Blood - Adverse Effects
Fluorinated and Fluoride Pesticides

beginning with
A-E F-G H-P • Q-Z

Some Definitions:

Anisocytosis: Variation in red cell size. Normal red blood cells are 7 to 8 micrometers, and have an average volume of 90 fl, with a normal range of 80-100 fl. RBCs which are smaller than normal are termed microcytic (MCV 100). Macrocytic anemia has many causes, including folate/vitamin B12 deficiency and some drugs (e.g., methotrexate, Zidovudine (AZT), and hydroxyurea).

Erythrocyte: A mature red blood cell. SYN. haemacyte, hemacyte, red blood cell, red corpuscle.

Erythropoiesis is the process of red blood cell production (which occurs in red bone marrow).•

Haemangioma (also known as a strawberry birthmark) is a type of birthmark caused by an abnormal collection of abnormal blood vessels just below the skin.

Heinz' bodies Small irregular, deep purple granules in red blood cells due to damage of the haemoglobin molecules. Seen in premature infants, in certain forms of drug sensitivity, characteristically in glucose-6-phosphate dehydrogenase deficiency following administration of oxidant drugs, e.g. primaquin. Also in certain type of hereditary haemolytic anaemia, especially in patients with thalassaemia. The bodies are best seen when the blood is stained with crystal violet. Heinz reported these bodies in the blood of guinea pigs treated with acetylphenylhydrazine. Also known as: Ehrlich's bodies Ehrlich Innenkšrper (German) Ehrlich hşmoglobinşmische Innenkšrper (German) Heinz-Ehrlich bodies

Hematopoietic. SYN hemopoietic (see below).

Hemopoietic. Pertaining to or relted to the formation of blood cells. SYN haemoplastic, hematogenic (1), hematogenous, hematoplastic, hematopoietic, hemogenic,hemoplastic, sanguifacient.•

Hematopoietic system. the blood making organs; in the embryo at different ages these are the yolk sac, liver, thymus, spleen, lymph nodes, and bone marrow; after birth they are principally the bone marrow, spleen, thymus, and lymph nodes.•

Hypochromasia: Decrease in hemoglobin concentration per red cell. Morphologically, this is reflected by increased size of the central pallor of the RBC when observed on a peripheral blood smear.

Leukocyte Histology ¥ a white or colorless cell of the blood, having a nucleus and either granular or nongranular cytoplasm; leukocytes function as bacterial or viral phagocytes, as detoxifiers of toxic proteins, and in the development of immunities. Also, WHITE BLOOD CELL.

Lipofuscin. This brownish pigment is left over from the breakdown and absorption of damaged blood cells. Lipofuscin is found in heart muscle and smooth muscles and is also called the "aging" pigment.

Methemoglobinemia. A condition in which the iron in the hemoglobin molecule (the red blood pigment) is defective, making it unable to carry oxygen effectively to the tissues.

Microcytic Anemia These are associated with an inability to produce hemoglobin. Hemoglobin consists of iron inserted into the prtoporphyrin ring complex to form heme which in turn is inserted into the globin chain. Hence these anemias are seen in: iron deficiency - absence of iron chronic disease - iron unavailable thalassemia - inability to produce globin chains sideroblastic anemia- inability to produce heme.

Polychromasia: Blue-gray coloration of young (anucleate) red cells when observed on a Wright-stained peripheral smear, due to the presence of residual RNA in the cytosol of the immature red cell. Polychromatic cells which are macrocytic suggest that this cell is a reticulocyte. Increased polychromasia occurs when the bone marrow releases immature RBC's into the peripheral blood in response to stress such as a hemolytic crisis.

Sulfhemoglobinemia. A morbid condition due to the presence of sulfmethemoglobin in the blood; it is marked by a persistent cyanosis, but the blood count does not reveal any special abnormality in blood cells; it is thought to be caused by the action of hydrogen sulfide absorbed from the intestine.•

Stedman's Concise Medical Dictionary for the Health Professions. Illustrated, 4th ed

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

-- 034 - 181176 ÒXDE-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 Ğ 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
-- (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)
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

CHRONIC EXPOSURE - Hydrogen fluoride and hydrofluoric acid are extreme irritants to any part of the body that they contact. The main route of exposure to hydrogen fluoride is inhalation, followed by dermal contact for acute exposure and ingestion for chronic exposure. Symptoms of the chronic effects of hydrofluoric acid include weight loss, malaise, anemia, leukopenia, discoloration of teeth, and osteosclerosis.
• Definition of Leukopenia: an abnormal lowering of the white blood cell count
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 blood for Sodium fluoride

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

-- 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)
-- 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)
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.

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

-- A 1-year feeding oral study was performed on dogs. The induction of normochromic microcytosis in animals fed diets containing 1800 ppm test material, although compensated by increased red cell production, reflects an adverse treatment-related effect. The microcytosis may have arisen from the inhibition of heme synthesis as indicated by the presence of brown to yellow/brown pigmentation in hepatocytes and reticuloendothelial cells of the liver. The microcytosis induced by sulfentrazone justifies an oral LOEL of 61.2 mg/kg/day for males and 61.9 mg/kg/day for females. The NOEL is 24.9 mg/kg/day for males and 29.6 mg/kg/day for females.
-- A 18-month feeding/carcinogenicity study in mice resulted a LOEL of 160.5 mg/kg/day in males and 198.0 mg/kg/day in females, based upon treatment-related decreases in hemoglobin and hematocrit. The NOEL is 93.9 mg/kg/day in males and 116.9 mg/kg/day in females.
-- A developmental toxicity study in rats resulted in a maternal (systemic) LOEL of 50.0 mg/kg/day based upon increased relative spleen weight and splenic extramedullary hematopoiesis. The maternal (systemic) NOEL is 25.00 mg/kg/day...
Ref: US EPA. Pesticide Fact Sheet. Sulfentrazone Reason for Issuance: Registration of a New Chemical Date Issued: February 27, l997.

