis, and necessitated
an interruption of the treatment in order to avoid mortality.
Histopathology revealed slight hepatocellular hypertrophy in one
male and one female. The NOEL of 100 ppm was equivalent to a mean
daily intake of 3.38 mg/kg in males and 3.37 mg/kg in female.
Ref: Federal Register: June 5, 1998 [Page
30750-30756]. Notice of Filing of Pesticide Petitions.
http://www.fluoridealert.org/pesticides/clodinafop-prop.fr.ju5.1998.htm
Bone
(click
on for all fluorinated pesticides)
In a developmental
toxicity study in rats, the highest dose level of 160 mg/kg resulted
in reduced body weight gain of the dams and signs of retarded
fetal body weight and incomplete ossification
of vertebrae and sternebrae...
The EPA's Hazard Identification Assessment Review Committee (HIARC)
concluded that based on an increase in bilateral distension and
torsion of the ureters and delayed ossification
in the fetuses, the developmental LOAEL was 40 mg/kg/day and the
NOAEL was 5 mg/kg/day.
Ref: Federal Register. Arpil 26, 2000. [PF-938;
FRL-6554-2]
http://www.epa.gov/fedrgstr/EPA-PEST/2000/April/Day-26/p10432.htm
Study # 870.3700a.
Prenatal Developmental Toxicity in Rats. Maternal NOAEL = 160
mg/kg/day Maternal LOAEL > 160 mg/kg/day based on lack of effect.
Developmental NOAEL = 5 mg/kg/day Developmental LOAEL = 40 mg/kg/day
based on increased incidences of bilateral distension and torsion
of the ureters,
unilateral 14th ribs, and incomplete ossification of the metacarpals
and various cranial bones (parietals, interparietals, occipital,
and squamosal).
Ref: US EPA Pesticide Fact Sheet. Reason
for Issuance: Conditional Registration. June 6, 2000.
http://www.epa.gov/opprd001/factsheets/clodinafop.pdf
Cancer:
Likely to be carcinogenic to humans - PROSTATE, OVARIAN, LIVER,
BLOOD (click
on for all fluorinated pesticides)
Suggestive
Evidence of Carcinogenic Potential.
Prostate gland adenomas in male Tif:RAIf(SPF)
rats at the high dose only cannot be discounted; Peroxisome Proliferator-Activated
Receptor Agonism MOA for liver tumors
in mice.
Ref: April
26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the
Office of Pesticide Programs. From: Jess Rowland, Chief Science
Information Management Branch Health Effect Division (7509C) Office
of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf
Likely
to be carcinogenic to humans.
Reviewed 12/ 7/ 99.
Ref:
List of Chemicals Evaluated for Carcinogenic Potential. Science
Information Management Branch, Health Effects Division, Office
of Pesticide Programs, U. S. Environmental Protection Agency.
March 15, 2002.
Carcinogenicity. In
accordance with the EPA Proposed EPA Weight-of-the-Evidence Categories,
August 1999, the Agency's Cancer Assessment Review Committee (CARC)
classified clodinafop-propargyl as "likely
to be carcinogenic to humans" by the oral route based on
the occurrence of prostate tumors in male
rats, ovarian tumors in female rats, and liver tumors in both
sexes of mice, as well as blood vessel tumors in female mice.
For the quantification of human cancer risk, the CARC recommended
a linear low-dose extrapolation approach based on the most potent
of these tumor types. This approach is supported by possible genotoxic
potential and the lack of confirmation of the mode of action of
clodinafop-propargyl. The most potent unit risk, Q1 * (mg/kg/day)
-1 , of those calculated for clodinafop-propargyl is that for
male mouse liver benign hepatoma and/or
carcinoma combined tumor rates at 0.129 (mg/kg/day) -1 in human
equivalents.
