Kidney - Adverse Effects
Fluorinated and Fluoride Pesticides
beginning with
A-E F-G H-P • Q-Z
See short description and definitions on kidney

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.

Quinoxyfen - Fungicide - CAS No. 124495-18-7

** 040 - 181140 "XDE-795: Two-Year Dietary Chronic Toxicity/Oncogenicity Study in Fischer 344 Rats-Final Report," (Redmond, J.M., Quast, J.F., Bond, D.M., Ormand, J.R.; The Toxicology Research Laboratory, Health and Environmental Sciences The Dow Chemical Company, Midland, MI; Laboratory ID#: DR-0325-7474-007; 6/29/95). XDE-795 (5,7-dichloro-4-[4-flurophenoxy]quinoline; 97.4% pure) was fed in diet to Fischer 344 rats at 0, 5, 20 or 80 mg/kg/day for 1 2 years. XDE-795 was administered for 2 years to 50/sex/dose for chronic/oncogenicity assessment. A satellite group (15/sex/dose) was sacrificed at 12 months (10/sex/dose for interim assessment of chronic toxicity; 5/sex/dose to assess neurotoxicity). NOEL = 20 mg/kg (Females at 80 mg/kg had increased perineal soiling (satellite & main group). Both sexes had decreased bodyweights and bodyweight gains at 80 mg/kg throughout the study. Urea nitrogen was increased in males at 80 mg/kg at 18 and 24 months. Alanine amino transferase (80 mg/kg) was decreased in males at 24 months. Females had cholesterol levels that were statistically significantly increased at 80 mg/kg at 18 and 24 months. Liver and kidney weights (absolute & relative) were statistically significantly increased in both sexes at 80 mg/kg at 12 months. Relative brain weights in both sexes were increased at 80 mg/kg by 24 months. Males had increased absolute and relative testes weights at 80 mg/kg and females had decreased relative heart and increased relative kidney weights at 80 mg/kg at 24 months. There was an increased incidence in chronic progressive glomerulonephropathy in males at 80 mg/kg37 versus 19 in control, p < 0.05.) No adverse effects. Acceptable. M. Silva, 8/21/01
-- 034 - 181176 "XDE-795: One Year Chronic Dietary Toxicity Study in Beagle Dogs," (Cosse, P.F., Stebbins, K.E., Redmond, J.M., Ormand, J.R.; The Toxicology Research Laboratory, Health and Environmental Sciences The Dow Chemical Company, Midland, MI; Laboratory ID#: DR-0325-7474-011; 4/21/95). XDE-795 (5,7-dichloro-4-[4-flurophenoxy]quinoline; 97.4% pure) was fed in diet to Beagle dogs (4/sex/dose) at 0, 5, 20 or 200 mg/kg/day for 1year. NOEL = 20 mg/kg (A male at 200 mg/kg was killed moribund, due to a severe weight decrease (2 kg), decreased hemoglobin and RBC counts. Both sexes had significantly decreased body weights and food consumption at 200 mg/kg. The report stated it was due to unpalatability of diet at the high dose, which persisted throughout the majority of the study. A treatment-related hematological effect was observed in 1/sex at 200 mg/kg. Alkaline phosphatase in both sexes at 200 mg/kg was statistically significantly increased. Liver weights (absolute & relative) were significantly increased in both sexes at 200 mg/kg. Statistically significantly increased relative organ weights were observed in both sexes at 200 mg/kg (brain, kidney, pituitary). Liver histopathology was observed in 3/sex at 200 mg/kg, primarily in the midzonal region (diffuse, increased size in hepatocytes, enlarged nuclei and prominent nucleoli). At 200 mg/kg, 1/sex had increased hepatocyte size, increased bile in centrilobular canaliculi. Possible adverse effect: At 200 mg/kg, 1/sex showed erythroid proliferation in spleen and liver, due to treatment-related anemia.) Acceptable. M. Silva, 8/15/01
-- ** 035 - 181177 "XDE-795: Potential Tumorigenic Effects in Prolonged Dietary Administration to CD-1 Mice," (Bellringer, M.E.; J.R.; Huntingdon Research Centre, Ltd., Cambridgeshire, UK; HRC Project ID#: DWC/657; 6/5/95). XR-795 (5,7-dichloro-4-[4-flurophenoxy]quinoline; 97.4% pure) was fed in diet to Crl:CD-1 (ICR)BR mice (50/sex/dose) at 0, 20, 80 and 250 mg/kg/day for 80 weeks. NOEL = 80 mg/kg (There was a significantly decreased bodyweight gain in both sexes at 250 mg/kg (primarily females). The effect was intermittent in males throughout the study. Relative (to bodyweight) liver and kidney weights were significantly increased in females at 250 mg/kg.) There were no histological (neoplastic or non-neoplastic) effects due to treatment. No adverse effects. Acceptable. M. Silva, 8/24/01
-- ** 039 181139 "XDE-795: Two-Generation Dietary Reproduction Study in Sprague-Dawley Rats," (Liberacki, A.B., Breslin, W.J., Zwinker, G.M., Johnson, K.A., Freshour, N.L.; The Toxicology Research Laboratory, Health and Environmental Sciences, The Dow Chemical, Midland, MI; Laboratory ID#s: DR-0325- 7474-013 [P1, F0, W1, FB, WB, P2, F2 & W4]; 5/23/95). XDE-795 (97.4% pure) was fed in diet to Sprague-Dawley rats (30/sex/dose) at 0, 5, 20 and 100 mg/kg/day, 7 days/week for 2 generations. Systemic NOEL = 20 mg/kg (Kidney pathology was observed in P1 and P2 females at 100 mg/kg. Males showed liver, kidney and epididymal histopathology at 100 mg/kg in P1 and P2 adults.) Reproductive NOEL = 100 mg/kg/day (There were no treatment-related reproductive effects in either sex.) Pup NOEL = 20 mg/kg/ (F1a & F1b pups showed decreased bodyweights at 21 days of lactation and this was considered to be due to excessive dose and decreased food consumption.) No adverse effect. Acceptable. M. Silva, 8/9/01
-- 030; 181170; "XR-795: Four Week Dietary Toxicity Study in Fischer 344 Rats" (Szabo, J.R. and Davis, N.L., Health and Environmental Sciences-Texas Lake Jackson Research Center, The Dow Chemical Company, Freeport, Texas, Laboratory Project Study ID TXT: DR-0325-7474-002, 10/12/92). XR-795 (TSN100003, DECO-36-106, purity = 97.6%) was admixed to the diet at dose levels of 0 (untreated diet only), 250, 500, or 1000 mg/kg/day and fed continuously to 5 Fischer 344 rats per sex per dose for 4 weeks. No clinical signs were observed. A treatment-related decrease in mean body weight at all dose levels in both sexes was observed. Treatment-related increases in mean relative liver (in both sexes at all dose levels) and in mean relative kidney (in males at all dose levels and in females at 500 and 1000 mg/kg/day) weights and a treatment-related decrease in mean relative testes weight at 1000 mg/kg/day were observed. Macroscopic examination revealed bilateral testicular atrophy in 3/5 animals at 1000 mg/kg/day. Microscopic examination revealed a moderate to severe decrease in spermatogenesis in 4/5 animals at 1000 mg/kg/day. Possible adverse effect indicated: testicular atrophy with a decrease in spermatogenesis. NOEL (M/F) < 250 mg/kg/day (based on body weight and mean relative organ weight data). Supplemental (only 5 animals per sex per dose were used and the animals were only dosed for 4 weeks). (Corlett, 8/27/01)
Ref: October 4, 2001. SUMMARY OF TOXICOLOGY DATA QUINOXYFEN (XDE-795 & XR-795). California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.

