Note: This is not an exhaustive list.
When time allows more information will be added.

Fipronil - Acaricide, Insecticide, Wood Preservative - CAS No. 120068-37-3

• Reproductive and developmental toxicity. In a two-generation rat study, the NOEL for parental (systemic) toxicity was 3 ppm (0.26 mg/kg/day for both sexes combined), based on increased weight of the thyroid glands and liver in males and females, decreased weight of the pituitary gland in females, and an increased incidence of follicular epithelial hypertrophy in females at 30 ppm.
• Subchronic toxicity. The NOAEL for systemic toxicity in rat was 5 ppm (0.35 mg/kg/day for both sexes combined), based on alterations in serum protein values and increased weight of the liver and thyroid at 30 ppm (1.93 and 2.28 mg/kg/day for males and females, respectively).
• Chronic toxicity. The NOAEL for systemic toxicity in mice was 0.5 ppm (0.06 mg/kg/day) based on decreased body weight gain, decreased food conversion efficiency in males, increased liver weights, and liver histopathology at 10 ppm (1.3 mg/kg/day).
Ref: August 24, 2005. Federal Register. Fipronil; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluorideaction.org/pesticides/fipronil.fr.aug.24.2005.html

Short-term toxicity.
-- 28 day dietary administration to rats. Technical-grade fipronil (batch number IGB 464, purity, 93%) was administered in the diet for four weeks to groups of five Cr1:CD (SD) BR rats of each sex at concentrations of 25, 50, 100, 200, or 400 ppm, equal to 3.4, 6.9, 13, 24, or 45 mg/kg bw per day for males and 3.5, 6.7, 13, 25, or 55 mg/kg bw per day for females ... The target organs were the liver and thyroid. Liver weights were significantly increased in females at all doses and in males at 200 and 400 ppm. At necropsy, liver enlargement was observed in one or both sexes starting at 50 ppm, and five males and three females at 400 pm had enlarged livers. Generalised hepatocyte enlargement was observed microscopically in one male at 100 ppm, with increasing incidence in animals of each sex at 200 and 400 ppm. Thyroid follicular-cell hypertropy, generally of minimal severity but of moderate severity in several males at 200 and 400 ppm, was found in almost all treated animals but not in the controls. (page 77)
-- 90-day dietary administration to rats. In a 13-week study, rats (CD strain 10/sex/group) received dietary administration of either 1, 5, 30 or 300 ppm fipronil (batch number PGS 963, 95.4% purity). This was equivalent to 0.07, 0.3, 2.1 or 22 mg/kg/d. Doses were selected after a preliminary 14-d study showed deaths (3/10 animals by 5 d) and muscular spasms at 30 mg/kg/d ... In males, the absolute liver weight was significantly increased at the top dose only (42%). In females liver weights were elevated in all treatment groups (4.6-35%) at 1-300 ppm), achieving statistical significance at ≥5 ppm. Absolute thyroid weights were elevated (4.2-100% at 5-300 ppm) achieving statistical significance at ≥30 ppm in females and at 300 ppm in males ... Histopathological examination found treatment-related effects at the top dose in the thyroids and livers of both sexes. Oil red O staining revealed a high incidence of fat deposits in all liver samples, including controls. A statistically significant increase in panacinar hepatic fatty vacuolation (controls 0/10 and 7/10 at 300 ppm) was reported in males only. (page 78-79)
Ref: April 204. Evaluation on : Fipronil (Horticultural Uses). No. 212. UK Dept. for Environment, Food and Rural Affairs, Pesticides Safety Directory.
http://www.fluorideaction.org/pesticides/fipronil.uk.report.apr.2004.pdf

Flazasulfuron - Herbicide - CAS No. 104040-78-0

• Short term toxicity Target / critical effect: Liver (centrolobulillar hepatocyte hypertrophy). Lowest relevant oral NOAEL / NOEL: 2 mg/kg bw/day, 13-week dogs and 1-year dogs.
• Long term toxicity and carcinogenicity . Target / critical effect: Liver (centrolobulillar hypertrophy) in mice and kidney (chronic nephropathy) in rats. Lowest relevant NOAEL: 1.3mg/kg bw/day: 2-years rats. No evidence for carcinogenic potential.

