Return to Thiazopyr Index Page

Activity: Herbicide (Pyridine carboxylic acid)
Structure:

Adverse Effects:
Amyloidosis
Blood
Body Weight Decrease
Bone
Cancer: Likely to be a Human Carcinogen - THYROID, KIDNEY
Cholesterol
Endocrine: Pituitary (disruption of the thyroid-pituitary hormonal feedback mechanism)
Endocrine: Suspected Disruptor
Endocrine: Thyroid
Eye
Kidney
Liver
Environmental

Amyloidosis (click on for all fluorinated pesticides)

-- A mouse carcinogenicity study at doses of 0, 0.17, 1.6, 16.9, 66.3 or 128.4 mg/kg/day (males) and 0,0.24, 2.6, 26.8, 108.1 or 215.9 mg/kg/day (female) with a systemic NOEL of 0.1 mg/kg/day. The effects were hepatocellular hypertropy and amyloid deposition. At 66.3 mg/kg/day the same lesions plus increased liver weights, random and periportal hepatocellular vacuolation were observed. At 128.4 mg/kg/day the same lesions plus distended abdonen, slight increase in ALP, SGOT and SGPT, abnormal coloration and enlargement of liver, decrease in absolute and relative spleen weights, increase in absolute and relative kidney weights, increase in eosinophilia in hepatocytes, kidney nephropathy and lymphocytic hyperplasia of the nesenteric lymph nodes were observed. There was no evidence of oncoenicity at any dose level.
Ref: US EPA. Pesticide Fact Sheet. Thiazopyr Reason for Issuance: Registration of a New Chemical Date Issued: February 20, l997.
http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf

Blood (click on for all fluorinated pesticides)

-- Thiazopyr technical produced organ toxicity following multiple exposures at high doses. The primary target organs for thiazopyr toxicity in the rat, mouse and dog were the liver, thyroid, kidney and blood, with the liver being the most sensitive indicator of toxicity. In chronic dietary feeding studies, the dog was the most sensitive species. An RfD for thiazopyr of 0.008 mg/kg/day was established by the RfD Committee of the USEPA Health Effects Division, based on the NOEL of 0.8 mg a.i./kg/day (20 ppm) from the chronic dog study and a 100-fold safety factor to account for intraspecies extrapolation and intraspecies variability.
-- 90-day Oral (Rat): NOEL (systemic) =100 ppm (6.60 mg /kg/day and 7.99 mg/kg/day for males and females, respectively). The LOEL was 1000 ppm (68 - 79 mg/kg/day in males and females, respectively) based on increased liver, thyroid and kidney weights, changes in clinical chemistry and hematological parameters and on gross and microscopic changes observed in the liver and thyroid at does levels of 68 mg/kg/day and higher. At the 201 mg/kg/day dose diffused thyroid follicular cell hypertrophy/ hyperplasia was observed.
-- 90-day Oral (Dog): NOEL (systemic) =10 ppm. (0.2 mg/kg/day(m); 0.3 mg/kg/day(f)), based on decreased body weight gain and increased SGPT [serum glutamic-oxaloacetic transaminase] levels at 3 and 6 m/kg/day for males and females, respectively and above; decreased total protein and albumin concentration and albumin/globulin ratio, increased AP, hepatocytic hypertrophy, oval cell proliferation and increased hepatocytic fatty content at 35 mg/kg/day and above; and decreased calcium concentration which is thought to be related to hypoalbuminemia, decreased cholesterol and triglyceride concentrations, slightly increased GGT and SGPT, follicular hyperplasia of thyroid, increased colloid content in follicles and increased relative thyroid weight at 175 mg/kg/day.
-- A 1 year feeding study in dogs at 0, 0.8, 7.8, 86.0 with males, and 0.8, 8.8, and 78.0 with females with a NOEL of 0.8 mg/kg/day. The Loel was based on hepatocellular hypertrophy and hyperplasia. A 10% increase in prothrombin time and several and several changes in blood chemistry: increased SGOT, SGPT, GGT and ALK levels and decreased cholesterol, albumin and total protein and calcium were observed in high- dose dogs. There were increases in absolute weights, liver and body weight and liver to brain weight, heptotoxicity characterized by enlargement and/or discoloration in some high dose animals and by hepatocellular hypertrophy/hyperplasia in the 0.8 and 7.8 mg/kg/day dogs. The NOEL was based on hepatocellular hypertrophy and hyperplasia.
-- A two year rat carcinogenicity study at doses of 0, 0.04, 4.4, 44.2 or 136.4 mg/kg/day (Males) 0, 0.06, 0.6, 5.6, 56.3 or 177.1 mg/kg/day (female) with a NOEL of 4.4 mg/kg/day. The effects were protruding eyes, evidence of mild anemia, increased GGT and cholesterol, increased absolute and relative liver, kidney and thyroid weights and significant increase in microscopic lesions in the liver (hypertrophy and vacuolar changes), kidney (nephropathy) and thyroid (hypertrophy and hyperplasia); decreased mean body weight and body weight gain and food consumption. A statistically significant increase in thyroid follicular cell adenomas/cystadenomas were observed in males at 44.2 and 136.4 mg/kg/day. A nonsignificant increase in renal tubular adenomas in high-dose females was considered to be equivocal.
Ref: US EPA. Pesticide Fact Sheet. Thiazopyr Reason for Issuance: Registration of a New Chemical Date Issued: February 20, l997.
http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf