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

In addition to cardiovascular, neuromuscular and gastrointestinal derangements, acute fluoride poisoning causes major adverse effects on two other organ systems, the brain and the kidneys. The more critical dysfunctions are those of the brain. Toxic signs occasionally include headache, excessive salivation, nystagmus and dilated pupils. Transient convulions have been described, but lethargy, stupor and coma are far more common, and death is often ascribed to respiratory failure, presumably of central origin. Whatever the causes of these brain derangements, it is noteworthy that coma and respiratory arrest may develop in the presence of a normal blood pressure. Apparently the central neural effects of fluoride are not solely secondary to an inadequate cerebral circulation. /Fluoride/ [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. III-187]
Ref: Hazardous Substances Data Bank for SODIUM HYDROGEN DIFLUORIDE CASRN: 1333-83-1

Sodium fluoride - Wood preservative, EPA List 4B Inert - CAS No. 7681-49-4

Due to length, see special section on adverse effects on kidney from Sodium fluoride


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).
-- Mouse strain, 70 mg/ kg (LD 50 ; 0.37 mmol/ kg); Toxic effects were observed in the peripheral nerves and sensation (flaccid paralysis without anesthesia, generally neuromuscular blockage) and in behavior (ataxia and muscle contraction or spasticity). RTECS* (1997)
-- 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.

