Bladder and Urinary Tract - Adverse Effects
Fluorinated and Fluoride Pesticides


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.

Bifenthrin - Acaracide, Insecticide - CAS Numbers: 82657-04-3 (Cis); 83322-02-5 (Trans)

A chronic/carcinogenicity study in mice fed at doses of 0, 50, 200, 500, or 600 ppm (0, 2.5, 10, 25, or 30 mg/kg/day) in the diet for 87 weeks (males) or 92 weeks (females). Chronic LOEL is 10 mg/kg/day based on the incidence of tremors in both sexes. Chronic NOEL is 2.5 mg/kg/day. Carcinogenic potential was evidenced by a statistically significant increased trend for hemangiopericytomas in the urinary bladders of males, a significant dose-related trend for combined hepatocellular adenomas and carcinomas in males, and a significantly higher incidence of combined lung adenomas and carcinomas in females.
Carcinogenicity. Using its Guidelines for Carcinogen Risk Assessment published September 24, 1986 (51 FR 33992) the Carcinogenicity Peer Review Committee (CPRC) has classified bifenthrin as a Group C chemical, possible human carcinogen, based on urinary bladder tumors in mice, but did not recommend assignment of a cancer potency factor Q* (Q star) for a linear quantitative cancer risk assessment, instead, the CPRC recommended the RfD approach. Based on CPRC's recommendation that the RfD approach be used to assess dietary cancer risk, a quantitative linear dietary cancer risk assessment was not performed. Human health risk concerns due to long term consumption of bifenthrin residues are adequately addressed by the dietary risk evaluation chronic exposure analysis using the RfD.
Ref: Federal Register: November 26, 1997. Bifenthrin; Pesticide Tolerances. Final Rule.

Abstract: Bifenthrin, a synthetic pyrethroid insecticide/miticide, has been fed to male and female Swiss Webster mice at levels of 0, 50, 200, 500, and 600 ppm in the diet for between 604 and 644 days. Tumors of the urinary bladder were observed and initially reported as leiomyosarcomas. Subsequently, the bladders were reviewed and the tumors showed a pattern of both epithelioid cells and spindle cells forming irregular vascular channels. The tumors appeared to arise from the trigone of the bladder and, in some cases, invaded the bladder wall. No metastases were recorded. The tumor is usually considered rare; however, in this study, it was commonly observed in all groups but predominantly in males. The histogenesis of the tumor is uncertain, but from its pleomorphic histological features, including smooth muscle and vascularity, it is probably derived from vascular mesenchyme.
Mesenchymal tumors of the mouse urinary bladder with vascular and smooth muscle differentiation; by Butler WH, Cohen SH, Squire RA. Toxicol Pathol. 1997 May-Jun;25(3):268-74.

... In a rat teratology study, an increased incidence of hydroureter (without hydronephrosis) was noted in fetuses at 2 mg/kg/day (LOEL). The NOEL was 1 mg/kg/day. EPA believes that there is sufficient evidence for listing bifenthrin on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available neurological and developmental 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.

Clodinafop-propargyl - Herbicide - CAS No. 105512-06-9

Study # 870.3700a. Prenatal Developmental Toxicity in Rats. Maternal NOAEL = 160 mg/kg/day Maternal LOAEL > 160 mg/kg/day based on lack of effect. Developmental NOAEL = 5 mg/kg/day Developmental LOAEL = 40 mg/kg/day based on increased incidences of bilateral distension and torsion of the ureters, unilateral 14th ribs, and incomplete ossification of the metacarpals and various cranial bones (parietals, interparietals, occipital, and squamosal).
Ref: US EPA Pesticide Fact Sheet. Reason for Issuance: Conditional Registration. June 6, 2000.

Ethalfluralin - Herbicide - CAS No. 55283-68-6

Group C -- Possible Human Carcinogen. Mammary tumors (F); Suggestion of bladder tumors (F) and kidney tumors (M & F); Fischer 344 rats.
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.

