Liver - Adverse Effects
Fluorinated and Fluoride Pesticides
beginning with
A-E F-G H-P • Q-Z
 
 
See some background information and definitions on liver

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
-- Subchronic Study: 029 - 181169 "XR-795: 13-Week Dietary Toxicity Study in CD-1 Mice," (Grandjean, M., Szabo, J.R.; Health and Environmental Sciences - Texas, Lake Jackson Research Center, The Dow Chemical, Freeport, TX; Laboratory ID#: DR-0325-7474-003; 10/12/92). XR-795 (5,7-dichloro-4-[4-flurophenoxy]quinoline; 98.7% pure) was fed in diet to CD-1 mice (10/sex/dose) at 0, 10, 50, 100 or 500 mg/kg/day for 13 weeks. NOEL = 100 mg/kg (Relative liver weights were significantly increased in both sexes at 500 mg/kg. All animals (both sexes) had hepatocellular hypertrophy (centrilobular & midzonal-diffuse) at 500 mg/kg only. Hepatic inflammation (1/10-M) and hepatocellular necrosis (3/10-M, 4/10-F) occurred only at 500 mg/kg.) No adverse effects. Not acceptable but possibly upgradeable with submission of results of ophthalmological examination. 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
-- Rangefinding Study: 037 181136 "XDE-795: Oral Gavage Teratology Probe Study in New Zealand White Rabbits," (Zablotny, C.L., Yano, B.L., Breslin, W.J.; The Toxicology Research Laboratory, Health and Environmental Sciences, The Dow Chemical, Midland, MI; Laboratory Project #: DR-0325-7474-014; 11/29/93). XDE-795 (96.2% pure) was administered by oral gavage to time-mated New Zealand white rabbits (7/dose) at 0 (0.5% METHOCEL A4M), 100, 300, 600 and 1000 mg/kg/day, days 7-19 of gestation. Due to extreme maternal toxicity, treatment was discontinued at 600 and 1000 mg/kg from gestation day 15. Effects included decreased fecal output, weight loss, extreme decrease in food consumption. Maternal NOEL = 100 mg/kg (There were increased clinical observations, as well as decreased body weight, body weight gain and food consumption at > 300 mg/kg. Liver weights were significantly increased at 300 mg/kg.) Developmental NOEL > 300 mg/kg (There were no treatment-related effects at 100 or 300 mg/kg.) No adverse effect. These data are supplemental. M. Silva, 8/29/01
-- (90-day feeding study) 031; 181173; "XR-795: 13-Week Dietary Toxicity Study with 4-Week Study in Fischer 344 Rats" (Szabo, R.A. et al., Health and Environmental Sciences-Texas, Lake Jackson Research Center, The Dow Chemical Company, Freeport, TX, Laboratory Project Study ID TXT: DR-0325-7474-005, 12/21/92). 821. XR-795 (TSN100010, DECO-104-116, purity = 99.0%) was admixed to the diet at dose levels of 0 (untreated diet), 10, 100, or 250 mg/kg/day and fed to 10 Fischer 344 rats per sex per dose for 13 weeks (an additional 10 rats per sex per dose at the control and high dose levels were included to test for recovery for 4 weeks following dosing). No treatment-related clinical signs were observed. A treatment-related increase in mean relative liver weight was observed at 100 and 250 mg/kg/day in animals of both sexes sacrificed after 13 weeks of treatment; in recovery group animals at 250 mg/kg/day, a treatment-related increase in mean relative liver weight was observed in males but not females. Microscopic examination revealed treatment-related hepatocellular hypertrophy with increased basophilia at 100 and 250 mg/kg/day in animals of both sexes sacrificed after 13 weeks of treatment persisting in recovery group males but not in recovery group females. No adverse effects. NOEL (M/F) = 10 mg/kg/day (based on increased mean relative liver weights and hepatocellular hypertrophy). Unacceptable and not upgradeable because no ophthalmological examinations were conducted. (Corlett, 9/5/01)
-- 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)
-- 030; 181172; "XDE-795: Four-Week Dietary Toxicity Study in Beagle Dogs" (Szabo, J.R. and Davis, N.L., Health and Environmental Sciences-Texas Lake Jackson Research Center, The Dow Chemical Company, Midland, MI, Texas, Laboratory Project Study ID: DR-0325-7474-008, 2/19/93). XDE-795 (TSN100010, Lot # DECO-104-116, purity = 99.0%) was admixed to the diet at dose levels of 0 (untreated diet only) or 250 mg/kg/day and fed continuously to 2 beagle dogs per sex per dose for 4 weeks. No clinical signs were observed. Treatment-related decreases in mean body weight and in mean feed consumption were observed in both males and females. Microscopic examination revealed treatment-related vacuolation of midzonal and centrilobular hepatocytes in both males and females. No adverse effects. NOEL (M/F) < 250 mg/kg/day (based on body weight and feed consumption data and microscopic findings). Supplemental (only 2 animals per sex per dose were used, only 1 treatment level was used, and the animals were only dosed for 4 weeks). (Corlett, 8/29/01)
-- 029 - 181169 "XR-795: 13-Week Dietary Toxicity Study in CD-1 Mice," (Grandjean, M., Szabo, J.R.; Health and Environmental Sciences - Texas, Lake Jackson Research Center, The Dow Chemical, Freeport, TX; Laboratory ID#: DR-0325-7474-003; 10/12/92). XR-795 (5,7-dichloro-4-[4-flurophenoxy]quinoline; 98.7% pure) was fed in diet to CD-1 mice (10/sex/dose) at 0, 10, 50, 100 or 500 mg/kg/day for 13 weeks. NOEL = 100 mg/kg (Relative liver weights were significantly increased in both sexes at 500 mg/kg. All animals (both sexes) had hepatocellular hypertrophy (centrilobular & midzonal-diffuse) at 500 mg/kg only. Hepatic inflammation (1/10-M) and hepatocellular necrosis (3/10-M, 4/10-F) occurred only at 500 mg/kg.) No adverse effects. Not acceptable but possibly upgradeable with submission of results of ophthalmological examination. M. Silva, 8/15/01
Ref: October 4, 2001. SUMMARY OF TOXICOLOGY DATA QUINOXYFEN (XDE-795 & XR-795). California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.