Ref: US EPA Pesticide Fact Sheet. Reason
for Issuance: Conditional Registration. June 6, 2000.
http://www.epa.gov/opprd001/factsheets/clodinafop.pdf
Clastogenicity
(click
on for all fluorinated pesticides)
SUBCHRONIC AND CHRONIC
TOXICITY
-- 870.5315 Chromosome Studies; Human Lymphocytes in vitro. Owing
to the conflicting results from the cytotoxicity assessment and
the presence of rare complex chromosome
aberrations both with and without S9 activation, the study is
considered inconclusive.
Ref: US EPA Pesticide Fact Sheet. Reason
for Issuance: Conditional Registration. June 6, 2000.
http://www.epa.gov/opprd001/factsheets/clodinafop.pdf
Dermal
(click
on for all fluorinated pesticides)
Proposal for classification as a "extrmeme sensitizer"
to skin.
n an optimization test, clodinafop-propargyl was sensitising to
the skin of guinea pig. The concentration
used for repeated intradermal induction was 0.1% and this resulted
in 100% sensitisation using dermal or intradermal challenge.
No information is provided by the sensitisation expert group for
potency categorisation based on the optimization test. However,
the induction concentration of 0.1% is equal to or below the concentration
needed to grade a substance as an extreme sensitizer in all other
sensitisation tests for which a proposal for potency categorisation
was provided in ECBI/81/02 Rev.2. Therefore, categorisation
of clodinafop-propargyl as an extreme sensitizer is proposed.
This results in a specific concentration limit of 0.001% for R43.
Ref: March 2005. Clodinafop-propargyl (P623/NL).
Proposal for specific concentration limits for the R43 classification,
The Netherlands. Doc
document: ECBI/155/04 Add. 2.
http://www.fluorideaction.org/pesticides/clodinafop-propargyl.skin.html
SUBCHRONIC AND CHRONIC
TOXICITY
-- 870.3150 90-Day Oral Toxicity in Dogs NOAEL = M: 0.346 mg/kg/day,
F: 1.89 mg/kg/day. LOAEL = M: 1.73 mg/kg/day ; F: 7.16 mg/kg/day
based on occurrence of skin lesions.
-- 870.4100b Chronic Toxicity -Nonrodent NOAEL = M: 3.38 mg/kg/day;
F: 3.37 mg/kg/day LOAEL = M: 15.2 mg/kg/day ; F: 16.7 mg/kg/day
based on occurrence of skin lesions,
clinical signs, and reduced body weight
gain and food consumption.
Ref: US EPA Pesticide Fact Sheet. Reason
for Issuance: Conditional Registration. June 6, 2000.
http://www.epa.gov/opprd001/factsheets/clodinafop.pdf
Chronic toxicity. In
a 12-month feeding study in dogs, 500 ppm resulted in transient
dermatitis and reduced body weight
gain. Two females were more severely affected and showed inappetence,
body weight loss, tremors and severe
dermatitis, and necessitated an interruption of the treatment
in order to avoid mortality. Histopathology revealed slight hepatocellular
hypertrophy in one male and one female. The NOEL of 100 ppm was
equivalent to a mean daily intake of 3.38 mg/kg in males and 3.37
mg/kg in female.
Ref: Federal Register: June 5, 1998 [Page
30750-30756]. Notice of Filing of Pesticide Petitions.
http://www.fluoridealert.org/pesticides/clodinafop-prop.fr.ju5.1998.htm
Endocrine:
Ovary (click
on for all fluorinated pesticides)
-- Top dose group males
showed a higher incidence of prostate adenoma,
while prostate hyperplasia was reduced. However, the total incidence
of proliferative changes in the prostate remained unchanged
indicating a progression from prostate hyperplasia to adenoma.
Females treated at the same high dose had higher incidences of
ovary tubular adenoma. The
slightly enhanced incidences of these lesions are likely a consequence
of the severe disturbance of the general metabolic balance due
to excessive liver toxicity. In fact, male rats fed 750 ppm exhibited
a marked increase in peroxisomal oxidation, and an increase in
cytochrome P450 4A1/ A3 and 4A2 in their livers. Further, a decrease
in cytochrome P450 isoenzymes including CYP 2A, CYP 3A, and male-specific
CYP 2C11 was observed. The total oxidation rate of
testosterone, aromatase (CYP
19A1) activity plasma estradiol concentration and plasma-- dihydrotestosterone
are altered at this level of treatment. Clodinafop-propargyl is
a potent peroxisome proliferator in the rat liver and this peroxisomal
prolifering activity manifests itself by altering Cytochrome P450-dependent
monooxygenses which are involved in steroid hormone homeostasis.