Flumequine - Microbiocide - CAS No. 42835-25-6

-- PubMed Abstract: In order to elucidate the tumor-initiating potential of flumequine (FL) in the liver, male C3H mice were given dietary administration of 4000 ppm FL throughout the study or for 2 weeks at the initiation stage, and then received 2 intraperitoneal injections of D-galactosamine (Gal) at weeks 2 and 5, with or without 500 ppm phenobarbital (PB) in their drinking water for 13 weeks to provide tumor-promoting effects. Hepatocellular foci were observed in 2 out of 8 and 6 out of 7 animals in the FL/PB + Gal and FL/FL + Gal groups, respectively. In addition, in an alkaline single-cell gel electrophoresis (comet) assay that was performed using adult, infant, or partial hepatectomized male ddY mice to evaluate the potential of FL at 500 mg/kg or less, to act as a DNA damaging agent. FL induced dose-dependent DNA damage in the stomach, colon, and urinary bladder of adult mice at 3 h but not at 24 h after its administration. Similarly, DNA damage was noted in the regenerating liver and the livers of infant mice at the 3 h time point. Furthermore, in in vitro assays that were conducted to investigate the potential of FL to inhibit eukaryotic topoisomerase II, which is responsible for the double-strand DNA breakage reaction as well as bacterial gyrase, inhibitory effects of FL on topoisomerase II were high relative to the influence on bacterial gyrase. The results of our studies thus strongly suggest that FL has initiating potential in the livers of mice that is attributable to its induction of DNA strand breaks.
Ref: Toxicol Sci 2002 Oct;69(2):317-21; Mechanistic study on flumequine hepatocarcinogenicity focusing on DNA damage in mice; Y Kashida et al.

Fluorouracil - Former insect Chemosterilant; now used as a pharmaceutical - CAS No. 51-21-8

POTENTIAL ADVERSE EFFECTS ON FETUS: Exposure in first trimester resulted in skeletal abnormalities; hypoplasia of aorta, lungs, thymus, and gastrointestinal tract; and urinary tract abnormalities. Fetus exposed in third trimester had cyanosis and clonus.
Ref: TOXNET profile from Hazardous Substances Data Base.

Fluoxastrobin - Fungicide - CAS No. 193740-76-0

-- Subchronic toxicity. A subchronic toxicity feeding study with rats over 90 days demonstrated a NOAEL of 7.3 and 18.3 mg/kg bwt/day for males and females, respectively, based on reduced body weights and alterations in several urinary tract-related clinical chemistry parameters, at the higher dose levels...
Ref: Federal Register: April 23, 2003. Fluoxastrobin; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

-- 90-Day oral toxicity-rats. reduced body weight gain and food intake, vacuolation in the zona fasciculate of the adrenal cortex, calculi in the urethra and kidney, and histological lesions in kidney, urinary bladder, and urethra.
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.

Flurprimidol - Plant Growth Regulator - CAS No. 56425-91-3

A rat teratology study using doses of 0, 2.5, 10, 45 or 200 mg/kg/day of flurprimidol had a maternal toxicity NOEL of 10 mg/kg/day and a LEL of 45 mg/kg/day based on decreased body weight gain and food consumption. The developmental NOEL was 10 mg/kg/day and the LEL was 45 mg/kg/day based on decreased fetal weight, increased incidence of hydronephrosis, hydroureter and numerous developmental skeletal anomalies.
Ref: US EPA Pesticide Fact Sheet. February 22, 1989.