http://www.fluoridealert.org/pesticides/quinoxyfen.ca.epa.2001.pdf

Sodium fluoride - Insecticide, Wood Preservative - CAS No. 7681-49-4

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


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

Sheep, Awassi breed, 1- to 3- yr- old, 5F technical sodium hexafluorosilicate, 25, 50, 200, 1500, and 2000 mg/ kg (0.13, 0.27, 1.06, 7.976, and 10.63 mmol/ kg) suspended in water; duration and observation period n. p. With the 25- and 50- mg/ kg doses, animals exhibited grinding of teeth (an indication of pain), dullness, and mild diarrhea. At 200 mg/ kg, additional symptoms were experienced and included staggering and severe diarrhea. Animals died on day 6. With the two higher doses, licking of the lips, kicking of the belly, grinding of the teeth, falling down (after 1.5 h), frothing at the mouth, congested conjunctiva, protrudation of the tongue, forced and labored breathing, fever, and increased respiration and heart rates were observed. Animals died 3 h after administration of 1500 mg/ kg and 2.5 h after administration of 2000 mg/ kg. Post- mortem examination showed serous pericardial fluid (few milliliters), a slightly friable liver, mild edema in the lungs, and froth in the trachea. Hemorrhages occurred on the spleen and mucosal folds of the abomasum, and a gelatinous fluid was present in the colon. For the 1500 mg/ kg- dose group, the change in GOT went from 132% (of pretreatment activity) at 1.5 hours to 230% at 2.5 hours. For LDH, the change was 158% at death. The serum ICDH [isocitrate dehydrogenase] change increased from 168% after one hour to 984% at death. Egyed and Shlosberg (1975)
-- Toxicological Data. Human Data. Chronic exposure to sodium hexafluorosilicate dust at levels above the eight-hour TWA can result in severe calcification of the ribs, pelvis, and spinal column ligaments; effects on the enzyme system; pulmonary fibrosis; stiffness; irritation of the eyes, skin, and mucous membranes; weight loss; anorexia; anemia; cachexia; wasting; and dental effects. Long-term or repeated exposure to the skin can result in skin rash. A probable oral lethal dose of 50-500 mg/kg, classified as very toxic, has been reported for a 150-pound (70-kg) person receiving between 1 teaspoon and 1 ounce of sodium hexafluorosilicate. Cases of sodium hexafluorosilicate ingestion reported symptoms such as acute respiratory failure, ventricular tachycardia and fibrillation, hypocalcemia, facial numbness, diarrhea, tachycardia, enlarged liver, and cramps of the palms, feet, and legs.
Ref: Sodium Hexafluorosilicate [CASRN 16893-85-9] and Fluorosilicic Acid [CASRN 16961-83-4]. Review of Toxicological Literature. October 2001. 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.

http://www.fluoridealert.org/pesticides/Fluorosilicates.NIH.2001.pdf

Sulfentrazone - Herbicide - CAS No. 122836-35-5

-- Chronic toxicity. A 12-month feeding study in dogs was dosed at levels of 0.0, 24.9, or 61.2 mg/kg/day for male dogs and 0.0, 10.4, 29.6, or 61.9 [[Page 11100]] mg/kg/day for female dogs in the control through high-dose groups, respectively, with a NOAEL of 24.9 mg/kg/day for males and 29.6 mg/kg/ day for females based on hematology effects and microscopic liver changes.
--
In a 90-day subchronic feeding study in dogs administered by dietary admix at doses of 0, 10, 28, or 57 mg/kg/day for males and 0, 10, 28, or 73 mg/kg/day for females, a NOAEL of 28 mg/kg/day was determined for both males and females based on decreases in Hgb and HCT, elevated alkaline phosphatase levels, increased liver weights and microscopic liver as well as splenic changes.
Ref: Federal Register, March 7, 2003 (Volume 68, Number 45)] [Notices] [Page 11096-11100]. Notice of Filing Pesticide Petitions to Establish Tolerances for a Certain Pesticide Chemical in or on Food.

http://www.fluoridealert.org/pesticides/Sulfentrazone.FR.Mar.7.2003.htm

-- 90-Day oral toxicity in nonrodents (dogs) - [870.3150] NOAEL = 28 mg/kg/day LOAEL = 57 mg/kg/ day for males and 73 mg/kg/day for females based on decreased body weights (7-10%) and body weight gains during first 5 weeks of study; decreased hemoglobin, hematocrit, mean cell volume, mean cell hemoglobin and mean cell hemoglobin concentration, and increased absolute liver weights and alkaline phosphatase levels, and microscopic changes in the liver and spleen (pigmented sinusoidal microphages in the liver, swollen centrilobular hepatocytes and pigmented reticuloendotheli al cells in the spleen)
Ref: Federal Register: September 24, 2003. Sulfentrazone; Pesticide Tolerances. Final Rule.

http://www.fluorideaction.org/pesticides/sulfentrazone.fr.sept24.03.htm

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

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

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.

http://www.epa.gov/tri/frnotices/59fr1788.htm

Teflon (PTFE: polytetrafluoroethylene) - EPA List 3 Inert - CAS No. 9002-84-0

Abstract: Information on potential occupational hazards from exposure to carbonyl fluoride (353-50-4) was reviewed. Topics discussed included chemical and physical properties, production, use, manufacturers and distributors, manufacturing processes, occupational exposure, and biological effects. Potential exposure to carbonyl fluoride occurs as a result of the thermal decomposition of polytetrafluoroethylene (PTFE) in air. Effects of acute exposure in animal studies included extreme malaise and weakness which preceded death. Subchronic exposure studies with PTFE pyrolysis products revealed pathologic changes in the respiratory tracts and livers of exposed animals. Protein, glucose, ketones, and occult blood appeared in the urine following exposure. No information was available concerning chronic exposures, carcinogenicity, mutagenicity, teratogenicity, or reproductive effects.
Ref: 1987. Information Profiles on Potential Occupational Hazards: Carbonyl Fluoride. Second Draft. Syracuse Research Corp., NY. Center for Chemical Hazard Assessment. Sponsored by National Inst. for Occupational Safety and Health, Rockville, MD. Report No. NTIS/PB87-174330.

