Thyroid - Adverse Effects
Fluorinated and Fluoride Pesticides
beginning with
A-G • H-Z
 
 
See - brief information on the thyroid

The Endocrine System


Illustration by K. Born in Our Stolen Future (1996)
by Theo Colborn, Dianne Dumanoski and JP Myers

The use of high doses increases the likelihood that potentially significant toxic effects will be identified. Findings of adverse effects in any one species do not necessarily indicate such effects might be generated in humans. From a conservative risk assessment perspective however, adverse findings in animal species are assumed to represent potential effects in humans, unless convincing evidence of species specificity is available.

-- Food and Agricultural Organization of the United Nations

Note: This is not an exhaustive list.
When time allows more information will be added.

Haloxyfop - Herbicide - CAS No. 69806-34-4

The subchronic toxicity of haloxyfop (2-(4-((3-chloro-5-(trifluoromethyl)-2- pyridinyl)oxy)phenoxy)propanoic acid) herbicide, a peroxisome proliferator, was evaluated in rats, mice, dogs and monkeys. Male rats given 0.2 or 2.0 mg/kg/day and female rats given 2.0 mg/kg/day in feed for 16 weeks had peroxisome associated hepatocellular hypertrophy. Male and female rats given 2.0 mg/kg/day for 37 weeks also had increased renal tubular pigment. Mice given 2.0 mg/kg/day in feed for 13 weeks had peroxisome associated hepatocellular hypertrophy. Dogs fed 20 mg/kg/day and monkeys gavaged with 30 mg/kg/day for 13 weeks had hepatocellular hypertrophy, decreased size of thyroid follicles, and decreased red blood cell counts and serum cholesterol. Hepatocellular effects in dogs and monkeys were not associated with peroxisome proliferation. No-observed effect levels were between 0.02 and 0.2 mg/kg/day for rats, 0.2 mg/kg/day for mice, and 2 mg/kg/day for dogs and monkeys. There were no effects on reproduction in rats at dose levels up to 1.0 mg/kg/day or evidence of teratogenicity in rats or rabbits at dose levels up to 7.5 or 20 mg/kg/day, respectively.
Ref: Subchronic and reproductive toxicity and teratology of haloxyfop herbicide. Authors: Quast JF Yano BL Dietz FK Marler RM Hayes WC. Source: Toxicologist 1990 Feb;10(1):175. As cited at Toxnet.

Haloxyfop-methyl - Herbicide - CAS No. 69806-40-2

-- 2) 13-Week Feeding - dog: Dietary levels tested: 0, 2, 5, and 20 mg/kg/day; Beagle dogs (4/sex/dose level) were administered haloxyfop-methyl in the diet for 13 weeks. A statistically significant decrease in serum cholesterol values was reported for males fed 2 mg/kg/day. A statistically significant decrease in serum cholesterol values was reported for males and females fed 5 mg/kg/day. A significant decrease in male and female triiodothyronine and free thyroxine values was accompanied by a significant decrease in male and female relative thyroid/parathyroid weights. Hepatic peroxisomal fatty acid beta-oxidation was increased in males and females fed 5 mg/kg/day. Histological changes reported at this level were hepatocellular enlargement with increased glycogen content, decrease in follicular size and hypertrophy of the follicular epithelial cells of the thyroid, and decrease size of the testicular tubules. The LEL for systemic toxicity is 2 mg/kg/day, the lowest dose tested, based on decreases in serum cholesterol values in males. A NOEL for systemic toxicity was not established; core grade minimum (Dow Chemical Co., 1987a)
Ref: Health Assessment. US EPA Integrated Risk Information System (IRIS).
http://www.fluoridealert.org/pesticides/haloxyfop.methyl.iris.htm

Isoxaflutole - Herbicide - CAS No. 141112-29-0

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

-- 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

Lactofen - Herbicide - CAS No. 77501-63-4

Dog chronic toxicity LOAEL = 3.96 mg/kg/day based on increased incidence of
proteinaceous casts in the kidneys, and statistically significant increases in the absolute weights of the thyroid and adrenal glands in males.
Ref: Sept 24, 2004. Lactofen. Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluorideaction.org/pesticides/lactofen.fr.sept.24.2004.htm