Flocoumafen - Rodenticide - CAS No. 90035-08-8

Sub-acute Toxicity. ... Male and female Fischer 344 rats received 0, 0.01, 0.05, 0.1 or 0.2 ppm flocoumafen (cis:trans ration - 55:44) in the diet for 28 days. (3 ppm vitamin K3 was also incorporated into the diet.) There were no deaths and no clinical signs of toxicity were reported. small increases were observed in the prothrombin and activated partial thromboplastin times in both sexes receiving 0.2 ppm and total protein was decreased in females receiving 0.1 and 0.2 ppm and in males receiving 0.2 ppm. The majority of males receiving 0.2 ppm had treatment-related histopathological changes in the liver (reduced periportal glycogenic vacuolation and increased histiocytic foci). 0.05 ppm (equivalent to 0.0025 mg/kg bw per day) was the no-effect level.
Ref: Evaluation on Flocoumafen. April 1987. UK Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool 3 Peasholme Green, York YO1 7PX. Also available at
http://www.pesticides.gov.uk/citizen/evaluations/evallist.htm

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

-- Reproductive and developmental toxicity. A developmental toxicity study in rats resulted in the maternal and developmental no observed adverse effect levels (NOAELs) of 100 mg/kg/day. The maternal lowest observed adverse effect level (LOAEL) was 500 mg/kg/day based on the treatment-related effects observed on the liver and kidney of the dams in the highest dose group. The developmental LOAEL was 500 mg/kg/ day based on the increases in placental weights and incidences of fetal skeletal variations seen only at maternally toxic doses of 500 mg/kg/ day.
-- In the multi-generation rat reproduction study, the NOAEL was 300 ppm for both parental animals (13.5-32.8 and 16.3-67.0 mg/kg/day, respectively, for males and females) and their offspring. The effects at the highest dose of 1,800 ppm included the following: increased kidney weights and gross and histopathological alterations in the kidney. Findings noted in the top dose females included delayed vaginal opening and increased liver, kidney and spleen weights in the F1 generation...
-- 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.
-- 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.
-- In the 18-month mouse study, effects were observed in the lung, liver, spleen and bone marrow at 250 ppm or higher. Findings included, centrilobular hepatocellular hypertrophy...
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)
-- Prenatal developmental toxicity (rats). Maternal. NOAEL is 100 mg/kg bw/day. LOAEL is 500 mg/kg bw/day, based on increased liver weight, and liver and kidney pathological changes (hypertrophy of centrilobular hepatocytes in liver and vacuolation of proximal tubular cell in kidneys).
-- 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.
Ref: August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluoridealert.org/pesticides/flonicamid.fr.aug.31.2005.html

Floransulam - Herbicide - CAS No. 145701-23-1

Short term toxicity. Target / critical effect: Anemia, hepatotoxicity , renal hypertrophy epithelial cells, collecting ducts, adrenal vacuolation(dog ) Lowest relevant oral NOAEL / NOEL: 1 y & 90 d dog (oral feed) ; 5 mg/kg bw/d;...
Ref: September 18, 2002 - Review report for the active substance florasulam. European Commission Health & Consumer Protection Directorate-General.
http://www.fluoridealert.org/pesticides/Florasulam.EU.Sept.2002.pdf

-- The subchronic and chronic toxicity of florasulam was investigated in the mouse, rat and dog. A 28-d repeat dose dermal toxicity study was also carried out in rats. In the subchronic and chronic studies, treatment-related findings were observed in the kidney in all species and in the liver and adrenal glands in dogs. In the kidney, hypertrophy of the epithelial cells of the collecting ducts occurred in all species tested.
-- In subchronic and chronic dietary studies, treatment-related findings were observed in the kidneys in mice, rats and dogs and in the liver and adrenal glands in the dog. In the kidney, hypertrophy of the epithelial cells of the collecting duct was observed in all species tested. In rats, hypertrophy of the epithelial cells correlated with elevated serum bicarbonate levels, urinary acidification, decreased urinary specific gravity and increased kidney weights. In dogs, treatment-related findings associated with the liver included increased ALP activity, decreased serum albumin and protein levels, increased liver weights and increased incidence or severity of hepatic vacuolation. Dogs also exhibited slight vacuolization of the zona reticularis and zona fasciculata in the adrenal glands; however, in the absence of any associated inflammation, necrosis or other changes, the toxicological significance was uncertain. The most appropriate NOAEL for subchronic and chronic toxicity end points is 5.0 mg/kg bw/d in the 90-d and 1-year dietary studies in dogs. At the LOAEL, 50 mg/kg bw/d, treatment-related findings were observed in the kidneys and liver in the 90-d and 1-year dietary studies and in the adrenal glands in the 1-year dietary study.
-- In the dog, an increased incidence and severity of hypertrophy of the epithelial cells was observed in both sexes at 50 mg/kg bw/d and above in both the 90-d and 1-year dietary study. There were no treatment-related urinalysis findings in either the 90-d or 1-year dietary study. The severity (slight) of the hypertrophy did not appear to increase with prolonged exposure. In the 90-d dietary study treatment-related findings associated with the liver included increased alkaline phosphatase (ALP) activity in both sexes at 50 and 100 mg/kg bw/d, increased liver weights in both sexes at 100 mg/kg bw/d and a slight increased incidence or severity of hepatic vacuolation in both sexes at 50 and 100 mg/kg bw/d. Increased liver weights and hepatic vacuolation were not observed in the 1-year dietary study. In the 1-year dietary study, treatment-related findings associated with the liver, included increased alanine aminotransferase (ALAT) and ALP activity and decreased serum albumin and protein levels in both sexes at 100 mg/kg bw/d. After the high dose was reduced to 50 mg/kg bw/d (week 15), ALP activity remained elevated and serum albumin and protein levels remained lower in both sexes. In the 1-year dietary study, no histopathological findings were evident in the liver. In the 1-year dietary study, slight vacuolization of the zona reticularis and zona fasciculata in the adrenal glands was observed in the high-dose males and females; however, in the absence of any associated inflamation, necrosis or other changes, the toxicological significance of this finding was uncertain. The vacuolization was consistent with fatty changes. Body weight, body-weight gain and food consumption were significantly lower in both sexes at 100 mg/kg bw/d and remained lower in the high-dose females after the high dose was reduced in the 1-year dietary study. Body weight, body-weight gain and food consumption were unaffected by treatment in the 90-d dietary study.
-- Ref: Florasulam EF-1343 Suspension Concentrate Herbicide. REF2001-12. September 21, 2001. Canadian Pest Management Regulatory Agency. Health Canada.
http://www.hc-sc.gc.ca/pmra-arla/english/pdf/reg/reg2001-12-e.pdf

