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). http://www.kumc.edu/instruction/medicine/pathology/ed/keywords/kw_anisocyt.html

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. http://www.heros.org.uk/health/health.ihtml?step=4&Healthpid=818

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 Innenkörper (German) Ehrlich hĢmoglobinĢmische Innenkörper (German) Heinz-Ehrlich bodies http://www.whonamedit.com/synd.cfm/658.html

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. http://www.kumc.edu/instruction/medicine/pathology/ed/keywords/kw_hypochro.html

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. http://www.academicpress.com/inscight/10011998/leukocy1.htm

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.
http://www.nlm.nih.gov/medlineplus/ency/article/002242.htm

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. http://www.nlm.nih.gov/medlineplus/ency/article/000562.htm

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. http://www.cariboo.bc.ca/schs/medtech/RICE/intromicroanemia.html

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. http://www.kumc.edu/instruction/medicine/pathology/ed/keywords/kw_polychro.html

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.

Flonicamid - Insecticide - CAS No. 158062-67-0

-- In a 90-day rat feeding study the NOAEL was established at 200 ppm (12.11 mg/kg/day) for males and 1,000 ppm (72.3 mg/kg/day) for females. The NOAELs were based on effects on hematology, triglycerides, and pathology in the liver and kidney.
-- In a 13-week mouse study, the NOAEL was 100 ppm (15.25 mg/kg/day in males and 20.1 mg/kg/day in females). The LOAEL is 1,000 ppm (153.9 mg/kg/day in males and 191.5 mg/kg/day in females) based on hematology effects and changes in glucose, creatinine, bilirubin, sodium, chloride and potassium levels, increased liver and spleen weights and histopathology findings in the bone marrow, spleen and kidney.
-- Chronic toxicity. In the chronic dog study with administration via using capsules, the NOAEL was 8 mg/kg/day. The LOAEL was 20 mg/kg/ day based on reduced body weights in females and effects on the circulating red blood cells.
-- In a rat 24-month combined chronic and oncogenicity study, flonicamid technical was not carcinogenic in rats. The NOAEL was 200 ppm (7.32 mg/kg/day) for males and 1,000 ppm (44.1 mg/kg/day) for females. The LOAEL was 1,000 ppm for males and 5,000 ppm for females based on histopathology in the kidney, hematology effects, hepatic effects including changes in biochemical parameters, increased organ weights, and histopathological changes. Atrophy of striated muscle fibers, cataract and retinal atrophy observed in the high dose females were considered to be due to acceleration of spontaneous age-related lesions.
Ref: Federal Register: May 23, 2003 (Volume 68, Number 100)] [Notices] [Page 28218-28222]. Flonicamid; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluorideaction.org/pesticides/flonicamid.fr.may23.2003.htm

-- 90-Day oral toxicity rodents (rats). 28-day range-finding. NOAEL is 100 ppm (7.47 mg/kg/day) for males and 1,000 ppm (81.9 mg/kg/day) for females.
LOAELs were 500 ppm (36.45 mg/kg/day) for males based on changes in the kidney (hyaline deposition) and 5,000 ppm for females (372.6mg/kg/day) based on kidney (hyaline deposition), liver changes (centrilobularhypertrophy), hematological effects (anemia) and clinical chemistry (increased cholesterol)
-- 90-Day oral toxicity (nonrodents- dogs). NOAEL is 8 mg/kg/day in males and 20 mg/kg/day for female. LOAEL is 20 mg/kg/day in males and 50 mg/kg/day in females, based on acute clinical signs in males and females (vomiting, first observed on Day 1 and last observed on Day 90), clinical pathology at 7 weeks (increased total protein levels in males, lower red blood cells and higher reticulocytes counts in females), increased adrenal weights in males, decreased thymus gland weights in males, and increased kidney tubular vacuolation in females at study termination
-- Chronic toxicity (dogs). NOAEL is 8 mg/kg/day. LOAEL is 20 mg/kg/day, based on acute clinical signs(vomiting, mostly within the first week), clinical pathology at 12 months (higher reticulocytes counts) in males and females.
-- Carcinogenicity (mice). NOAEL was not established. LOAEL is 250 ppm (equivalent to 29/38mg/kg/ day [M/F]), based on minimal to moderate centrilobular hepatocellular hypertrophy, minimal to severe extramedullary hematopoiesis, minimal to moderate pigment deposition in the sternal bone marrow, and increased incidence of tissue masses/nodules in the lungs in the males, and minimal to moderate decreased cellularity in the femoral bone marrow and hyperplasia/hypertrophy of the epithelial cells of the terminal bronchioles of the females. At the doses tested, the carcinogenic potential of IKI-220 (flonicamid) is positive at 250 ppm in males and females based on the increased incidence of alveolar/bronchiolar adenomas, carcinomas, and combined adenomas/carcinomas. Dosing was considered adequate based on increased incidence of tissue masses/nodules in the lungs and microscopic findings in the liver, spleen, bone marrow, and lungs. However, data were provided suggesting this effect is specific to sensitive strains of mice. Carcinogenic in mice.