-- 90-Day oral toxicity rodents (mice) - [870.3100] NOAEL = 60 mg/kg/day for males and 79.8 mg/kg/day for females LOAEL = 108.4 mg/ kg/day for males and 143.6 mg/kg/ day for females based on decreased body weights, body weight gains, red blood cells, hemoglobin, hematocrit, and severity of splenic micropathology (increased incidence and severity of extramedullary hematopoiesis)
-- 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)
-- Carcinogenicity mice - [870.4200] NOAEL = 93.9 mg/kg/ day for males and 116.9 mg/kg/day for females LOAEL = 160.5 mg/ kg/day for males and 198.0 mg/kg/ day for females based on dose- related decreases in hemoglobin and hematocrit by study termination. No evidence of carcinogenicity
-- Combined chronic toxicity/carcinogenicity rats - [870.4300] NOAEL = 40 mg/kg/day for males and 36.4 mg/kg/day in females LOAEL = 82.2 mg/kg/ day for males and 67 mg/kg/day for females based on dose-related decreased body weights (11 and 19%), body weight gains (13 and 26%), food consumption (13 and 19%), hemoglobin, hematocrit, mean cell volume, and mean cell hemoglobin. Increased nucleated red blood cells and reticulocytes in bone of females at 124.7 mg/kg/ day. No evidence of carcinogenicity

Ref: Federal Register: September 24, 2003. Sulfentrazone; Pesticide Tolerances. Final Rule.

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

Poisonings and fatalities have been reported in humans following inhalation exposure to sulfuryl fluoride... A second person died of cardiac arrest after sleeping in the house overnight following fumigation. A plasma fluoride level of 0.5 mg/L (10 times normal) was found in this person following exposure. Prolonged chronic inhalation exposure to concentrations of sulfuryl fluoride gas significantly above the TLV of 5 ppm have caused fluorosis in humans because sulfuryl fluoride is converted to fluoride anion in the body. Fluorosis is characterized by binding of fluoride anion to teeth (causing mottling of the teeth) and to bone.
Ref: Federal Register: September 5, 2001 (Volume 66, Number 172). Sulfuryl Fluoride; Proposed Pesticide Temporary Tolerances.

-- 2-Week inhalation study--dog NOAEL = 26/27 (M/F) mg/kg/day
LOAEL = 79/80 (M/F) mg/kg/day based on intermittant tremors and tetany during exposure, minimal inflammatory changes in upper respiratory tract, decreased body weight (F only).
Note: Increased serum fluoride at >= 26/27 mg/kg/day
-- 90-Day inhalation toxicity--mouse NOAEL = 38/36 (M/F) mg/kg/day

LOAEL = 125/121 (M/F) mg/kg/day based on miscroscopic lesions in caudate-putamen nucleus and external capsule of the brain, decreased body weight, decreased body weight gain, follicular cell hypertrophy in thyroid.
Note: Increased serum fluoride at >= 26/27 mg/kg/day
Ref: January 23, 2004. Sulfuryl Fluoride; Pesticide Tolerance.
40 CFR Part 180 [OPP-2003-0373; FRL-7342-1]. Final Rule. Federal Register

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

Abstract: The cases of three patients with acute pulmonary oedema caused by inhalation of fumes from heated polytetrafluoroethylene (PTFE) in a plastic factory are described. One patient died from profound hypoxemia and shock shortly after admission, and the other two patients survived after medical treatment. This is the first report of fatal pulmonary oedema in a worker exposed to PTFE heated in a plastic extruding operation. From this observation, it appears that inhalation exposure to pyrolytic products from polytetrafluoroethylene can cause fatal respiratory complications. Special precautions are warranted in this kind of operation to prevent workers from being exposed to these substances.
Ref: Fatal acute pulmonary oedema after inhalation of fumes from polytetrafluoroethylene (PTFE) by LEE CH, GUO YL, TSAI PJ, CHANG HY, CHEN CR, CHEN CW, HSIUE T-R. EUROPEAN RESPIRATORY JOURNAL; 10 (6). 1997. 1408-1411.

Definition of hypoxemia: low blood oxygen: inadequate oxygen in the blood

Abstract: A case of marked progression of chronic obstructive pulmonary disease after several episodes of occupational inhalation fever in a carding machine operator was reported. The patient was a 45 year old male with a history of exertional dyspnea who experienced recurrent episodes of flu like symptoms beginning 2 weeks after starting work at a synthetic textile plant. After approximately 9 months on the job the patient was hospitalized with fever, chills, chest pain, productive cough, and malaise that had not responded to antibiotic treatment. A decreased white cell count was seen along with evidence of moderately severe obstructive disease. The patient returned to work after the acute symptoms resolved; however, he experienced dyspnea with mild exertion at this time. The flu like illnesses continued to recur over the next 18 months at which time the patient stopped working on the advice of his physician. He was hospitalized 1 month later with chest pain and diaphoresis. Severe obstruction with a significant bronchodilator response was seen and he was placed on disability leave. Polymer fume fever due to exposure to polytetrafluoroethylene (9002-84-0) was suspected as the cause of his illness. A subsequent examination of the patient's workplace demonstrated that major renovations had been done since his departure to improve chemical contamination and air quality; however, potential for significant exposures to formaldehyde (50000) were still evident. The authors conclude that polymer fume fever may not always be a benign, self limiting disease and may result in permanent airways damage. Long term follow up is recommended.
Ref: Progression of Chronic Obstructive Pulmonary Disease after Multiple Episodes of an Occupational Inhalation Fever by Kales SN, Christiani DC. Journal of Occupational Medicine, Vol. 36, No. 1, Grant No. T15-OH-07096, pages 75-78, 10 references, 1994.