Teflubenzuron - Insecticide - CAS No. 83121-18-0

-- Short term repeat dose toxiciity tests in rats, mice and dogs revealed that the major target organ for the toxic effect of teflubenzuron is the liver. The main findings attributed to hepatoxiciity were increased liver weights and liver lesions, such as hepatocellular swellings, collapsed stroma, fatty changes, necrosis and cell infilitration.
-- In a 18-month carcinogenicity study in mice, teflubenzuron was given via the diet at concentrations of 0, 15, 75 or 375 mg/kg feed, equal to 0, 2.1, 10.5 or 53.6 mg/kg bw/day in males and 0, 3.1, 15.4 or 71.7 mg/kg bw/day in females... Non-neoplastic dose-dependent hepatic changes were observed in both sexes of all treated groups, such as hypertrophy, hyperplasia, single cell necrosis, phagocytic cell foci, lipofuscin accumulation and glycogen storage. The incidence of hepatocellular adenomas at 18 months (terminal kill) was significantly increased in males at the two highest dose groups: 22% in the mid-dose group and 32% in the high dose group versus 12% in the concurrent control group and 16% in the historical control group. There were no changes in the incidence of hepatocellular carcinomas. Since the increased incidence of hepatocellular adenomas is likely to be secondary to the hepatoxicity of teflubenzuron and was of a type generally not considered to be of concern for human health if not accompanied by other evidence for carcinogenicity, the mouse study was considered not to provide evidence for carcinogenicity of teflubenzuron.
-- The FAO/WHO Joint Meeting on Pesticides Residues (JMPR) evaluated teflubenzuron in 1994 and established an ADI of 0.01 mg/kg bw/day, based on the dose-related effects in the target tissue liver in the mouse carcinogenicity study submitted.
January 1999 - Summary Report. Committee for Veterinary Medicinal Products. The European Agency for the Evaluation of Medicinal Products.

http://www.fluoridealert.org/pesticides/Teflubenzuron.Review.1999.pdf

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

-- In a chronic/oncogenicity study, mice were dosed at 0, 25, 100, or 400 ppm (actual dose levels were equivalent to 3.4, 13.5, or 54.4 mg/kg/day) for 104 weeks. The chronic LOEL is 13.5 mg/kg based on hemangiomatous changes of the uterus and liver necrosis observed in the mid- and high-dose females. The chronic NOEL is 3.4 mg/kg. Under the conditions of this study, there was no evidence of carcinogenic potential.
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

Likely to be Carcinogenic to Humans. Hepatocellular adenomas, carcinomas and combined adenomas/carcinomas in both sexes; Crl:CD-1 (ICR) mice.
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.

Likely to be carcinogenic to humans. Reviewed 1/ 11/ 00.
Ref: List of Chemicals Evaluated for Carcinogenic Potential. Science Information Management Branch, Health Effects Division, Office of Pesticide Programs, U. S. Environmental Protection Agency. March 15, 2002.
http://www.biomuncie.org/chemicals_evaluated_for_carcinog.htm

• Metbolism nd 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)
-- In a carcinogenicity study, mice received 0, 10, 90, 800 or 1250 ppm of tetraconazole in the diet for 80 weeks. In the liver, increased weight and masses and enlarged and discoloured liver were noted at 90 ppm and above with a dose-related increase in the incidence and degree of generalised hepatocyte enlargement, vacuolation, fat deposition and bile duct hyperplasia at 90 ppm (males) and higher doses. There were also increased basophilic hepatocyte foci, eosinophilic hepatocytes, pericholangitis, granulomatous inflammation and pigmented macrophages in mice at 800 and 1250 ppm. Hepatocyte necrosis was detected in some females of each treated group (page 4) ... Benign and malignant liver cell tumors were increased at 800 and 1250 ppm, and resulted in the high mortality at 1250 ppm. The NOEL was 10 ppm (1.4 mg/kg bw/day). (page 5)
• Sub chronic studies. Mice received 0, 5, 25, 125 or 625 ppm of tetraconazole in the diet for 13 weeks. In males at 625 ppm and females at 125 and 625 ppm, decreased BUN was detected, and elevated alanine aminotransferase (ALT) and AST activities were associated with increased liver weights. Mice at 625 ppm exhibited pale and enlarged liver with lobular markings accentuated. Hepatocyte enlargement was a major finding in the majority of mice at 25 ppm and above. Hepatocyte necrosis, degeneration or congestion developed at 125 and 625 ppm, and a higher incidence of hepatocyte vacuolation appeared at 625 ppm. 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.
http://www.fluorideaction.org/pesticides/tetraconazole.2005.report.australia.pdf

-- Carcinogenicity. Tetraconazole has not been classified with respect to carcinogenic potential by EPA. However, based on the tumorigenic results in the mouse carcinogenicity study, EPA has made an initial determination that a Q1* should be determined based on the male mouse benign liver tumors, excluding the highest dose. The Q1* is 0.037 (mg/kg/day)-1.
-- Aggregate cancer risk for U.S. population. Tetraconazole produced statistically significant increases in male and female mouse liver adenomas and carcinomas. Based on a determination of the Q1* for this tolerance setting action only, the Q1* was determined to be 3.7 x 10-2 based on benign tumors in males with the exclusion of the high dose group. The cancer risk for the U.S. population is, without adjustment, 2.5 x 10-6. Because this is an emergency exemption use of tetraconazole, it is considered appropriate to divide the cancer risk by a factor of 14 [5 years for potential emergency exemption use/70 years lifetime = 1/14]. The adjusted cancer risk for the U.S. population is 1.8 x 10-7 and this adjusted cancer risk is below EPA's level of concern.
-- Reproductive toxicity study-- Rats. In the 2-generation reproductive toxicity study in rats, the maternal (systemic) NOAEL was 0.7 mg/kg/day, based on dystocia, delayed vaginal opening, and increased liver weight at the LOAEL of 5.9 mg/kg/day. The developmental (pup) NOAEL was 0.7 mg/kg/day, based on increased time to observation of balanopreputial skin fold and liver weight at the LOAEL of 5.9 mg/ kg/day. At the high dose of 35.5 mg/kg/day, there was a decrease in the mean number of live pups per litter on lactation days 0 and 4 (precull) in the presence of significant maternal toxicity.
Ref: Federal Register: December 6, 1999. Tetraconazole; Pesticide Tolerances for Emergency Exemptions. Final Rule.

