Adverse Effects
Isoxaflutole
CAS No. 141112-29-0

 
 

Return to Isoxaflutole Index Page

Activity: Herbicide (cyclopropylisoxazole)
Structure:


Adverse Effects:
Amyloidosis
- Systemic
Blood

Body Weight Decrease
Bone
Cancer: Probable Human Carcinogen - LIVER, THYROID
Cholesterol
Endocrine: Pituitary - disruption in the thyroid-pituitary hormonal feedback mechanisms
Endocrine: Thyroid
Eye
Liver
Lymph node
Sciatic nerve
Environmental

As of February 16, 2005, this herbicide is permitted in or on 28 food commodities in the United States - see list at bottom of page.


Amyloidosis (click on for all fluorinated pesticides)

An oncogenicity study in mice administered 0, 25, 500 and 7,000 ppm with a NOEL of 25 ppm based on a slight effect on liver weight and body weight gain at the LEL of 500 ppm. An increased incidence of hepatocellular adenomas and carcinomas was observed at 7,000 ppm in both sexes. Increased liver weight, non-neoplastic cellular changes in the liver, and amyloidosis in the duodenum, ileum, jejunum, kidneys, heart ventricle, mesenteric lymph node, and thyroid were also observed at 7,000 ppm.
Ref: Federal Register: February 26, 1997 (Volume 62, Number 38)] [Notices] [Page 8737-8740]. Rhone-Poulenc Ag Company; Pesticide Tolerance Petition Filing.

http://www.epa.gov/EPA-PEST/1997/February/Day-26/p4628.htm

Blood (click on for all fluorinated pesticides)

Short term toxicity. Target / critical effect: Periacinar hypertrophy in liver, ocular lesions, haematological effects. Lowest relevant oral NOAEL / NOEL: 3 mg/kg bw/d, rat. Lowest relevant dermal NOAEL / NOEL: 100 mg/kg bw/d, 21d rat. Lowest relevant inhalation NOAEL / NOEL: no data available, not required.
April 2003 - Review report for the active substance isoxaflutole. Isoxaflutole Sanco/3136/99-Final. 7 April 2003. Finalised in the Standing Committee on the Food Chain and Animal Health at its meeting on 15 April 2003 in view of the inclusion of isoxaflutole in Annex I of Directive 91/414/EEC.
http://www.fluorideaction.org/pesticides/isoxaflutole.eu.april.2003.pdf

Body Weight Decrease (click on for all fluorinated pesticides)