Body Weight Decrease (click on for all fluorinated pesticides)

-- 90-day Oral (Dog): NOEL (systemic) =10 ppm. (0.2 mg/kg/day(m); 0.3 mg/kg/day(f)), based on decreased body weight gain and increased SGPT [serum glutamic-oxaloacetic transaminase] levels at 3 and 6 m/kg/day for males and females, respectively and above; decreased total protein and albumin concentration and albumin/globulin ratio, increased AP, hepatocytic hypertrophy, oval cell proliferation and increased hepatocytic fatty content at 35 mg/kg/day and above; and decreased calcium concentration which is thought to be related to hypoalbuminemia, decreased cholesterol and triglyceride concentrations, slightly increased GGT and SGPT, follicular hyperplasia of thyroid, increased colloid content in follicles and increased relative thyroid weight at 175 mg/kg/day.
-- A developmental toxicity study in rats at 0, 10, 100 and 250 mg/kg/day with a maternal toxicity NOEL of 100 mg/kg/day. The effect were increased liver weight, increased salivation, significantly decreased body weight gain and decreased food consumption. The developmental NOEL was also 100 mg/kg/day. The effects at the high dose were increased incidence of unossified sternebrae and 7th cervical rib variation. No development effects were observed below the maternally toxic doses.
-- A two year rat carcinogenicity study at doses of 0, 0.04, 4.4, 44.2 or 136.4 mg/kg/day (Males) 0, 0.06, 0.6, 5.6, 56.3 or 177.1 mg/kg/day (female) with a NOEL of 4.4 mg/kg/day. The effects were protruding eyes, evidence of mild anemia, increased GGT and cholesterol, increased absolute and relative liver, kidney and thyroid weights and significant increase in microscopic lesions in the liver (hypertrophy and vacuolar changes), kidney (nephropathy) and thyroid (hypertrophy and hyperplasia); decreased mean body weight and body weight gain and food consumption. A statistically significant increase in thyroid follicular cell adenomas/cystadenomas were observed in males at 44.2 and 136.4 mg/kg/day. A nonsignificant increase in renal tubular adenomas in high-dose females was considered to be equivocal.
-- a. Thiazopyr was administered through the diet at 0 and 150 mg/kg/day rats to determine the subchronic effect on hormone level and other biochemical endpoints. Animals were assayed at 7, 14, 28, 56 or 90 days. Significant decreases in body weight gain were observed at 90 days. Early in the study the treated rats showed increases in TSH (ranging from 133 to 200% of controls) and decreases in T4 (ranging from 43% to 76% of controls). In addition there were increases in liver and thyroid weights and increases in thyroid follicular cell hypertrophy/hyperplasia. Reverse T3 was increased at 28 days, and T3 was either not affected or increased. There were indications of increases in hepatic UDPGT activity and significant increases in T4 UDPGT activity. Hepatic 5'-monodeiodinase activity was either not affected or decreased. The effects observed in this study were supportive of the theory that thiazopyr may induce thyroid tumors through a disruption in the thyroid-pituitary hormonal feedback mechanisms.
Ref: US EPA. Pesticide Fact Sheet. Thiazopyr Reason for Issuance: Registration of a New Chemical Date Issued: February 20, l997.
http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf

Bone (click on for all fluorinated pesticides)

-- A developmental toxicity study in rats at 0, 10, 100 and 250 mg/kg/day with a maternal toxicity NOEL of 100 mg/kg/day. The effect were increased liver weight, increased salivation, significantly decreased body weight gain and decreased food consumption. The developmental NOEL was also 100 mg/kg/day. The effects at the high dose were increased incidence of unossified sternebrae and 7th cervical rib variation. No development effects were observed below the maternally toxic doses.
Ref: US EPA. Pesticide Fact Sheet. Thiazopyr Reason for Issuance: Registration of a New Chemical Date Issued: February 20, l997.
http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf

Cancer: Likely to be a Human Carcinogen - THYROID, KIDNEY (click on for all fluorinated pesticides)

Group C -- Possible Human Carcinogen. Statistically significant increase in thyroid follicular cell tumors (M). Increases in renal tubular adenomas (M & F); however statistically significant positive trend in F only; Sprague-Dawley 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

Group C--Possible Human Carcinogen. Reviewed 5/ 25/ 94.
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