http://www.fluoridealert.org/pesticides/Tetraconazole.FR.Dec.1999.htm

-- Subchronic toxicity. A 90-day oral subchronic toxicity study was conducted with technical grade tetraconazole in rats at 10, 60, and 360 ppm in the diet. Treatment related increased liver weights and centrilobular hepatocyte enlargement were observed at the two highest dose levels. The NOAEL was 10 ppm (0.8 mg/kg/day), by comparison with data from the zero-dose control group.
-- A 90-day oral subchronic toxicity study was conducted in mice with dietary concentrations of technical grade tetraconazole at 5, 25, 125, and 625 ppm. The two highest dosages resulted in liver enlargement, accentuated lobular markings and liver pallor. Microscopic tissue alterations related to tetraconazole were liver enlargement at the three highest doses and single cell necrosis/degeneration and/or areas of necrosis at the two highest doses. The NOAEL was 5 ppm (1 mg/kg/ day).
-- Chronic toxicity. A 12-month chronic oral toxicity study in Beagle dogs was conducted with technical tetraconazole at dose levels of 0.7, 2.8, and 5.6 mg/kg/day (22.5, 90, and 360 ppm dietary concentrations, respectively). At the highest dose, liver and kidney weights and cholesterol levels were elevated, and liver injury occurred based upon increased levels of GPT, -GT and OCT. The no effect level was 0.7 mg/kg/day, as compared with zero-dose control animals.
-- A chronic (full-lifetime) feeding/carcinogenicity study was conducted with Crl:CD(SD)BR rats fed tetraconazole at dietary levels of 10, 80, 640, and 1,280 ppm for 104 weeks in males and 10, 80, and 640 ppm for 104 weeks in females. In the liver, changes such as hepatocyte enlargement and increased incidence of eosinophilic hepatocytes, seen at doses of 80, 640, or 1,280 ppm were associated with hepatic enzyme induction.
-- At 90 ppm, non-neoplastic changes were detected in bone and the epididymides in addition to liver changes. No treatment-related findings were seen in mice treated at 10 ppm (approximately 1.5 mg/kg/ day), and this dose level was defined as the NOAEL. In this same study, an increased incidence of benign liver cell tumors was observed in males and females fed 800 ppm, and an increased incidence of benign and malignant liver cell tumors in males and females given 1,250 ppm. These tumors were associated with increased signs of hepatotoxicity including hepatocyte vacuolation and fat deposition at 90, 800, and 1,250 ppm; granulomatous inflammation, pigmented macrophages, bile duct hyperplasia and pericholangitis in mice given 800 and 1,250 ppm. In addition, there was evidence of treatment-related hepatocellular enlargement and increased numbers of altered foci of eosinophilic and basophilic hepatocytes in both sexes given 800 and 1,250 ppm; eosinophilic hepatocytes were noted in male (only) mice receiving 90 ppm.
-- Tetraconazole is a triazole, and this class of compounds is known to induce liver microsomal enzymes. A special mechanistic study was conducted in order to more fully determine the potential role of microsomal enzyme induction by tetraconazole administered in the diet upon the formation of tumors in mouse. Dietary administration of tetraconazole to mice for 4 weeks results in the induction of cytochrome P450-related activities, as well as the concentrations of microsomal protein and cytochrome P450, and of the phase II activity, and p-nitrophenol UDP- [[Page 55720]] glucuronyl transferase activity. The effects of tetraconazole on the cytochrome P450-dependent MFO system were somewhat different from those of phenobarbital. Many of these enzymes have not been as well- characterized in mice compared to rats. However, the phase II enzyme activity increases were similar to those of phenobarbital. It is concluded from these studies that prolonged induction of liver microsomal enzymes and/or production of sustained liver injury can lead to the formation of liver tumors in mice.
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

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.

http://www.fluorideaction.org/pesticides/1,1,1,2-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.
-- 3.7 Subchronic and Chronic Toxicity and Carcinogenicity (pages 138 - 139)
... groups of 85 male and 85 female rats were exposed to concentrations at 0, 2,500, 10,000, or 50,000 ppm for 6 h/d, 5 d/wk for 104 wk (Collins et al. 1995). Exposure conditions and analytical measurements were identical to procedures followed in the 13 week study. Ten animals from each group were sacrificed at 52 wk. At 52 and 104 wk there were no effects on clinical condition, food consumption, growth, survival, hematology, clinical chemistry, or urinary parameters. Absolute liver weights of females were increased in the groups exposed at 2,500 and 50,000 ppm but not in the group exposed at 10,000 ppm. Males in groups that received 10,000 or 50,000 ppm for 104 wk had an increased incidence of enlarges testes (not statistically significant), and males in the group that received 50,000 ppm for 104 wk had a statistically significant increase in incidence of Leydig cell hyperplasia (40 vs. 27 in the concurrent control group) and Leydig cell adenomas (23 vs. 9 in the concurrent control group). There was no evidence of progression to malignancy. As discussed earlier, these tumors are not relevant to humans.