-- In a chronic toxicity study with dogs, a LOAEL was established 453 mg/kg/day for males and 498 mg/kg/day for females, based on reduced weight gains compared to controls and intravascular hemolysis with associated clinical chemistry and histopathological findings. The NOEL is 44.81 mg/kg/day for males and 45.33 mg/kg/day for females.
-- In a combined chronic toxicity/carcinogenicity study in rats, evidence of systemic toxicity was observed at 500 mg/kg/day and included: abnormal gait, limited use of limbs, lower body weight gains and food consumption, decreased food efficiency during the first 14 weeks of the study, elevated cholesterol levels throughout the 104-week study, increased absolute and relative liver weights, and thyroid hyperplasia. Increased incidence of periacinar hepatocytic hypertrophy, portal tract (senile) bile duct changes, focal cystic degeneration of the liver was observed in males at 20 mg/kg/day and greater, females at 500 mg/kg/day. Eye opacity, gross necropsy changes in eyes, corneal lesions, degeneration of sciatic nerve and thigh muscles was observed in males at 20 mg/kg/day and higher doses and in females at 500 mg/kg/day. The chronic LOAEL is 20 mg/kg/day based on liver, thyroid, ocular, and nervous system toxicity in males and liver toxicity in females. The chronic NOEL is 2.0 mg/kg/day.
-- In a developmental toxicity study in rats, maternal toxicity was observed at 500 mg/kg/day, manifested as an increased incidence of salivation, decreased body weight, weight gain, and food consumption during the dosing period. The maternal LOAEL is 500 mg/kg/day, based on increased incidence of clinical signs and decreased body weights, body weight gains, and food consumption. The maternal NOEL is 100 mg/kg/day. Developmental toxicity, observed at 100 and 500 mg/kg/day, were manifested as increased incidences of fetuses/litters with various anomalies: growth retardations (decreased fetal body weight; increased incidence of delayed ossification of sternebrae, metacarpals and metatarsals
). In addition, an increased incidence of vertebral and rib anomalies and high incidence of subcutaneous edema were observed at 500 mg/kg/day. The incidences of these anomalies were higher than the concurrent control values and in some cases exceeded the range for historical controls. The LOAEL for developmental toxicity is 100 mg/kg/day, based on decreased fetal body weights and increased incidences of skeletal anomalies. The developmental NOEL is 10 mg/kg/day.
-- In a developmental toxicity study in rabbits, maternal toxicity was observed at 100 mg/kg/day, manifested as increased incidence of clinical signs (little diet eaten and few feces) and decreased body weight gain and food consumption during the dosing period. The maternal LOAEL is 100 mg/kg/day, based on increased incidence of clinical signs, decreased body weight gains and food consumption. The maternal NOEL is 20 mg/kg/day. Developmental toxicity, observed at 5 mg/kg/day, consisted of increased incidence of 27th pre-sacral vertebrae. Additional findings noted at 20 and 100 mg/kg/day were manifested as increased number of postimplantation loss and late resorptions, as well as growth retardations in the form of generalized reduction in skeletal ossification, and increased incidence of 13 pairs of ribs. At 100 mg/kg/day, an increased incidence of fetuses with incisors not erupted was also observed. Incidences of these anomalies, on a litter basis, were higher than the concurrent control values and in some cases exceeded the range for historical controls. The LOAEL for developmental toxicity is 5 mg/kg/day, based on increased incidence of fetuses with 27th pre-sacral vertebrae. The developmental NOEL was not established.
-- Reproductive Toxicity. In a 2-generation reproduction study in rats, evidence of toxicity was observed in the male and female parental rats of both generations: at 20 and 500 mg/kg/day, increased absolute and relative liver weights associated with liver hypertrophy was observed; at 500 mg/kg/day (HDT), decreased body weight, body weight gain and food consumption during premating and gestation, and increased incidence of subacute inflammation of the cornea of the eye
in F0 adults as well as keratitis in F1 adults were reported. There were no other systemic effects that were attributed to treatment, nor was there any indication, at any treatment level, of an effect on reproductive performance of the adults. Treatment-related effects were observed in F1 and F2 offspring: at 20 and 500 mg/kg/day, reduction in pup survival was noted; at 500 mg/kg/day, decrease in body weights of F1 and F2 pups throughout lactation, increased incidence of chronic keratitis, low incidence of inflammation of the iris, as well as retinal and vitreous bleeding in F2 pups and weanlings were observed. Necropsy of F1 and F2 pups culled on Day 4 revealed an increased number of pups with no milk in the stomach and underdeveloped renal papillae. The Systemic LOAEL is 17.4 mg/kg/day for males and females, based upon increased liver weights and hypertrophy and the Systemic NOEL is 1.76 mg/kg/day for males and females. The Reproductive LOAEL is greater than 437 mg/kg/day, based on lack of reproductive effects and the Reproductive NOEL is greater than or equal to 437 mg/kg/day.
-- In a subchronic neurotoxicity study in rats, treatment-related effects observed in high-dose males consisted of decreases in body weight and body weight gain. The LOAEL was established at 25 mg/kg/day based on significant decreases in mean hind limb grip strength in male rats at 25 mg/kg/day (LDT) during both trials at week 13 as well as a non-significant decrease in mean forelimb grip strength at week 13.
Ref: US EPA. Pesticide Fact Sheet. Isoxaflutole Reason for Issuance: Conditional Registration Date Issued: September 15, 1998.

http://www.epa.gov/opprd001/factsheets/isoxaflutole.pdf

Bone (click on for all fluorinated pesticides)