Sulfluramid - Acaricide, Insecticide - CAS No. 4151-50-2

Abstract: BIOSIS COPYRIGHT: BIOL ABS. The cellular effects of sulfluramid (N-ethylperfluorooctane sulphonamide, NEPFOS) and its major metabolite perfluorooctane sulphonamide (PFOS) were examined using a suspension of rabbit renal proximal tubules as a model. NEPFOS and PFOS were potent stimulators of proximal tubule basal oxygen consumptions (QO2), with initial effects exhibited at 5-10 muM and maximal effects at 50-200 muM. The increase in basal QO2 was ouabain insensitive, which suggests that NEPFOS and PFOS may act by uncoupling oxidative phosphorylation. Exposure of tubule suspensions to NEPFOS or PFOS concentrations of 100 muM or higher for 60 min produced tubule death, indicated by an increase in the release of lactate dehyrogenase. The tubule death did not appear to result from alkylation or lipid peroxidation, since glutathione and malondialdehyde levels were unaffected. To determine the mechanism by which NEPFOS and PFOS increased tubule QO2, the effects of NEPFOS and PFOS on isolated renal cortical
Ref: SCHNELLMANN RG (1990). The cellular effects of a unique pesticide sulfluramid (N-ethylperfluorooctanesulfonamide) on rabbit renal proximal tubules. TOXICOL IN VITRO; 4 (1).. 71-74.

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

-- In 2-week inhalation studies in rats, dogs and rabbits, different target organs were affected. In rats, the primary target organ was the kidneys, in which severe histopathological lesions were observed. These lesions included papillary necrosis, hyperplasia of the epithelial cells of the papillae, and degeneration/regeneration of collecting tubules and proximal tubules...
-- In subchronic (90-day) inhalation studies in rats, dogs, rabbits and mice, the brain was the major target organ. Malacia and/or vacuolation were observed in the white matter of the brain in all four species. The portions of the brain most often affected were the caudate-putamen nucleus in the basal ganglia, the white fiber tracts in the internal and external capsules, and the globus pallidus of the cerebrum. In dogs and rabbits, clinical signs of neurotoxicity (including tremors, tetany, incoordination, convulsions and/or hind limb paralysis) were also observed. Inflammation of the nasal passages and histiocytosis of the lungs were observed in rats and rabbits; but not in dogs, in which species inflammation of the upper respiratory tract was more prominent in the 2-week study. In rats, kidney damage was also observed...
-- In chronic (1-2 year) inhalation studies in rats, dogs and mice, target organs were the same as in the 90-day studies. In rats, severe kidney damage caused renal failure and mortalities in many animals. Additional gross and histopathological lesions in numerous organs and tissues were considered to be secondary to the primary effect on the kidneys...
-- In a developmental toxicity inhalation study in rats, no developmental toxicity was observed in the pups. Although no maternal toxicity was observed in this study at the highest dose tested (225 ppm), significant maternal toxicity (decreased body weight, body weight gain and food consumption; increased water consumption and kidney weights; and gross pathological changes in the kidneys and liver) was observed in a previously conducted range-finding study at a slightly higher dose level (300 ppm)...

Ref: Federal Register: September 5, 2001 (Volume 66, Number 172). Sulfuryl Fluoride; Proposed Pesticide Temporary Tolerances.

The primary effects of sulfuryl fluoride in humans are respiratory irritation and central nervous system depression, followed by excitation and possibly convulsions. Rabbits exposed via inhalation (6 hours/day, 5 days/week, for 2 weeks) to sulfuryl fluoride showed hyperactivity, convulsions and vacuolation of the cerebrum at 600 ppm (2.5 mg/L). Renal lesions were present in all rats exposed by inhalation (6 hours/day, 5 days/week, for 2 weeks) to 600 ppm (2.5 mg/ L) sulfuryl fluoride. Minimal renal changes were noted in rats exposed to 300 ppm (1252 mg/L), whereas no effects occurred at 100 ppm (4.2 mg/ L). Convulsions at near lethal concentrations were reported in rabbits, mice, and rats. In a 30-day inhalation study, loss of control, tremors of the hind quarters, and histopathological changes in the lung, liver, and kidney were reported in rabbits exposed to 400 ppm (1.6 mg/L) for 7 hours/day, 5 days/week for 5 weeks. The NOEL was 200 ppm (0.83 mg/L). Cerebral vacuolation and/or malacia and inflammation of nasal tissues were observed in rabbits exposed by inhalation to 100 or 300 ppm (0.4 or 1.25 mg/L) for 13 weeks. The NOEL was 30 ppm (0.125 mg/L). Rats exposed by inhalation to 100 to 600 ppm (0.4 to 0.25 mg/L) sulfuryl fluoride for 13 weeks developed mottled teeth (indicative of fluoride toxicity), renal and respiratory effects, and cerebral vacuolation. EPA believes that there is sufficient evidence for listing sulfuryl fluoride on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available neurological, renal, and respiratory 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.