Flusilazol / Flusilazole - Fungicide - CAS No. 85509-19-9

--The chronic toxicity/carcinogenicity studies in the rat, the target organs identified were consistent with the sub-chronic administration studies, i.e., liver and bladder. Flusilazole was found to be oncogenic at the higher doses, causing bladder transitional cell neoplasia in both sexes and testicular Leydig cell adenoma in males. There is evidence of a proliferative effect of flusilazole in the bladder transitional epithelium, which is likely the mechanism of tumorigenesis. Therefore, the urinary bladder tumors are considered to be caused by an epigenetic, threshold-associated mechanism. Interference of flusilazole with hypothalmic- pituitary-gonadal (HPG) axis is suggested as a possible mechanism of testicular tumor induction. Evidence in support of this theory was provided by a comparative study with the aromatase inhibitor, ketoconazole. Flusilazole did cause a slight reduction in both serum and testicular - testosterone and a dose-dependent decrease in serum estradiol, but was far less potent than ketoconazole. It would avoear reasonable to conclude that a threshold exists for the induction by flusilazole of testicular aienomas. The NOEL for neoplasms was 375 ppm (14.8 and 20.5 mg/kg/day in males and females, respectively). (Page 29)
In mouse chronic studies, the target organs were the liver, kidney, urinary bladder and urethra. The incidence of hepatocellular adenomas was increased at L 1000 ppm. Based on the combined results of two studies, the NOEL for oncogenicity in mice is 200 ppm (36 mgrkglday) in females and 500 ppm (73.1 mg/kg/day) for males. Since tumors occurred in excess of the MTD, and were preceded at lower doses by histopathological change consistent with induction-related hepatotoxicity, it is reasonable to conclude that the induction of such tumors is related to cytotoxicity, which demonstrates a clear threshold. (Pages 29-30)
-- Flusilazole was found to exert a clear systemic toxicity on sub-chronic and chronic administration to rats, mice and dogs. A similar pattern of effects was apparent across the three species, with the liver, urinary system and blood system targeted to varying degrees. It was found to be oncogenic at high dose levels in both mice and rats, inducing bladder transitional cell neoplasia in rats and testicular adenoma in male rats and hepatocellular adenomas and carcinomas in mice. (Page 30)
Ref: DuPont Punch (Active ingredient: Flusilazole) and DuPont Charisma (Active ingredients: Flusilazole and Famoxadone): Summary of data compiled in support of a Section 18 Emergency Exemption request for control of Asian soybean rust on soybeans. By DuPont authors: Cosgrove T, Czochor L, Dinter A, Jemberg K, Klemens A, Marcon A, McInnes B, Mullin L, Russell M, Ryan D, Singles S, Vanderbroeck V. Revision No. 1: February 2, 2005.

-- 2-Year Feeding (oncogenic) - mouse: Systemic NOEL=3.4 mg/kg/day; Systemic LEL=27 mg/kg/day (increased absolute and relative liver weight and increased hepatocellular fatty change in male and females); core grade supplementary (E.I. du Pont de Nemours & Co., Inc., 1985d)
-- 90-Day Feeding - rat: NOEL=125 ppm (6.25 mg/kg/day); LEL=375 ppm (18.75 mg/kg/day) (bladder hyperplasia, elevated cholesterol); core grade minimum (E.I. du Pont de Nemours & Co., Inc., 1983a)
-- 90-Day Feeding - dog: NOEL=25 ppm (0.625 mg/kg/day); LEL=125 ppm (3.13 mg/kg/day) (bladder hyperplasia, elevated alanine aminotransferase/serum glutamate pyruvate transaminase, uric acid, decreased total protein Ca albumen, cholesterol, increased liver weight); core grade minimum (E.I. du Pont de Nemours & Co., Inc., 1983b)
Ref: US EPA IRIS. NuStar CASRN: 85509-19-9. Available October 6, 2003, at Toxnet.

Haloxyfop-etotyl - Herbicide - CAS No. 87237-48-7

Reproductive Effects: In rats, oral doses of 10 and 50 mg/kg/day of haloxyfop-ethoxyethyl from days 6 to 16 of pregnancy reduced the number of live offspring per litter and caused vaginal bleeding in the mother (5). Teratogenic Effects: Oral doses of 50 mg/kg/day of haloxyfop-ethoxyethyl in rats between days 6 and 16 of pregnancy caused developmental abnormalities in the offspring's urogenital system and death to the fetus (5). Oral doses of 7.5 mg/kg/day of haloxyfop-methyl given to rats from days 6 to 15 of pregnancy caused delayed bone formation in the offspring (6).
Ref: EXTOXNET Pesticide Information Profile

Penoxsulam - Herbicide - CAS No. 219714-96-2

-- Subchronic toxicity. Dietary exposure to penoxsulam identified the liver and/or urinary tract (kidneys and bladder) as target organs in rats, mice, and dogs following a 4-week and 13-week administration. Effects on the liver were reflected in increased liver weights and hepatocellular hypertrophy, but these effects were not associated with increases in mixed function oxidase (MFO) enzyme activity. Effects noted in the kidneys included crystal deposition, most likely from precipitation of penoxsulam from the urine, with resultant irritation, inflammation, and hyperplasia of renal pelvic transitional epithelium. Other than the crystal deposition in the kidneys, all effects following subchronic exposure to rats appeared to be reversible. Very high doses were associated with significant decreases in body weight, weight gain, and feed consumption.
-- Chronic toxicity. Chronic exposure in the dog indicated that the renal effects were not exacerbated with long-term exposure. Following long-term exposure in rats, the kidneys and urinary bladder were the primary target organs. Histologic changes seen at the end of 2 years of exposure consisted of inflammation and hyperplasia of the renal pelvic transitional epithelium, crystal deposition in the kidneys and urinary bladder, and hyperplasia of the mucosa of the urinary bladder...
Ref: August 6, 2003. Federal Register: August 6, 2003 (Volume 68, Number 151)] [Notices] [Page 46609-46613]. Penoxsulam; Notice of Filing a Pesticide Petition To Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
•• See also page 15: June 18, 2007 - Penoxsulam. Human Health Risk Assessment for Proposed Uses on Fish and Shellfish. Docket: EPA-HQ-OPP-2006-0076-0004. USEPA.