-- In a developmental toxicity study in rats, maternal toxicity was observed at 500 mg/kg/day, manifested as an increased incidence of salivation, decreased body weight, weight gain, and food consumption during the dosing period. The maternal LOAEL is 500 mg/kg/day, based on increased incidence of clinical signs and decreased body weights, body weight gains, and food consumption. The maternal NOEL is 100 mg/kg/day. Developmental toxicity, observed at 100 and 500 mg/kg/day, were manifested as increased incidences of fetuses/litters with various anomalies: growth retardations (decreased fetal body weight; increased incidence of delayed ossification of sternebrae, metacarpals and metatarsals). In addition, an increased incidence of vertebral and rib anomalies and high incidence of subcutaneous edema were observed at 500 mg/kg/day. The incidences of these anomalies were higher than the concurrent control values and in some cases exceeded the range for historical controls. The LOAEL for developmental toxicity is 100 mg/kg/day, based on decreased fetal body weights and increased incidences of skeletal anomalies. The developmental NOEL is 10 mg/kg/day.
-- In a developmental toxicity study in rabbits, maternal toxicity was observed at 100 mg/kg/day, manifested as increased incidence of clinical signs (little diet eaten and few feces) and decreased body weight gain and food consumption during the dosing period. The maternal LOAEL is 100 mg/kg/day, based on increased incidence of clinical signs, decreased body weight gains and food consumption. The maternal NOEL is 20 mg/kg/day. Developmental toxicity, observed at 5 mg/kg/day, consisted of increased incidence of 27th pre-sacral vertebrae. Additional findings noted at 20 and 100 mg/kg/day were manifested as increased number of postimplantation loss and late resorptions, as well as growth retardations in the form of generalized reduction in
skeletal ossification, and increased incidence of 13 pairs of ribs. At 100 mg/kg/day, an increased incidence of fetuses with incisors not erupted was also observed. Incidences of these anomalies, on a litter basis, were higher than the concurrent control values and in some cases exceeded the range for historical controls. The LOAEL for developmental toxicity is 5 mg/kg/day, based on increased incidence of fetuses with 27th pre-sacral vertebrae. The developmental NOEL was not established.
Ref: US EPA. Pesticide Fact Sheet. Isoxaflutole Reason for Issuance: Conditional Registration Date Issued: September 15, 1998.

http://www.epa.gov/opprd001/factsheets/isoxaflutole.pdf

Cancer: Probable Human Carcinogen - LIVER, THYROID (click on for all fluorinated pesticides)

Likely to be carcinogenic to Humans. Statistically significant increases in liver tumors in both sexes of CD-1 mice & Sprague-Dawley rats; statistically significant increases in thyroid tumors in male rats.
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 8/ 6/ 97.
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.
http://www.biomuncie.org/chemicals_evaluated_for_carcinog.htm


-- Isoxaflutole demonstrates developmental toxicity and has been classified as a Group B2 carcinogen (probable human carcinogen).

-- In a combined chronic toxicity/carcinogenicity study in rats, evidence of systemic toxicity was observed at 500 mg/kg/day... Under the conditions of this study, isoxaflutole induced benign and malignant tumors of the liver in both sexes at 500 mg/kg/day hepatocellular adenomas and hepatocellular carcinomas. Combined incidences of liver adenoma/carcinoma in males and females showed animals bearing carcinomas in the majority. Thyroid follicular adenomas occurred with increased frequency in 500 mg/kg/day males. The tumor incidences exceeded the historical incidence of these tumors for this strain in the laboratory. The study demonstrated that isoxaflutole is carcinogenic to rats at a dose of 500 mg/kg/day. The chemical was administered at a dose sufficient to test its carcinogenic potential. At 500 mg/kg/day, there were alterations in most of the parameters measured including clinical signs of toxicity, body weight gain, food consumption, food conversion efficiency, and clinical as well as post-mortem pathology. Thyroid stimulating hormone (TSH) was not measured in this study. However, in a separate special study investigating the mechanism of action of isoxaflutole on the thyroid, tested at the same doses as this study, TSH was indirectly measured since there was a significant reduction in T4 level and thyroid gland weights were significantly increased. These results were sufficient to support the hypothesis that isoxaflutole may have induced thyroid tumors in male rats through a disruption in the thyroid-pituitary hormonal feedback mechanisms.
-- Among scheduled and unscheduled deaths in the 78-week study, there were significant occurrences of hepatocellular adenomas in 52% of the males and 29% of the females, and carcinomas in 33% of the males and 8% of the females (non-significant). The incidences of these tumors exceeded the corresponding historical incidence with this species in the laboratory. Combined adenoma and carcinoma incidences at 7,000 ppm were 73% for males and 35% for females. At 500 ppm, the incidences of 17% adenomas and 15% carcinomas in males and 2% adenomas in females were not statistically significant, but exceeded the means for historical controls. The 52- and 78-week studies revealed a dose-related decrease in the first occurrence of carcinomas in males; the earliest carcinomas were observed at 78, 71, 52, and 47 weeks at the 0 through 7,000 ppm doses. There were no carcinomas in females up to 78 weeks at 0, 25, or 500 ppm, although, the earliest finding at 7000 ppm was at 60 weeks. The LOAEL for this study is 64.4 mg/kg/day for males and 77.9 mg/kg/day for females (500 ppm), based on decreased body weight gains, increased liver weights, and increased incidences of histopathological liver changes. The NOEL is 3.2 mg/kg/day for males and 4.0 mg/kg/day for females (25 ppm). Although body weight was decreased marginally in females at 25 ppm, there were no corroborating findings of toxicity at this dose. Under conditions of this study, isoxaflutole appears to induce hepatocellular adenomas and carcinomas in male and female CD-1 mice. The chemical was tested at doses sufficient to measure its carcinogenic potential.
Ref: US EPA. Pesticide Fact Sheet. Isoxaflutole Reason for Issuance: Conditional Registration Date Issued: September 15, 1998.