Tembotrione - Herbicide - CAS No. 335104-84-2

The primary target organs were the eyes, liver and kidneys. In the kidney, increased weight, and papillary mineralization were observed in the rat and mouse following chronic exposure (page 6).
• 90-Day Oral Toxicity - Rat study : In females, the following microscopic changes were observed at an increased incidence: multifocal corticotubular basal vacuolation (slight) in the kidneys occurred in a dose-dependent manner 1-6/10 in all treated groups compared to 0/10 in controls; diffuse hypertrophy of the interstitial gland in the ovaries was observed in the 1500 ppm and 7000 ppm groups (3/10) compared to 0/10 in controls. These effects were considered treatment-related (page 56).
• In a combined chronic/carcinogenicity study (MRID 46695708) Wistar male rats/dose in the dietat dose levels of 0, 1, 20, 200 or 800 ppm (equivalent to 0, 0.04, 0.79, 8.3 or 31.7 mg/kg bw/day) in the diet for 104 weeks. In the kidney,
a minimal to severe chronic nephropathy was significantly increased (p≤0.01) in the 20, 200, and 800 ppm group, (87%, 87%, 92%, and 83%, respectively) compared to in the control group (63%). Changes within the kidney included one or more of the following changes: tubular cell regeneration, thickened basement membranes (glomerular and tubular), interstitial fibrosis, inflammation, dilated/cystic tubules, protein casts, pigmentation, mineralization, debris, mesangial proliferation, glomerular sclerosis, and hypertrophy/hyperplasia of tubular epithelium. Severity grades moderate or higher generally reflected a kidney with most of the above- mentioned changes, some reflecting end-stage renal disease (probable cause of death) (page 72).
Reference: Tembotrione. Human-Health Risk Assessment for Proposed Uses on Field Corn, Sweet Corn and Popcorn. USEPA. September 7, 2007.
Dose and Endpoint for Establishing RfD:
(page 22)
------ Study Selected: Chronic Toxicity/Carcinogenicity (Feeding)/Rat MRID No.: 46695708
------ The NOAEL of 0.04 mg/kg/day was based on neovascularization and edema of the cornea and snow flake-like corneal opacity, unilateral or bilateral keratitis of the eye, decreased mean body weight and mean body-weight gain, increased total cholesterol, higher ketone levels and lower pH values, higher protein levels, increased kidney weight, kidney to body weight and kidney to brain weight ratios, chronic nephropathy and atrophy of the sciatic nerve observed in the male at 0.79 mg/kg/day (LOAEL).
------ UF(s): An UF of 100 was applied to account for interspecies extrapolation (10X)
------ Comments about Study/Endpoint/UF: This study provided the lowest NOAEL in the database (most sensitive endpoint) and will also provide the most protective limits for human effects.
• Thyroid gland toxicity was observed in the 21/28-day dermal toxicity study in the rat and chronic oral toxicity study in the dog. Dermal exposure (21/28-day study) resulted in colloid alteration and hypertrophic follicular epithelium in the thyroid gland in the rat. Also observed were degenerative changes in the pancreas, increased proteinacious material in the Ratche pouch in the pituitary gland and basophilic tubules in the kidneys. Pigmentation of the thyroid gland
along with hematological changes and microscopic changes in the sciatic nerve were observed in the dog.
Reference: Tembotrione. Human-Health Risk Assessment for Proposed Uses on Field Corn, Sweet Corn and Popcorn. USEPA. September 7, 2007.

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

Chronic Toxicity: The liver and kidney are the primary target organs of tetraconazole.
Ref: April 2005. Pesticide Fact Sheet: Tetraconazole. US EPA.