Lambda-cyhalothrin - see Cyhalothrin, lambda

Norflurazon - Herbicide - CAS No. 27314-13-2

Congestion of the liver, hepatocyte swelling and increased liver weights, and increase in colloid vacuole in the thyroid were observed in dogs fed 450 ppm (10.25 mg/kg/day) norflurazon for 6 months. The NOEL was 150 ppm (3.75 mg/kg/day). An oral RfD of 0.04 mg/ kg/day has been determined. Increased relative liver weight and hypertrophy of the thyroid with depletion of colloid were seen in rats fed 2,500 ppm (125 mg/kg/day) norflurazon for 90 days. The NOEL was 500 ppm (25 mg/kg/day). Hepatic hyperplasia and hypertrophy and increased relative liver weight were noted in a 28-day feeding study in rats. The LOEL was 1,000 ppm (50 mg/kg/day) and the NOEL was 500 ppm (25 mg/kg/ day). Increased relative liver weight and diffuse and smooth granular livers were seen in a 28-day feeding study in mice. The LOEL was 2,520 ppm (328 mg/kg/day) and the NOEL was 420 ppm (55 mg/kg/day). EPA believes that there is sufficient evidence for listing norflurazon on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available hepatic and thyroid toxicity data.
Ref: USEPA/OPP. Support Document for the Addition of Chemicals from Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) Active Ingredients to EPCRA Section 313. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.

-- A nine-month oral toxicity study (MRID 00091056) was conducted using the F generation of rats from a two-year carcinogenicity study (MRID 00082019). In this study, rats were given technical norflurazon in the diet at dose levels of 0, 125, 250, or 500 ppm (0, 6.25, 12.5, and 25 mg/kg/day) for 39 weeks... At 500 ppm... Thyroid weight was decreased in males by approximately 30% vs control, while thyroid weight was increased in females between 11-47% vs control. Gonadal weight (left gonad) was increased in female rats by 30%. At 250 ppm, thyroid weight was decreased by 30% in male rats, but was increased by 11-29% in female rats. However, there were no reported microscopic alterations in this organ at any dose level tested. Gonadal weight in female rats was increased by 17% vs. control. The systemic NOEL was determined to be 250 ppm (12.5 mg/kg/day) in both sexes. The systemic LEL was determined to be 500 ppm (25 mg/kg/day) in both sexes, based on the dose-related increase in liver weight in male and female rats at 39 weeks, the increase in gonad weight of females, and the microscopic changes observed in kidneys of both sexes. Although dramatic effects on thyroid weight were observed at 250 ppm in both sexes, there were no data indicating any alteration in histology of this organ. Thus, the weight change, while indicative of an effect of norflurazon, is not supported as a toxic effect based on available data (guideline: non-guideline study; classified as core supplementary; MRID 00091056).
-- A chronic toxicity and carcinogenicity study was conducted in Sprague-Dawley rats. In this study, technical norflurazon was administered in the diet at dose levels of 0, 125, 375, or 1025 ppm (0, 6.25, 18.75, or 51.25 mg/kg/day) for 104 weeks... The weight of the thyroid was also increased at the 1025 ppm dose in male rats at 104 weeks. An increased incidence of hydronephrosis was observed in high dose male rats at 52 weeks vs control, while the incidence of nephritis
was increased in male rats (terminal sacrifice + dying on test) at the 1025 ppm dose. The incidence of tubular casts was increased in female rats at the high dose in those rats surviving to study termination. Other microscopic alterations observed at the high dose included an increased incidence of parathyroid hyperplasia (both sexes), hemosiderin pigment deposition in the spleen (males only) and liver (both sexes), and endometritis and squamous metaplasia of the uterus (females). The systemic NOEL was determined to be 375 ppm (18.75 mg/kg/day) for both sexes. The systemic LEL was determined to be 1025 ppm (51.25 mg/kg/day) in both sexes, based on the increased kidney weight and accompanying microscopic pathologic changes, as well as the increase in liver weight in male and female rats and the increase in thyroid weight in males. There was no evidence of carcinogenicity for norflurazon (guideline 83-5; MRIDs 00111617 and 00082019). As a result of the July 18, 1990 meeting of the OPP/Health Effects Division Carcinogenicity Peer Review Committee, norflurazon was classified as a non quantifiable Group C - possible human carcinogen - based upon statistically significant pair-wise comparisons of the incidence of liver adenomas and combined liver adenomas/ carcinomas as well as statistically positive trends for these lesions in male CD-1 mice receiving 218.8 mg/kg/day norflurazon technical in the diet for up to 104 weeks (MRID 00111649).
Ref: US EPA REREGISTRATION ELIGIBILITY DECISION NORFLURAZON. LIST A. CASE 0229.