-- Chronic dietary. 2-Generation Reproduction rat. Parental LOAEL = 22 mg/kg/day based on increased kidney weights, kidney hyaline deposition, increased blood serum LH (F1 females)
Ref: August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluoridealert.org/pesticides/
flonicamid.fr.aug.31.2005.html

Fluazifop-butyl - Herbicide - CAS No. 69806-50-4

**411-083 069476 Virgo, D. M., “Fluazifop-butyl: 55 week oral toxicity study in beagle dogs,” Life Science Research, Stock, Essex, England, 10/15/82. LSR Report No. 81/ILK019/620. Six dogs/sex/group were dosed for 55 weeks with Fluazifop-butyl, 99.6% purity, by gelatin capsules at dose levels of 0, 5, 25, and 125 mg/kg/day in a chronic study. Test article within capsules was dissolved in 0.4 ml/kg corn oil vehicle. NOEL = 5 mg/kg/day... All other noteworthy findings were limited to the high dose group, as follows. Seven 125 mg/kg/day dogs (5 M, 2 F) were killed in extremis prior to term, generally after at least 29 weeks on study. Fluazifop-butyl caused ulcerations in the g.i. tract, specifically in the tongue, lip, mouth lining, stomach pylorus, or cecum. Ulcerations may have contributed to low RBC parameters in both sexes (reduced HCT, Hb levels, and RBC counts, particularly in males). Platelet counts were reduced by about half in both sexes. Bone marrow samples taken at weeks 10 and 52 for smear analyses showed “reduced numbers of megakaryocytes,” suggesting reduced production as a reason for low platelet counts. Other hematology-related findings included increased incidence/degree of thymic involution, decreased lymphocyte counts, increased degree of hemosiderin-laden Kupffer cells, hypercellular sternal marrow, and severe extramedullary hematopoiesis in 4 male and 1 female decedent. Four of the latter 5 dogs also had substantially increased splenic weights, 'pallor' in clinical signs as part of moribund condition, and their final hematology red cell values (RBC count, Hb, HCT) were very low. Eyes of eight high dose dogs had cataracts, usually accompanied by miliary ('seed-like' appearance) vacuolation of the lens. Liver dysfunction was indicated by periacinar hepatocytic degeneration and thinning of hepatic cords in some dogs, other hepatocytic changes such as vacuolation and/or granular cytoplasm, and occasional bile plugs in the canaliculi. Most clinical chemistry changes were plausibly related to liver toxicity, including elevated alkaline phosphatase, ALT, and occasionally AST. Substantially increased BSP retention was consistent with biliary disturbance. Urine was typically bright yellow or orange due to high bile pigment concentrations. Cholesterol was consistently reduced. Male reproductive toxicity included testicular tubular degeneration and reduced/absent spermatozoa in epididymides. Possible adverse effects (many-faceted toxicity, including mortalities, at 125 mg/kg/day). Acceptable. Aldous, 5/20/02.
Ref: May 20, 2002. SUMMARY OF TOXICOLOGY DATA FLUAZIFOP-P-BUTYL. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch.

http://www.fluoridealert.org/pesticides/fluazifop-p-butyl.caepa.02.pdf

Fluazifop-P-butyl - Herbicide - CAS No. 79241-46-6

Chronic/Subcrhonic Toxicity Studies: Chronic toxicity studies in rodents have shown liver changes (cellular hypertrophy). The No Effect Level (LEL) in rats is 10 ppm (0.5 mg/kg/day). Long term feeding studies in dogs produced a range of potentially serious effects at high dose rates (red cell, bone marrow and lymphadenopathy changes and liver and spleen damage) with a No Effect Level of 25 mg/kg/day.
Target Organs: Liver, skin, kidney, eye, bone marrow, blood, reprodu
ctive system.
Ref: Material Safety Data Sheet for Fusilade DX (active indredient Fluazifop-P-Butyl). Syngenta. January 21, 2002.