• Metbolism and Toxicokinetics. Tetraconazole was broadly distributed to all organs and tissues tested, with the highest level detected in the liver, followed by kidneys, gonads, brain and bones. Low residual levels were still detected in the liver and gastrointestinal tract (sometimes bones) at 72 hr.
Chronic & Carcinogenicity Studies. Dogs received 0, 22.5, 90 or 360 ppm of tetraconazole in the diet for 1 year. Histopathology detected apparent hepatocyte enlargement, eosinophilic inclusions in hepatocytes, centrilobular hepatocyte rarefaction, or centrilobular fat in the liver at 90 and 360 ppm, and cortical tubular hypertrophy and apoptotic bodies in the kidneys at 360 and/or 90 ppm. The NOEL was 22.5 ppm (0.7 mg/kg bw/day). (page 5)
• Sub-chronic studies.
Rats received 0, 10, 60 or 360 ppm of tetraconazole in the diet for 13 weeks. Enlarged or swollen liver was seen at 360 ppm. Increased liver weight was associated with minimal centrilobular hepatocyte enlargement at 60 and 360 ppm, and a higher incidence of liver fat deposition at 360 ppm. Increased kidney weight in females and reduced testes weight in males were also observed at 360 ppm. The NOEL was 10 ppm (0.7 mg/kg bw/day).
-- Mice received 0, 5, 25, 125 or 625 ppm of tetraconazole in the diet for 13 weeks. Some males at 625 ppm showed lymphocyte aggregation and foci in the kidneys. The NOEL was 5 ppm (1 mg/kg bw/day). (page 4)
Ref: August 2005 - Evaluation of Tetraconazole in the product Domark 40ME Fungicide. Australian Pesticides and Veterinary Medicines Authority.

1,1,1,2-Tetrafluoroethane (HFC-134a) - Propellant, US EPA List 4B Inert - CAS No. 811-97-2

Comparative potency studies showed that 1,1,1,2-tetrafluoroethane, dichlorodifluoromethane, or 1,1,2,2-tetrafluoro-1,2-dichloroethane (25% gas phase) inhibited gluconeogenesis about equally while as little as 300 ppm halothane was effective and 1,1,1,2,2-pentafluoro-2-chloroethane (25%) was without effect. Considering that the threshold for alteration of the rate of glucose metabolism in this in vitro paradigm is about 12.5% 1,1,1,2-tetrafluoroethane, it was concluded that toxicologically significant alteration of glucose-linked bioenergetics is unlikely at the levels of 1,1,1,2-tetrafluoroethane exposure anticipated in workplace or environment. [Olson MJ et al; Fundam Appl Toxicol 15 (2): 270-80 (1990)]
Note from FAN: Definition Gluconeogenesis: The process of making glucose (sugar) from its own breakdown products or from the breakdown products of lipids (fats) or proteins. Gluconeogenesis occurs mainly in cells of the liver or kidney.
Ref: Hazardous Substances Data Bank for 1,1,1,2-TETRAFLUOROETHANE CASRN: 811-97-2.,1,1,2-tetrafluoroe.toxnet.htm

-- groups of 16 male and 16 female rats were exposed at concentrations of 9, 1000, 10,000, or 50,000 ppm 6 h/d for 20 d of a 28-d period (Riley et al. 1979). No treatment-related effects were observed with regard to body weight, clinical signs, hematology, blood chemistry, urine composition, or ophthalmoscopy. Changes in liver, kidney, and gonad weights of male rats in the group exposed to 50,000 ppm were noted with a significant increase in liver weight in the 10,000-ppm group also. In the absence of pathological changes in these organs, Riley et al. (1979) considered these changes physiological adaptations to treatment.
-- Riley RA, Bennett IP, Chart IS, Gore CW, Robinson M, Weight TM. 1979. Arcton-134a: Subacute toxicity to the rat by inhalation. ICI Report No. CTL/P/463. Central Toxicology Laboratory, Alderly Park, Macclesfield, Cheshire, UK.
Ref: National Research Council. 2002. Acute Exposure Guideline Levels for Selected Airborne Chemicals. Volume 2. Subcommittee on Acute Exposure Guideline Levels. Committee on Toxicology, Board of Environmental Studies and Toxicology, Division of Earth and Life Studies. National Academy Press, Washington DC. Available from: National Academy Press, 2101 Constitution Ave, NW, Box 285, Washington DC 20055. ISBN 0-309-08511-X. Online at:

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.
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.

-- 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.

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

-- Carcinogenicity rodents (mouse). NOAEL = 76.3/123.9 mg/ kg/day (M/F) LOAEL = 375.8/610.8 mg/kg/day (M/F), based on skeletal, liver, and kidney changes No evidence of carcinogenicity
Ref: Federal Register: September 25, 2002. Tolylfluanid; Pesticide Tolerance. Final Rule. Federal Register.