http://www.epa.gov/opprd001/factsheets/isoxaflutole.pdf

Cholesterol (click on for all fluorinated pesticides)

In a combined chronic toxicity/carcinogenicity study, isoxaflutole was continuously administered to 75 Sprague-Dawley rats/ sex/dose at dietary levels of 0, 0.5, 2, 20 or 500 mg/kg/day for 104 weeks. An additional 20 rats/sex/group were treated for 52 weeks, after which 10 rats/sex/group were sacrificed and the remainder were held for a maximum of 8 weeks without treatment in order to assess reversibility of treatment-related changes. Evidence of systemic toxicity observed at 500 mg/kg/day in one or both sexes included: abnormal gait, limited use of limbs, lower body weight gains and food consumption, decreased food efficiency during the first 14 weeks of the study, elevated cholesterol levels throughout the 104-week study, increased absolute and relative liver weights, and thyroid hyperplasia.
Ref: Federal Register: September 23, 1998. Isoxaflutole; Pesticide Tolerance. Final Rule.

http://www.fluoridealert.org/pesticides/Isoxaflutole.FR.Sept23.1998.htm

Endocrine: Pituitary (click on for all fluorinated pesticides)

-- Isoxaflutole demonstrates developmental toxicity and has been classified as a Group B2 carcinogen (probable human carcinogen).
-- In a combined chronic toxicity/carcinogenicity study in rats, evidence of systemic toxicity was observed at 500 mg/kg/day and included: abnormal gait, limited use of limbs, lower body weight gains and food consumption, decreased food efficiency during the first 14 weeks of the study, elevated cholesterol levels throughout the 104-week study, increased absolute and relative liver weights, and thyroid hyperplasia. Increased incidence of periacinar hepatocytic hypertrophy, portal tract (senile) bile duct changes, focal cystic degeneration of the liver was observed in males at 20 mg/kg/day and greater, females at 500 mg/kg/day. Eye opacity, gross necropsy changes in eyes, corneal lesions, degeneration of sciatic nerve and thigh muscles was observed in males at 20 mg/kg/day and higher doses and in females at 500 mg/kg/day. The chronic LOAEL is 20 mg/kg/day based on liver, thyroid, ocular, and nervous system toxicity in males and liver toxicity in females. The chronic NOEL is 2.0 mg/kg/day.
-- Under the conditions of this study, isoxaflutole induced benign and malignant tumors of the liver in both sexes at 500 mg/kg/day hepatocellular adenomas and hepatocellular carcinomas. Combined incidences of liver adenoma/carcinoma in males and females showed animals bearing carcinomas in the majority. Thyroid follicular adenomas occurred with increased frequency in 500 mg/kg/day males. The tumor incidences exceeded the historical incidence of these tumors for this strain in the laboratory. The study demonstrated that isoxaflutole is carcinogenic to rats at a dose of 500 mg/kg/day. The chemical was administered at a dose sufficient to test its carcinogenic potential. At 500 mg/kg/day, there were alterations in most of the parameters measured including clinical signs of toxicity, body weight gain, food consumption, food conversion efficiency, and clinical as well as post-mortem pathology. Thyroid stimulating hormone (TSH) was not measured in this study. However, in a separate special study investigating the mechanism of action of isoxaflutole on the thyroid, tested at the same doses as this study, TSH was indirectly measured since there was a significant reduction in T4 level and thyroid gland weights were significantly increased.
These results were sufficient to support the hypothesis that isoxaflutole may have induced thyroid tumors in male rats through a disruption in the thyroid-pituitary hormonal feedback mechanisms.
Ref: US EPA. Pesticide Fact Sheet. Isoxaflutole Reason for Issuance: Conditional Registration Date Issued: September 15, 1998.

http://www.epa.gov/opprd001/factsheets/isoxaflutole.pdf

Endocrine: Thyroid (click on for all fluorinated pesticides)