http://www.fluoridealert.org/pesticides/fluazifop-p-butyl.MSDS.pdf

Fluchloralin - Herbicide - CAS No. 33245-39-5

PubMed Abstract: Basalin, a herbicide, was administered orally to male rats at doses ranging from 60 mg to 1.92 g/kg for 13 weeks. Oral LD50 of the compound was 1.65 g/kg. Toxic effects included hyperexcitability and tremors. The cumulative lethal dose (CLD50) at the end of week 13 was 135 mg/kg with a cumulative toxicity factor (CTF) of 12.22. At 1.92 g/kg, no animals survived to 13 weeks. At 60 and 120 mg/kg, there were no significant changes in body weight gain compared with the controls and a significant decrease in total leukocyte count (TLC), erythrocyte sedimentation rate (ESR) and Hb was observed. There was a decrease in spermatogenesis and infiltration of mononucleated cells in the liver.
Ref: Toxicol Lett 1983 Aug;18(1-2):13-8. Subacute toxicity of Basalin in rats. Gupta PK, Singh YP, Parihar NS.
http://www.fluoridealert.org/pesticides/fluchloralin.pubmebabstract.htm

Flufenacet - Herbicide - CAS No. 142459-58-3

-- In the rat chronic feeding / carcinogenicity study the NOEL was less than 1.2 mg/kg/day in males and less than 1.5 mg/kg/day in females and the LOEL was 1.2 mg/kg/day in males and 1.5 mg/kg/day in females based on methemoglobinemia and multi-organ effects in blood, kidney, spleen, heart, and uterus. Under experimental conditions the treatment did not alter the spontaneous tumor profile. In the mouse carcinogenicity study the NOEL was less than 7.4 mg/kg/day in males and was 9.4 mg/kg/day for females and the LOEL was 7.4 mg/kg/day for males and was 38.4 mg/kg/day for females based on cataract incidence and severity. There was no evidence of carcinogenicity for flufenacet in this study.
-- Chronic Feeding/ Carcinogenicity (rat): NOEL < 25 ppm [1.2 mg/kg/day in males and 1.5 mg/kg/day in females]. LOEL = 25 ppm [1.2 mg/kg/day in males and 1.5 mg/kg/day in females] based on methemoglobinemia and multi-organ effects in blood, kidney, spleen, heart, and uterus. Under experimental conditions the treatment did not alter the spontaneous tumor profile.
Ref: US EPA. Pesticide Fact Sheet. Flufenacet Reason for Issuance: Conditional Registration Date Issued: April 1998.
http://www.epa.gov/opprd001/factsheets/flufenacet.pdf

Flufenoxuron - Acaracide, Insecticide, Herbicide - CAS No. 101463-69-8

The critical toxicological effects of flufenoxuron in mammals are on the hemopoeitic [sic hematopoietic] system. These effects include shifts in red blood cell parameters (decreased in hemoglobin, hematocrit, red blood cells and erythroid: myloid ratio) resulting in mild anemia and enhanced levels of methemoglobin and sulfhemoglobin in dogs and rats. Dogs appears to be more susceptible to the hematopoetic effects described above. It is likely that a metabolite (aniline metabolite (4-[2chloro, á, á, á-trifluoro-p-tolyoxy]-2-fluoroaniline) is responsible for the formation of methemoglobin and sulfhemoglobin. Two oncogenicity studies in mice and one in rat; were conducted at doses exceeding 4 - 7.5x limit dose.
Reference: August 15, 2006. US EPA Human Health Risk Assessment for proposed tolerances on apples, pears, grapes, organges and livestock commodities imported into US. http://www.fluorideaction.org/pesticides/flufenoxuran.hra.epa.2006.pdf

-- Repeat dose mammalian studies. Studies submitted were 28 d rat, 90 d rat/mouse/dog, 12 and 24 month rat, and 12 month dog. In both the rat and dog there was evidence of regenerative anaemia and increased methaemoglobin levels with NELs of 5 mg.kg-1 (rat 28- and 90- day) and 2.5 mg.kg-1.d-1 (dog 12 month). In mice the NEL was 7.5 mg.kg-1.d-1 based on increased plasma bilirubin. Plasma bilirubin was also increased in rats (24 month). Evidence of regenerative anaemia (increased methaemoglobin, decreased erythrocyte parameters, increased reticulocytes, increased marrow cellularity and increased spleen weight) was seen in most studies. In addition at higher doses triglycerides were decreased and heart weight increased in the rat.
-- Repeat dose studies. Sub-Acute Toxicity. In an adequately conducted study 7/sex/dose Fischer 344 rats were administered 0, 50, 500, 5000, 10000 or 50000 ppm flufenoxuron [in] the diet for 28 days... Haematology parameters were measured at necropsy. Methaemoglobin concentrations were increased 100% at and above 500 ppm in males and 5000 ppm in females...
Ref:
December 1995. Evaluation of Flufenoxuron use as a public hygiene insecticide. UK: Health and Safety Executive, Biocides & Pesticides Assessment Unit. Available at
http://www.pesticides.gov.uk/citizen/evaluations/143_confirm-box.htm