-- The thyroid tumors were determined in three special thyroid function studies to be secondary to a disturbance of thyroid/pituitary homeostasis and were attributed to a hormonally-mediated mechanism for thyroid tumor induction. The effects were dose-responsive and with the exception of thyroid weight, all effects were completely reversible when thiazopyr was removed from the diet. Based on limited evidence for carcinogenicity, thiazopyr is classified as Category C, possible human carcinogen, by the USEPA Health Effects Division Carcinogenicity Peer Review Committee. A NOEL of 4.4 mg/kg/day and a Margin of Exposure approach were selected for use in carcinogenicity risk assessment...
-- A two year rat carcinogenicity study at doses of 0, 0.04, 4.4, 44.2 or 136.4 mg/kg/day (Males) 0, 0.06, 0.6, 5.6, 56.3 or 177.1 mg/kg/day (female) with a NOEL of 4.4 mg/kg/day. The effects were protruding eyes, evidence of mild anemia, increased GGT and cholesterol, increased absolute and relative liver, kidney and thyroid weights and significant increase in microscopic lesions in the liver (hypertrophy and vacuolar changes), kidney (nephropathy) and thyroid (hypertrophy and hyperplasia); decreased mean body weight and body weight gain and food consumption. A statistically significant increase in thyroid follicular cell adenomas/cystadenomas were observed in males at 44.2 and 136.4 mg/kg/day. A nonsignificant increase in renal tubular adenomas in high-dose females was considered to be equivocal.
-- The EPA Health Effects Division Carcinogenicity Peer Review Committee classified thiazopyr as a Group C, possible human carcinogen and recommended that for the purpose of risk characterization a Margin of Exposure (M.O.E.) approach should be used in evaluation of the consequences of human exposure.
-- Special mechanistic studies for mode of toxic action on thyroid function. The results of three studies on the effects of thiazopyr on thyroid function and mechanisms involved in the disposition of T4 in rats were reviewed. These studies are described below:
---- a. Thiazopyr was administered through the diet at 0 and 150 mg/kg/day rats to determine the subchronic effect on hormone level and other biochemical endpoints. Animals were assayed at 7, 14, 28, 56 or 90 days. Significant decreases in body weight gain were observed at 90 days. Early in the study the treated rats showed increases in TSH (ranging from 133 to 200% of controls) and decreases in T4 (ranging from 43% to 76% of controls). In addition there were increases in liver and thyroid weights and increases in thyroid follicular cell hypertrophy/hyperplasia. Reverse T3 was increased at 28 days, and T3 was either not affected or increased. There were indications of increases in hepatic UDPGT activity and significant increases in T4 UDPGT activity. Hepatic 5'-monodeiodinase activity was either not affected or decreased. The effects observed in this study were supportive of the theory that thiazopyr may induce thyroid tumors through a disruption in the thyroid-pituitary hormonal feedback mechanisms.
---- b. A second study on the effects of thiazopyr on the biochemical mechanisms of thyroid toxicity in rats at doses of 0, 0.5, 1.5, 5, 15, 50 or 150 mg/kg/day was conducted. Dose response effects on various biochemical parameters were observed. Two groups of the rats in the study were observed for reversibility of effects observed up to 56 and 112 days. Doses at 15, 50 and 150 mg/kg/day significantly increased the liver weights. Thyroid weights were increased at doses of 50 and 150 mg/kg/day. There were no significant effect on body weight or body weight gains during the study. The T4 UDPGT levels were increased by 117 and 376% above controls at the 50 and 150 mg/kg/day dosages. Effects of 150 mg/kg/day were increases in T3, TSH and rT3 serum concentrations, and increased incidence of follicular cell hypertrophy/hyperplasia at the 150 mg/kg/day dose. A NOEL of 1.5 mg/kg/day was determined based on liver weight increases. Thyroid weight was the only parameter that did not return to those similar to the controls. At the 56 and 112 day recovery periods the thyroid weights were 120 and 123% of control values, respectively.
---- c. A third thyroid function study on the biochemical mechanisms involved with disposition of T4 in rats fed dosages of 0 and 150 mg/kg/day for 56 days was conducted. Rats feed thiazopyr had increase T4 UDPGT activity and total deiodinase activity in their livers. There was also a two-fold increase in mixed function oxidase enzyme activity.
-- Results of the three studies suggest that increased glucuronidation, deiodination of T4 and T3, and increased rate of clearance of T4 from the blood and excretion of the hormone and its metabolites in the bile could significantly reduce the level of circulating T4 in the male rat. Results of these studies support the hypothesis tht thiazopyr may induce thyroid tumors through a disruption of the thyroid-pituitary hormonal feedback mechanism circulating T4 in the male rat.
Ref: US EPA. Pesticide Fact Sheet. Thiazopyr Reason for Issuance: Registration of a New Chemical Date Issued: February 20, l997.
http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf

Cholesterol (click on for all fluorinated pesticides)