The NOAEL of 10 ppm was equivalent to a mean daily dose
of 0.32 mg/kg in males and 0.37 mg/kg in females. The EPA HIARC
concluded that based on hepatocellular hypertrophy and kidney
findings, the NOAEL was 1 ppm (0.031 in males and 0.034 in females.
-- Dietary treatment of rats with concentrations over 2 years
resulted in initial inappetence in males and reduced body weight
development in both sexes treated at 750 ppm. The main target
organ of toxicity was the liver. Changes in plasma protein and
lipid levels, strongly enhanced serum activities of liver enzymes,
increased liver weights, and severe liver necroses were observed
at dietary doses of 300 and 750 ppm in males and at 750 ppm in
females. The degenerative lesions provide strong evidence that
these dose levels exceeded a maximum tolerated dose (MTD). Top
dose group males showed a higher incidence
of prostate adenoma, while
prostate hyperplasia was reduced. However, the total incidence
of proliferative changes in the prostate remained unchanged indicating
a progression from prostate hyperplasia to adenoma. Females treated
at the same high dose had higher incidences of ovary
tubular adenoma. The slightly enhanced incidences of these
lesions are likely a consequence of the severe disturbance of
the general metabolic balance due to excessive liver toxicity.
In fact, male rats fed 750 ppm exhibited a marked increase in
peroxisomal oxidation, and an increase in cytochrome P450 4A1/
A3 and 4A2 in their livers. Further, a decrease in cytochrome
P450 isoenzymes including CYP 2A, CYP 3A, and male-specific CYP
2C11 was observed. The total oxidation rate of testosterone, aromatase
(CYP 19A1) activity plasma estradiol concentration and plasma--
dihydrotestosterone are altered at this level of treatment. Clodinafop-
propargyl is a potent peroxisome proliferator in the rat liver
and this peroxisomal prolifering activity manifests itself by
altering Cytochrome P450-dependent monooxygenses which are involved
in steroid hormone homeostasis. The NOAEL of 10 ppm was equivalent
to a mean daily dose of 0.32 mg/kg in males and 0.37 mg/kg in
females. The EPA HIARC concluded that based on hepatocellular
hypertrophy and kidney findings, the NOAEL was 1 ppm (0.031 in
males and 0.034 in females...
8. Endocrine disruption. No special studies investigating potential
estrogenic or endocrine effects of clodinafop-propargyl have been
conducted. However, the standard battery of required studies has
been completed. These studies include an evaluation of the potential
effects on reproduction and development and an evaluation of the
pathology of the endocrine organs following repeated or long-term
exposure. Although prostate adenomas and
ovarian adenomas were observed to be statistically increased in
rats at the highest feeding level with clodinafop-propargyl, this
feeding level clearly exceeded the MTD and the livers in these
rats were severely compromised. These findings in the endocrine
organs were considered to be secondary to the severe liver effects.
Ref: Federal Register: April 26, 2000 [Page
24471-24477]. Notice of Filing a Pesticide Petition to Establish
a Tolerance for Certain Pesticide Chemicals in or on Food.