Chronic toxicity. Chronic toxicity studies on tolylfluanid were done in the rat, mouse and dog. Tolylfluanid was tested in two rat chronic dietary studies. Increased growth of the incisors of the upper jaw and skeletal changes (hyperostosis in the skull and ribs) resulted from the high fluorine content of the compound. Hepatotoxicity and renal toxicity were seen in rats, mice, and dogs. Hepatotoxicity was evidenced by hepatocellular cytoplasmic changes, vacuolation, and focal fatty changes in rats, hepatocellular hypertrophy and single cell necrosis in mice, decreased liver enzymes in rats, and increased liver enzymes in mice and dogs. Renal toxicity (microscopic kidney lesions, increased relative kidney weights, effects on urinalysis parameters) was probably attributable to the effects of fluoride on renal tubules. A second chronic toxicity study in dogs is currently ongoing (results not yet available).
Ref: Federal Register: August 11, 1997 (Volume 62, Number 154). Page 42980-42986. Notice of Filing of Pesticide Petitions.

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 administrationwith 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.
-- In 2 yr studies the NOEL for non-neoplastic findings in the rat was 20 ppm (1 mg kg d) based on efffects in the kidney (increased organ weight, pigment deposition and glomerulonephrosis) at 200 ppm and above). In the mouse, the NOEL was 10 ppm in males (based on increases in liver weight, hepatocyte hypertrophy at 1000 ppm and fluoride accumulation at 100 ppm). It was not possible to set a NOEL for females as increases in serum cholesterol, protein and albumin were reported at the lowest dose.
-- Reproductive Toxicity. Developmental studies in both the rat and rabbit provided no evidence of teratogenicity when transfluthrin was administered at 125 and 150 mg kg d respectively. One death occurred at 125 mg kg d in the rat study and 2 deaths (1 each at 50 and 150 mg kg d) occurred in the rabbit study. NOELs of 15 and 15 mg kg d were established for maternal toxicity in the rat and rabbit respectively. These were based tremors at 55 mg kg d in the rat and mortality (following severe tremors) at 50 mg kg d in the rabbit. In a dietary multi-generation reproductive toxicity study in the rat there was no evidence of teratogenicity, foetotoxicity or maternal reproductive toxicity in rats administered transfluthrin at doses up to 191 mg kg d. NOELS of 62-191 and 9-38 mg kg d were established for maternal reproductive and parental toxicity respectively. The NOEl for parental toxicity was based on the following observations at 1000 ppm: - decreased body weight and body weight gain, increased absolute and relative liver and kidney weights, increased relative kidney weight, decreased hepatic triglyceride content, increased incidence of tubular pigmentation, tubular casts and pelvic calcinosis.
-- 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. Of animals dying during treatment that could be examined (5/7), the females exhibited slight congestion and haemorrhage of the lung with 2 cases of focal alveolar emphysema and 1 of alveolar oedema. The male had congested kidneys. There was no other treatment-related pathology during treatment or at the end of the post-treatment periods. The NOEL was 50 mg kg d based on the effects seen at 250 mg kg d (organ weight changes in both sexes which had reversed by 46 d).
-- In a 90 d study Bor: WISW (SPF Cpb) rats (10 animals/sex/group) were administered diets containing 0, 10, 50, 500 or 5000 ppm transfluthrin (95% pure) in food moistened with peanut oil to avoid dust. The main study groups were treated for 13 w and 2 satellite groups had been intended as recovery groups from weeks 14-18 but were treated by accident. Animals were observed twice daily and clinical laboratory examinations carried out at 1 and 3 months. An opthalmological examination was carried out at the start of the study, at 13 w and in the satellite group at 17 w. At necropsy fluoride levels in teeth and bone were measured. During the study 2 female, treated at 10 and 0 ppm, died during weeks 6 and 18 respectively. One died during blood sampling, the other was sacrified due to eye trauma... There was a dose-dependent increase in tooth fluoride content (significant above 50 ppm) reaching ~ 525% in males, ~350% in females at 14 w. ... At necropsy there was evidence of effects on the liver and kidney at 500 and 5000 ppm... In addition at 5000 ppm there was a significant increase (50%) in the numbers of animals of both sexes with degenerated hepatocytes. Relative and absolute kidney weights were increased in males at 13 and 19 w by 10-15% at and above 50 ppm. In females a slight increase (! 5%) was reported in relative weight only at 19 w. Histopathological examination showed proximal convoluted tubule degeneration in both sexes at 13 w not 19 w and a significant increase (~ 30%) in animals with basophilic tubules. 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.
-- Dermal. In a repeat dose study groupsof HC:NZW New Zealand white rabbits (5 animals/sex/group) received applications of 0, 20, 200 or 1000 mg kg transflurthrin (95% pure) in cremophor E1 (2 ml kg) under a gauze dressing for 6 h d 5 d w for 3 w. Further groups were treated with 0 and 1000 mg kg and then observed for a further 14 day. ... At necropsy white, yellow, glazing and/or cratering were noted in kidneys at the end of both the treatment and post treatment periods. Kidney weights were increased by ~ 35% relative in males at 20 mg kg at the end of the treatment period but not at the end of the post-treatment period. These were attributed to an infestation of Nosema cuniculi. Histopathological examination revealed effects on the kidney (unspecified nephropathy at the end of both treatment and post treatment in all groups)...
-- 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.... Fluoride accumulation occurred in both teeth and bone (femur) at 200 and 2000 ppm in males and females at 1 and 2 yr. The reported increases were approximately 2 and 5 fold for teeth (from 0.1 to 0.8 mg F/g ash) and 2 and 4 fold for bone (0.5-3 mg F/g ash). The main target organs were the liver and kidney. ... 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
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.