-- A two year rat carcinogenicity study at doses of 0, 0.04, 4.4, 44.2 or 136.4 mg/kg/day (Males) 0, 0.06, 0.6, 5.6, 56.3 or 177.1 mg/kg/day (female) with a NOEL of 4.4 mg/kg/day. The effects were protruding eyes, evidence of mild anemia, increased GGT and cholesterol, increased absolute and relative liver, kidney and thyroid weights and significant increase in microscopic lesions in the liver (hypertrophy and vacuolar changes), kidney (nephropathy) and thyroid (hypertrophy and hyperplasia); decreased mean body weight and body weight gain and food consumption. A statistically significant increase in thyroid follicular cell adenomas/cystadenomas were observed in males at 44.2 and 136.4 mg/kg/day. A nonsignificant increase in renal tubular adenomas in high-dose females was considered to be equivocal.
Ref: US EPA. Pesticide Fact Sheet. Thiazopyr Reason for Issuance: Registration of a New Chemical Date Issued: February 20, l997.
http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf

Endocrine: Pituitary (click on for all fluorinated pesticides)

-- There was no evidence of carcinogenic effects in an 18-month chronic/oncogenicity study in mice at dose levels up to and including 800 ppm (216 mg/kg/day). In rats, an increased incidence of thyroid follicular tumors in males at the two highest doses, 1000 (44.2 mg/kg/day, males) and 3000 ppm, (136.4 mg/kg/day) was observed, and there was a low incidence of renal tubular adenoma at the high dose only in females. The thyroid tumors were determined in three special thyroid function studies to be secondary to a disturbance of thyroid/pituitary homeostasis and were attributed to a hormonally-mediated mechanism for thyroid tumor induction. The effects were dose-responsive and with the exception of thyroid weight, all effects were completely reversible when thiazopyr was removed from the diet. Based on limited evidence for carcinogenicity, thiazopyr is classified as Category C, possible human carcinogen, by the USEPA Health Effects Division Carcinogenicity Peer Review Committee. A NOEL of 4.4 mg/kg/day and a Margin of Exposure approach were selected for use in carcinogenicity risk assessment.
-- Special mechanistic studies for mode of toxic action on thyroid function. The results of three studies on the effects of thiazopyr on thyroid function and mechanisms involved in the disposition of T4 in rats were reviewed. These studies are described below:
---- a. Thiazopyr was administered through the diet at 0 and 150 mg/kg/day rats to determine the subchronic effect on hormone level and other biochemical endpoints. Animals were assayed at 7, 14, 28, 56 or 90 days. Significant decreases in body weight gain were observed at 90 days. Early in the study the treated rats showed increases in TSH (ranging from 133 to 200% of controls) and decreases in T4 (ranging from 43% to 76% of controls). In addition there were increases in liver and thyroid weights and increases in thyroid follicular cell hypertrophy/hyperplasia. Reverse T3 was increased at 28 days, and T3 was either not affected or increased. There were indications of increases in hepatic UDPGT activity and significant increases in T4 UDPGT activity. Hepatic 5'-monodeiodinase activity was either not affected or decreased. The effects observed in this study were supportive of the theory that thiazopyr may induce thyroid tumors through a disruption in the thyroid-pituitary hormonal feedback mechanisms.
---- b. A second study on the effects of thiazopyr on the biochemical mechanisms of thyroid toxicity in rats at doses of 0, 0.5, 1.5, 5, 15, 50 or 150 mg/kg/day was conducted. Dose response effects on various biochemical parameters were observed. Two groups of the rats in the study were observed for reversibility of effects observed up to 56 and 112 days. Doses at 15, 50 and 150 mg/kg/day significantly increased the liver weights. Thyroid weights were increased at doses of 50 and 150 mg/kg/day. There were no significant effect on body weight or body weight gains during the study. The T4 UDPGT levels were increased by 117 and 376% above controls at the 50 and 150 mg/kg/day dosages. Effects of 150 mg/kg/day were increases in T3, TSH and rT3 serum concentrations, and increased incidence of follicular cell hypertrophy/hyperplasia at the 150 mg/kg/day dose. A NOEL of 1.5 mg/kg/day was determined based on liver weight increases. Thyroid weight was the only parameter that did not return to those similar to the controls. At the 56 and 112 day recovery periods the thyroid weights were 120 and 123% of control values, respectively.
---- c. A third thyroid function study on the biochemical mechanisms involved with disposition of T4 in rats fed dosages of 0 and 150 mg/kg/day for 56 days was conducted. Rats feed thiazopyr had increase T4 UDPGT activity and total deiodinase activity in their livers. There was also a two-fold increase in mixed function oxidase enzyme activity.
-- Results of the three studies suggest that increased glucuronidation, deiodination of T4 and T3, and increased rate of clearance of T4 from the blood and excretion of the hormone and its metabolites in the bile could significantly reduce the level of circulating T4 in the male rat. Results of these studies support the hypothesis tht thiazopyr may induce thyroid tumors through a disruption of the thyroid-pituitary hormonal feedback mechanism circulating T4 in the male rat.
Ref: US EPA. Pesticide Fact Sheet. Thiazopyr Reason for Issuance: Registration of a New Chemical Date Issued: February 20, l997.
http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf

Endocrine: Suspected Disruptor (click on for all fluorinated pesticides)

Suspected Endocrine Disruptor
Ref: June 14, 2001 - Implementation of the Community Strategy for Endocrine Disruptors - a range of substances suspected of interfering with the hormone systems of humans and wildlife. Communication from the Commission to the Council and the European Parliament. Commission of the European Communities, Brussels COM (2001) 262 final.
http://www.fluoridealert.org/pesticides/Endocrine.Disruptors.EC2001.pdf
- More information available at:
http://europa.eu.int/eur-lex/en/com/cnc/2001/com2001_0262en01.pdf

Endocrine: Thyroid (click on for all fluorinated pesticides)

-- There was no evidence of carcinogenic effects in an 18-month chronic/oncogenicity study in mice at dose levels up to and including 800 ppm (216 mg/kg/day). In rats, an increased incidence of thyroid follicular tumors in males at the two highest doses, 1000 (44.2 mg/kg/day, males) and 3000 ppm, (136.4 mg/kg/day) was observed, and there was a low incidence of renal tubular adenoma at the high dose only in females. The thyroid tumors were determined in three special thyroid function studies to be secondary to a disturbance of thyroid/pituitary homeostasis and were attributed to a hormonally-mediated mechanism for thyroid tumor induction. The effects were dose-responsive and with the exception of thyroid weight, all effects were completely reversible when thiazopyr was removed from the diet. Based on limited evidence for carcinogenicity, thiazopyr is classified as Category C, possible human carcinogen, by the USEPA Health Effects Division Carcinogenicity Peer Review Committee. A NOEL of 4.4 mg/kg/day and a Margin of Exposure approach were selected for use in carcinogenicity risk assessment.
-- Thiazopyr technical produced organ toxicity following multiple exposures at high doses. The primary target organs for thiazopyr toxicity in the rat, mouse and dog were the liver, thyroid, kidney and blood, with the liver being the most sensitive indicator of toxicity. In chronic dietary feeding studies, the dog was the most sensitive species. An RfD for thiazopyr of 0.008 mg/kg/day was established by the RfD Committee of the USEPA Health Effects Division, based on the NOEL of 0.8 mg a.i./kg/day (20 ppm) from the chronic dog study and a 100-fold safety factor to account for intraspecies extrapolation and intraspecies variability.
-- 90-day Oral (Rat): NOEL (systemic) =100 ppm (6.60 mg /kg/day and 7.99 mg/kg/day for males and females, respectively). The LOEL was 1000 ppm (68 - 79 mg/kg/day in males and females, respectively) based on increased liver, thyroid and kidney weights, changes in clinical chemistry and hematological parameters and on gross and microscopic changes observed in the liver and thyroid at does levels of 68 mg/kg/day and higher. At the 201 mg/kg/day dose diffused thyroid follicular cell hypertrophy/ hyperplasia was observed.
-- 90-day Oral (Dog): NOEL (systemic) =10 ppm. (0.2 mg/kg/day(m); 0.3 mg/kg/day(f)), based on decreased body weight gain and increased SGPT levels at 3 and 6 m/kg/day for males and females, respectively and above; decreased total protein and albumin concentration and albumin/globulin ratio, increased AP, hepatocytic hypertrophy, oval cell proliferation and increased hepatocytic fatty content at 35 mg/kg/day and above; and decreased calcium concentration which is thought to be related to hypoalbuminemia, decreased cholesterol and triglyceride concentrations, slightly increased GGT and SGPT, follicular hyperplasia of thyroid, increased colloid content in follicles and increased relative thyroid weight at 175 mg/kg/day.
-- A 3 week dermal study in rabbits at 0, 100, 500 and 1000 mg/kg/day with a NOEL of 100 mg/kg/day. The effects were increased mean absolute and relative kidney weights and minimal multifocal or periportal hypatocyte vacuolation.
-- A two year rat carcinogenicity study at doses of 0, 0.04, 4.4, 44.2 or 136.4 mg/kg/day (Males) 0, 0.06, 0.6, 5.6, 56.3 or 177.1 mg/kg/day (female) with a NOEL of 4.4 mg/kg/day. The effects were protruding eyes, evidence of mild anemia, increased GGT and cholesterol, increased absolute and relative liver, kidney and thyroid weights and significant increase in microscopic lesions in the liver (hypertrophy and vacuolar changes), kidney (nephropathy) and thyroid (hypertrophy and hyperplasia); decreased mean body weight and body weight gain and food consumption. A statistically significant increase in thyroid follicular cell adenomas/cystadenomas were observed in males at 44.2 and 136.4 mg/kg/day. A nonsignificant increase in renal tubular adenomas in high-dose females was considered to be equivocal.
-- The EPA Health Effects Division Carcinogenicity Peer Review Committee classified thiazopyr as a Group C, possible human carcinogen and recommended that for the purpose of risk characterization a Margin of Exposure (M.O.E.) approach should be used in evaluation of the consequences of human exposure.
-- Special mechanistic studies for mode of toxic action on thyroid function. The results of three studies on the effects of thiazopyr on thyroid function and mechanisms involved in the disposition of T4 in rats were reviewed. These studies are described below:
---- a. Thiazopyr was administered through the diet at 0 and 150 mg/kg/day rats to determine the subchronic effect on hormone level and other biochemical endpoints. Animals were assayed at 7, 14, 28, 56 or 90 days. Significant decreases in body weight gain were observed at 90 days. Early in the study the treated rats showed increases in TSH (ranging from 133 to 200% of controls) and decreases in T4 (ranging from 43% to 76% of controls). In addition there were increases in liver and thyroid weights and increases in thyroid follicular cell hypertrophy/hyperplasia. Reverse T3 was increased at 28 days, and T3 was either not affected or increased. There were indications of increases in hepatic UDPGT activity and significant increases in T4 UDPGT activity. Hepatic 5'-monodeiodinase activity was either not affected or decreased. The effects observed in this study were supportive of the theory that thiazopyr may induce thyroid tumors through a disruption in the thyroid-pituitary hormonal feedback mechanisms.
---- b. A second study on the effects of thiazopyr on the biochemical mechanisms of thyroid toxicity in rats at doses of 0, 0.5, 1.5, 5, 15, 50 or 150 mg/kg/day was conducted. Dose response effects on various biochemical parameters were observed. Two groups of the rats in the study were observed for reversibility of effects observed up to 56 and 112 days. Doses at 15, 50 and 150 mg/kg/day significantly increased the liver weights. Thyroid weights were increased at doses of 50 and 150 mg/kg/day. There were no significant effect on body weight or body weight gains during the study. The T4 UDPGT levels were increased by 117 and 376% above controls at the 50 and 150 mg/kg/day dosages. Effects of 150 mg/kg/day were increases in T3, TSH and rT3 serum concentrations, and increased incidence of follicular cell hypertrophy/hyperplasia at the 150 mg/kg/day dose. A NOEL of 1.5 mg/kg/day was determined based on liver weight increases. Thyroid weight was the only parameter that did not return to those similar to the controls. At the 56 and 112 day recovery periods the thyroid weights were 120 and 123% of control values, respectively.
---- c. A third thyroid function study on the biochemical mechanisms involved with disposition of T4 in rats fed dosages of 0 and 150 mg/kg/day for 56 days was conducted. Rats feed thiazopyr had increase T4 UDPGT activity and total deiodinase activity in their livers. There was also a two-fold increase in mixed function oxidase enzyme activity.
-- Results of the three studies suggest that increased glucuronidation, deiodination of T4 and T3, and increased rate of clearance of T4 from the blood and excretion of the hormone and its metabolites in the bile could significantly reduce the level of circulating T4 in the male rat. Results of these studies support the hypothesis tht thiazopyr may induce thyroid tumors through a disruption of the thyroid-pituitary hormonal feedback mechanism circulating T4 in the male rat.
Ref: US EPA. Pesticide Fact Sheet. Thiazopyr Reason for Issuance: Registration of a New Chemical Date Issued: February 20, l997.
http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf

Eye (click on for all fluorinated pesticides)

-- It is considered to be moderately irritating to the skin and substantially irritating to the eye.
-- A two year rat carcinogenicity study at doses of 0, 0.04, 4.4, 44.2 or 136.4 mg/kg/day (Males) 0, 0.06, 0.6, 5.6, 56.3 or 177.1 mg/kg/day (female) with a NOEL of 4.4 mg/kg/day. The effects were protruding eyes, evidence of mild anemia, increased GGT and cholesterol, increased absolute and relative liver, kidney and thyroid weights and significant increase in microscopic lesions in the liver (hypertrophy and vacuolar changes), kidney (nephropathy) and thyroid (hypertrophy and hyperplasia); decreased mean body weight and body weight gain and food consumption. A statistically significant increase in thyroid follicular cell adenomas/cystadenomas were observed in males at 44.2 and 136.4 mg/kg/day. A nonsignificant increase in renal tubular adenomas in high-dose females was considered to be equivocal.
Ref: US EPA Pesticide Fact Sheet. February 20, 1997.
http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf

Kidney (click on for all fluorinated pesticides)

Group C -- Possible Human Carcinogen. Statistically significant increase in thyroid follicular cell tumors (M). Increases in renal tubular adenomas (M & F); however statistically significant positive trend in F only; Sprague-Dawley 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