http://www.fluoridealert.org/pesticides/clodinafop-prop.apr26.2000.htm
Endocrine:
Prostate (click
on for all fluorinated pesticides)
-- Dietary treatment
of rats with concentrations over 2 years resulted in initial inappetence
in males and reduced body weight development in both sexes treated
at 750 ppm. The main target organ of toxicity was the liver. Changes
in plasma protein and lipid levels, strongly enhanced serum activities
of liver enzymes, increased liver weights, and severe liver necroses
were observed at dietary doses of 300 and 750 ppm in males and
at 750 ppm in females. The degenerative lesions provide strong
evidence that these dose levels exceeded a maximum tolerated dose
(MTD). Top dose group males showed a higher
incidence of prostate adenoma, while prostate hyperplasia
was reduced. However, the total incidence of proliferative changes
in the prostate remained unchanged
indicating a progression from prostate hyperplasia
to adenoma. Females treated at the same high dose had higher
incidences of ovary tubular adenoma. The
slightly enhanced incidences of these lesions are likely a consequence
of the severe disturbance of the general metabolic balance
due to excessive liver toxicity. In fact, male rats fed 750 ppm
exhibited a marked increase in peroxisomal oxidation, and an increase
in cytochrome P450 4A1/ A3 and 4A2 in their livers. Further, a
decrease in cytochrome P450 isoenzymes including CYP 2A, CYP 3A,
and male-specific CYP 2C11 was observed. The total oxidation rate
of testosterone, aromatase (CYP 19A1) activity plasma estradiol
concentration and plasma-- dihydrotestosterone are altered at
this level of treatment. Clodinafop- propargyl is a potent peroxisome
proliferator in the rat liver and this peroxisomal prolifering
activity manifests itself by altering Cytochrome P450-dependent
monooxygenses which are involved in steroid hormone homeostasis.
The NOAEL of 10 ppm was equivalent to a mean daily dose of 0.32
mg/kg in males and 0.37 mg/kg in females. The EPA HIARC concluded
that based on hepatocellular hypertrophy and kidney findings,
the NOAEL was 1 ppm (0.031 in males and 0.034 in females...
8. Endocrine disruption. No special studies investigating potential
estrogenic or endocrine effects of clodinafop-propargyl have been
conducted. However, the standard battery of required studies has
been completed. These studies include an evaluation of the potential
effects on reproduction and development and an evaluation of the
pathology of the endocrine organs following repeated or long-term
exposure. Although prostate adenomas and
ovarian adenomas were observed to be statistically increased in
rats at the highest feeding level with clodinafop-propargyl, this
feeding level clearly exceeded the MTD and the livers in these
rats were severely compromised. These findings in the endocrine
organs were considered to be secondary to the severe liver effects.
Ref: Federal Register: April 26, 2000 [Page
24471-24477]. Notice of Filing a Pesticide Petition to Establish
a Tolerance for Certain Pesticide Chemicals in or on Food.
http://www.fluoridealert.org/pesticides/clodinafop-prop.apr26.2000.htm
Endocrine:
Thymus
(click
on for all fluorinated pesticides)
Subchronic toxicity.
A 90-day feeding study in rats at 1,000 ppm resulted in reduced
body weight gain, increased liver weights, hematological changes,
and increased serum activities of the alkaline phosphatase. Target
organs were liver (increased weight), thymus
(atrophy) and spleen (reduced weight). The changes were
reversible during 4 weeks of recovery. The NOAEL was 15 ppm (0.92
mg/kg in males and 0.94 mg/kg in females). The EPA HIARC suggested
the NOAEL in female rats was 8.24 mg/kg bw/day.
Ref: Federal Register: April 26, 2000 [Page
24471-24477].
http://www.fluoridealert.org/pesticides/Clodinafop-prop.Apr26.2000.htm
Kidney
(click on for all fluorinated
pesticides)
Reproductive and developmental
toxicity... Target organs were liver
(adults) and kidney (adults and pups).
The treatment had no effect on reproductive organs. The NOAEL
for toxicity to the parental rats and offspring was 50 ppm, corresponding
to a mean daily intake of 3.2 mg/kg clodinafop-propargyl. The
NOAEL for reproductive toxicity was 1,000 ppm (64.2 milligram/kilogram
body weight/day (mg/kg bw/day))... The EPA HIARC concluded that
based on hepatocellular hypertrophy and
kidney findings, the NOAEL was 1 ppm (0.031 in males and
0.034 in females.