http://www.fluoridealert.org/PESTICIDES/Norflurazon.RED.EPA.pdf

Oxyfluorfen - Herbicide - CAS No. 42874-03-3

Absolute and relative thymus weights were decreased in mid-dose males (-14%/-10%)and high-dose males (-32%/- 18%)...Vacuolation of the adrenal cortex was present in high-dose females. Thymic atrophy occurred in high-dose males and females.... Fine vacuolation of adrenal glands (slight)and cortical atrophy of the thymus (slight) were increased in high-dose males... Absolute and/or relative organ weights in the high-dose groups that showed statistically significant changes relative to control weights (thyroid gland in both sexes and kidney in females at 12 months and brain, pituitary, and spleen in females sacrificed at 24 months) had no microscopic correlates and are not considered toxicologically significant.
Ref: US EPA. Toxicology Chapter for RED. August 8, 2001.

http://www.epa.gov/oppsrrd1/reregistration/oxyfluorfen/oxytoxchapter.pdf

PFOS - PFOS - Insecticide, US EPA List 3 Inert

Due to length, click here for effects page


Picolinafen - Herbicide - CAS No. 137641-05-5

-- In a study in which groups of two dogs per sex were fed picolinafen at dietary concentrations of 0, 100, 1000, 2000, or 10000 ppm for 28 days, food consumption and body weight gain were reduced at 10000 ppm... Thyroid weight was increased in a dose-related manner in dogs at all doses and thyroid enlargement accompanied by histopathological changes was observed at 1000 ppm.
-- In groups of four dogs per sex fed picolinafen at dietary concentrations of 0, 50, 500 or 2500 ppm for 90 days haemoglobin... Thyroids were enlarged at 2500 ppm and thyroid weights were increased in males at 500 ppm and in females at 2500 ppm... Follicular hypertrophy was observed in the thyroid at 500 and 2500 ppm with hyperplasia at 2500 ppm. The NOEL in this study was 50 ppm equal to 1.7 mg/kg bw/day in males and 1.8 mg/kg bw/day in females.
-- In dogs fed picolinafen at dietary concentrations of 0, 50, 150 or 1500 ppm for 12 months body weight gains were decreased in all groups of treated males... Enlarged thyroids and increased thyroid weights were observed at 1500 ppm. Increased follicular hypertrophy in the thyroid was observed in both sexes at 1500 ppm and hyperplasia in the thyroid was observed in females at 1500 ppm. A NOEL could not be established in this study since body weight gain was reduced at all tested doses. The LOEL in this study was 50 ppm, equal to 1.4 mg/kg bw/day in males and 1.6 mg/kg bw/day in females.
Ref: Public Release Summary on Evaluation of the new active PICOLINAFEN in the products SNIPER HERBICIDE & PARAGON HERBICIDE. Australia. National Registration Authority for Agricultural and Veterinary Chemicals November 2000.

http://www.nra.gov.au/publications/prspic.pdf

-- Although findings indicative of hemolytic anemia were noted in dogs following 90-day and 1-year dietary administration, the main target organ appeared to be the thyroid as indicated by increased thyroid weight, diffuse hypertrophy of the thyroid follicular epithelial cells, and scattered foci of thyroid follicular cell hyperplasia, at 500 ppm (17.3 and 20.2 mg/kg bw/d and above for males and females, respectively) and above following 90-day dietary administration and at 1500 ppm (42.7 and 47.1 mg/kg bw/d for males and females, respectively) and above following 1-year dietary administration (the differences noted following 90-day and 1-year dietary administration were due to dose selection). Hormone levels (thyroxine, tri-iodothyronine and thyroid stimulating hormone [TSH]) were not determined. Lower body weight and/or body-weight gain were also noted in dogs at 2500 ppm (equal to 87.5 and 92.1 mg/kg bw/d for males and females, respectively) following 90-day dietary administration and at 150 ppm (1.7 and 1.8 mg/kg bw/d and above for males and females, respectively) and above following 1-year dietary administration. The NOAEL following 90-day dietary administration was 50 ppm (equal to 1.7 and 1.8 mg/kg bw/d for males and females, respectively). The NOAEL following 1-year dietary administration was 50 ppm (equal to 1.4 and 1.6 mg/kg bw/d for males and females, respectively).
-- The treatment-related findings noted in the thyroid (increased thyroid weight, diffuse hypertrophy of the thyroid follicular epithelial cells, and scattered foci of thyroid follicular cell hyperplasia) in dogs following 90-day and 1-year dietary administration may be suggestive of a neurotoxicity potential. Similar lesions were not observed in the rat (including neonates) or mouse following subchronic or chronic dietary exposure and there was no other evidence in any species tested to indicate a neurotoxicity potential. Thyroid hormone (thyroxine, tri-iodothyronine, and TSH) levels were not determined. Thyroid hormones are crucial to normal growth and development in the central nervous system and in the absence of the hormone, brain development can be retarded; therefore, in the absence of thyroid hormone data and in the absence of any human data, these lesions cannot be disregarded and must be considered relevant to humans.