-- Collins MA, Rusch GM, Sato F, Hext PM, Millischer RJ. 1995. 1,1,1,2-Tetrafluoroethane: repeat exposure inhalation toxicity in the rat, developmental toxicity in the rabbit, and genotoxicity in vitro and in vivo. Fundam Appl Toxicol 25:271-280.
-- 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:
http://books.nap.edu/books/030908511X/html/index.html

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

-- Thiazopyr technical produced organ toxicity following multiple exposures at high doses. The primary target organs for thiazopyr toxicity in the rat, mouse and dog were the liver, thyroid, kidney and blood, with the liver being the most sensitive indicator of toxicity. In chronic dietary feeding studies, the dog was the most sensitive species. An RfD for thiazopyr of 0.008 mg/kg/day was established by the RfD Committee of the USEPA Health Effects Division, based on the NOEL of 0.8 mg a.i./kg/day (20 ppm) from the chronic dog study and a 100-fold safety factor to account for intraspecies extrapolation and intraspecies variability.
-- 21-Day Dermal (Rat): NOEL =100 mg/kg/day. The LOEL was 500 mg/kg/day based on minimal hepatocellular vacuolation in females.
-- 90-day Oral (Rat): NOEL (systemic) =100 ppm (6.60 mg /kg/day and 7.99 mg/kg/day for males and females, respectively). The LOEL was 1000 ppm (68 - 79 mg/kg/day in males and females, respectively) based on increased liver, thyroid and kidney weights
, changes in clinical chemistry and hematological parameters and on gross and microscopic changes observed in the liver and thyroid at does levels of 68 mg/kg/day and higher. At the 201 mg/kg/day dose diffused thyroid follicular cell hypertrophy/ hyperplasia was observed.
-- 90-day Oral (Dog): NOEL (systemic) =10 ppm. (0.2 mg/kg/day(m); 0.3 mg/kg/day(f)), based on decreased body weight gain and increased SGPT levels at 3 and 6 m/kg/day for males and females, respectively and above; decreased total protein and albumin concentration and albumin/globulin ratio, increased AP, hepatocytic hypertrophy, oval cell proliferation and increased hepatocytic fatty content at 35 mg/kg/day and above; and decreased calcium concentration which is thought to be related to hypoalbuminemia, decreased cholesterol and triglyceride concentrations, slightly increased GGT and SGPT, follicular hyperplasia of thyroid, increased colloid content in follicles and increased relative thyroid weight at 175 mg/kg/day.
-- A 1 year feeding study in dogs at 0, 0.8, 7.8, 86.0 with males, and 0.8, 8.8, and 78.0 with females with a NOEL of 0.8 mg/kg/day. The Loel was based on hepatocellular hypertrophy and hyperplasia. A 10% increase in prothrombin time and several and several changes in blood chemistry: increased SGOT, SGPT, GGT and ALK levels and decreased cholesterol, albumin and total protein and calcium were observed in high- dose dogs. There were increases in absolute weights, liver and body weight and liver to brain weight, heptotoxicity characterized by enlargement and/or discoloration in some high dose animals and by hepatocellular hypertrophy/hyperplasia in the 0.8 and 7.8 mg/kg/day dogs. The NOEL was based on hepatocellular hypertrophy and hyperplasia.

-- A two-generation reproductive in rats at 0, 0.75, 7.5 and 75.0 mg/kg/day with a parental toxicity NOEL of 7.5 mg/kg/day. The toxic effects were increased absolute and relative liver weight, hepatic discoloration, histologic evidence of hepatic hypertrophy and vacuolization in females in both generations. No adverse efects were observed in adults or their offspring up to 75 mg/kg/day, the highest dose tested.
-- A mouse carcinogenicity study at doses of 0, 0.17, 1.6, 16.9, 66.3 or 128.4 mg/kg/day (males) and 0,0.24, 2.6, 26.8, 108.1 or 215.9 mg/kg/day (female) with a systemic NOEL of 0.1 mg/kg/day. The effects were hepatocellular hypertropy and amyloid deposition. At 66.3 mg/kg/day the same lesions plus increased liver weights, random and periportal hepatocellular vacuolation were observed. At 128.4 mg/kg/day the same lesions plus distended abdonen, slight increase in ALP, SGOT and SGPT, abnormal coloration and enlargement of liver, decrease in absolute and relative spleen weights, increase in absolute and relative kidney weights, increase in eosinophilia in hepatocytes, kidney nephropathy and lymphocytic hyperplasia of the nesenteric lymph nodes were observed. There was no evidence of oncoenicity at any dose level.
-- A two year rat carcinogenicity study at doses of 0, 0.04, 4.4, 44.2 or 136.4 mg/kg/day (Males) 0, 0.06, 0.6, 5.6, 56.3 or 177.1 mg/kg/day (female) with a NOEL of 4.4 mg/kg/day. The effects were protruding eyes, evidence of mild anemia, increased GGT and cholesterol, increased absolute and relative liver, kidney and thyroid weights and significant increase in microscopic lesions in the liver (hypertrophy and vacuolar changes), kidney (nephropathy) and thyroid (hypertrophy and hyperplasia
); decreased mean body weight and body weight gain and food consumption. A statistically significant increase in thyroid follicular cell adenomas/cystadenomas were observed in males at 44.2 and 136.4 mg/kg/day. A nonsignificant increase in renal tubular adenomas in high-dose females was considered to be equivocal.
-- The EPA Health Effects Division Carcinogenicity Peer Review Committee classified thiazopyr as a Group C, possible human carcinogen and recommended that for the purpose of risk characterization a Margin of Exposure (M.O.E.) approach should be used in evaluation of the consequences of human exposure.
-- A second study on the effects of thiazopyr on the biochemical mechanisms of thyroid toxicity in rats at doses of 0, 0.5, 1.5, 5, 15, 50 or 150 mg/kg/day was conducted. Dose response effects on various biochemical parameters were observed. Two groups of the rats in the study were observed for reversibility of effects observed up to 56 and 112 days. Doses at 15, 50 and 150 mg/kg/day significantly increased the liver weights. Thyroid weights were increased at doses of 50 and 150 mg/kg/day. There were no significant effect on body weight or body weight gains during the study. The T4 UDPGT levels were increased by 117 and 376% above controls at the 50 and 150 mg/kg/day dosages. Effects of 150 mg/kg/day were increases in T3, TSH and rT3 serum concentrations, and increased incidence of follicular cell hypertrophy/hyperplasia at the 150 mg/kg/day dose. A NOEL of 1.5 mg/kg/day was determined based on liver weight increases. Thyroid weight was the only parameter that did not return to those similar to the controls. At the 56 and 112 day recovery periods the thyroid weights were 120 and 123% of control values, respectively.
Ref: US EPA. Pesticide Fact Sheet. Thiazopyr Reason for Issuance: Registration of a New Chemical Date Issued: February 20, l997.