Abstract. Workers at a polytetrafluoroethylene (9002-84-0) (PTFE) plastic production plant were investigated to ascertain whether chronic exposure to this chemical was correlated with changes in biochemical indicators of toxicity. The exposed group comprised 129 workers (47 male and 82 female), of mean age 33.5 years (yr) and mean exposure period 8 months. A group removed from exposure was comprised of 32 workers (mean age 32.1yr) who had been exposed for a mean duration of 2.2yr, but had left the workplace and had been unexposed for more than 1yr (mean duration 1.8yr). A control group of 74 subjects had been employed in nonproduction work at the factory for more than 1yr and had never been exposed to the chemical. Urine and blood samples were collected at the start of the workday. Inorganic fluorides in urine were detected using an ion selective electrode method, and blood cholinesterase (ChE) levels were determined by colorimetry, using acetylthiocholine-iodide as substrate. Results showed that the urinary inorganic fluorides in the exposed group were significantly higher than in the controls. The group removed from exposure was not tested. ChE activities of whole blood, erythrocytes and plasma in the exposed group were higher than those of the group removed from exposure group, and both were significantly higher than those of the control group (23.2%, 17.5%, and 33.7% above control levels, respectively, in the exposed group and 11.2%, 11.2% and 8.7% above control levels, respectively, in the formerly exposed group). ChE activities in males of the exposed group were much higher than in females; whole blood, erythrocyte and plasma activities were enhanced by 22%, 22.5%, and 47.9%, respectively, in males, as opposed to 21.1%, 17.5% and 35.2%, respectively, in females. The authors conclude that exposure to organic fluorides during PTFE production results in a reversible increase in ChE activity in whole blood, erythrocytes, and plasma, which may indicate a protective response in the exposed worker. An increase in urinary inorganic fluoride may be used as an indicator of exposure.

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

In a 3-month rat study, dietary administration of 10 mg/kg/day produced plasma, red blood cell, and brain cholinesterase inhibition. The NOEL was 5 mg/kg/day. In a 6-month dog study, dietary administration of 10 mg/kg/day (LOEL) produced plasma cholinesterase inhibition. The NOEL was 1 mg/kg/day. In a 21-day rat dietary study, administration of 20 mg/kg/day (LOEL for females) produced decreased platelet counts, increased white blood cell, lymphocyte, and neutrophil counts in males and females. The NOEL for females was 5 mg/kg/day... EPA believes that there is sufficient evidence for listing tefluthrin on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available developmental, neurological, hepatic, and hematological 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

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

• This non-guideline study (MRID 46695732) [2004] was performed to evaluate the effects of AE 0172747 on blood tyrosine levels in pregnant rabbits following administration by gavage from GD 6-28. AE 0172747 (Tembotrione) has been shown to inhibit 4- hydroxyphenylpyruvate dioxygenase (HPPDase). HPPDase is involved in L-tyrosine catabolism, and inhibition of this enzyme leads to an increase in systemic L-tyrosine concentrations. In this study, AE 0172747 (95.0% a.i.; Bacth # PFI 0195) in aqueous 0.5PFI 0195) in aqueous 0.5% methylcellulose was administered daily via oral gavage at a dose volume of 4 mL/kg to groups of 6 presumed pregnant New Zealand White (KBL [NZW]) rabbits/dose at dose levels of 0 or 10 mg/kg bw/day on gestation days (GD) 6-28. Clinical observations, body weights, and food consumption were recorded at regular intervals during treatment. Blood samples were taken from each animal on GD 4, 10, 15, 22, and 29, and the levels of tyrosine were determined. All surviving does were killed on GD 29 for examination of their uterine contents. Pre-treatment (GD 4) L-tyrosine levels were similar between the treated and control groups. Control group tyrosine levels also remained relatively constant throughout the study (GD 4-29). Animals treated with AE 0172747 displayed marked increases in blood tyrosine levels at all time points examined (39.33-98.93 mg/L) compared to controls (10.00-15.32 mg/L), and the changes in blood tyrosine levels relative to GD 4 were significantly (p≤0.01) higher than controls for all intervals measured during treatment (page 92).
• The dog appeared to be more sensitive to hematological effects. In the subchronic and chronic dog toxicity studies hematological changes indicative of anemia were seen [decreased mean corpuscular hemoglobin (MCH) and mean corpuscular volume (MCV)]. Similar hematological effects were also observed in the chronic toxicity study in the mouse (page 6).
• Chronic/carcinogenicity mouse study. MRID 46695706 (2005). 0, 30, 300, 1000, or 3000 ppm. M: 0, 4, 43, 146, 440 mg/kg/day. F: 0, 5, 54, 179, 552 mg/kg/day. NOAEL was not established. LOAEL =M/F: 4/5 mg/kg/day based on based on gallstones, eosinophilic cytoplasmic alteration, subepithelial mixed cell infiltrate, and dilatation in/of the gallbladder; hepatocellular vacuolation, hepatocellular hypertrophy, and increased liver weight in males and females; and papillary mineralization of the kidney and changes in hematological parameters indicative of anemia in females (page 49).
• Inhibition of 4- Hydroxyphenylpyruvate Dioxygenase in Rats and In Vitro study. MRID 46695733 and 46695734 (2005). In vivo: 0, 10 mg/kg. AE0172747 (Tembotrione) increased plasma tyrosine levels by 20-fold. In vivo: AE1417286 increased plasma tyrosine levels by 5-fold.
Reference: Tembotrione. Human-Health Risk Assessment for Proposed Uses on Field Corn, Sweet Corn and Popcorn. USEPA. September 7, 2007.