-- Isoxaflutole demonstrates developmental toxicity and has been classified as a Group B2 carcinogen (probable human carcinogen).
-- In a combined chronic toxicity/carcinogenicity study in rats, evidence of systemic toxicity was observed at 500 mg/kg/day and included: abnormal gait, limited use of limbs, lower body weight gains and food consumption, decreased food efficiency during the first 14 weeks of the study, elevated cholesterol levels throughout the 104-week study, increased absolute and relative liver weights, and
thyroid hyperplasia. Increased incidence of periacinar hepatocytic hypertrophy, portal tract (senile) bile duct changes, focal cystic degeneration of the liver was observed in males at 20 mg/kg/day and greater, females at 500 mg/kg/day. Eye opacity, gross necropsy changes in eyes, corneal lesions, degeneration of sciatic nerve and thigh muscles was observed in males at 20 mg/kg/day and higher doses and in females at 500 mg/kg/day. The chronic LOAEL is 20 mg/kg/day based on liver, thyroid, ocular, and nervous system toxicity in males and liver toxicity in females. The chronic NOEL is 2.0 mg/kg/day.
-- Under the conditions of this study, isoxaflutole induced benign and malignant tumors of the liver in both sexes at 500 mg/kg/day hepatocellular adenomas and hepatocellular carcinomas. Combined incidences of liver adenoma/carcinoma in males and females showed animals bearing carcinomas in the majority.
Thyroid follicular adenomas occurred with increased frequency in 500 mg/kg/day males. The tumor incidences exceeded the historical incidence of these tumors for this strain in the laboratory. The study demonstrated that isoxaflutole is carcinogenic to rats at a dose of 500 mg/kg/day. The chemical was administered at a dose sufficient to test its carcinogenic potential. At 500 mg/kg/day, there were alterations in most of the parameters measured including clinical signs of toxicity, body weight gain, food consumption, food conversion efficiency, and clinical as well as post-mortem pathology. Thyroid stimulating hormone (TSH) was not measured in this study. However, in a separate special study investigating the mechanism of action of isoxaflutole on the thyroid, tested at the same doses as this study, TSH was indirectly measured since there was a significant reduction in T4 level and thyroid gland weights were significantly increased. These results were sufficient to support the hypothesis that isoxaflutole may have induced thyroid tumors in male rats through a disruption in the thyroid-pituitary hormonal feedback mechanisms.
Ref: US EPA. Pesticide Fact Sheet. Isoxaflutole Reason for Issuance: Conditional Registration Date Issued: September 15, 1998.

http://www.epa.gov/opprd001/factsheets/isoxaflutole.pdf

Eye (click on for all fluorinated pesticides)

-- In a combined chronic toxicity/carcinogenicity study in rats, evidence of systemic toxicity was observed at 500 mg/kg/day and included: abnormal gait, limited use of limbs, lower body weight gains and food consumption, decreased food efficiency during the first 14 weeks of the study, elevated cholesterol levels throughout the 104-week study, increased absolute and relative liver weights, and thyroid hyperplasia. Increased incidence of periacinar hepatocytic hypertrophy, portal tract (senile) bile duct changes, focal cystic degeneration of the liver was observed in males at 20 mg/kg/day and greater, females at 500 mg/kg/day. Eye opacity, gross necropsy changes in eyes, corneal lesions, degeneration of sciatic nerve and thigh muscles was observed in males at 20 mg/kg/day and higher doses and in females at 500 mg/kg/day. The chronic LOAEL is 20 mg/kg/day based on liver, thyroid, ocular, and nervous system toxicity in males and liver toxicity in females. The chronic NOEL is 2.0 mg/kg/day.
-- Reproductive Toxicity. In a 2-generation reproduction study in rats, evidence of toxicity was observed in the male and female parental rats of both generations: at 20 and 500 mg/kg/day, increased absolute and relative liver weights associated with liver hypertrophy was observed; at 500 mg/kg/day (HDT), decreased body weight, body weight gain and food consumption during premating and gestation, and increased incidence of subacute inflammation of the cornea of the eye in F0 adults as well as keratitis in F1 adults were reported. There were no other systemic effects that were attributed to treatment, nor was there any indication, at any treatment level, of an effect on reproductive performance of the adults. Treatment-related effects were observed in F1 and F2 offspring: at 20 and 500 mg/kg/day, reduction in pup survival was noted; at 500 mg/kg/day, decrease in body weights of F1 and F2 pups throughout lactation, increased incidence of chronic keratitis, low incidence of inflammation of the iris, as well as retinal and vitreous bleeding in F2 pups and weanlings were observed. Necropsy of F1 and F2 pups culled on Day 4 revealed an increased number of pups with no milk in the stomach and underdeveloped renal papillae. The Systemic LOAEL is 17.4 mg/kg/day for males and females, based upon increased liver weights and hypertrophy and the Systemic NOEL is 1.76 mg/kg/day for males and females. The Reproductive LOAEL is greater than 437 mg/kg/day, based on lack of reproductive effects and the Reproductive NOEL is greater than or equal to 437 mg/kg/day.
Ref: US EPA. Pesticide Fact Sheet. Isoxaflutole Reason for Issuance: Conditional Registration Date Issued: September 15, 1998.