-- A two year rat carcinogenicity study at doses of 0, 0.04, 4.4, 44.2 or 136.4 mg/kg/day (Males) 0, 0.06, 0.6, 5.6, 56.3 or 177.1 mg/kg/day (female) with a NOEL of 4.4 mg/kg/day. The effects were protruding eyes, evidence of mild anemia, increased GGT and cholesterol, increased absolute and relative liver, kidney and thyroid weights and significant increase in microscopic lesions in the liver (hypertrophy and vacuolar changes), kidney (nephropathy) and thyroid (hypertrophy and hyperplasia); decreased mean body weight and body weight gain and food consumption. A statistically significant increase in thyroid follicular cell adenomas/cystadenomas were observed in males at 44.2 and 136.4 mg/kg/day. A nonsignificant increase in renal tubular adenomas in high-dose females was considered to be equivocal.
-- Thiazopyr technical produced organ toxicity following multiple exposures at high doses. The primary target organs for thiazopyr toxicity in the rat, mouse and dog were the liver, thyroid, kidney and blood, with the liver being the most sensitive indicator of toxicity. In chronic dietary feeding studies, the dog was the most sensitive species. An RfD for thiazopyr of 0.008 mg/kg/day was established by the RfD Committee of the USEPA Health Effects Division, based on the NOEL of 0.8 mg a.i./kg/day (20 ppm) from the chronic dog study and a 100-fold safety factor to account for intraspecies extrapolation and intraspecies variability.
-- 90-day Oral (Rat): NOEL (systemic) =100 ppm (6.60 mg /kg/day and 7.99 mg/kg/day for males and females, respectively). The LOEL was 1000 ppm (68 - 79 mg/kg/day in males and females, respectively) based on increased liver, thyroid and kidney weights, changes in clinical chemistry and hematological parameters and on gross and microscopic changes observed in the liver and thyroid at does levels of 68 mg/kg/day and higher. At the 201 mg/kg/day dose diffused thyroid follicular cell hypertrophy/ hyperplasia was observed.
-- A 3 week dermal study in rabbits at 0, 100, 500 and 1000 mg/kg/day with a NOEL of 100 mg/kg/day. The effects were increased mean absolute and relative kidney weights and minimal multifocal or periportal hypatocyte vacuolation.
-- A mouse carcinogenicity study at doses of 0, 0.17, 1.6, 16.9, 66.3 or 128.4 mg/kg/day (males) and 0,0.24, 2.6, 26.8, 108.1 or 215.9 mg/kg/day (female) with a systemic NOEL of 0.1 mg/kg/day. The effects were hepatocellular hypertropy and amyloid deposition. At 66.3 mg/kg/day the same lesions plus increased liver weights, random and periportal hepatocellular vacuolation were observed. At 128.4 mg/kg/day the same lesions plus distended abdonen, slight increase in ALP, SGOT and SGPT, abnormal coloration and enlargement of liver, decrease in absolute and relative spleen weights, increase in absolute and relative kidney weights, increase in eosinophilia in hepatocytes, kidney nephropathy and lymphocytic hyperplasia of the nesenteric lymph nodes were observed. There was no evidence of oncoenicity at any dose level.
Ref: US EPA. Pesticide Fact Sheet. Thiazopyr Reason for Issuance: Registration of a New Chemical Date Issued: February 20, l997.
http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf

Liver (click on for all fluorinated pesticides)