NOTE ON TYROSINE: Tembotrione [FLUORINATED], mesotrione, pyrasulfotole [FLUORINATED], isoxaflutole [FLUORINATED] and topramezone belongs to a class of herbicides that inhibit the liver enzyme HPPD, which is involved in the catabolism (metabolic breakdown) of tyrosine (an amino acid derived from proteins in the diet). Inhibition of HPPD can result in elevated tyrosine levels in the blood, a condition called tyrosinemia (see Note 2 below). HPPD- inhibiting herbicides have been found to cause a number of toxicities in laboratory animal studies including ocular, developmental, liver and kidney effects. Of these toxicities, it is the ocular effect (corneal opacity) that is highly correlated with the elevated blood tyrosine levels. In fact, rats dosed with tyrosine alone show ocular opacities similar to those seen with HPPD inhibitors. Although the other toxicities may be associated with chemically-induced tyrosinemia, other mechanisms may also be involved.

There are marked differences among species in the ocular toxicity associated with inhibition of HPPD. Ocular effects following treatment with HPPD-inhibitor herbicides are seen in the rat, but not in the mouse. Monkeys also seem to be recalcitrant to the ocular toxicity induced by HPPD inhibition. The explanation of this species-specific response in ocular opacity is related to the species differences in the clearance of tyrosine. A metabolic pathway exists to remove tyrosine from the blood that involves a liver enzyme called tyrosine aminotransferase (TAT). In contrast to rats where ocular toxicity is observed following exposure to HPPD-inhibiting
herbicides, mice and humans are unlikely to achieve the levels of plasma tyrosine necessary to produce ocular opacities because the activity of TAT in these species is much greater compared to rats. Thus, humans and mice have a highly effective metabolic process for handling excess tyrosine. (page 37 )
Reference: Tembotrione. Human-Health Risk Assessment for Proposed Uses on Field Corn, Sweet Corn and Popcorn. USEPA. September 7, 2007.

NOTE 2: TYROSINEMIA. Elevated blood tyrosine levels are associated with several clinical entities. The term tyrosinemia was first given to a clinical entity based on observations (eg, elevated blood tyrosine levels) that have proven to be common to various disorders, including transient tyrosinemia of the newborn (TTN), hereditary infantile tyrosinemia (tyrosinemia I), Richner-Hanhart syndrome (tyrosinemia II), and tyrosinemia III. In addition, a mysterious entity called tyrosinosis has been described once in the literature. This designation was chosen at a time when specific enzymatic diagnosis was unavailable, leaving a clinical description that has not been duplicated in the 50 years since its publication.

Transient tyrosinemia is believed to result from delayed enzyme maturation in the tyrosine catabolic pathway. This condition is essentially benign and spontaneously disappears with no sequelae. Transient tyrosinemia is not categorized as an inborn error of metabolism because it is not caused by a genetic mutation.

Hereditary infantile tyrosinemia, or tyrosinemia I, is a completely different disease. Patients have a peculiar (cabbagelike) odor, renal tubular dysfunction (Fanconi syndrome), and survival of less than 12 months of life if untreated. Fulminant onset of liver failure occurs in the first few months of life. Some patients have a later onset, usually before age 6 months, with a somewhat protracted course.

For many years, the diagnosis was based on the observation that plasma tyrosine and methionine levels were significantly elevated. Postmortem examination revealed that both the liver and the kidney had a highly unusual pattern of nodular cirrhosis, the histopathologic hallmark of the disease. In the early 1970s, researchers discovered that most severe liver diseases caused such findings regardless of etiology, and, in the late 1970s, the biochemical and enzymatic causes of the disease were reported.

Tyrosinemia II is a disease with a clinical presentation distinctly different from that described above. This presentation includes herpetiform corneal ulcers and hyperkeratotic lesions of the digits, palms, and soles, as well as mental retardation. The biochemical and enzymatic basis for the disease bears no relationship to that of tyrosinemia I, and tyrosinemia II is not discussed further in this article.

Tyrosinemia III is an extremely rare cause of intermittent ataxia, without hepatorenal involvement or skin lesions, and is also not discussed further in this article.
Reference: Tyrosinemia by Karl S. Roth, MD.