http://www.epa.gov/opprd001/factsheets/isoxaflutole.pdf

Liver (click on for all fluorinated pesticides)

-- Isoxaflutole demonstrates developmental toxicity and has been classified as a Group B2 carcinogen (probable human carcinogen).
-- In a combined chronic toxicity/carcinogenicity study in rats, evidence of systemic toxicity was observed at 500 mg/kg/day and included: abnormal gait, limited use of limbs, lower body weight gains and food consumption, decreased food efficiency during the first 14 weeks of the study, elevated cholesterol levels throughout the 104-week study, increased absolute and relative liver weights, and thyroid hyperplasia. Increased incidence of periacinar hepatocytic hypertrophy, portal tract (senile) bile duct changes, focal cystic degeneration of the liver was observed in males at 20 mg/kg/day and greater, females at 500 mg/kg/day. Eye opacity, gross necropsy changes in eyes, corneal lesions, degeneration of sciatic nerve and thigh muscles was observed in males at 20 mg/kg/day and higher doses and in females at 500 mg/kg/day. The chronic LOAEL is 20 mg/kg/day based on liver, thyroid, ocular, and nervous system toxicity in males and liver toxicity in females. The chronic NOEL is 2.0 mg/kg/day.
-- Under the conditions of this study, isoxaflutole induced benign and malignant tumors of the liver in both sexes at 500 mg/kg/day hepatocellular adenomas and hepatocellular carcinomas. Combined incidences of liver adenoma/carcinoma in males and females showed animals bearing carcinomas in the majority...
-- In a 78-week carcinogenicity study, isoxaflutole had no significant effect on the survival of animals. Systemic signs of toxicity in the treated groups included: decreased body weight gain in both sexes at 500 ppm and 7,000 ppm and for females at 25 ppm group; food consumption was unaffected except food efficiency was lower for both sexes at 7000 ppm during the first 14 weeks of the study; absolute and relative/body liver weights w
ere significantly increased in both sexes at 7,000 ppm and at 500 ppm relative liver weight was increased in males at 52 weeks and in females at 78 weeks; gross necropsy at 78-week sacrifice revealed increased occurrences of liver masses in both sexes at 7,000 ppm; non-neoplastic lesions of the liver occurred at 52-week sacrifice in males at 500 ppm and in males and females at 7,000 ppm. At termination, the 500 ppm group males exhibited increased incidence of hepatocyte necrosis. At 7,000 ppm, significant increase in non-neoplastic lesions in both sexes included periacinar hepatocytic hypertrophy, necrosis, and erythrocyte-containing hepatocytes. In addition, males at the high dose had pigment-laden hepatocytes and Kupffer cells, basophilic foci, and increased ploidy; extramedullary hemopoiesis in the spleen was noted in both sexes; increase incidences of hepatocellular adenoma and carcinoma were observed in both sexes at 7,000 ppm in the 52-week and 78-week studies.
-- Among scheduled and unscheduled deaths in the 78-week study, there were significant occurrences of hepatocellular adenomas in 52% of the males and 29% of the females, and carcinomas in 33% of the males and 8% of the females (non-significant). The incidences of these tumors exceeded the corresponding historical incidence with this species in the laboratory. Combined adenoma and carcinoma incidences at 7,000 ppm were 73% for males and 35% for females. At 500 ppm, the incidences of 17% adenomas and 15% carcinomas in males and 2% adenomas in females were not statistically significant, but exceeded the means for historical controls. The 52- and 78-week studies revealed a dose-related decrease in the first occurrence of carcinomas in males; the earliest carcinomas were observed at 78, 71, 52, and 47 weeks at the 0 through 7,000 ppm doses. There were no carcinomas in females up to 78 weeks at 0, 25, or 500 ppm, although, the earliest finding at 7000 ppm was at 60 weeks. The LOAEL for this study is 64.4 mg/kg/day for males and 77.9 mg/kg/day for females (500 ppm), based on decreased body weight gains, increased liver weights, and increased incidences of histopathological liver changes. The NOEL is 3.2 mg/kg/day for males and 4.0 mg/kg/day for females (25 ppm). Although body weight was decreased marginally in females at 25 ppm, there were no corroborating findings of toxicity at this dose. Under conditions of this study, isoxaflutole appears to induce hepatocellular adenomas and carcinomas in male and female CD-1 mice. The chemical was tested at doses sufficient to measure its carcinogenic potential.
-- Reproductive Toxicity. In a 2-generation reproduction study in rats, evidence of toxicity was observed in the male and female parental rats of both generations: at 20 and 500 mg/kg/day, increased absolute and relative liver weights associated with liver hypertrophy was observed.. The Systemic LOAEL is 17.4 mg/kg/day for males and females, based upon increased liver weights and hypertrophy and the Systemic NOEL is 1.76 mg/kg/day for males and females...
Ref: US EPA. Pesticide Fact Sheet. Isoxaflutole Reason for Issuance: Conditional Registration Date Issued: September 15, 1998.