Ref: February 17, 2003 - Canada. Picolinafen. Regulatory Note REG2003-02. Alternative Strategies and Regulatory Affairs Division, Pest Management Regulatory Agency.
http://www.fluorideaction.org/pesticides/picolinafen.canada.feb.2003.pdf

Occupational exposure will be predominately via the dermal route, and of short- to intermediate-term duration. Although a 4-week repeat dose dermal toxicity study is available, it is not considered adequate for occupational and bystander risk assessment since it does not adequately account for the treatment-related findings noted in the thyroid in dogs following 90-day and 1-year dietary administration. To account for these findings, it is recommended that the dog 90 day dietary study be used for the proposed exposure scenarios. The recommended NOAEL is 1.7 mg/kg bw/d. A safety factor of 100 to account for intraspecies and interspecies variations is considered to be adequate; no additional safety factors were used because there was an adequate MOE to the NOAEL of 4.4 mg/kg bw/d for thyroid effects in the 1-year dietary dog study.
Ref: Nov 2005 - AC 900001 (Picolinafen). Proposed Regulatory Decision Document. PRDD2005-5. Canadian Pest Management Regulatory Agency (PMRA).
http://www.fluorideaction.org/pesticides/picolinafen.canada.nov05.pdf

Primisulfuron-methyl - Fungicide, Herbicide- CAS No. 86209-51-0

-- Chronic toxicity: Doses of 125 mg/kg/day administered in the diet to dogs over a 1-year period produced decreased body weight gain, anemia, increased liver weight, and thyroid hyperplasia (abnormal growth) [15]. Rats fed dietary doses of about 180 mg/kg/day over 90 days showed effects similar to those noted in dogs, as well as spleen weight increases [24]. In another study, doses of 480 mg/kg/day in rats over 18 months produced increased incidence of tooth disorders, chronic nephritis (kidney damage), and testicular atrophy [4]. In two 18-month studies in mice, testicular atrophy, chronic nephritis, and increased tooth and bone disorders were seen at doses of 180 mg/kg/day and 360 mg/kg/day, respectively [4].
Ref: E X T O X N E T Extension Toxicology Network Pesticide Information Profiles. Revised June 1996.

http://ace.ace.orst.edu/info/extoxnet/pips/primisul.htm

In a 90-day dog feeding study, reduced thyroid weights accompanied by colloid depletion and parafollicular hyperplasia and anemia were observed at the LOEL of 25 mg/kg/day. The NOEL was 0.625 mg/kg/day. In a 1-year dog study, dietary administration of 250/125 mg/kg/day (LOEL: the dose was changed after week 10 in the study) produced thyroid hyperplasia, anemia, increased platelet levels, vacuolar changes, and increased absolute and relative liver weights. The NOEL was 25 mg/kg/day. In an 18-month study in mice, dietary administration of 1.7 mg/kg/day produced increased absolute and relative liver weights in females. No NOEL was established. Based on this study, an oral RfD of 0.006 mg/kg/day was derived. In a 2-year mouse study, increases in absolute and relative liver weights were observed at 408 mg/kg/day in males and 1.7 mg/kg/day in females. The systemic LOEL and NOEL in males was 408 mg/kg/day and 40.2 mg/kg/day, respectively. The systemic LOEL in females was 1.7 mg/kg/day and a NOEL could not be established. EPA believes that there is sufficient evidence for listing primisulfuron on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available thyroid and liver toxicity data for this chemical.
Ref: USEPA/OPP. Support Document for the Addition of Chemicals from Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) Active Ingredients to EPCRA Section 313. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.