In subchronic and chronic feeding studies in rats and dogs, the most sensitive target organ was the urothelium of the urinary system. Due to limited solubility in urine, penoxsulam (and/or its metabolites) formed crystals/calculi, which were regularly observed in the pelvis of the kidney and the lumen of the urinary bladder. These crystals/calculi apparently irritated the urothelium in these organs and following repeated dosing lead to numerous secondary effects which resulted in significant damage to the urinary system. In various studies, these secondary effects were manifested as altered clinical chemistry parameters (increased blood urea nitrogen), altered urinalyses parameters (increased urine volume, decreased urine specific gravity), increased absolute and relative kidney weights, gross pathological findings in the kidneys (calculi and roughened surface), and a variety of histopathological findings in the kidney and urinary bladder, particularly hyperplasia, inflammation and mineralization in the pelvic epithelium of the kidney and hyperplasia in the mucosa of the urinary bladder.
Reference: September 2004. US EPA Fact Sheet on Penoxsulam. Page 4.

PFOS - PFOA - Insecticide, EPA List 3 Inert

The toxicity profile of PFOS is similar among rats and monkeys. Repeated exposure results in hepatotoxicity and mortality; the dose-response curve is very steep for mortality. This occurs in animals of all ages, although the neonate may be more sensitive. In addition, a 2-year bioassay in rats has shown that exposure to PFOS results in hepatocellular adenomas and thyroid follicular cell adenomas; the hepatocellular adenomas do not appear to be related to peroxisome proliferation. Further work to elucidate the species differences in toxicokinetics and in the mode of action of PFOS will increase our ability to predict risk to humans. Epidemiologic studies have shown an association of PFOS exposure and the incidence of bladder cancer; further work is needed to understand this association.
Ref: November 21, 2002 report: Hazard Assessment of Perfluorooctane sulfonate (PFOS) and its salts. Organisation for Economic Co-operation and Development. ENV/JM/RD(2002)17/FINAL.

A retrospective cohort mortality study was performed on employees at the Cottage Grove, MN
plant which produces APFO (Gilliland and Mandel,1993). At this plant, APFO production was
limited to the Chemical Division.The cohort consisted of workers who had been employed at the
plant for at least 6 months between January 1947 and December 1983. Death certificates of all of the workers were obtained to determine cause of death. There was almost complete follow-up
(99.5%)of all of the study participants. ...
An update of this study was conducted to include the death experience of employees through
1997 (Alexander,2001a). The cohort consisted of 3992 workers. The eligibility requirement was
increased to 1 year of employment at the Cottage Grove plant, and the exposure categories were
changed to be more specific. Workers were placed into 3 exposure groups based on job history
information: definite PFOA exposure (n =492, jobs where cell generation, drying, shipping and
packaging of PFOA occurred throughout the history of the plant); probable PFOA exposure (n = 1685, other chemical division jobs where exposure to PFOA was possible but with lower or
transient exposures); and not exposed to fluorochemicals (n =1815,primarily non-chemical
division jobs). In this new cohort, 607 deaths were identified: 46 of these deaths were in the PFOA exposure group, 267 in the probable exposure group, and 294 in the non-exposed group. When all employees were compared to the state mortality rates, SMRs were less than 1 or only slightly higher for all of the causes of death analyzed. None of the SMRs were statistically significant at p =.05. The highest SMR reported was for bladder cancer (SMR =1.31,95%CI =0.42 – 3.05)). Five deaths were observed (3.83 expected).
Ref: April 10, 2003: Preliminary Risk Assessment of the Developmental Toxicity associated with Exposure to Perfluorooctanoic Acid and its Salts. US EPA Office of Pollution Prevention and Toxics. 63 pages.