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

A 3-month rat feeding study demonstrated hepatocyte hypertrophy in males (the LOEL was 5 mg/kg/day; the NOEL was 0.5 mg/kg/ day). In a 1-year feeding study, dogs had changes in serum alkaline phosphatase and alanine aminotransferase and/or alanine sulfatransferase (the LOEL was 25 mg/kg/day; the NOEL was 5 mg/kg/day). Similar changes were also reported in dogs following 3 months exposure in their diet (the LOEL was 125 mg/kg/day). In a carcinogenicity study, male mice fed 20 ppm (2.6 mg/kg/day, the LOEL) had an increased incidence of hepatocyte hypertrophy. The NOEL was 5 ppm or 0.65 mg/kg/ day. Male and female mice exposed to a higher dose of 80 ppm (10.4 mg/ kg/day) had increased liver weight (relative and absolute) and hypertrophy of periacinal hepatocytes. Males in this dose group also had increased pigmentation in hepatocytes and Kupffer cells. In a teratogenicity study in Sprague-Dawley rats exposed via oral gavage, delayed ossification and an increased incidence of hydroureter were observed in fetuses (the fetotoxic LOEL was 5 mg/kg/day; the NOEL 1 mg/kg/day) and a teratogenic LOEL of 200 mg/kg/day (the NOEL was 10 mg/kg/day) was determined based on the incidence of diaphragmatic hernia. Maternal toxicity was observed in this study at doses higher than those causing fetotoxicity and included reduced body weight gain and decreased gravid uterus (the maternal LOEL was 200 mg/kg/day; the NOEL was 10 mg/kg/day). In a 2-generation reproductive toxicity dietary study in Wistar rats, the reproductive LOEL of 250 ppm (12.5 mg/kg/day; the NOEL was 80 ppm or 4 mg/kg/day) was based on reduced litter sizes, reduced viability, reduced testis and epididymis weights and tubular atrophy in offspring. Fetotoxicity (delayed ossification and eye opacities) was also demonstrated in New Zealand White rabbits (the LOEL was 30 mg/kg/day; the NOEL was 10 mg/kg/day). EPA believes that there is sufficient evidence for listing fluazifop butyl on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available hepatic and developmental toxicity data for this chemical.
Ref: USEPA/OPP. Support Document for the Addition of Chemicals from Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) Active Ingredients to EPCRA Section 313. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.
http://www.epa.gov/tri/frnotices/59fr1788.htm

-- Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subchronic oral toxicity in beagle dogs (4/sex/group) administered doses of 0 (vehicle control, corn oil), 5, 25 and 250 mg/kg/day in gelatin capsules for 13 weeks. Severe corneal ulceration, requiring humane sacrifice of 2 males and 1 female of a 250 mg/kg/day dosage during Week 4, prompted adjustment of this regimen to 125 mg/kg/day for the remainder of study... Distended gall bladders, large friable livers and congested caecum and colon from engorgement of the blood vessels were noted upon necropsy. Histopathological evaluation confirmed treatment-related lesions of the eyes, liver, testes and gastrointestinal tract. [ICI AMERS INC; Butyl 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy) propionate: 13-Week Oral Toxicity Study in Beagle Dogs; 04/24/80; EPA Doc No. 88-920006846; Fiche No. OTS0543851]
-- Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subchronic dietary toxicity in Wistar rats (20/sex/group) receiving 0, 10, 100 and 2000 ppm by dietary inclusion for 13 weeks. Mean achieved dosages during 13-week treatment were 0, 0.7, 7.1 and 144.5 mg/kg/day in males of the respective treatment groups and 0, 0.8, 8.0 and 161.9 mg/kg/day in females... Upon terminal necropsy, only high-dose males had evidence of hepatic enlargement or swelling (7/20), although higher absolute and relative liver weights were significant (p < 0.01, Student's t-test) in both males and females of the 2000 ppm group... Histopathology confirmed a specific liver toxicity in male rats, marked by significant dose-related hepatocytic hypertrophy with isolated instances of vesicular nuclei and or periacinal hepatocytic necrosis... [ICI AMERICAS INC; 13 Week Dietary Toxicity Study with PP009 in Rats (Final Report); 05/29/80; EPA Doc No. 88-920006943; Fiche No. OTS0545346]
-- -- Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subacute oral toxicity in Wistar albino rats (10/sex/group) administered 10 ml/kg doses in corn oil of 0, 4, 20, 100 and 500 mg/kg/day by oral gavage, 5 days/week for 2 weeks. Five-day weekly treatment periods were each followed by 2-day recovery... Male rats of 100 and 500 mg/kg/day dosages had higher absolute and relative liver weights that was not seen in their female counterparts. Microscopic examination confirmed a particular liver pathology of treated males, characterized by dosage-related hepatocytic hypertrophy and necrosis (study lethalities), and dosage-related slight to moderate periacinal hepatocytic hypertrophy... [ICI AMERS INC; 14 Day Subacute Oral Toxicity Study with PP009 in Rats; 07/11/80; EPA Doc No. 88-920007017; Fiche No. OTS0545392]
-- Fluazifop butyl (CAS # 69806-50-4) was evaluated for developmental toxicity in the progeny of Sprague-Dawley CD rats administered oral doses of 0 (corn oil vehicle control), 10, 50 and 200 mg/kg/day by gavage on gestation days 6-20... Relative liver weights were also significantly (p < 0.05) greater in high-dose dams... [ICI AMERS INC; Butyl 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy) propionate butyl: Effects of Oral Administration Upon Pregnancy in Rats; 05/23/80; EPA Doc No. 88-920006839; Fiche No. OTS0543844]
-- Fluazifop butyl was evaluated for reproductive and developmental effects in 2 successive generations of Charles River Wistar strain rats (30/sex/group) exposed continuously to 0, 10, 80 and 250 ppm in the diet. Each respective parent generation had received treatment for a minimum of 100 days (F0) and 120 days (F1) prior to mating. F0 and F1 dams weaned their progeny for 25 days postpartum to time of offspring selection for mating and continued study (F1) or sacrifice (F1, F2). Thirty days after sacrifice of their offspring, the surviving F1 females and select F1 males were sacrificed and with representative F1 and F2 offspring were examined histologically... Liver and kidney weights were significantly high (250 ppm) relative to controls, while spleen weights were low in both sexes (80, 250 ppm)... [ICI AMERS INC; Fluazifop butyl: Effects Upon Reproductive Performance of Rats Treated Continuously Through 2 Generations (Final Report); 03/17/81; EPA Doc No. 88-920006849; Fiche No. OTS05543854]
-- Fluazifop-butyl (CAS # 69806-50-4) was evaluated for subchronic oral toxicity in beagle dogs (4/sex/group) administered doses of 0 (vehicle control, corn oil), 5, 25 and 250 mg/kg/day in gelatin capsules for 13 weeks. Severe corneal ulceration, requiring humane sacrifice of 2 males and 1 female of a 250 mg/kg/day dosage during Week 4, prompted adjustment of this regimen to 125 mg/kg/day for the remainder of study. Prior to sacrifice... Histopathological evaluation confirmed treatment-related lesions of the eyes, liver, testes and gastrointestinal tract. [ICI AMERS INC; Butyl 2-(4-(5-trifluoromethyl-2-pyridyloxy)phenoxy) propionate: 13-Week Oral Toxicity Study in Beagle Dogs; 04/24/80; EPA Doc No. 88-920006846; Fiche No. OTS0543851]
Ref: Fluazifop-butyl. TOXNET profile from Hazardous Substances Data Bank.
http://www.fluoridealert.org/pesticides/Fluazifop-butyl.TOXNET.HSDB.htm

**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... 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
• Canaliculi - In liver, small channels between hepatocytes through which bile flows to the bile duct and thence to the intestinal lumen.