Prodiamine - Herbicide - CAS No. 29091-21-2

Group C -- Possible Human Carcinogen. Thyroid follicular cell neoplasia (M & F); Pancreatic adenomas (F) in Sprague-Dawley rats. Fibrosarcomas; CD-1 mice (M).
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

Abstract: Of 240 pesticides screened for carcinogenicity by the U.S. Environmental Protection Agency Office of Pesticide Programs, at least 24 (10%) produce thyroid follicular cell tumors in rodents. Thirteen of the thyroid carcinogens also induce liver tumors, mainly in mice, and 9 chemicals produce tumors at other sites. Some mutagenic data are available on all 24 pesticides producing thyroid tumors. Mutagenicity does not seem to be a major determinant in thyroid carcinogenicity, except for possibly acetochlor; evidence is less convincing for ethylene thiourea and etridiazole. Studies on thyroid-pituitary functioning, including indications of thyroid cell growth and/or changes in thyroxine, triiodothyronine, or thyroid-stimulating hormone levels, are available on 19 pesticides. No such antithyroid information is available for etridiazole, N-octyl bicycloheptene dicarboximide, terbutryn, triadimefon, and trifluralin. Of the studied chemicals, only bromacil lacks antithyroid activity under study conditions. Intrathyroidal and extrathyroidal sites of action are found: amitrole, ethylene thiourea, and mancozeb are thyroid peroxidase inhibitors; and acetochlor, clofentezine, fenbuconazole, fipronil, pendimethalin, pentachloronitrobenzene, prodiamine, pyrimethanil, and thiazopyr seem to enhance the hepatic metabolism and excretion of thyroid hormone. Thus, with 12 pesticides that mode of action judgments can be made, 11 disrupt thyroid-pituitary homeostasis only; no chemical is mutagenic only; and acetochlor may have both antithyroid and some mutagenic activity. More information is needed to identify other potential antithyroid modes of thyroid carcinogenic action.
Ref: Hurley PM (1998). Mode of carcinogenic action of pesticides inducing thyroid follicular cell tumors in rodents. Environ Health Perspect; Aug;106(8):437-45.

-- Chronic/Subchronic Toxicity Studies. Prodiamine: Liver (alteration and enlargement) and thyroid effects (hormone imbalances) at high dose levels (rats); decreased body weight gains.
-- Carcinogenic Potential. Prodiamine: Benign thyroid tumors (rat). None observed (mouse).
-- Target Organs. Prodiamine: Liver and Thyroid.
Ref: Material Safety Data Sheet for Barricade 65WG Herbicide. Novartis. February 28, 2000.
http://www.fluoridealert.org/pesticides/prodiamine.msds.2000.pdf

Sodium bifluoride - Insecticide, Former US EPA List 3 Inert - CAS No. 1333-83-1

ENDOCRINE 0.2.16.2 CHRONIC EXPOSURE - Fluoride exposure can cause moderate functional changes in the hypophysis-thyroid gland system without any clinical manifestations. [FAN note: Hypophysis = Pituitary gland]
Ref: Hazardous Substances Data Bank for SODIUM HYDROGEN DIFLUORIDE CASRN: 1333-83-1
http://www.fluorideaction.org/pesticides/sodium.bifluoride.toxnet.htm

Sulfuryl fluoride - Fumigant insecticide - CAS No. 2699-79-8

-- In subchronic (90-day) inhalation studies - In mice, follicular cell hypertrophy was noted in the thyroid gland. Decreased body weights and body weight gains were also observed in rats, dogs and mice.
-- In chronic (1-2 year) inhalation studies - . In dogs and mice, increased mortalities, malacia and/or vacuolation in the white matter in the brain, histopathology in the lungs, and follicular cell hypertrophy in the thyroid gland were observed. Decreased body weights and body weight gains were also noted in all three species. No evidence of carcinogenicity was observed in either the combined chronic toxicity/ carcinogenicity study in rats or in the 18-month carcinogenicity study in mice.
Ref: Federal Register: September 5, 2001 (Volume 66, Number 172). Sulfuryl Fluoride; Proposed Pesticide Temporary Tolerances.

http://www.fluorideaction.org/pesticides/sulfuryl.flu.fr.sept.5.2001.htm

18-Month carcinogenicity NOAEL = 25/25 (M/F) mg/kg/day inhalation study--mouse LOAEL = 101/101 (M/F) mg/kg/day based (870.4200) on for both M/F cerebral vacuolation in brain, decreased body weight gain, follicular hypertrophy in thyroid (M only), increased mortality (F only), heart thrombus (F only), and lung congestion (F only). No evidence of carcinogenicity in M or F.
Ref: January 23, 2004. Sulfuryl Fluoride; Pesticide Tolerance.
40 CFR Part 180 [OPP-2003-0373; FRL-7342-1]. Final Rule. Federal Register