Ref: Federal Register. April 26, 2000. [PF-938;
FRL-6554-2]
http://www.fluoridealert.org/pesticides/clodinafop-prop.apr26.2000.htm
SUBCHRONIC AND CHRONIC
TOXICITY
-- 870.4300 Chronic/ Oncogenicity in the Rat. NOAEL = M:0.03 mg/kg/day
; F: 0.03 mg/kg/day LOAEL = M: 0.3 mg/kg/day; F: 0.4 mg/kg/day
based on hepatocytic hypertrophy,
chronic
progressive nephropathy,
and tubular pigmentation. Under the conditions of this study,
treatment with clodinafop-propargyl increased the incidence of
prostate and ovarian tumors in rats at 750 ppm. For males, an
increased incidence of prostate adenoma was seen in the high-dose
group. The chemical was administered at a dose sufficient to
test its carcinogenic potential.
Ref: US EPA Pesticide Fact Sheet. Reason
for Issuance: Conditional Registration. June 6, 2000.
http://www.epa.gov/opprd001/factsheets/clodinafop.pdf
Liver
(click on
for all fluorinated pesticides)
-- Carcinogenicity.
In accordance with the EPA Proposed EPA Weight-of-the-Evidence
Categories, August 1999, the Agency's Cancer Assessment Review
Committee (CARC) classified clodinafop-propargyl as "likely
to be carcinogenic to humans" by the oral route based on
the occurrence of prostate tumors in male rats, ovarian tumors
in female rats, and liver tumors in both
sexes of mice, as well as blood vessel tumors in female
mice. For the quantification of human cancer risk, the CARC recommended
a linear low-dose extrapolation approach based on the most potent
of these tumor types. This approach is supported by possible genotoxic
potential and the lack of confirmation of the mode of action of
clodinafop-propargyl. The most potent unit risk, Q1 * (mg/kg/day)
-1 , of those calculated for clodinafop-propargyl is that for
male mouse liver benign hepatoma and/or
carcinoma combined tumor rates at 0.129 (mg/kg/day) -1 in human
equivalents.
SUBCHRONIC AND CHRONIC TOXICITY
-- 870.3100/ 28-Day Oral Gavage in Rats NOAEL < 5 mg/kg LOAEL
= 5 mg/kg for M and F based on liver toxicity
(enzyme changes),
-- 870.3100/ 13 Week Oral Toxicity in Rodent NOAEL = M: 0.9 mg/kg;
F: 8.2 mg/kg/day LOAEL = M: 120 ppm (8.2 mg/kg/day); F: 1000 ppm
(71.1 mg/kg/day) decreased body weight;
based on increased liver weights and enzymes
(AlPtase); decreased thymus weight
(atrophy). Reversed after 28 day recovery period.
-- 870.3100/ 13 Week Oral Toxicity in Mice NOAEL = M: 0.9mg/kg/day;
F: 1.1mg/kg/day LOAEL = M: 7.3 mg/kg/day ; F: 8.6 mg/kg/day based
on clinical chemistry; glucose, sodium, and chloride increases
and hepatocellular hypertrophy in males
and females.
-- 870.3200 28-Day Dermal Toxicity in Rats. Systemic NOAEL = 50
mg/kg/day Systemic LOAEL = 200 mg/kg based on dose-related increases
in liver weights and clinical signs
(piloerection and hunched posture) in male rats. Dermal NOAEL
= 1000 mg/kg/day.
-- 870.3800 Two Generation Rat Reproduction Study Parental/Systemic
NOAEL= 3.2 mg/kg/day. Parental/Systemic LOAEL = 31.7 mg/kg/day
based on decrease
in body weight gain, reduced food consumption,
increased
liver and kidney weights and histopathological changes in the
liver and renal tubules...
-- 870.4200b Carcinogenicity -Mice NOAEL = M: 1.10 mg/kg/day;
F: 1.25 mg/kg/day LOAEL =M: 11.0 mg/kg/day; F: 12.6 mg/kg/day
based on increase in liver enzyme activity
and liver weights. Under the conditions of this study,
clodinafop-propargyl induced hepatocellular
tumors at 29.6 mg/kg. The chemical was tested at doses
sufficient to measure its carcinogenic potential.