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

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

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

-- 90-Day oral toxicity rodents (rat). NOAEL = 20.1 milligram/kilogram/ day (mg/kg/day) male (M) LOAEL = 108 mg/kg/ day, based on changes in clinical blood chemistry associated with the liver and thyroid (M) NOAEL = 131 mg/kg/day female (F) LOAEL = 736.1 mg/kg/ day, based on changes in clinical blood chemistry associated with the liver and thyroid and decreased body weights (F)
-- 90-Day oral toxicity in nonrodents (dog). NOAEL = 23.1/25 mg/kg/ day (F/M) LOAEL = 67.2/69.4 (F/ M) mg/kg/day, based on decreased body weight gains and changes in liver structure and function in both sexes

-- Prenatal developmental in nonrodents (rabbit). Maternal NOAEL = 25 mg/kg/day LOAEL = 70 mg/kg/day, based on evidence of hepatotoxicity (increased glutamate dehydrogenase (GLDH) and triglyceride levels and gross and microscopic liver pathology) and decreased food consumption and equivocal decreases in body weight gain. Developmental NOAEL = 25 mg/kg/day LOAEL= 70 mg/kg/day, based on increased malformations (arthrogryposis of front extremities and small orbital cavity/folded retina) and variations (floating rib and accelerated ossification).
-- 2-Generation reproduction and fertility effects (rat). Parental/systemic NOAEL = 7.9-10.5 mg/ kg/day LOAEL = 57.5-78.0 mg/ kg/day, based on decreased body weights, body weight gains, and liver weights in the P females Reproductive NOAEL = 7.9-10.5 mg/kg/day LOAEL = 57.5-78.0 mg/ kg/day, based on reduced litter size Offspring NOAEL = 7.9- 10.5 mg/kg/day LOAEL = 57.5-78.0 mg/ kg/day, based on decreased pup weights, increased pup deaths and related pup viability indices.

-- 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.
http://www.fluoridealert.org/pesticides/Tolylfluanid.FR.Sept25.2002.htm

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.
-- The NOEL's following 90 d oral administration were 10 ppm (equivalent to 0.85 mg kg d) in the rat and 50 ppm (equivalent to 1.9 mg kg d) in the dog. It was not possible to set a NOEL following dietary administration for 1 yr in the dog as there was some slight evidence of liver hypertrophy at the lowest dose (10 ppm)...
-- 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..
-- 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%). ... At necropsy there was evidence of effects on the liver and kidney at 500 and 5000 ppm. Relative and absolute liver weights were increased by ~ 15% at 500 ppm, ~45% at 5000 ppm (males at 13 w) and up to ~55% at 19 w. Histopathological examination showed centrilobular hepatocyte hypertrophy in all males, 9/10 females at 5000 ppm and 8/10 males, 4/10 females at 500 ppm. In addition at 5000 ppm there was a significant increase (50%) in the numbers of animals of both sexes with degenerated hepatocytes...
-- 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... Histopathological examination showed centrilobular hypertrophy in all animals at 2500 ppm and 1 female from this group with minimal hepatocytic single cell necrosis. The NOEL for this study was 50 ppm (1.9 kg d) based on the increase in N-demethylase activity in males at 350 ppm (14 mg 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. ... Microscopic pathology showed "ground galss cytoplasm" in the liver in both sexes at 2000 ppm (approx. 9/60 for males and females) and hepatocyte hyperplasia in males (0, 2, 1, 1 at 0, 20, 200 and 2000 ppm)...
-- B6C3F1 mice (60/group/sex) received 0, 10, 100 or 1000 ppm mg kg transfluthrin (94.8-95%) pure in the diet for up to 104 weeks with 10/sex/dose killed after one yar. Two additional groups(10/sex) received 0 or 1000 ppm for 13 weeks... Serum cholesterol levels were significantly raised from 13 weeks at 1000 ppm (20% in males and 54% in females) and from 100 ppm from week 53 (approximately 11 - 30%) and at week 103 from 10 ppm in females (approximately 50 - 70%) and at 1000 ppm in males )~ 20%). ... Fluoride accumulation in bone and teeth of both sexes were observed (in the 13 week study at 1000 ppm) and at 53 and 104 weeks from 100 ppm (approximately 2 fold at 100 ppm and 4-5 fold at 1000 ppm with respect to controls). ... The only gross pathological findings considered to be treatment related were nodules in the livers of females at 1000 ppm (incidence 6/42, 4/39, 3/42 and 15/44). On histopathological examination, at 1000 ppm, non neoplastic findings were periacinar hepatocyte hypertropy was observed at 53 weeks (slight to moderate in all males and minimal in 6/10 females) and more marked but consistent with liver enzyme induction at 104 weeks (38/50 males, 26/50 females). ... Based on the chronic toxicity, in males the NOEL is 10 ppm (2 mg kg d based on increases in liver weight and hepatocyte hypertrophy, at 1000 ppm and increased fluoride accumulation at 100 ppm). It is not possible to set a NOEL for females as increases in serum cholesterol, protein and albumin were reported at the lowest dose.
-- 3.2.4.1 Promotion Studies ... 3.2.3.2 Summary. An increased incidence of urinary bladder papillomas and carcinomas was seen following dietary administration of 2000 ppm to the rat. The mechanism of tumourigenicity is considered to be non genotoxic. Studies using rat hepatocytes showed that transfluthrin does not cause cell proliferation but acts as a weak promoter with a NOEL of 5 ppm. Transfluthrin is not carcinogenic in the mouse. In the rat the 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). In the male mouse the NOEL is 10 ppm (2 mg kg d, based on increases in liver weight and hepatocyte hypertrophy, at 1000 ppm and increased fluoride accumulation at 100 ppm). It is not possible to set a NOEL for females as increases in serum cholesterol, protein and albumin were reported at the lowest dose.
-- 3.2.5.1.2 Rabbit. In an adequately conducted teratology study, pregnant Himalayan rabbits (15/group) were administered transfluthrin (94% purity) in 0.5% (v/v) aqueous Cremophor EM emulsion by gavage at doses of 0, 15, 50 and 150 mg kg d during days of 6-18 of gestation. Control animals received vehicle alone... Dams were necropsied on day 29 of gestation following delivery of the foetuses by caesarean section. Two deaths occurred, one on day 18 at 50 mg kg d and one on day 19 at 150 mg kg d. Immediately prior to death both animals displayed symptoms consistent with CNS involvement inclusing spasms, severe tremor and prostration (animals found lying on their side). Autopsy of these animals revealed an enlarged lobulated liver and pale lobulated lungs at 50 mg kg d whereas no pathological fingings were observed at 150 mg kg d.
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/evallist_alphabet.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.