Trifloxystrobin - Fungicide - CAS No. 141517-21-7

-- Short term toxicity. Target / critical effect: Decreased bodyweight & food consumption. Liver: increased weight, hepatocellular hypertrophy and necrosis. Kidney: increased weight and acute tubular lesions. Pancreas: atrophy. Lowest relevant oral NOAEL / NOEL: 90-day rat: 100 ppm (6.4 mg/kg bw/day) Lowest relevant dermal NOAEL / NOEL: 28-day rat: 100 mg/kg bw/day Lowest relevant inhalation NOAEL / NOEL: No study - not required
-- Long term toxicity and carcinogenicity. Target / critical effect: Decreased bodyweight & food consumption. Liver: increased weight, hepatocellular hypertrophy, fatty change and necrosis. Kidney: increased weight. Lowest relevant NOAEL: 2-yr rat: 250 ppm (9.8 mg/kg bw/day) Carcinogenicity: No carcinogenic potential

Ref: Review report for the active substance trifloxystrobin. Trifloxystrobin. SANCO/4339/2000-Final. 7 April 2003. Finalised in the [European Commission] Standing Committee on the Food Chain and Animal Health at its meeting on 15 April 2003 in view of the inclusion of trifloxystrobin in Annex I of Directive 91/414/EEC.

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

-- In a 2-year chronic toxicity and carcinogenicity study, rats were fed diets containing trifloxysulfuron-sodium that resulted in average (sexes combined) daily test substance intakes of 0, 2.08, 22.0, 91.0 or 464 mg/kg/day... At terminal sacrifice, the testes to body weight ratio was increased by 19% in the 464 mg/kg/day group. Microscopical examination revealed a non-dose responsive increase in the incidence of kidney tubular atrophy in the two top dose groups of female rats, and an increase in Leydig cell hyperplasia in high dose males only. Both treatment-related lesions occurred late in age/ treatment, and were not seen in animals sacrificed in the initial year of the study... In conclusion, the MTD was reached or exceeded at 464 mg/kg/day for the 2-year rat feeding study. The NOAEL in males was 82.6 mg/kg/day based on the increased incidence of Leydig cell hyperplasia, and 23.7 mg/kg/day in females based on the increased incidence of kidney tubular atrophy. There was no evidence of a carcinogenic effect after 2 years of treatment with trifloxysulfuron-sodium in rats.
Ref: Federal Register: March 21, 2003. Trifloxysulfuron-sodium; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

Triflumizole - Fungicide - CAS No. 68694-11-1

-- Reproduction and fertility effects (rat): Reproductive NOAEL = not identified LOAEL = 3.5 mg/kg/ day based on increased gestation length in P. Offspring NOAEL = 8.5 mg/kg/ day LOAEL = 21 mg/kg/ day based on decreased pup body weight, survival indices, and litter sizes and a slight increased incidence of hydronephrosis in F1a pups.
Ref: Federal Register: June 12, 2002. Triflumizole; Pesticide Tolerance. Final Rule.