Flufenpyr-ethyl - Herbicide - CAS No. 188489-07-8

-- EPA has not had the opportunity to review the toxicity studies on flufenpyr-ethyl and has not established toxic endpoints.
-- Subchronic toxicity. Subchronic oral toxicity studies conducted with flufenpyr-ethyl in the rat, mouse and dog indicate a low level of toxicity. i. Rats. Pure (99.4%) flufenpyr-ethyl was tested in rats at dose levels of 0, 600, 2,000, 6,000, and 20,000 ppm in the diet for 13 weeks. Effects observed included urinary incontinence, increased food and water consumption, slight hematological and blood biochemistry changes...
-- In an additional study, flufenpyr-ethyl technical was tested in rats at dose levels of 0, 1,000, 10,000, and 20,000 ppm in the diet for 13 weeks. Effects observed included urinary incontinence, increased food and water consumption, and mild urinalysis, hematological and blood biochemistry changes...
-- Mice. In a 4-week study, CD-1 mice were fed pure flufenpyr- ethyl at dose levels of 0, 300, 1,000, 3,000, and 7,000 ppm. Effects were slight anemia, changes in blood biochemistry...
-- In a 13-week study, flufenpyr-ethyl technical was administered to mice at dose levels of 0, 300, 1,000, 3,000, and 7,000 ppm. Slight anemia and blood biochemistry changes were noted...

-- Mice. In a 78-week oncogenicity study with mice, flufenpyr- ethyl technical was administered at dose levels of 0, 350, 3,500, and 7,000 ppm. Male animals exhibited slight anemia. Females had increased liver and kidney weights (week 53 only)...
Ref: Federal Register: June 25, 2003 (Volume 68, Number 122)] [Notices] [Page 37813-37820]. Flufenpyr-ethyl; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluorideaction.org/pesticides/flufenpyr-ethyl.fr.june.03.htm

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

BIOLOGICAL DATA 2.1. Hepatotoxicity and carcinogenicity. In short-term and long-term studies of toxicity that were evaluated by the Committee at its forty-second and forty-eighth meetings, oral administration of flumequine caused dose-related hepatotoxic effects in rats and CD-1 mice. The liver damage was most pronounced in male mice, and included degenerative changes with hypertrophy, fatty vacuolation, focal necrosis and increased mitotic activity. After cessation of treatment with flumequine, the liver damage was reversed. Treatment with flumequine had little or no effect on P450-dependent hepatic drugmetabolizing enzymes or on glucuronyl transferase. Flumequine increased the plasma activities of alanine and aspartate aminotransferases, alkaline phosphatase and lactate dehydrogenase. The overall no-observed-effect level (NOEL) for hepatotoxic effects in mice was 25mg/kg bw per day...
Ref: 2004 - Flumequine (addendum). First draft prepared by Mrs. M.E.J. Pronk, Centre for Substances and Integrated Risk Assessment, National Institute for Public Health and the Environment. Bilthoven, The Netherlands.
http://www.fluorideaction.org/pesticides/flumequine.netherlands.2005pdf

Flumiclorac-pentyl - Herbicide - CAS No. 87546-18-7

-- Chronic Toxicity (Including Cancer): Studies with Flumiclorac Pentyl Technical indicate that repeated high exposures produced changes in liver, kidney, and red blood cells but did not produce cancer in test animals.
-- Potentially Aggravated Condition: Individuals with preexisting diseases of the liver, kidney, or red blood cells may have increased susceptibility to the toxicity of excessive exposures.
-- SUBCHRONIC: Compound-related effects noted at very high dose levels of Flumiclorac Pentyl Technical in rodents and/or dogs included: increased liver and kidney weights; histological changes in the kidney and liver; slight changes in blood biochemistry parameters; decreased red blood cell count, hemoglobin, and hematocrit; and slight decreases in body weight. The NOEL in rats and mice was 1000 ppm.
-- CHRONIC/CARCINOGENICITY: Effects of long-term high dose exposures to Flumiclorac Pentyl Technical in rodents and/or dogs consisted primarily of increases in kidney and liver weights, slight changes in blood biochemistry, and histological changes in the liver. The lowest NOEL was 300 ppm in the mouse study. Flumiclorac Pentyl Technical was not carcinogenic in either rats or mice.
Ref: Material Safety Data Sheet for RESOURCE TM Herbicide.