Tefluthrin - Insecticide - CAS No. 79538-32-2

-- In a subchronic oral toxicity study, dogs were dosed at 0, 0.1, 0.5, or 1.5 mg/kg/day for 90 days. The LOEL for this 90-day oral toxicity study is 1.5 mg/kg/day based on thyroid changes, and increased levels of plasma triglycerides and aspartate transaminase observed at the high-dose. The NOEL is 0.5 mg/kg/day.
-- Endocrine Disrupter Effects. EPA is required to develop a screening program to determine whether certain substances (including all pesticides and inerts) ``may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or such other endocrine effect...'' The Agency is currently working with interested stakeholders, including other government agencies, public interest groups, industry and research scientists in developing a screening and testing program and a priority setting scheme to implement this program. Congress has allowed 3 years from the passage of FQPA (August 3, 1999) to implement this program. At that time, EPA may require further testing of this active ingredient and end use products for endocrine disrupter effects.
Ref: Federal Register: November 26, 1997. Tefluthrin; Pesticide Tolerance. Final Rule. http://www.fluoridealert.org/pesticides/tefluthrin.fr.nov.1997.htm

Tetraconazole - Fungicide - CAS No. 112281-77-3

Chronic & Carcinogenicity Studies. Rats received 0, 10, 80, 640 or 1280 ppm (the last dose to males only) of tetraconazole in the diet for 2 years... Cystic follicular hyperplasia and follicular epithelial hypertrophy were increased in the thyroid of males at 1280 ppm. Tumor incidences were not increased by treatment. The NOEL was 10 ppm (0.4 mg/kg bw/day).
Ref: August 2005 - Evaluation of Tetraconazole in the product Domark 40ME Fungicide. Australian Pesticides and Veterinary Medicines Authority.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf

-- The class of compounds (triazoles) to which tetraconazole belongs is known to induce liver microsomal enzymes. The follicular cell hypertrophy and cystic follicular hyperplasia of the thyroid seen in male rats at 1,280 ppm are also likely to be linked to the hepatic changes. Compounds such as phenobarbital are also known to induce thyroid changes in rats due to increased hepatic clearance of thyroxin, mediated by hepatic enzyme induction.
Ref: Federal Register: October 14, 1999. Notice of Filing Pesticide Petitions to Establish a Tolerance for Certain Pesticide Chemicals in or on Food. PP 9F5066, 9F6023, and 7E4830.
http://www.fluoridealert.org/pesticides/tetraconazole.fr.oct14.1999.htm

Thiazopyr - Herbicide - CAS No. 117718-60-2

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

-- 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

Tolylfluanid - Fungicide - CAS No. 731-27-1

Likely to be Carcinogenic to Humans. Thyroid tumors in male and female Wistar rats. Linear low-dose extrapolation approach recommended.
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

Toxicity - General: The skeletal system (bones and teeth), liver and thyroid were identified as target organs in the animal studies.
Ref: US EPA Pesticide Fact Sheet. Reason for Issuance: Import Tolerance. September 2002.
http://www.fluorideaction.org/pesticides/tolylfluanid.epa.facts.2002.pdf

-- Cancer Classification: ``Likely to be carcinogenic to humans'' by the oral route, based on thyroid tumors in high-dose male and female rats. The FQPA SF Committee further recommended a linear low-dose extrapolation approach for the quantification of human cancer risk based on the thyroid tumors in rats. Q1* = 1.59 x 10-\3\ based upon male rat thyroid adenomas and/or carcinomas combined.
-- Combined chronic toxicity/carcinogenicity rodents (rat): NOAEL = 18.1/21.1 mg/ kg/day (M/F); LOAEL = 90.1/105.2 mg/ kg/day (M/F), based on skeletal changes. Evidence of thyroid follicular cell adenomas and/or carcinomas in high- dose males and females.
-- Combined chronic toxicity/carcinogenicity rodents (rat): NOAEL = 20/20 mg/kg/ day (M/F); LOAEL = 80/110 mg/kg/day (M/F), based on bone hyperostosis in males and females Evidence of thyroid follicular cell adenomas and/or carcinomas in high- dose males and females.
-- Non-guideline (rat) thyroid function: Thyroid-stimulating
hormone levels significantly increased (168-425%) in high-dose males and females. Slightly increased T3 levels in males rats above 119.3 mg/ kg/day.
-- Metabolite Non-guideline (mice). In vitro investigation of TTCA goitrogenic properties. Tolylfluanid's metabolite TTCA was shown to reversibly inhibit thyroid peroxidase (TPO)- mediated reactions involved with the initial stages of thyroid hormone synthesis... TTCA, unlike tolylfluanid, behaves as a goitrogenic compound with a potency approximately equal to propylthiouracil (PTU), a known thionamide inhibitor of initial thyroid hormone synthesis.