Abstract: The aim of this study was to determine the effect of herbicide fluazifop, on the early occurring changes in rat liver regarded as hepatic markers of peroxisome proliferators (PPs). Fluazifop was administered orally to male Wistar rats at increasing doses from 5.6 to 891 mg/kg body weight per day for 1, 2, 4, 7 and 14 consecutive days and peroxisome proliferation, induction of some peroxisome-associated enzymes and mitogenesis (S-phase, M-phase and percentage of binucleated hepatocytes) were studied. Short-term treatment of rats with fluazifop resulted in hepatomegaly due to time dependent proliferation of smooth endoplasmic reticulum (SER) and peroxisomes. The increase in the number of peroxisomes in the hepatocytes was supported by an increase in peroxisomal palmitoyl-CoA oxidation and catalase activity. In contrast to other PPs fluazifop induced low rate of rcplicative DNA synthesis and did not affect mitoses (M-phase). DNA synthesis was accompanied by the appearance of binucleated hepatocytes. Thus, we can conclude that fluazifop produces in male Wistar rats hepatomegaly due to cellular hypertrophy. The threshold dose for palmitoyl-CoA oxidation and DNA synthesis was 112 and 223 mg/kg body weight per day, respectively. The value for hepatomegaly and catalase activity was 56 mg/kg body weight per day. The results presented in this paper demonstrated that fluazifop can be classified as a weak rodent PPs.
Ref: Hepatocellular peroxisome proliferation and DNA synthesis in Wistar rats treated with herbicide fluazifop; by Kostka G, Palut D, Ludwicki JK, Kopec-Szlezak J, Wiadrowska B, Lembowicz K. Toxicology. 2002 Sep 16;178(3):221-8.

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, reproductive 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

Fluazinam - Fungicide - CAS No. 79622-59-6

Suggestive Evidence of Carcinogenicity to Humans. An increase in thyroid gland follicular cell tumors in male rats, and an increased incidence of hepatocellular tumors observed in the male mice was treatment-related.
Ref: April 26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the Office of Pesticide Programs. From: Jess Rowland, Chief Science Information Management Branch Health Effect Division (7509C) Office of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf

In subchronic and chronic toxicity studies, fluazinam targeted the following organs: liver, lung, uterus, testes, pancreas, thymus, thyroid, stomach, eyes and brain... Liver toxicity was evident in most studies including increased size and weight, fatty changes, pallor, as well as hepatocyte hypertrophy, necrosis and apoptosis...
Ref: Canada: Regulatory Note REG2003-12. Fluazinam. Pest Management Regulatory Agency. Health Canada. Ottawa. October 27, 2003.
http://www.fluorideaction.org/pesticides/fluazinam.canada.report2003.pdf