http://www.epa.gov/opprd001/factsheets/isoxaflutole.pdf

Lymph node (click on for all fluorinated pesticides)

An oncogenicity study in mice administered 0, 25, 500 and 7,000 ppm with a NOEL of 25 ppm based on a slight effect on liver weight and body weight gain at the LEL of 500 ppm. An increased incidence of hepatocellular adenomas and carcinomas was observed at 7,000 ppm in both sexes. Increased liver weight, non-neoplastic cellular changes in the liver, and amyloidosis in the duodenum, ileum, jejunum, kidneys, heart ventricle, mesenteric lymph node, and thyroid were also observed at 7,000 ppm.
Ref: Federal Register: February 26, 1997 (Volume 62, Number 38)] [Notices] [Page 8737-8740]. Rhone-Poulenc Ag Company; Pesticide Tolerance Petition Filing.
http://www.epa.gov/EPA-PEST/1997/February/Day-26/p4628.htm

Sciatic nerve (click on for all fluorinated pesticides)

-- In a combined chronic toxicity/carcinogenicity study in rats, evidence of systemic toxicity was observed at 500 mg/kg/day and included: abnormal gait, limited use of limbs, lower body weight gains and food consumption, decreased food efficiency during the first 14 weeks of the study, elevated cholesterol levels throughout the 104-week study, increased absolute and relative liver weights, and thyroid hyperplasia. Increased incidence of periacinar hepatocytic hypertrophy, portal tract (senile) bile duct changes, focal cystic degeneration of the liver was observed in males at 20 mg/kg/day and greater, females at 500 mg/kg/day. Eye opacity, gross necropsy changes in eyes, corneal lesions, degeneration of sciatic nerve and thigh muscles was observed in males at 20 mg/kg/day and higher doses and in females at 500 mg/kg/day. The chronic LOAEL is 20 mg/kg/day based on liver, thyroid, ocular, and nervous system toxicity in males and liver toxicity in females. The chronic NOEL is 2.0 mg/kg/day.
Ref: US EPA. Pesticide Fact Sheet. Isoxaflutole Reason for Issuance: Conditional Registration Date Issued: September 15, 1998.

http://www.epa.gov/opprd001/factsheets/isoxaflutole.pdf

Thyroid (click on for all fluorinated pesticides)

Likely to be carcinogenic to Humans. Statistically significant increases in liver tumors in both sexes of CD-1 mice & Sprague-Dawley rats; statistically significant increases in thyroid tumors in male rats.
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

Environmental (click on for all fluorinated pesticides)

-- The data available at this time indicate that isoxaflutole is very phytotoxic.
-- Isoxaflutole is persistent and mobile, and may leach and accumulate in groundwater and through surface water.