Ref: Federal Register: September 25, 2002. Tolylfluanid; Pesticide Tolerance. Final Rule. Federal Register.

http://www.fluorideaction.org/pesticides/tolylfluanid.fr.sept25.2002.htm

Transfluthrin - Insecticide - CAS No. 118712-89-3

3.2.2.1 Oral Route ... At 250 mg kg and 28 d, in both sexes, there were absolute and body weight relative increases in liver (15-20%) and kidney weights (~ 10%). In males absolute and body weight relative thyroid weight increases were also observed (20-25%). These changes were reversed by 56 d... In all males at 500 ppm and 5000 ppm and in three males treated for 19 w the thyroid follicular epithelium was hypertrophied and colloid was depleted. The NOEL for this study was 10 ppm (0.85 mg kg d) based on the effects at and above 50 ppm (4.0 mg kg d) of significant increase in fluoride levels in teeth and bone in both sexes and evidence of kidney toxicity (based on absolute and relative weight increases in both sexes and urinary protein content increases in males). In addition liver and thyroid toxicity was noted at 500 and 5000 pm.
-- In 90 d study Beagles (4/sex/group) were administered transfluthrin (94.5%0 pure via their food at nominal concentrations of 0, 50, 350 or 2500 ppm. Haematological and urine examinations were carried out on all grops pre study and at 3, 6 and 13 w. Ophthalmological examinations were carried out pre study, 6 and 13 w, and hearing tests were carried out pre study and 13 w. ... The haematological and urine examinations showed no treatment related changes. The clinical chemistry examination indicated treatment related effects on the liver. At 2500 ppm increases in cholesterol levels were noted in both sexes which increased with time (~ 35-70% in males and ~ 60-80% in females over `- 13 w). In addition at 13 w plasma lipid and triglyceride levels were increased in both sexes (~ 110-120%). N-demethylase activity was increased in both sexes at 2500 ppm (~ 35%). At 13 w the examination also noted a decrease in thyroxine levels in females (~ 45%) and a non-significant decrease in triiodothyronine (~ 40%) at 2500 ppm. At necropsy, gross pathological examination noted no treatment related changes. At 2500 ppm relative (to the brain) liver weights increased in both sexes (~ 30% in males and ~50% in females) and thyroid weight increased non-significantly in females (~ 70%)...
-- 3.3.3.4 Summary ... Following oral administratin the major target organ in the rat and dog was the liver, with evidence of kidney toxicity also seen in the rat. Fluoride determinations were undertaken in the rat only and showed evidence of accumulation in teeth and bone from 50 ppm (4 mg kg d). In the rat, mortalities and body tremors were seen at 250 mg kg d following gavage dosing. ... In the liver, absolute and relative organ weight increases (recovering following cessation of treatment) together with clinical chemistry and histopathological evidence of hepatocyte hypertrophy were observed from 500 ppm and at 250 mg kd d. There was also evidence of kidney toxicity from 50 ppm (absolute and body weight relative increases in kidney weight in both sexes ... In the thyroid, hypertrophy of the thyroid follicular epithelium and colloid depletion was reported from 500 ppm. The NOEl was 10 ppm (0.85 kg d).