http://www.horizononline.com/MSDS_Sheets/529.txt

Flumioxazin - Herbicide - CAS No. 103361-09-7

Subchronic, Chronic, and Other Toxicity
-- 870.3100 90-Day oral toxicity -rat NOAEL = mg/kg/day: 69.7 (M), 71.5 (F) LOAEL = mg/kg/day: 243.5 (M), 229.6 (F) based on a decrease in MCV [mean corpuscular volume] both sexes; increase in platelets F only
-- 870.3100 90-Day oral toxicity -rat NOAEL = mg/kg/day: 65.0 (M), 72.9 (F) LOAEL = mg/kg/day: 196.7 (M), 218.4 (F) based on hematology changes

-- 870.4300 Combined chronic carcinogenicity - rat NOAEL = mg/kg/day: males = 1.8, females = 2.2 LOAEL = mg/kg/day: males = 18.0, females = 21.8 based on increased chronic nephropathy in males and decreased hematological parameters in females (Hgb, MCV, MCH and MCHC) No evidence of carcinogenicity 870.5100 Gene mutation in S. typhimurium and E. coli Neither cytotoxic nor mutagenic up to 2000 g/plate. There were reproducible increases in revertant colonies of S. typhimurium strains TA1538 and TA98 in S9 activated phases of the preliminary cytotoxicity and both mutation assays. [Results considered to be equivocal.]
Ref: US EPA Pesticide Fact Sheet. April 12, 2001.

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

Human Toxicity Excerpts: ... Mild cholinesterase inhibitor & /causes/ ... an increased leukocyte count in circulating blood in exposed agricultural workers. [Gosselin, R.E., R.P. Smith, H.C. Hodge. Clinical Toxicology of Commercial Products. 5th ed. Baltimore: Williams and Wilkins, 1984.,p. II-331]
Ref: Hazardous Substance Data Bank for Fluometuron. Available at Toxnet

Abstract: On single oral administration of (14)C-S-53482 [7-fluoro-6-(3,4,5, 6-tetrahydrophthalimido)-4-(2-propynyl)-2H-1,4-benzoxazin-3( 4H)-one, Flumioxazin] labeled at the 1- and 2-positions of tetrahydrophthaloyl group to rats at 1 (low dose) or 100 (high dose) mg/kg, the radiocarbon was almost completely eliminated within 7 days after administration in both groups with generally very low residual (14)C tissue levels. The predominant excretion route was via the feces. The major fecal and urinary metabolites involved reduction or sulfonic acid addition reactions at the 1,2-double bond of the 3,4,5,6-tetrahydrophthalimide moiety and hydroxylation of the cyclohexene or cyclohexane ring. One urinary and four fecal metabolites were identified using chromatographic techniques and spectroanalyses (NMR and MS). Three of five identified metabolites were unique forms, reduced at the 1,2-double bond of the 3,4,5, 6-tetrahydrophthalimide moiety. On the basis of the metabolites identified in this study, the metabolic pathways of S-53482 in rats are proposed. To specify tissues forming reduced metabolites, an in vitro study was conducted. Reduction was found to take place in red blood cells.
Ref: Tomigahara Y et al. (1999). Metabolism of 7-fluoro-6-(3,4,5,6-tetrahydrophthalimido)-4- (2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (S-53482, flumioxazin) in the rat: II. Identification of reduced metabolites. J Agric Food Chem. Jun;47(6):2429-38.

http://www.fluorideaction.org/pesticides/flumioxazin.abstracts.htm

Abstract: An N-phenylimide herbicide, S-53482, inhibits protoporphyrinogen oxidase, an enzyme common to chlorophyll and heme biosynthesis, and produces embryolethality, teratogenicity [mainly ventricular septal defects (VSD) and wavy ribs], and growth retardation in rats. In order to elucidate the mechanism of the developmental toxicity, in particular VSD, effects of the herbicide on rat embryonic blood cells were investigated histologically at the light and electron microscopic levels at 6, 12, 24, 36, and 48 h after oral administration of the chemical to pregnant rats on day 12 of gestation, the most sensitive day for toxicity. Electron and light microscopy demonstrated mitochondrial lesions, including abnormal iron deposits that were probably due to inhibition of heme biosynthesis, in erythroblasts derived from the yolk sac. Subsequently, degeneration of these erythroblasts occurred followed by erythrophagocytosis. Histologically hearts from exposed embryos had a thin ventricular wall, which may reflect a compensatory reaction to a loss of embryonic blood cells. Thus, the herbicide may induce VSD due to hematological dysfunction caused by the inhibition of heme biosynthesis rather than by direct injurious effects on the heart.
Ref: Kawamura S et al (1996). Histological changes in rat embryonic blood cells as a possible mechanism for ventricular septal defects produced by an N-phenylimide herbicide. Teratology. Nov;54(5):237-44.