-- 870.4300 Chronic/ Oncogenicity in the Rat. NOAEL = M:0.03 mg/kg/day
; F: 0.03 mg/kg/day LOAEL = M: 0.3 mg/kg/day; F: 0.4 mg/kg/day
based on hepatocytic hypertrophy,
chronic progressive nephropathy,
and tubular pigmentation. Under the conditions of this study,
treatment with clodinafop-propargyl increased the incidence of
prostate and ovarian tumors in rats at 750 ppm. For males, an
increased incidence of prostate adenoma was seen in the high-dose
group. The chemical was administered at a dose sufficient
to test its carcinogenic potential.
-- Special Study: The Effect Of CGA 184927 On Selected Biochemical
Parameters In The Rat Liver. Following
Subchronic Administration. The effects of clodinafop-propargyl
on selected liver enzymes in the rat were similar to the effects
seen after subchronic treatment with known peroxisome proliferators
(hypolipidemic compounds, phenoxyacetic acid derivatives). Hence,
clodinafop-propargyl was considered to most
likely be a peroxisome proliferator in the rat liver.
-- Special Study: Trendelenburg, C. Effects on Selected Plasma
Concentrations and Biochemical Parameters in the Liver upon Subchronic
Administration to Male Adult Rats. Clodinafop-propargyl may act
as a peroxisomal proliferating agent and
alters monooxygenase activity in subfamilies of cytochrome P450
which are known to be involved in the synthesis or catabolism
of steroid hormones.
Ref: US EPA Pesticide Fact Sheet. Reason
for Issuance: Conditional Registration. June 6, 2000.
http://www.epa.gov/opprd001/factsheets/clodinafop.pdf
Dietary treatment of
rats with concentrations over 2 years resulted in initial inappetence
in males and reduced body weight development in both sexes treated
at 750 ppm. The main target organ of toxicity
was the liver. Changes in plasma protein and lipid levels,
strongly enhanced serum activities of liver
enzymes, increased liver weights,
and severe liver necroses were observed
at dietary doses of 300 and 750 ppm in males and at 750 ppm in
females. The degenerative lesions provide strong evidence that
these dose levels exceeded a maximum tolerated dose
(MTD). Top dose group males showed a higher incidence of prostate
adenoma, while prostate hyperplasia was reduced. However, the
total incidence of proliferative changes in the prostate remained
unchanged indicating a progression from prostate hyperplasia to
adenoma. Females treated at the same high dose had higher incidences
of ovary tubular adenoma. The slightly enhanced incidences of
these lesions are likely a consequence of the severe disturbance
of the general metabolic balance due to excessive liver
toxicity. In fact, male rats fed 750 ppm exhibited a marked increase
in peroxisomal oxidation, and an increase in cytochrome P450 4A1/
A3 and 4A2 in their livers. Further,
a decrease in cytochrome P450 isoenzymes including CYP 2A, CYP
3A, and male-specific CYP 2C11 was observed. The total oxidation
rate of testosterone, aromatase (CYP 19A1) activity plasma estradiol
concentration and plasma-- dihydrotestosterone are altered at
this level of treatment. Clodinafop- propargyl is a potent peroxisome
proliferator in the rat liver and
this peroxisomal prolifering activity manifests itself by altering
Cytochrome P450-dependent monooxygenses which are involved in
steroid hormone homeostasis. The NOAEL of 10 ppm was equivalent
to a mean daily dose of 0.32 mg/kg in males and 0.37 mg/kg in
females. The EPA HIARC concluded that based on hepatocellular
hypertrophy and kidney findings, the NOAEL was 1 ppm (0.031 in
males and 0.034 in females. Carcinogenicity. The EPA HIARC recommended,
based on the increased incidence of prostate and ovarian tumors
in rats and hepatocellular tumors in mice, that the Cancer Assessment
Review Committee review clodinafop-propargyl... The scientific
evidence available amply demonstrates that exposure to substances
that produce tumors by a peroxisome proliferator mode of action
does not represent a risk of tumor development in man. Novartis,
therefore, has concluded that clodinafop-propargyl is not a carcinogen
of relevance to humans.