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

Chronic & Carcinogenicity Studies. Dogs received 0, 22.5, 90 or 360 ppm of tetraconazole in the diet for 1 year. Some dogs of each group including control suffered body weight loss which was more pronounced at 360 ppm. In dogs at 360 ppm, prolonged activated partial thromboplastin times, lower albumin and higher globulin and cholesterol levels, and increased AP, ALT, gamma glutamyl transferase and ornithine carbamoyl transferase activities, as well as increased inorganic phosphorus were observed.
-- Rats received 0, 10, 80, 640 or 1280 ppm (the last dose to males only) of tetraconazole in the diet for 2 years; Mortality and body weight gain were lower at 640 and 1280 ppm. Slight anemia at 640 and erythrocyte counts. (page 5)
• Sub-chronic studies. Rats received 0, 10, 60 or 360 ppm of tetraconazole in the diet for 13 weeks. Slightly lower AP, ALT and AST, and slightly higher cholesterol and calcium levels (males) were observed at 360 ppm, and some of these changes also occurred at 60 ppm.
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. (page 4)
Short Term Studies. Male rats received 0, 2, 5, 15 or 40 ppm of tetraconazole in the diet for 4 weeks. No treatment-induced changes were observed except for increased plasma aspartate aminotransferase (AST) and glutamate dehydrogenase at 40 ppm. (page 4)
Ref: August 2005 - Evaluation of Tetraconazole in the product Domark 40ME Fungicide. Australian Pesticides and Veterinary Medicines Authority.

1,2,4-triazole - Hematological changes, including slightly decreased hemoglobin and/or hematocrit, have also been seen in multiple studies and species (in rats at doses of 33 mg/kg/day and above, and in mice at doses of 487 mg/kg/day and above). Studies depicting the effects of chronic exposure to free triazole or its conjugates are not currently available.
Ref: Human Health Aggregate Risk Assessment for Triazole-derivative Fungicide Compounds (1,2,4-Triazole, Triazole Alanine, Triazole Acetic Acid). US EPA, February 7, 2006.

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

HFC-134a (1,1,1,2-Tetrafluoroethane): Subject #3 was the first volunteer exposed to HFC-134a. The exposure concentration was 4000 ppm (0.4% v/v) and was scheduled to last for 30 minutes with a 5-minute postexposure evaluation period as was accomplished in the Halon 1301 portion of the study. Approximately 4.5 minutes into the exposure, the subject lost consciousness and both pulse and blood pressure dropped to zero. The exposure was immediately aborted and the subject was removed from the exposure apparatus. Medical personnel intervened and after pulse and blood pressure were restored the subject was administered 100% oxygen. Blood pressure and pulse remained low (approximately 1/2 of baseline) and the subject could not maintain consciousness in a seated position. The subject was reclined and moved to an operating room recovery area where he rested for approximately 1 hour after which the subject's vital signs had returned to pre-exposure values. Subject #3 displayed a rapid rise in blood concentration of HFC-134a which reached 1.29 mg/L at the 2.5 minute point in the exposure (Figure 3). The blood sample scheduled for 3 minutes was not collected. The medical representative had considerable difficulty getting blood from the cannula at the 3-minute point and significant manipulation of the indwelling cannula was noted. No further blood samples were taken. Subject #5 was also exposed to 4000 ppm (0.4% v/v) HFC-134a. There was some difficulty with blood collection and manipulation of the cannula was noted, but exposure was uneventful through the first 10 minutes of exposure. Breathing effort and rate appeared normal. At approximately 10.5 minutes into the exposure the subject's blood pressure and pulse began to rise rapidly and the subject gave the hand signal for possible trouble. His pulse rose rapidly until it was double the pre-exposure value, at which time the subject gave the hand signal to terminate the exposure. The exposure was aborted and the subject began breathing room air, but the in-dwelling cannula was not removed from the subject. After 30 seconds, the subject's blood pressure and pulse were at pre-exposure levels. The HFC-134a concentration in blood reached 0.70 mg/L at the point where the exposure was terminated (Figure 3). Subject #5 breathed room air for 1 hour and was then re-exposed to 2000 ppm (0.2% v/v) HFC-134a. After 2.5 minutes of exposure, the subject's blood pressure and pulse again rose rapidly, the subject signaled trouble and the exposure was terminated. The subject's vital signs returned to pre-exposure levels within 30 seconds after the exposure was terminated. The in-dwelling cannula remained attached to the subject and blood was drawn for an additional 10 minutes at 1-minute intervals. The venous blood concentration of HFC-134a was 0.16 mg/L at the start of the 2000 ppm exposure and reached 0.38 mg/L at the time of exposure termination (Figure 3). The HFC-134a concentration was still at 0.2 mg/L 10 minutes after the exposure was terminated. No further human HFC-134a exposures were conducted. In addition to the monitored effects, there were several subjective effects associated with the inhalation exposures to HFC-134a. Subject #3 reported problems with dizziness and balance following the exposure. At the time of this report (6 weeks post exposure), both the dizziness and balance problems still persisted. Subject #5 reported chest tightness and a headache with associated dizziness immediately following the exposure. The headache subsided by the time the subject woke up the day following the exposure. The day following the exposure, subject #5 reported unusual feelings in the chest resembling "flutters". The chest tightness was reported to subside within 3 days of the exposure and the "flutters" within 2 weeks of the exposure. As with subject #3, subject #5 was still experiencing dizziness and balance problems at the time of this report (6 weeks post exposure). Subject #5 also reported persistent ringing in the ears which was still present at the time of this report. The adverse events observed during the exposures to HFC-134a and HFC-227ea were unexpected and inconsistent with the published data. Based on the published data on HFC-134a and HFC-227ea, no adverse effects should have been observed at the 0.4% v/v and 0.6% levels, respectively, used in this study. Both HFC-134a and HFC-227ea have been considered to be inert compounds which exert toxic effects only after their concentrations are so high that oxygen depravation effects prevail (Graepel and Alexander, 1991)... Rats and mice have shown no acute toxicity during or after a 1-hour inhalation exposure to 810,000 ppm HFC-134a and dogs were essentially unaffected following an 80,000 ppm exposure (Alexander, 1995). Based on the laboratory animal data, Alexander, 1995, concluded that HFA-134a is devoid of acute and long term toxicity, is poorly absorbed and is rapidly excreted. In addition to the claims of inertness, the chemicals of interest have been reported to rapidly leave the human system with an apparent half-life of only 5.1 minutes (Harrison, 1996). Similarly, another report states that only 10% of the administered dose of HFC-134a remained 10 minutes after termination of the exposure (Woodcock, 1995). The 5.1 minute half-life for HFC-134a and extremely rapid elimination is in contrast to the 31 minute apparent half-life reported as part of a clinical pharmacology study (Ventresca, 1995). While the sample size was extremely small in our study due to unplanned termination, the apparent half-lives of HFC-134a and HFC-227ea are estimated to be 12.6 and 7.5 minutes, respectively (Figures 2 and 3). This probably represents only the rapid elimination phase since data were not available to assess any slower elimination phases that may be present. As such, the half-life estimates could be quite low especially since measurable levels of HFC-134a were present 1 hour after the exposure was terminated (Figure 2). The presence of HFC-134a in the blood 1 hour after exposure was unexpected. Alexander, 1995, reported that there was no carry over in blood after 30 minutes. Halon 1301 cleared more rapidly with an estimated half-life of 3.6 minutes. Based on published work, regulatory approval and commercial use of Halon 1301, HFC-134a and HFC-227ea, the exposure levels selected for the 30-minute inhalation exposures were expected to be without adverse effects in humans. Since the study was designed to collect only kinetic information for use in PBPK model validation and only at "no effect" concentration levels, clinical type experimental design was not adopted. Additionally, the subjects participating in the study were scientists or technicians and they were knowledgeable about the study results as they occurred... In summary, all 7 human volunteers completed the Halon 1301 exposures without incident while both the HFC-134a and HFC-227ea exposures were terminated due to the adverse effects described in this report. Additionally, no adverse effects were reported during "blank" exposures where all conditions were the same as in chemical exposures except the test material was air. Based on the chemical similarity between HFC-134a and HFC-227ea and the similar human responses during the exposures, it became the opinion of the investigators that further exposures would constitute a study of human effects rather than simply of kinetics. Given this opinion, the study was terminated. In view of the sample size and experimental design, no conclusion or speculation about cause and effect is offered at this time. Rather, the purpose of this document is to report the unexpected events that occurred during human inhalation of HFC-134a and HFC-227ea under controlled conditions.
Ref: 1997. Human Inhalation of Halon 1301, HFC-134a and HFC-227ea for Collection of Pharmacokinetic Data.
- also available at