http://www.fluorideaction.org/pesticides/flumioxazin.abstracts.htm

Fluometuron - Herbicide - CAS No. 2164-17-2

E. Subchronic Studies. Subchronic feeding studies were conducted to determine the two concentrations (referred to in this report as "low" and "high" doses) to be used in the chronic studies. Fluometuron was administered in the diet for 90 days at doses of 0, 250, 500, 1,000, 2,000, 4,000, 8,000, or 16,000 ppm to groups consisting of 10 males and 10 females of each species (Tables 1 and 2) (page 5) ... A second 90-day subchronic study, described in Table 3, was undertaken to investigate in-depth the effects of feed containing 0 to 4,000 ppm fluometuron on the spleens of rats.... Gross lesions observed at necropsy included varying degrees of splenomegaly in all dosed groups. This change was dose related with the spleens being larger, heavier, darker, and firmer than the control spleens. In male rats, an increase in the mean weights of spleens occurred at 1,000 ppm, and the mean spleen weight at 4,000 ppm was twice that of the control. In female rats, the mean weight of spleens in the group receiving 250 ppm was greater than that of the control, and those of the groups receiving 2,000 ppm or 4,000 ppm were respectively twice and almost three times that of the control. A dose-related increased incidence of red blood cells with polychromasia and anisocytosis was observed for both male and female rats. Microscopically, the pathologic changes were congestion of the red pulp with corresponding decrease of white pulp. (page 8)
Reference: 1980. Bioassay of fluometuron for possible carcinogenicty. NCI-CG-TR-195. NTPO-80-11. National Cancer Institute. Carcinogenesis. Technical Report Series No. 195. NTP No. 80-11.
http://www.fluorideaction.org/pesticides/fluometuron.ntp.1980.pdf

-- Organ Toxicity. Toxic injury to the liver, kidneys, gut and brain is induced when lethal doses of fluometuron are administered experimentally (10). An increase in spleen weight and in the incidence of abnormalities in red-blood cells, and decreased weight gain in females were observed in a 90-day study of rats (18).
-- Carcinogenic Effects. EPA has determined that there is not enough evidence that fluometuron causes cancer in animals to justify its classification as a carcinogen. Fluometuron is not classified as a carcinogen by the EPA (20). An increased incidence of liver-cell tumors in male mice
was noted in a study of rats and mice. In the same study, no carcinogenic effects were observed in female mice or in rats of either sex (18). Mice that were given oral doses of 87 mg/kg for two years had evidence of liver tumors and leukemia, a condition characterized by uncontrolled growth in the number of white blood cells in the blood stream (7).
-- ACUTE TOXICITY. ... It may be fatal if inhaled, swallowed, or absorbed through skin, as it is irritating to the mucous membrane lining the skin, gastrointestinal tract, and respiratory system (2). While there have been no reports of cases of fluometuron poisoning in humans, this herbicide is considered a mild inhibitor of cholinesterase. Cholinesterase is an essential enzyme of the nervous system. Cholinesterase inhibition was observed in guinea pigs exposed by inhalation to 588 mg/m3 for 2 hours (18). (For more information, refer to the Toxicology Information Brief on Cholinesterase-Inhibition). Fluometuron caused an increased white blood cell count in agricultural workers (3).
Ref: Flumeturon. EXTOXNET. Pesticide Information Profile. March 1994.

http://pmep.cce.cornell.edu/profiles/extoxnet/dienochlor-glyphosate/fluometuron-ext.html

-- PubMed abstract: Twelve of fifteen 6-9-mo-old clinically healthy Desert sheep were given single or repeated daily doses of 25 to 4000 mg cotoran/kg by drench. Cotoran poisoning was characterized by grinding of the teeth, ruminal tympany, mydriasis, dyspnea, staggering, paresis of the hind and forelimbs, and recumbency. Lesions were widespread congestion and hemorrhage, hepatic fatty change, catarrhal enteritis and degeneration of the epithelial cells of the renal proximal convoluted tubules. These were accompanied by significant increases in the activities of GOT, LDH and GGT and decreases in serum total protein and calcium.
Ref: Vet Hum Toxicol 1995 Jun;37(3):214-6.
Toxicity of cotoran (fluometuron) in Desert sheep; by Mohamed OS, Ahmed KE, Adam SE, Idris OF.
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7571346&dopt=Abstract