-- Carcinogenicity mice NOAEL = Males:1.1 mg/kg/day; Females: 1.2 mg/kg/day [[Page 46732]] LOAEL = Males: 10.7 mg/kg/day; Females: 11.7 mg/kg/day based on increased incidences of brown macrophages in the liver of both sexes, eosinophilic vacuolated hepatocytes in males, and increased liver weight in females. Clear evidence of carcinogenicity (hepatocellular tumors) in male mice, but not in females.
-- 90-Day oral toxicity rats NOAEL: Males = 3.8 mg/kg/day; Females = 4.3 mg/kg/day [[Page 46731]] LOAEL Males = 38 mg/kg/day; Females = 44 mg/kg/day based on increased liver weights and liver histopathology in males, and increased lung and uterus weights in females.
-- 90-Day oral toxicity dogs NOAEL = 10 mg/kg/day LOAEL = 100 mg/kg/day based on retinal effects, increased relative liver weight, liver histopathology and possible increased serum alkaline phosphatase in females and possible marginal vacuolation of the cerebral white matter (equivocal).
-- Prenatal developmental toxicity Maternal NOAEL = 4 mg/kg/day rabbits LOAEL = 7 mg/kg/day based on decreased food consumption and increased liver histopathology...
-- Reproduction and fertility effects Parental/Systemic NOAEL = 1.9 mg/ rats kg/day LOAEL = 9.7 mg/kg/day based on liver pathology in F1 males...
-- Combined chronictoxicity/ NOAEL = Males: 0.38 mg/kg/day; carcinogenicity rats Females: 0.47 mg/kg/day LOAEL = Males: 3.8 mg/kg/day; Females: 4.9 mg/kg/day based on liver toxicity in both sexes, pancreatic exocrine atrophy in females and testicular atrophy in males. Some evidence of carcinogenicity (thyroid gland follicular cell tumors) in male rats, but not in females.
-- Carcinogenicity mice NOAEL = Males:<126 mg/kg/day, Females: <162 mg/kg/day LOAEL = Males: 126 mg/kg/day; Females: 162 mg/kg/day based on increased liver weights and liver and brain histopathology in both sexes Equivocal/some evidence of carcinogenicity (hepatocellular tumors) in male mice, but not in females,
-- Special studies: 4-Week dietary (Range-finding) rats NOAEL = Males: 5.1 mg/kg/day; Females: 5.3 mg/kg/day LOAEL = Males: 26.4 mg/kg/day; Females: 25.9 mg/kg/day based on decreased body weight gain and food consumption, increased serum phospholipids, increased total cholesterol, increased relative liver weights, and liver histopathology.
-- 4-Week dietary (Range-finding) mice NOAEL = not identified (Males; <555 mg/kg/day; Females: <658 mg/ kg/day) LOAEL = Males: 555 mg/kg/day; Females: 658 mg/kg/day based on vacuolation of white matter in brain, increased liver weights, histopathology in liver.
-- 90-Day dietary (Special liver study) rats NOAEL = not determined (Males: <37.6 mg/kg/day, Females: <44.7 mg/kg/day) LOAEL = Males: 37.6 mg/kg/day, Females: 44.7 mg/kg/day based on increased relative liver weights and liver histopathology...
Ref: Federal Register. September 7, 2001. Fluazinam; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fluazinam.FR.Sept.7.2001.htm

-- Metabolism and pharmacokinetics rats. Only 33-40% of the administered dose was absorbed. Most of the administered dose was recovered in the feces (>89%). Excretion via the urine was minor (<4%). Total biliary radioactivity, however, represented 25- 34% of the administered dose, indicating considerable enterohepatic circulation [Recycling of certain compounds between the small intestine and the liver].
-- Cancer (oral, dermal, inhalation). `Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential'' 2 . Quantification of human cancer risk not required. 2 Increases in thyroid gland follicular cell tumors in male rats; increases in hepatocellular (liver) tumors in male mice.2 (Ref 2: 2Cancer Assessment Document - Evaluation of the Carcinogenic Potential of Fluazinam, March 29, 2001, HED Doc. No. 014512.)
-- Cancer. Since fluazinam has been classified as ``Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential,'' an exposure assessment was not performed.
Ref: Federal Register: April 18, 2002. Fluazinam; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fluazinam.FR.Apr.18.2002.htm

Flubendiamide - Insecticide - CAS No. 272451-65-7

Results of a reproductive toxicity study in rats (exposure route not stated):
• Increased incidence of eyeball enlargement and dark-colored liver in 2000 and 20000 ppm F1 and F2 pups.
• Thyroid, liver, uterine, thymus, and spleen weight changes in 2000 and 20000 ppm F1 and F2 pups.
Ref: TSCA Health & Safety Study Cover Sheet "Public Display Copy"
http://www.epa.gov/opptintr/tsca8e/doc/8ehq/2004/november04/8ehq-1004-15768a.pdf
•• This document was cited at EPA's site: "TSCA 8(e) and FYI Submissions Received from 11-15-04-11-26-04". It is important to note this as the document itself does not identify flubendiamide or its CAS No.
•• This study was conducted in the laboratory of The Institute of Environmental Toxicology - Japan
•• Source of Data/Study Sponsor: Bayer Material Science Corporation, 100 Bayer Road, Pittsburg PA 15205