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

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

-- The main hazards associated with repeat exposure to product are systemic effects (effects on liver, haematopoietic system and testes). No worker exposure data were available for trifloxysulfuron sodium or ENVOKE HERBICIDE. NOHSC used UK POEM to estimate mixer/loader and applicator exposure. The repeat dose risk assessment indicated that workers should wear elbow- length PVC gloves when preparing spray.
-- Dogs were given trifloxysulfuron at doses of 0, 50, 200 or 500 mg/kg bw/day in gelatin capsules for 28 days. There were no mortalities, changes in food consumption, clinical signs of toxicity or effects on body weight gain. A white material in the faeces of animals at 500 mg/kg bw/day was confirmed by analysis to be the test material. Red blood cell count, haematocrit, haemoglobin, platelet counts and clotting times, plasma bilirubin, protein and albumin were lower and globulin and chloride were higher in both sexes at 500 mg/kg bw/day. Plasma bilirubin was also lower in females at 200 mg/kg bw/day and plasma potassium and calcium were lower in males at 500 mg/kg bw/day...
Ref: August 2002 -
Evaluation of the new active Trifloxysulfuron-sodium in the product ENVOKE HERBICIDE. Public Release Summary. National Registration Authority for Agricultural and Veterinary Chemicals 2002 ISSN1443-1335.

-- Subchronic toxicity. Trifloxysulfuron-sodium technical was evaluated in a number of subchronic studies. In a 3-month rat feeding study the NOAEL was 65.7 mg/kg with hematologic and liver effects noted. In a 3-month mouse feeding study, the NOAEL was 67.9 mg/kg. Effects seen were adaptive liver effects. In a 3-month feeding study in dogs the NOAEL was 19.6 mg/kg and hematopoietic and liver effects were seen. In a 28-day dermal (rat) study, the NOAEL was 100 mg/kg. In this study only body weight effects were noted, and only occurred at 1,000 mg/kg.
-- Chronic toxicity. Trifloxysulfuron-sodium technical was not oncogenic in rats or mice. In a 12-month feeding study in dogs fed diets containing trifloxysulfuron-sodium that resulted in average (sexes combined) daily test substance intakes of 0, 1.67, 6.71, 15.0, 48.2 or 122 mg/kg/day, all animals survived... There was a tendency for a decrease in the erythrocyte count, hemoglobin concentration and hematocrit for both sexes at 122 mg/kg/day at the end of treatment, and for males throughout the treatment period... Administration of trifloxysulfuron-sodium to dogs for 12 months caused a tendency for decrease in red blood cell parameters in both sexes at 122 mg/kg/day. There was neither histopathological nor functional evidence for compound related neurotoxicity. Based on the effects at 48.2 and 122 mg/kg/day, the NOAEL was established at 15.0 mg/kg/day for males and 14.9 mg/kg/day for females.