Trichlorotrifluoromethane - Solvent, US EPA List 2 Inert - CAS No. 76-13-1

Studies of 4 to 6-weeks duration, conducted at concn <25,000 ppm, reported variable findings. After 19 seven-hr exposures at 5000 ppm, some rats developed slight, diffuse, degenerative fatty infiltration; no such changes or other pathological findings were observed in three subsequent similar studies. No clinical, biochemical, or pathologic changes developed after twenty 3.5 hr daily exposures of rats & guinea pigs, or rats & dogs after 20 six-hr exposures at 5100 ppm or in rats after 30 seven-hr exposures at 2520 ppm; however, after inhaling 5000 ppm, 7 hr/day for 30 days, body-weight gain was depressed in the rat. After 14 days of continuous exposure of monkeys, dogs, mice, and rats at 2000 ppm, no adverse effects could be detected. The only morphologic & biochemical changes noted in male Wistar rats inhaling 1000 or 2000 ppm CFC-113, 6 hr/day, 5 days/week were proliferation of hepatic smooth endoplasmic reticulum & induction of hepatic microsomal enzymes. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I, II, III. Cincinnati, OH: ACGIH, 1991.1632]
-- Animal Toxicity Studies: Non-Human Toxicity Excerpts: THE CHIEF EFFECTS OF EXPOSURE TO ... /TRICHLOROTRIFLUOROETHANE/ ARE DEPRESSION OF THE CENTRAL NERVOUS SYSTEM AND IRRITATION OF THE RESPIRATORY TRACT. SUCH EFFECTS OCCUR IN ANIMALS AT CONCENTRATIONS ABOVE 12000 PPM. MILD LIVER CHANGES HAVE BEEN NOTICED AT LEVELS SOMEWHAT BELOW THIS. [American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values for Substances in Workroom Air. Third Edition, 1971. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists, 1971. (Plus supplements to 1979)267]
Ref: Hazardous Substances Data Bank for 1,1,2-TRICHLORO-1,2,2-TRIFLUOROETHANE CASRN: 76-13-1.
http://www.fluorideaction.org/pesticides/trichlorotrifluorome.toxnet.htm

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

-- Subchronic toxicity. In subchronic studies, several mortality related changes were reported for the top dose in dogs (500 mg/kg) and rats (800 mg/kg). At these dose levels, excessive toxicity has resulted in body weight loss and mortality with the associated and non-specific changes in several organs (such as atrophy in the thymus, pancreas, bone marrow, lymph node, and spleen) which are not considered specific target organs for the test compound. In the dog, specific effects were limited to hepatocellular hypertrophy at 150 mg/kg and hyperplasia of the epithelium of the gall bladder at 500 mg/kg. Target organ effects in the rat were noted as hepatocellular hypertrophy (200 mg/kg) and the related liver weight increase (50 mg/kg). In the mouse, target organ effects included single cell necrosis (300 mg/kg) and hypertrophy (1,050 mg/ kg) in the liver and extramedullary hematopoiesis (300 mg/ kg) and hemosiderosis in the spleen (1,050 mg/kg). In general, definitive target organ toxicity, mostly in the liver, was seen at high feeding levels of over 100 mg/kg for an extended treatment period. At the lowest observed adverse effect level (LOAEL), no serious toxicity was observed other than mostly non-specific effects including a reduction in body weight and food consumption or liver hypertrophy.
-- Chronic toxicity. The liver appears to be the major primary target organ based on the chronic studies conducted in mice, rats, and dogs. It was identified as a target organ in both the mouse and the dog studies with trifloxystrobin. However, no liver effect was seen in the chronic rat study which produced the lowest NOAEL of 2.5 mg/kg based on reduced body weight gain and food consumption seen at higher dose levels.
Ref: Federal Register. November 14, 2001. [PF-1048; FRL-6806-6]

http://www.fluoridealert.org/pesticides/Trifloxystrobin.FR.Nov14.01.htm

-- Other toxicological studies. Investigations into replicative DNA synthesis: No evidence of replicative DNA synthesis in rat or mouse heptocytes following 3-months administration in diet. Investigations into mitochondrial function: In vitro studies in isolated rat liver mitochondria indicated trifloxystrobin caused a significant concentration dependant inhibition of mitochondrial respiration....
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.
http://www.fluorideaction.org/pesticides/trifloxystrobin.eu.april.03.pdf

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

-- 90-Day oral toxicity in nonrodents. NOAEL = 3.9/3.7 (m/f) mg/kg/day LOAEL = 146.9/159.9 (m/f) mg/kg/day based on decreased mean body weight and body weight gain, decreased hematocrit, hemoglobin, RBC`s, SGOT, SGPT, ALP, absolute and relative liver and testes weight; microscopic abnormalities of the liver and testes.
-- Carcinogenicity mice NOAEL = 14.6 mg/kg/day LOAEL = 349 mg/kg/day based on increased liver weight and increased hepatic cell tumors (adenomas and/or carcinomas combined. (Possible) evidence of carcinogenicity
Ref: Federal Register: June 12, 2002 (Volume 67, Number 113). Triflusulfuron Methyl; Pesticide Tolerance. Final Rule.