Fluoroglycofen-ethyl - Herbicide - CAS No. 77501-90-7

In the mouse 1 and 3 month study, the rat 1 month study and the dog 52 week study, reductions in haemoglobin levels, red blood cell numbers and packed cell volume were variously seen, predominantly at the top doses. Nucleated and polychromatic red blood cell numbers were raised in the rat study only. These effects appeared reversible, in both the 1 month rat and mouse studies. It would appear that any potential haemolytic effects, possibly from aniline-derivatives, are of secondary importance to other subchronic effects...
Ref: Evaluation on: Fluoroglycofen-ethyl. May 1992. Issue No. 50. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, UK.
http://www.pesticides.gov.uk/citizen/evaluations/050_confirm-box.htm

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

Major toxic effects result from myelosuppressive action. Clinical effects are leukopenia, thrombocytopenia, and anemia. Loss of hair, occasionally progressing to total alopecia, nail changes, dermatitis, and increased pigmentation and atrophy of skin may occur.
Ref: OXNET profile from Hazardous Substances Data Base for FLUOROURACIL.

http://www.fluoridealert.org/pesticides/fluorouracil.toxnet.hsdb.htm

• Definitions
Leukopenia - an
abnormal lowering of the white blood cell count
Thrombocytopenia - a blood disease characterized by an abnormally small number of platelets in the blood

Fluquinconazole - Fungicide - CAS No. 136426-54-5

-- Oral long-term toxicity and carcinogenicity. 2-year dietary study in rats. groups of 50 male and 50 female outbred albino Sprague-Dawley CRL :COBS CD(SD)BR rats were administered fluquinconazole (93.2% purity) in the diet at concentrations of 0 (control), 1, 20 or 100 ppm. Additionally 20 animals/sex/dose designated for the interim-kill received the test compound at concentrations of 0, 1, 5, 10 or 100 ppm for 12 months... There was a very slight reduction in red blood cells, haemoglobin and haematocrit in females during the first 12 months. At 24 months, the mean cell volume, mean corpuscular haemoglobin (MCH) and haemoglobin values were statistically significantly lower at the 100 ppm dose level than in controls. In males, the mean cell volume, mean corpuscular haemoglobin (MCH) and haemoglobin values were statistically significantly lower than controls at 12 months only. The main changes in clinical chemistry were related to serum protein content...
-- Short Term Toxicity. Oral route. Rat. (b)... Groups of 5 male and 5 female outbrd albino Sprague-Dawley Crl:COBS CD(SD)BR rats were each administered fluquinconazole (100% purity) either in the diet at concentrations of 0 (control), 5, 20, 100 and 400 ppm or by gavage dissolved in 1 % aqueous methlcellulose at a dose level of 10 mg/kg bw/day for 28 days. Due to mortalities at the 400 ppm dose level, a supplementary gorups of 5 male and 5 female animals were administered fluquinconazole at a dose level of 200 ppm... Minimal statistically non-significant differences were noted in surving male rats at the 200 ppm were reduction in white blood cells, reduction in lymphocytes and increased mean cell haemoglobin concentration. Changes in clinical chemistry parameters were related primarly to plasma proteins...
-- Short Term Toxicity. Oral route. Rat. (c). In a 3-month feeding study, groups of 10 male and 10 female outbred albino Spraque-Dawley CRL:COBS CD(SD)BR rats were administered fluquinconazole (>96.2% purity) at concentrations of 0 (controls), 1, 5, 15, or 100 ppm. Additional groups of animals at the 0 (control) and 100 ppm dose levels were kept on an untreated diet for 4 weeks in order to invetigate the regressivity of effects. Blood samples were taken after 6 and 13 weeks of treatment for haematological and clinical chemistry investigations... Haematology, clinical chemistry and urinalysis parameters showed incidences of statistically significant changes which were considred to be of limited toxicological significance because they were either not dose-related or were reported to be withing the range of historical data.
Ref: Evaluation on: Fluquinconazole. May 1999. No. 184. Evaluation of Fully Approved or Provisionally Approved Products. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7 PX, UK. Available online:
http://www.pesticides.gov.uk/citizen/evaluations/evallist.htm