Flucarbazone-sodium - Herbicide - CAS No. 181274-17-9

SUBCHRONIC/CHRONIC TOXICITY
-- Study # 870.3150. 90-Day oral toxicity in nonrodents (dogs) NOAEL = 33.8 mg/kg/day in males and 35.2 mg/kg/day in females with the occurrence of slight, adaptive induction of hepatic microsomal enzymes. LOAEL = 162 mg/kg/day in males and 170 mg/kg/day in females based on decreased T4 levels, increased thyroxine-binding capacity, induction of microsomal enzymes, gross pathology and histopathology in the stomach, and histopathology in the liver in both sexes.
-- Study # 870.3800. Reproduction and fertility effects in rats Parental/Systemic NOAEL = 287 mg/kg/day for males and 340 mg/kg/day for females with a slight, increased incidence of moderate cecal enlargement occurring as an adaptive response to treatment. LOAEL = 800 mg/kg/day for males based decreased liver weight and 991 mg/kg/day for females based on decreased uterine weight and increased incidence of severe cecal enlargement. Reproductive/Offspring NOAEL = 287 mg/kg/day for males and 340 mg/kg/day for females LOAEL = 800 mg/kg/day for males and 991 mg/kg/day for females based on reduced pup weights, decreased liver weight in male pups, marbled liver, air filled stomach
-- Study # 870.4100b. Chronic toxicity in dogs NOAEL = 35.9 mg/kg/day in males and 37.1 mg/kg/day in females. LOAEL = 183 mg/kg/day in males and 187 mg/kg/day in females based upon body weight gain depression and increased N-demethylase levels in both sexes, decreased T4 levels and marginally increased liver weight in females.
-- Study # 870.3150. 28-Day oral toxicity in nonrodents (dogs) NOAEL = 164 mg/kg/day in males and 171 mg/kg/day in females. LOAEL = 1,614 mg/kg/day in males and 1,319 mg/kg/day in females based on decreased body weight gain, decreased food consumption, decreased T4 levels and increased thyroxine-binding capacity, induction of microsomal enzymes, increased liver weight and liver histopathology in both sexes.
Ref: US EPA Pesticide Fact Sheet for Flucarbazone-sodium. September 29, 2000. http://www.epa.gov/opprd001/factsheets/flucarbazone.pdf

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

PubMed Abstract: Basalin [Fluchloralin], 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 by Gupta PK, Singh YP, and Parihar NS.
http://www.fluoridealert.org/pesticides/Fluchloralin.PubMebAbstract.htm

Flucythrinate - Acaricide, Insecticide - CAS No. 70124-77-5

Groups of 50 male and 50 female CD-1 mice received technical flucythrinate (80% pure) in the diet at 0, 30, 60, or 120 ppm daily for 18 months. Skin lesions (abrasions, ulceration and scabs) were observed in high-dose males and females. No treatment-related symptoms or treatment-related changes in survival were found. No haematology, clinical chemistry or urinalysis were undertaken. At necropsy, hepatocellular adenomas were found in all control and treated groups. The incidence was variable and statistically- significant only in high-dose males. Hepatocellular adenocarcinoma and hepatocellular carcinoma were found in low incidence in all male groups, but only in control and low-dose female mice. The incidences of these neoplasms were similar to those previously found in mice and were apparently unrelated to treatment.
Ref: 1985 World Health Organization Review for Flucythrinate.
http://www.fluoridealert.org/pesticides/Flucythrinate.1985.WHO.htm

Abstract: Male Sprague-Dawley rats dosed with N-nitrosodiethylamine (NDEA) 24 h after two-thirds partial hepatectomy were treated with the pyrethroid insecticides fenvalerate, flucythrinate or cypermethrin in the diet for 20 weeks. Altered hepatic foci were analyzed by quantitative stereology from paraffin-embedded sections stained for gamma-glutamyltranspeptidase (GGT) or glutathione S-transferase P (GST-P). The present results demonstrate that the pyrethroids tested all enhance the development of NDEA-initiated, GGT-positive foci in rat liver at non-hepatotoxic doses. On the contrary, the volume fractions of GST-P-positive foci were not elevated as compared to the control group. The three pyrethroids tested all inhibited the transfer of Lucifer Yellow CH between WB-F344 rat liver epithelial cells in culture, supporting the increase of GGT-positive foci and suggesting that these substances can act as tumour promoters. The discrepancy between the results from analyses using GGT or GST-P as markers emphasizes the importance of understanding the mechanism underlying the expression of different markers for preneoplastic lesions and the importance of such effects in tumour promotion.
Ref: Carcinogenesis 1993 Dec;14(12):2531-5. Enhancement of altered hepatic foci in rat liver and inhibition of intercellular communication in vitro by the pyrethroid insecticides fenvalerate, flucythrinate and cypermethrin. Hemming H, Flodstrom S, Warngard L.