Sodium fluorosilicate (Sodium Hexafluorosilicate) - Insecticiide; Wood Preservative; EPA List 3 Inert - CAS No. 16893-85-9

-- Mice orally given sodium hexafluorosilicate (70 mg/kg; 0.37 mmol/kg) exhibited toxic effects in the peripheral nerves, sensation, and in behavior. In rats, an oral dose (248 mg/kg; 1.32 mmol/kg) administered intermittently for one month produced toxic effects in the kidney, ureter, and/or bladder, as well as musculoskeletal and biochemical effects (RTECS, 1997). Using guinea pigs, inhalation experiments (13-55 mg/m 3 [1.7-7.2 ppm] sodium hexafluorosilicate in air for 6 hours) resulted in pulmonary irritation; the lowest concentration that caused death was 33 mg/m 3 (4.3 ppm) (Patty, 1963; cited by HSDB, 2000b).
-- Rats, oral; 248 mg/ kg (1.32 mmol/ kg) for 30 days intermittent; Toxic effects in the kidney,
ureter, and/ or bladder (other changes in urine composition) were observed. Musculoskeletal (other changes) and biochemical (enzyme inhibition, induction, or changes in blood or tissue [phosphatases] levels) effects were seen. RTECS* (1997)
-- Rats, 70 mg/ kg (LD Lo ; 0.37 mmol/ kg); Fatty liver degeneration and other changes in the liver and toxic effects in the kidney,
ureter, and bladder primarily changes in glomeruli were observed. RTECS* (1997)
Ref: Review of Toxicological Literature. October 2001. Sodium Hexafluorosilicate [CASRN 16893-85-9] and Fluorosilicic Acid [CASRN 16961-83-4]. Prepared for Scott Masten, Ph.D. National Institute of Environmental Health Sciences P.O. Box 12233 Research Triangle Park, North Carolina 27709. Contract No. N01-ES-65402. Submitted by Karen E. Haneke, M.S. (Principal Investigator) Bonnie L. Carson, M.S. (Co-Principal Investigator) Integrated Laboratory Systems P.O. Box 13501 Research Triangle Park, North Carolina 27709.

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

-- The target organs were the liver (rat, mouse and dog) and kidney (rat). There was evidence of liver hypertrophy in the rat from 250 mg kg d (28 study) and after administration for 90 d at 500 ppm (equivalent to 40 mg kg d), in the dog from 350 ppm (equivalent to 14 mg kg d) after 90 d administration and from 30 ppm (equivalent to1 mg kg d) after 1 yr and in the mouse, from 1000 pppm (equivalent to 280 mg kg d) after 2 yr administration. Increased kidney weights, proximal tubule degeneration and regenertion and increases in protein in the urine were observed in male rats from 50 ppm and in females from 500 ppm. Similar pathological findings were seen after 2 yr dietary administration with focal hyperplasia in the urinary bladder in both sexes at 2000 ppm in the rat and hepatocyte hypertrophy at 1000 ppm in the mouse. In the rat, increases in fluoride content of teeth and bone were observed from 50 ppm in oral studies and at 200 mg m3 following inhalation exposure in 90 d studies.
-- Carcinogenicity. There is an increased incidence of urinary blader papillomas and carcinomas (at a very low incidence) in males and females at 2000 ppm in mice (females only) at 1000 ppm. Both types of tumour are considered to arise via a non genotoxic mechanism. Studies using rat hepatocytes showed that transfluthrin does not cause cell proliferation but acts as a weak promotor with a NOEL of 5 ppm.
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
• 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.

Trifloxysulfuron-sodium - Herbicide - CAS No. 199119-58-9

Chronic toxicity dogs NOAEL: 51.1/45.3 mg/kg/day (M/F) LOAEL: 123/121 mg/kg/day (M/F): M = gray- white foci in lungs, fibrous thickening of lung pleura, equivocal decreased body weight gain; F = equivocal increased incidence and severity of chronic urinary bladder inflammation.
Ref: Federal Register: September 17, 2003 (Volume 68, Number 180)] Rules and Regulations. Trifloxysulfuron; Pesticide Tolerance. Final Rule.

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.
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.

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.

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

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