-- Thiazopyr technical produced organ toxicity following multiple exposures at high doses. The primary target organs for thiazopyr toxicity in the rat, mouse and dog were the liver, thyroid, kidney and blood, with the liver being the most sensitive indicator of toxicity. In chronic dietary feeding studies, the dog was the most sensitive species. An RfD for thiazopyr of 0.008 mg/kg/day was established by the RfD Committee of the USEPA Health Effects Division, based on the NOEL of 0.8 mg a.i./kg/day (20 ppm) from the chronic dog study and a 100-fold safety factor to account for intraspecies extrapolation and intraspecies variability.
-- 21-Day Dermal (Rat): NOEL =100 mg/kg/day. The LOEL was 500 mg/kg/day based on minimal hepatocellular vacuolation in females.
-- 90-day Oral (Rat): NOEL (systemic) =100 ppm (6.60 mg /kg/day and 7.99 mg/kg/day for males and females, respectively). The LOEL was 1000 ppm (68 - 79 mg/kg/day in males and females, respectively) based on increased liver, thyroid and kidney weights, changes in clinical chemistry and hematological parameters and on gross and microscopic changes observed in the liver and thyroid at does levels of 68 mg/kg/day and higher. At the 201 mg/kg/day dose diffused thyroid follicular cell hypertrophy/ hyperplasia was observed.
-- 90-day Oral (Dog): NOEL (systemic) =10 ppm. (0.2 mg/kg/day(m); 0.3 mg/kg/day(f)), based on decreased body weight gain and increased SGPT levels at 3 and 6 m/kg/day for males and females, respectively and above; decreased total protein and albumin concentration and albumin/globulin ratio, increased AP, hepatocytic hypertrophy, oval cell proliferation and increased hepatocytic fatty content at 35 mg/kg/day and above; and decreased calcium concentration which is thought to be related to hypoalbuminemia, decreased cholesterol and triglyceride concentrations, slightly increased GGT and SGPT, follicular hyperplasia of thyroid, increased colloid content in follicles and increased relative thyroid weight at 175 mg/kg/day.
-- A 1 year feeding study in dogs at 0, 0.8, 7.8, 86.0 with males, and 0.8, 8.8, and 78.0 with females with a NOEL of 0.8 mg/kg/day. The Loel was based on hepatocellular hypertrophy and hyperplasia. A 10% increase in prothrombin time and \several changes in blood chemistry: increased SGOT, SGPT, GGT and ALK levels and decreased cholesterol, albumin and total protein and calcium were observed in high- dose dogs. There were increases in absolute weights, liver and body weight and liver to brain weight, heptotoxicity characterized by enlargement and/or discoloration in some high dose animals and by hepatocellular hypertrophy/hyperplasia in the 0.8 and 7.8 mg/kg/day dogs. The NOEL was based on hepatocellular hypertrophy and hyperplasia.
-- A two-generation reproductive in rats at 0, 0.75, 7.5 and 75.0 mg/kg/day with a parental toxicity NOEL of 7.5 mg/kg/day. The toxic effects were increased absolute and relative liver weight, hepatic discoloration, histologic evidence of hepatic hypertrophy and vacuolization in females in both generations. No adverse efects were observed in adults or their offspring up to 75 mg/kg/day, the highest dose tested.
-- A mouse carcinogenicity study at doses of 0, 0.17, 1.6, 16.9, 66.3 or 128.4 mg/kg/day (males) and 0,0.24, 2.6, 26.8, 108.1 or 215.9 mg/kg/day (female) with a systemic NOEL of 0.1 mg/kg/day. The effects were hepatocellular hypertropy and amyloid deposition. At 66.3 mg/kg/day the same lesions plus increased liver weights, random and periportal hepatocellular vacuolation were observed. At 128.4 mg/kg/day the same lesions plus distended abdonen, slight increase in ALP, SGOT and SGPT, abnormal coloration and enlargement of liver, decrease in absolute and relative spleen weights, increase in absolute and relative kidney weights, increase in eosinophilia in hepatocytes, kidney nephropathy and lymphocytic hyperplasia of the nesenteric lymph nodes were observed. There was no evidence of oncoenicity at any dose level.
-- A two year rat carcinogenicity study at doses of 0, 0.04, 4.4, 44.2 or 136.4 mg/kg/day (Males) 0, 0.06, 0.6, 5.6, 56.3 or 177.1 mg/kg/day (female) with a NOEL of 4.4 mg/kg/day. The effects were protruding eyes, evidence of mild anemia, increased GGT and cholesterol, increased absolute and relative liver, kidney and thyroid weights and significant increase in microscopic lesions in the liver (hypertrophy and vacuolar changes), kidney (nephropathy) and thyroid (hypertrophy and hyperplasia); decreased mean body weight and body weight gain and food consumption. A statistically significant increase in thyroid follicular cell adenomas/cystadenomas were observed in males at 44.2 and 136.4 mg/kg/day. A nonsignificant increase in renal tubular adenomas in high-dose females was considered to be equivocal.
-- The EPA Health Effects Division Carcinogenicity Peer Review Committee classified thiazopyr as a Group C, possible human carcinogen and recommended that for the purpose of risk characterization a Margin of Exposure (M.O.E.) approach should be used in evaluation of the consequences of human exposure.
-- A second study on the effects of thiazopyr on the biochemical mechanisms of thyroid toxicity in rats at doses of 0, 0.5, 1.5, 5, 15, 50 or 150 mg/kg/day was conducted. Dose response effects on various biochemical parameters were observed. Two groups of the rats in the study were observed for reversibility of effects observed up to 56 and 112 days. Doses at 15, 50 and 150 mg/kg/day significantly increased the liver weights. Thyroid weights were increased at doses of 50 and 150 mg/kg/day. There were no significant effect on body weight or body weight gains during the study. The T4 UDPGT levels were increased by 117 and 376% above controls at the 50 and 150 mg/kg/day dosages. Effects of 150 mg/kg/day were increases in T3, TSH and rT3 serum concentrations, and increased incidence of follicular cell hypertrophy/hyperplasia at the 150 mg/kg/day dose. A NOEL of 1.5 mg/kg/day was determined based on liver weight increases. Thyroid weight was the only parameter that did not return to those similar to the controls. At the 56 and 112 day recovery periods the thyroid weights were 120 and 123% of control values, respectively.
Ref: US EPA. Pesticide Fact Sheet. Thiazopyr Reason for Issuance: Registration of a New Chemical Date Issued: February 20, l997.
http://www.epa.gov/opprd001/factsheets/thiazopyr.pdf