Ref: Federal Register. April 26, 2000. [PF-938;
FRL-6554-2]
http://www.epa.gov/fedrgstr/EPA-PEST/2000/April/Day-26/p10432.htm
Tremors
(click on for all fluorinated pesticides)
Chronic toxicity. In
a 12-month feeding study in dogs, 500 ppm resulted in transient
dermatitis and reduced body weight gain. Two females were more
severely affected and showed inappetence, body weight loss, tremors
and severe dermatitis, and necessitated an interruption of the
treatment in order to avoid mortality. Histopathology revealed
slight hepatocellular hypertrophy in one male and one female.
The NOEL of 100 ppm was equivalent to a mean daily intake of 3.38
mg/kg in males and 3.37 mg/kg in female.
Ref: Federal Register: June 5, 1998 [Page
30750-30756]. Notice of Filing of Pesticide Petitions.
http://www.fluoridealert.org/pesticides/Clodinafop-prop.FR.Ju5.1998.htm
Environmental
(click on for all fluorinated
pesticides)
--
Ecological Characteristics. Aquatic: Clodinafop-propargyl
is highly toxic to freshwater fish
and no more than moderately toxic to freshwater invertebrates
(LC50 = 0.30 ppm and EC50 > 2.0 ppm, respectively). The
primary degradate, CGA-193469, is no more than moderately
toxic to freshwater invertebrates (EC50 > 9.2 ppm). Plants:
Tier II seedling emergence tests with clodinafop-propargyl
indicate that ryegrass (shoot weight) at 0.031 lb. ai/Acre
is the most sensitive species of all monocot and dicots
tested. For Tier II vegetative vigor, corn (phytotoxicity)
at 0.0048 lb. ai/Acre is the most sensitive species of all
species tested. Aquatic plant testing with clodinafop-propargyl
indicates that the vascular plant, Lemna gibba, and the
nonvascular plant, Navicula pelliculosa, are the most sensitive
species (EC50 > 2.4 ppm and 3.0 ppm, respectively). Based
on the estimated environmental concentrations (EECs) of
clodinafop-propargyl and its acid metabolite, CGA-193469,
the use of Discoverª Herbicide is not expected to pose a
risk to non-target organisms, with the exception of non-target
plants. There is a concern for endangered
terrestrial plants inhabiting dry and semi-aquatic areas
adjacent to wheat fields when Discoverª is applied by air.
--
the major degradate, CGA-193469, is
persistent and highly mobile in low and moderate organic
matter soils and has the potential to contaminate drinking
water.
Ref: US EPA Pesticide Fact
Sheet. Reason for Issuance: Conditional Registration. June
6, 2000. http://www.epa.gov/opprd001/factsheets/clodinafop.pdf
|
A
February
17, 2005,
check at the Code
of Federal Regulations for Clodinafop-propargyl (and its
acid metabolite): this herbicide and plant growth regulator
is permitted in or on 4
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: 40CFR180.559]
[Page 504]
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. 180.559 Clodinafop-propargyl;
tolerances for residues.
(a) General. Tolerances are established for
combined residues of
clodinafop-propargyl (propanoic acid, 2-[4-(5-chloro-3-fluoro-2-
pyridinyl)oxy]phenoxy]-,2-propynyl ester, (2R)-) and
its acid metabolite
(propanoic acid, 2-[4-[(5-chloro-3-fluoro-2-pyridinyl)oxy]phenoxy]-,
(2R)-), in or on wheat, grain at 0.1 ppm ; wheat, forage at
0.1 ppm;
wheat, hay at 0.1 ppm; and wheat, straw at 0.50 ppm. |
Commodity |
As
of
September 5,
2003
PPM |
As
of
February 17,
2005
PPM |
Wheat,
forage |
0.1 |
0.1 |
Wheat,
grain |
0.1 |
0.1 |
Wheat,
hay |
0.1 |
0.1 |
Wheat,
straw |
0.5 |
0.5 |
(b)
Section 18 emergency exemptions. [Reserved]
(c) Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved] |
|