-- Potential to Contaminate Groundwater. Isoxaflutole is mobile and is expected to persist and accumulate in surface water and groundwater. Modeling data show that parent isoxaflutole and its primary metabolite RPA 202248 may accumulate to concentrations that would result in harm to non-target plants. Isoxaflutole’s terminal metabolite RPA 203328 is expected to persist and accumulate, but does not demonstrate phytotoxicity. Additional studies, including prospective groundwater studies and surface water monitoring, will be conducted to determine whether isoxaflutole and its primary metabolite RPA 202248 do or do not exceed concentrations deemed potentially harmful to the environment.
-- Aquatic - Freshwater. Isoxaflutole is moderately toxic to the rainbow trout (96-hour LC50 > 1.7 ppm) and to the bluegill sunfish (96-hour LC50 > 4.5 ppm). It is also moderately toxic to Daphnia magna (48-hour EC50 > 1.5 ppm).
-- Aquatic - Estuarine/Marine. Isoxaflutole is highly toxic to the mysid shrimp (96-hour LC50 /EC50 = 0.018 ppm) and moderately toxic to the eastern oyster (96-hour LC50 /EC50 = 3.3 ppm). It is moderately toxic to the sheepshead minnow (96-hour LC50 > 6.4 ppm)
-- Plants. Isoxaflutole is highly toxic terrestrial plants (EC25 = 1 X 10 -5 pounds active ingredient./Acre). Due to the low vapor pressure of this herbicide, and due to the fact that it is only to be applied using ground equipment, risk to nontarget plant species is not expected from the parent compound. The primary metabolite RPA 202248, however, is mobile and is expected to move off-site. Additional studies, including prospective groundwater studies and surface water monitoring, will be conducted to determine whether isoxaflutole and its primary metabolite RPA 202248 do or do not exceed concentrations deemed potentially harmful to the environment.

Ref: US EPA. Pesticide Fact Sheet. Isoxaflutole Reason for Issuance: Conditional Registration Date Issued: September 15, 1998.
http://www.epa.gov/opprd001/factsheets/isoxaflutole.pdf


A  February 16, 2005, check at the Code of Federal Regulations for Isoxaflutole: this herbicide is permitted in or on 28 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: 40CFR180.537]
[Page 495-496]

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. 180.537 Isoxaflutole; tolerances for residues.
(a) General. (1) Tolerances are established for combined residues of
the herbicide isoxaflutole
[5-cyclopropyl-4-(2-methylsulfonyl-4-
trifluoromethyl benzoyl) isoxazole] and its metabolites 1-(2-
methylsulfonyl-4-trifluoromethylphenyl)-2-cyano-3-cyclopropyl propan-
1,3-dione (RPA 202248) and 2-methylsulphonyl-4-trifluoromethyl benzoic
acid (RPA 203328), calculated as the parent compound, in or on the
following raw agricultural commodities:
Commodity

As of
October 11, 2003

PPM

As of
February 16, 2005

PPM

CFR

Corn, field, forage 1.0 1.0 180.537
Corn, field, grain 0.20 0.20 180.537
Corn, field, stover 0.50 0.50 180.537
2) Tolerances are established for combined residues of the
herbicide isoxaflutole
[5-cyclopropyl-4-(2-methylsulfonyl-4-
trifluoromethyl benzoyl) isoxazole] and its metabolite 1-(2-
methylsulfonyl-4-trifluoromethylphenyl)-2-cyano-3-cyclopropyl propan-
1,3-dione (RPA 202248), calculated as the parent compound, in or on the
following raw agricultural commodities:
Cattle, fat 0.20 0.20 180.537
Cattle, liver 0.50 0.50 180.537
Cattle, meat 0.20 0.20 180.537
Cattle, meat byproducts, except liver 0.10 0.10 180.537
Egg 0.01 0.01 180.537
Goat, fat 0.20 0.20 180.537
Goat, liver 0.50 0.50 180.537
Goat, meat 0.20 0.20 180.537
Goat, meat byproducts, except liver 0.10 0.10 180.537
Hog, fat 0.20 0.20 180.537
Hog, liver 0.50 0.50 180.537
Hog, meat 0.20 0.20 180.537
Hog, meat byproducts, except liver 0.10 0.10 180.537
Horse, fat 0.20 0.20 180.537
Horse, liver 0.50 0.50 180.537
Horse, meat 0.20 0.20 180.537
Horse, meat byproducts, except liver 0.10 0.10 180.537
Milk 0.02 0.02 180.537
Poultry, fat 0.20 0.20 180.537
Poultry, liver 0.30 0.30 180.537
Poultry, meat 0.20 0.20 180.537
Sheep, fat 0.20 0.20 180.537
Sheep, liver 0.50 0.50 180.537
Sheep, meat 0.20 0.20 180.537
Sheep, meat byproducts, except liver 0.10 0.10 180.537
(b) Section 18 emergency exemptions. [Reserved]
(c) Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved]
 
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