--
3.2.4 Carcinogenicity Studies. ... In a combined chronic toxicity and carcinogenicity study, groups of 60 Wistar rats (strain Bor:WISW (SPF Cpb) of both sexes were administered transfluthrin (94.5-95% pure) in the diet at concentrations of 0, 20, 200 or 2000 ppm for 109 weeks. In addition, groups of 10 male and 10 female rats were treated identically for full interim necropsy at 52 weeks... At 52 weeks at 2000 ppm in males there was an increased incidence of "cuboidal follicular epithelium" in the thyroid (in 7/10 animals) and at the end of the study, a slight increase in thryoid follicular cell hyperplasia in males and females at 200 and 2000 ppm (incidences 0, 0, 3. 3 and 0. 0, 1, 2 at 0, 20, 200 and 2000 ppm). ... There is no evidence of a treatment related increase in thyroid tumour incidence and the low numbers of hepatocellular adenoma/carcinoma are considered to be within the historical control range. Benign adrenal tumours seen in males are within the control ranges for Wistar rats. There is a low but increased incidence of urinary bladder tumours at 2000 ppm in both sexes. The mechanixm is considered to be non genotoxic given the increased incidence of urinary epithelial hyperplasia in both sexes, at this dose. ... A NOEL for non-neoplastic findings is 20 ppm ( 1 mg kg d, based on effects in the kidney (increased organ weight, pigment deposition and glomerulonephrosis) at 200 ppm and above).
-- 3.2.4 Carcinogenicity Studies. The two available studies, in the rate and mouse both combine chronic toxicity and carcinogenicity... Single incidences of tumours occurring in treated groups but not controls were reported in the kidneys, ovaries, brain, parathyroid and skeletal muscle. Neither these, nor the occasional incidences of systemic tumors presented in Table 3.3 were considered to be treatment related (page 23).
Ref: Evaluation on: Transfluthrin Use as a Public Hygiene Insecticide. September 1997. Prepared by: the UK Health and Safety Executive, Biocides & Pesticides Assessment Unit, Magdalen House, Stanley Precinct, Bootle, Merseyside L20 3QZ. Available from: Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX. UK. Also at
http://www.pesticides.gov.uk/citizen/evaluations/165_confirm-box.htm
Note: This was transcribed from the copy available on the web. While one can easily read this report on the web, the report is inaccessible, or locked, to any attempt to copy it. Any errors are mine. EC.

Trifluralin - Herbicide - CAS No. 1582-09-8

Group C -- Possible Human Carcinogen. Thyroid (follicular celladenomas & carcinomas); Neoplasms of the renal pelvis (M); Benign urinary bladder tumors (F); Fischer 344 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

Long term toxicity and carcinogenicity (Annex IIA, point 5.5). Carcinogenicity. Evidence of carcinogenic potential in Fischer 344 rat, (tumour formation in various tissues, i.e. kidney, urinary bladder, thyroid, Leydig cell). The mechanism of tumour formation is not identified. R40. (page 46)
Ref: March 14, 2005. European Food Safety Authority: Conclusion regarding the peer review of the pesticide risk assessment of the active substance trifluralin. EFSA Scientific Report (2005) 28, 1-77.
http://www.fluoridealert.org/pesticides/trifluralin.eu.long.2005.pdf

-- EPA has classified trifluralin as a Group C (possible human) carcinogen. Classification is based on the induction of urinary tract tumors (renal pelvis carcinomas and urinary bladder papillomas) and thyroid tumors (adenomas/carcinomas combined) in one rat study.
Ref: March 2000. Public Health Assessment Cenex Supply and Marketing, Inc. Quincy, Washington. CERCLIS # WAD058619255. Draft for Public Comment.. Prepared by: Washington State Department of Health Under Cooperative Agreement with the Agency for Toxic Substances and Disease Registry. Also available at
http://www.doh.wa.gov/ehp/oehas/Cenex%20PHA%20Draft%20Public%20Review.pdf

Cancer Classification The OPP Carcinogenicity Peer Review Committee evaluated all the available carcinogenicity data on trifluralin (April 4, 1986), and it concluded that there is limited evidence of carcinogenicity in male and female rats based upon an increase in combined malignant and benign urinary bladder tumors in females, renal pelvis carcinomas in male rats, and thyroid gland follicular cell tumors (adenomas plus carcinomas combined) in males. Trifluralin has been classified as a Group "C" possible human carcinogen with a Q of 0.0077 (mg/kg/day) . The upper bound 1 * -1 dietary cancer risk is is approximately 1.0 x 10 . -6
Ref: Reregistration Eligibility Decision (RED) Trifluralin. US EPA, Office of Prevention, Pesticides and Toxic Substances. EPA 738-R-95-040. April 1996.

http://www.fluoridealert.org/pesticides/trifluralin.red.1996.epa.pdf

Preliminary evaluation of carcinogenicity and exposure data: There is a MEDIUM level of carcinogenicity concern over trifluralin. Concern is due to dose-dependent increases in the incidences of tumors of the transitional epithelium of the bladder and renal pelvis in male and female F344 rats, and significant increases in thyroid follicular tumors in males.
Ref:
PRIORITIZED CANDIDATE CHEMICALS UNDER CONSIDERATION FOR CARCINOGENICITY EVALUATION: BATCH #1. Office of Environmental Health Hazard Assessment, California Environmental Protection Agency May 1997.
http://www.oehha.ca.gov/prop65/pdf/batch1.pdf

 
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