http://www.fluorideaction.org/pesticides/triflusulfuron.m.fr.june.02.htm

-- Chronic toxicity dogs NOAEL = 26.9 mg/kg/day LOAEL = 116.6 mg/kg/day based on increased liver weight, alkaline phosphatase, and hepatocellular hypertrophy.
Ref: Federal Register: June 12, 2002 (Volume 67, Number 113). Triflusulfuron Methyl; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/triflusulfuron.m.fr.june.02.htm

In another 90-day subchronic study, dogs were fed dosages of 3.87, 146.1, or 267.6 mg/kg/day (males) or 3.72, 159.9, or 250.7 mg/kg/day (females). Triflusulfuron methyl was found to be hepatotoxic at 4,000 ppm (146.1 mg/kg/day males and 159.9 mg/kg/day females), and greater elevated hepatic enzyme levels and postmortem evidence, including elevation in liver weights and microscopic evidence of bile stasis. Other microscopic findings considered to be treatment related were testicular atrophy and decreased testicular weights and hypercellularity of the sternal and femoral bone marrow, with a corresponding increase in reticulocyte and leukocyte counts seen in the high-dose males and females. Based on the microscopic findings in the liver and testes of the 4,000 ppm and greater treated animals, the NOAEL was 3.87 mg/kg/day (males) and 3.72 mg/kg/day (females).
Ref: Federal Register. August 8, 2001. [PF-1036; FRL-6795-4]
http://www.fluoridealert.org/pesticides/Triflusulfuron.M.FR.Aug8.01.htm

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

-- Reproduction and fertility effects (rat): ... Parental/Systemic: LOAEL = 21 mg/kg/ day based on decreased body weight and overall body weight gain, increased relative liver weights, and increased mortality in females.
-- Chronic toxicity nonrodents (dog): LOAEL = Males: 34.10 mg/kg/day; Females: 35.17 mg/ kg/daybased on increased alkaline phosphatase activity and a mild, macrocytic anemia in males, increased absolute and relative liver weights in both sexes, and on macroscopic findings in the liver of both sexes.
-- Carcinogenicity (mouse): LOAEL = Males: 67.4 mg/kg/day; Females: 86.1 mg/ kg/day based on microscopic lesions of the liver. No evidence of carcinogenicity.
-- 90-Day oral toxicity rodents (rats): LOAEL = Males: 176.5 mg/kg/day; Females: 217.9 mg/ kg/daybased on increased kidney and liver weights and the accumulation of fat droplets in the liver.
Ref: Federal Register: June 12, 2002. Triflumizole; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Triflumizole.FR.June12.2002.htm

-- 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. Although there was an accompanying increase in organ weights, no carcinogenic effects were seen. In the chronic feeding study in mice, the results of blood chemistry, organ weights and gross and histological examinations also indicate the liver as the target organ...
-- 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...
-- A 2-year feeding/oncogenicity study with male and female mice using dietary concentrations of 0, 100, 400 and 1600 ppm equivalent to 0, 15, 60 and 240 mg/kg/day was conducted. There were interim sacrifices at 26, 54, 78 and 104 weeks. Major effects were seen in the liver at all doses tested. Clinical chemistry changes reflecting liver toxicity included changes in alkaline phosphatase, BUN, SGOT, SGPT and cholesterol. Absolute and relative liver weights were increased at all time periods in the high dose males and females and in some animals of the mid dose groups. At sacrifice, liver changes in all dose groups included hepatic nodules and cytoplasmic alterations. The systemic NOEL was less than 100 ppm. Although there was a slight increase the incidence of lymphoma in both treated males and females, it was judged not be compound-related.
-- A 30-day feeding study with rats was conducted using dietary concentrations of 20, 200 and 2000 ppm equivalent to 0, 2, 20 and 200 mg/kg/day. The NOEL was 200 ppm and the LEL was 2000 ppm based on liver changes, necrosis and fatty metamorphosis.
Ref: EPA Pesticide Fact Sheet September 1991. Triflumizole (Terraguard, Procure).
http://pmep.cce.cornell.edu/profiles/fung-nemat/tcmtb-ziram/triflumizole/fung-prof-triflumizole.html

Abstract: The hepatotoxic effects of 22 pesticides were studied. Hepatocytes, mitochondria, and microsomes were prepared from Sprague-Dawley-rats and incubated with the test substances in-vitro ... Hepatic mitochondrial respiration was affected by ... triflumizole (68694-11-1).
Ref: Effects of pesticides on isolated rat hepatocytes, mitochondria, and microsomes II; by YAMANO T, MORITA S. ARCHIVES OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY; 28 (1). 1995. 1-7.

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

• Long term toxicity (Annex IIA, point 5.5). Target/critical effect ‡ Body weight reduction, anemia, liver & kidney effects (mouse, rat). (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.
http://www.fluoridealert.org/pesticides/trifluralin.eu.long.2005.pdf

Triflusulfuron-methyl - Herbicide - CAS No. 126535-15-7

In another 90-day subchronic study, dogs were fed dosages of 3.87, 146.1, or 267.6 mg/kg/day (males) or 3.72, 159.9, or 250.7 mg/kg/day (females). Triflusulfuron methyl was found to be hepatotoxic at 4,000 ppm (146.1 mg/kg/day males and 159.9 mg/kg/day females), and greater elevated hepatic enzyme levels and postmortem evidence, including elevation in liver weights and microscopic evidence of bile stasis. Other microscopic findings considered to be treatment related were testicular atrophy and decreased testicular weights and hypercellularity of the sternal and femoral bone marrow, with a corresponding increase in reticulocyte and leukocyte counts seen in the high-dose males and females. Based on the microscopic findings in the liver and testes of the 4,000 ppm and greater treated animals, the NOAEL was 3.87 mg/kg/day (males) and 3.72 mg/kg/day (females).
Ref: Federal Register. August 8, 2001. [PF-1036; FRL-6795-4]

http://www.fluoridealert.org/pesticides/Triflusulfuron.M.FR.Aug8.01.htm

 
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