Adverse Effects
Clodinafop-propargyl
CAS No. 105512-06-9
 
 

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 Discover™ 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 Discover™ 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]
 
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