-- Chronic feeding/oncogenicity studies were conducted in both the rat and mouse. The chronic feeding study in the rat suggests that the liver is the main target organ with the ovary and kidney as secondary target organs...
-- A 2-year feeding/oncogenicity study with Sprague-Dawley rats was conducted. Rats were fed 0, 5, 20 or 80 mg/kg/day doses of triflumizole equivalent to 0, 100, 400 and 1600 ppm triflumizole for 104 weeks with an interim sacrifice at 52 weeks. Numerous organ weights, clinical chemistry and hematology parameters and microscopic changes indicate the main target organ is the liver, with fatty vacuolization and periacinar hepatic hypertrophy seen at all dose levels tested. Ovarian organ weights as well as well-developed follicles indicate the ovary as a target. Kidney weights were affected as well with increased cortical cysts seen in the kidneys of mid and high dose animals. The NOEL is greater than 100 ppm, based on fatty vacuolization and periacinar hepatic hypertrophy seen at all dose levels tested. An increase in tumor incidence was not noted in any treatment groups.
Ref: Ref: EPA Pesticide Fact Sheet September 1991. Triflumizole (Terraguard, Procure).

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)
Absorption, distribution, excretion and metabolism in mammals (Annex IIA, point 5.1). Widely distributed; highest concentration in adrenals, fat, kidneys, liver, skin and blood (page 45)
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.

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.

Definition of Renal Pelvis - The area at the center of the kidney. Urine collects here and is funneled into the ureter, the tube that connects the kidney to the bladder.

High doses of trifluralin are associated with increases in kidney, bladder, and thyroid tumors.
Ref: March 2000. 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.

Public Health Assessment Cenex Supply and Marketing, Inc. Quincy, Washington
Also available at

-- 002, 003 952930, 952931 "The chronic toxicity of compound 36352 (trifluralin) given as a component of the diet to Fischer 344 rats for two years." (Lilly research, 9/16/80, R-87 and R-97) Trifluralin, 100%, no nitrosamine, lots P-65469 and 326EF8; 60 Fischer 344 Rats/sex/group, 30 in each of two replicate studies; fed at 0, 813, 3250 or 6500 ppm in the diet - dose selection based on NCI study (Record no. 027205); diet analyses at 11 intervals; adverse effects: microcytic anemia (both sexes) at 3250 and 6500 ppm, transitional cell carcinoma of renal pelvis epithelium and bladder (both sexes) and thyroid follicular adenoma and carcinoma (males only); sys NOEL = 813 ppm (decreased body weight gain), chronic NOEL < 813 ppm (progressive glomerulonephroses, renal calculi); Complete; ACCEPTABLE. (JPC, 5/21/85 and JG, 5/18/87). No EPA one-liner available. [In the Guidance for the Reregistration of Pesticide Products Containing Trifluralin as the Active Ingredient, August 1986, CDFA Record #51346, Document 207-097, this study is discussed with the footnote that additional data in the Fischer 344 rat is required to resolve the adverse kidney effects "since a NOEL for non-oncogenic kidney effects was not demonstrated...." The EPA states at least one dose should be lower than 813 ppm. JG, 5/14/87.]
-- 109 062079, 062080, "A Special Urinalysis Study in Fischer 344 Rats Maintained on Diets Containing Trifluralin (Compound 36352) for Three Months", (Lilly Research Laboratories, study # R04785, August 1985 and 1986), trifluralin, 96.45% purity, administered in the diet for 3 months to males only with 60/group at 0 and 2.6 mg/kg/day, and with 40/group at 10.7, 42.2, 170.2, and 342.1 mg/kg/day time-weighted average. NOEL for non-oncogenic kidney effects in male Fischer 344 rats = 2.6 mg/kg/day (approx. 50 ppm) (increased urinary K, Ca, AST, LDH, and Alpha 1, Alpha 2 and Beta globulins; increased renal tubular epithelial hyaline droplets). Some were continued on the diets for 4 months followed by 6 weeks on control diet. Treatment effects were reversible in all but the highest dose group. Note: this study was conducted to determine a NOEL for the non-oncogenic kidney effects of trifluralin in the Fischer 344 rat. This question surfaced in the combined rat feeding study record #s 952930, 952927, and 952931 previously reviewed (JPC, 5/21/85 and JG, 5/18/87, 10/9/88).

Ref: SUMMARY OF TOXICOLOGY DATA TRIFLURALIN. California EPA, Department of Pesticides, Medical Toxicology Branch. Revised as of 11/29/95.

Fluoride Action Network | Pesticide Project | 315-379-9200 |