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.

Triflumuron - Insecticide - CAS No. 64628-44-0

Abstract: The effects of five benzoylphenylurea insecticides, diflubenzuron (35367385), flufenoxuron (101463698), hexaflumuron (86479063), teflubenzuron (83121180), and triflumuron (64628440) were comparatively evaluated on hematological parameters in rats. Sixty adult Wistar-rats were divided into five dose groups and a control group. Daily doses of 100mg/kg of each tested insecticide were administered by gavage for 28 days, after which rats were sacrificed and blood was taken for examination. Parameters measured were red blood cell count, hemoglobin (Hb), hematocrit, mean corpuscular volume, mean corpuscular Hb concentration, methemoglobin (metHb), and reticulocyte counts. Results showed that treatment with insecticides at the dose given did not produce any overt signs of toxicity. However, with regard to hematological parameters, both diflubenzuron and triflumuron induced elevated metHb levels. The no observed effect level for metHb was 45mg/kg. The reticulocyte level was increased in all treated groups, even at dose levels of 50mg/kg. The authors conclude that the metHb level increase and reticulocyte increase are the most sensitive parameters, but that one might be independent of the other.
Ref: 1993. J Appl Toxicol; Jan-Feb;13(1):67-8. Comparative study on the effects of five benzoylphenylurea insecticides on haematological parameters in rats, by Tasheva M, Hristeva V.

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

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.

High doses of trifluralin are associated with increases in kidney, bladder, and thyroid tumors. Dogs chronically exposed to trifluralin in their diet showed decreased weight gain, changes in hematological parameters, and increased liver weight. Skeletal abnormalities were observed in the offspring of mice exposed via gavage (experimentally introducing trifluralin into the stomach). The RfD for trifluralin is based on increased liver weights and an increase in methemoglobinemia in dogs.
Ref: March 2000. Public Health Assessment Cenex Supply and Marketing, Inc. Quincy, Washington. CERCLIS #WAD058619255. Draft for Public Comment.. Prepared by: Washington State Department of Health Under Cooperative Agreement with the Agency for Toxic Substances and Disease Registry. Also available at

Teratology - rat: Maternal NOEL=100 mg/kg/day; Maternal LEL=500 mg/kg/day (decreased food consumption and increased liver and spleen weights); Developmental NOEL=none; LEL=20 mg/kg/day (reduced skeletal maturity and increased vascular fragility); core grade supplementary (Hoechst Aktiengesellschaft, 1983)
Ref: US EPA IRIS for Trifluralin CASRN: 1582-09-8.
• Vascular:   pertaining to blood vessels.

3-Trifluoromethyl aniline - Intermediate for herbicides (eg, Fluometron & Norflurazon), and pharmaceuticals, Breakdown product - CAS No. 98-16-8

-- HEMATOLOGIC. ACUTE EXPOSURE. Methemoglobinemia is a possibility with exposure to m-trifluoroaniline.
-- CHRONIC EXPOSURE. Methemoglobin was evident in rats exposed to m-trifluoromethylaniline for five months... No reproductive studies were found. Methemoglobin inducers are considered especially dangerous to the fetus.
-- ACUTE EXPOSURE. m-Trifluoromethylaniline is toxic by the oral, inhalation, dermal, or IP routes.
Ref: TOXNET profile from Hazardous Substances Data Bank.

Abstract: Conclusions of this criteria document: 3-trifluoromethylaniline has been show to irritate the skin and mucous membranes. Animal experiments show it to be a strong, indirect methaemoglobin-forming agent.
Monograph title: 3-Trifluoromethylaniline (3-trifluoromethylbenzeneamine). Corporate Name: Gesellschaft Deutscher Chemiker (GDCh) - Advisory Committee on Existing chemicals of Environmental Relevance (BUA).
Source: VCH Verlagsgesellschaft mbH, D-W-6940 Weinheim, Germany, 1991. 43p. Bibl.ref.Language: English.
As cited on Toxline at Toxnet.

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

Carcinogenicity rats NOAEL = 2.44 mg/kg/day LOAEL = 30.6 mg/kg/day based on decreased body weight and body weight gain, alteration in hematology (mainly males) and increased incidences of interstitial cell hyperplasia in the testes. (Possible) evidence of carcinogenicity
Ref: Federal Register: June 12, 2002 (Volume 67, Number 113). Triflusulfuron Methyl; Pesticide Tolerance. Final Rule.

CHRONIC STUDIES: Triflusulfuron methyl Chronic Feeding Study in Rats - Non-oncogenic in female rats. Increased incidence of Leydig cell adenomas were observed in males following chronic and excessive exposures at 750 and 1500 ppm. The NOELs for male and female rats were 100 and 750 ppm, respectively. These were based on increased adenomas and reduced circulating red cell mass among higher-dosed males and reduced body weights and increased incidence or severity of species- and age-specific effects among male and female rats at higher doses...
Ref: Nov 2001 - Material Safety Data Sheet for DuPont "UPBEET" HERBICIDE.