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

-- In a one-year feeding study, dogs were given flusilazole in the diet at concentrations of 0, 5,20, and 75 pprn (MRID 400421 13). There were treatment-related effects on hematological parameters at 75 pprn including increased white blood cell count, ALP activity, and serum cholesterol. Serum total protein and albumin levels were lower in the male high dose group. Relative liver weight was increased at 75 ppm. Treatment-related histopathological changes included liver centrilobular hepatocellular enlargement and centrilobular inflammation and hyperplasia in the lymphoid nodules of the gastric mucosa observed in the high dose. In summary, the effects of feeding flusilazole to dogs for one year were a dose-related trend towards mild to moderate hepatotoxicity and a mild leucocytosis (inflammatory) response. The effects were mainly seen in the high dose group and most pronounced in males. The liver hypertrophy was considered likely to be an adaptive response to increased metabolic demand. Based on minimal liver histology at the mid-dose, 20 ppm (0.7 mgkglday) is considered a NOAEL. (Pages 18-19)
-- Short-term exposure toxicity of flusilazole was investigated in rats (gavage and dietary), mice (dietary), dogs (dietary) and in rabbits (dermal application). The targets identified were the blood system, liver and urinary bladder. The dog was found to be the most sensitive species to the hepatotoxicity and bladder toxicity of flusilazole. Degenerative liver disorder and evidence of cellular proliferation (hyperplasia) in the urinary bladder were seen at 125 ppm (4.3 mgikglday) in the dog. The NOAEL was 0.9 mgkgiday. (Page 29)
Ref: DuPont Punch (Active ingredient: Flusilazole) and DuPont Charisma (Active ingredients: Flusilazole and Famoxadone): Summary of data compiled in support of a Section 18 Emergency Exemption request for control of Asian soybean rust on soybeans. By DuPont authors: Cosgrove T, Czochor L, Dinter A, Jemberg K, Klemens A, Marcon A, McInnes B, Mullin L, Russell M, Ryan D, Singles S, Vanderbroeck V. Revision No. 1: February 2, 2005.
http://www.fluorideaction.org/pesticides/flusilazole.appendix1.pdf

Fluthiacet-methyl - Herbicide - CAS No. 117337-19-6

-- 90-day oral Toxicity, rats and mice. Rats: NOAEL = 6.19 milligrams/ kilograms day (mg/ kg/day) in males 6.80 mg/ kg/day in females LOAEL = 216 mg/ kg/day in males 249 mg/ kg/day in females Mice: NOAEL = 1.3 mg/kg/ day in males 1.6 mg/ kg/day in females LOAEL = 66 mg/kg/ day in males 83 mg/kg/ day in females. Based on decreased body weight gains as well as effects on hematology, clinical chemistry, urinalysis parameters, liver weights and microscopic pathology in rats; and on effects on the erythropoietic system and liver in mice.
-- Carcinogenicity rats. NOAEL in males = 2.1 mg/kg/day LOAEL in males = 130 mg/kg/day NOAEL in females = 2.5 mg/kg/day LOAEL in females = 154 mg/kg/dayIn males there were decreased body weight, liver toxicity, pancreatic toxicity and microcytic anemia. In females there were liver toxicity, uterine toxicity and slight microcytic anemia. In males only at 130 and 219 mg/kg/day there was respectively, an increase in the trend toward pancreatic exocrine adenomas and pancreatic islet cell adenomas.

-- In a 90-day rat feeding study the NOAEL was 6.19 mg/kg/day for males and 6.80 mg/kg/day for females. In a 6-week dog dietary study the NOAEL was 236 mg/kg/day for males and 77.7 mg/kg/day for females. In a 28-day rat dermal study the NOAEL was 1000 mg/kg/day [HDT]. In a 1-year dog chronic feeding study, the NOAEL was 57.6 mg/kg/day for males and 30.3 mg/kg/day for females and the Lowest Observed Adverse Effect Level (LOAEL) was 582 mg/kg/day for males and 145 mg/kg/day for females based on effects observed in the erythropoietic system [red blood cells] and the liver.
-- Chronic toxicity NOAEL in males = dogs 57.6 mg/kg/day LOAEL in males = 582 mg/kg/day NOAEL in females = 30.3 mg/kg/day LOAEL in females = 145 mg/kg/day The LOAELs were based on effects observed in the erythropoietic system and liver.
Ref: Federal Register: December 21, 2001. Fluthiacet-methyl; Pesticide Tolerance. Final Rule. http://www.fluoridealert.org/pesticides/fluthiacet.m.fr.dec.21.2001.htm

Fluvalinate - Acaracide, Insecticide - CAS No. 69409-94-5

Dietary administration of 2.5 mg/kg/day to rats for 13 weeks produced anemia in blood parameters (decreased hematocrit, hemaglobin, and red blood cells). The NOEL was 1.0 mg/kg/day. Dietary administration of 30 mg/kg/day (LOEL) to rats for 3 months produced decreased hemoglobin, hematocrit, and red blood cell count in rats. The NOEL was 3 mg/kg/day... EPA believes that there is sufficient evidence for listing fluvinate on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available developmental, dermal, 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 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.

Fomesafen - Herbicide - CAS No. 72178-02-0

Decreased plasma cholesterol and triglycerides and increased liver weights (reversible at 7 days post-treatment) were observed at 50 mg/kg/day (only dose tested) when administered in the diet of rats for 4 weeks.
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.

 
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