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]

Triphenyltin fluoride - Antifoulant, Algaecide, Herbicide - CAS No. 379-52-2

Abstract: Recent work in our laboratory has shown that oral administration of triphenyltin fluoride (TPTF) evokes hypertriglyceridemia in rabbits. The present experiments were conducted to elucidate the mechanism of TPTF-induced hypertriglyceridemia in rabbits by a combined biochemical and ultrastructural approach. After a single TPTF administration, fasting blood glucose and plasma triglyceride levels increased significantly (P less than 0.02) for about 20 days. On the other hand, both plasma and adipose tissue lipoprotein lipase (LPL) activity was markedly decreased (P less than 0.001) during this period, and triglyceride production rates on day 2 after TPTF administration was significantly decreased (P less than 0.01). Density-gradient ultracentrifugation showed a remarkable accumulation of chylomicron and VLDL in the composition of plasma lipoproteins. Insulin injection to the hypertriglyceridemic rabbits induced a significant recovery of the decreased plasma LPL activity with a concomitant decrease of plasma triglyceride levels, while abeyance of insulin injection resulted in a decrease of LPL activity again. A significant inhibition of insulin release in response to the loading of glucose, glucagon, or arginine was observed in the TPTF rabbits (P less than 0.02). Inhibition of glucagon release was also observed in the arginine-loading test (P less than 0.01). Electron microscopic studies showed small abnormalities in the pancreatic islets of TPTF-treated rabbits. These findings suggest that TPTF inhibits insulin release from rabbit islets, subsequently inducing diabetic lipemia due to the insulin deficiency. Furthermore, it is possible to provide a new animal model for diabetes and diabetic lipemia by administration of TPTF to rabbits.
Ref: Diabetes 1981 Dec;30(12):1013-21. Triphenyltin fluoride (TPTF) as a diabetogenic agent. TPTF induces diabetic lipemia by inhibiting insulin secretion from morphologically intact rabbit B-cell. Manabe S, Wada O.

• Definition of hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinaemia IIb and hyperlipoproteinaemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis.
•• see National Institutes of Health Consensus Development Conference Statement on Hypertriglyceridemia, September 27-29, 1983

Abstract. Recent studies have demonstrated that triphenyltin fluoride (TPTF) inhibits collagen-induced aggregation and ATP secretion of rabbit platelets in vivo [S. Manabe and O. Wada, J. Toxic. Sci. 6, 236 (1981)]. The aim of the present investigation was to test the effects in vitro of TPTF on platelet aggregation and to elucidate the mechanism of the inhibitory action by studying the release and metabolism of arachidonic acid and the cyclic AMP contents of rabbit platelets treated in vitro with TPTF. Although no inhibitory effect of TPTF was found on sodium arachidonate-induced platelet aggregation and ATP secretion, TPTF inhibited both reactions induced by collagen. Triphenylarsine and triphenylantimony did not inhibit, even at a concentration of 10(-3) M. The anti-aggregating concentration (IC50) of TPTF was 6.0 x 10(-6) M against collagen. TPTF had no inhibitory effect on the conversion of exogenous arachidonic acid to malondialdehyde (MDA) by platelets, while the collagen-induced production of arachidonate metabolites [MDA, 12-L-hydroxy-5,8,10-heptadecatrienoic acid (HHT) and thromboxane B2] was remarkably inhibited by TPTF. Furthermore, TPTF apparently inhibited the collagen-induced release of arachidonic acid from platelets, although the formation of phosphatidic acid was not inhibited. Total cyclic AMP content after TPTF exposure was not changed significantly. These results indicate that TPTF inhibited the collagen-induced arachidonic acid release from platelet phospholipids, presumably by acting on phospholipase A2. Furthermore, it seems unlikely that the inhibition of arachidonic acid release by TPTF can be explained by the level of cyclic AMP in platelets.
Ref: Triphenyltin fluoride in vitro inhibition of rabbit platelet collagen-induced aggregation and ATP secretion and blockade of arachidonic acid mobilization from membrane phospholipids; by S Manabe et al. Biochem Pharmacol 1983 May 15;32(10):1627-34.

Abstract. Recent studies have demonstrated that triphenyltin fluoride (TPTF), widely used as an agricultural chemical and a marine antifoulant, inhibits collagen-induced platelet aggregation and ATP secretion in rabbits ex vivo. The aim of the present investigation was to elucidate the mechanism of the inhibitory action of TPTF by investigating platelet malondialdehyde (MDA) formation, aggregation and ATP secretion following the stimulation by various stimuli of rabbit platelets treated in vitro with TPTF, other triphenyl metals and aspirin. Although no inhibitory effect of TPTF was found on sodium arachidonate-induced platelet aggregation and ATP secretion, TPTF inhibited dose-dependently both platelet aggregation and ATP secretion induced by collagen. The antiaggregating (IC50) concentration of TPTF was 6.0 X 10(-6) M against collagen. In addition, TPTF prevented the collagen-, and thrombin-induced formation of MDA, but had little inhibitory effect on the conversion of exogenous arachidonic acid to MDA in platelets. In contrast, aspirin (10(-3) M) inhibited platelet aggregation, ATP secretion and MDA formation induced by all the stimuli tested. Other triphenyl metals did not any inhibitory effect on collagen-, and sodium arachidonate-induced platelet aggregation and ATP secretion even at a final concentration at 10(-3) M. These results suggest that TPTF has a specific inhibitory effect on platelet aggregation and ATP secretion by acting at some step(s) of platelet membrane between the binding site of collagen and thrombin and the release of arachidonic acid.
Ref: [The effect of triphenyltin fluoride on aggregation, ATP secretion and malondialdehyde formation of rabbit platelets in vitro]. [Article in Japanese]; by S Manabe S et al. Sangyo Igaku 1983 Jan;25(1):15-22.

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