Fludioxonil - Fungicide - CAS No. 131341-86-1

-- Combined Chronic Toxicity/ Carcinogenicity in rats: NOAEL = 37 mg/kg/day (M) and 44 mg/kg/day (F) LOAEL = 113 mg/kg/day (M) and 141 mg/kg/day (F) based on decreased mean body weight gain, slight anemia (F), and increased incidence and severity of liver lesions (degeneration) in both sexes. There was no evidence of carcinogenicity in male rats, but there was a statistically significant increase, both trend and pairwise, of combined hepatocellular tumors in female rats. Classified as ``Group D'' by OPP Cancer Peer Review Committee. Carcinogenicity mice: increased incidence of mice convulsing when handled (M) and increased absolute liver weight and grossly enlarged livers (F). Statistically significant trend for malignant lymphomas in females...
-- 90-Day oral toxicity in NOAEL = 64 mg/kg/day (M) and 70 mg/kg/day rats (F) LOAEL = 428 mg/kg/day (M) and 462 mg/kg/day (F) based on decreased weight gain (both sexes), chronic nephropathy (M) and centrilobular hepatocyte hypertrophy (F).
-- In vivo Rat hepatocyte Male rats were orally dosed 1250, 2500 and micronucleus assay 5,000 mg/kg and hepatocytes were harvested. Micronucleated hepatocytes were found in Phase II at the low and mid dose levels but not at the high dose level and not in Phase I. Positive for mutagenicity in hepatocytes exposed in vivo.
Ref: Federal Register: December 29, 2000. Fludioxonil; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fludioxonil.FR.Dec.2000.htm

The kidney and liver have been identified as target organs in subchronic and chronic toxicity studies... In a 90-day subchronic dietary toxicity study in rats, the NOEL was 10 ppm based on liver toxicity.
Ref: Federal Register. Februry 5, 1997. [PF-695; FRL-5584-1]
http://www.epa.gov/docs/fedrgstr/EPA-PEST/1997/February/Day-05/p2711.htm

-- 13 Week Oral Feeding Study - rat. Systemic. NOAEL= 64 mg/kg/day. LOAEL = 428 mg/kg/day based on decreased body weight gain in both sexes, chronic nephropathy in males, and centrilobular hepatocyte hypertrophy in females.
-- The EPA classified Fludioxonil as a Group D - not classifiable as to human carcinogenicity. The evidence is inadequate and cannot be interpreted as showing either the presence or absence of a carcinogenic effect. In one mouse study, there was a significant trend for malignant lymphomas in female mice up to 3,000 ppm. However, in a second study up to 7,000 ppm, the limit dose, there was no evidence of carcinogenicity for either sex. In rats, fludioxonil produced a significant trend and pair- wise increase in hepatocellular tumors, combined, in female rats at doses adequate to assess carcinogenicity. The EPA determined that based on the increase in liver tumors in female rats that was statistically significant for combined adenoma/carcinoma only, the lack of tumorogenic response in male rats or in either sex of mice, and the need for additional mutagenicity studies, a Group D classification was appropriate. However, the Agency has since received the additional mutagenicity studies and based on the negative preliminary findings of the studies, the fact that the statistical increase in liver tumors in female rats occurred only at the highest dose, the lack of tumorigenic response in male rats and mice, the Agency has concluded that fludioxonil does not pose a significant cancer risk.
Ref: Federal Register: September 12, 2001. Fludioxonil; Pesticide Tolerances for Emergency Exemptions. Final Rule.
http://www.fluoridealert.org/pesticides/Fludioxonil.FR.Sept.12.2001.htm

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

Chronic feeding studies in dog and rat showed structural or functional alterations in liver, kidney, haematology, spleen, and thyroid. Flufenacet induces neuropathogical changes in the brain and spinal cord (axonal swelling) in rat and dog. The overall evaluation of the observed changes demonstrates that these effects occur only after repeated and prolonged exposure to high dose levels of flufenacet, which saturate metabolic pathways, and exceed the animal capacity to rapidly metabolise and excrete it. The liver was considered the primary target organ, with increases in organ weight, cell size and number, and/or associated changes in liver function tests.
Ref: European Commission, Health & Consumer Protection Directorate-General, Scientific Committee on Plants, October 17, 2001. SCP/FLUFEN/002-Final.
http://europa.eu.int/comm/food/fs/sc/scp/out112_ppp_en.pdf

-- 21-day dermal (rats): Dermal Irritation NOEL = 1000 mg/kg/day (males and females) Systemic NOEL = 20 mg/kg/day (males) Systemic NOEL = 150 mg/kg/day (females) Systemic LOEL = 150 mg/kg/day for males and 1000 mg/kg/day for females based on clinical chemistry data (decreased T4 and FT4 levels in both sexes) and centrilobular hepatocytomegaly in females.
-- Two Generation Reproduction (rat): Parental Systemic NOEL = 20 ppm [1.4 mg/kg/day in males and 1.5 mg/kg/day in females] Parental Systemic LOEL = 100 ppm [7.4 mg/kg/day in males and 8.2 mg/kg/day in females] based on increased liver weight in F1 females and hepatocytomegaly in F1 males. Reproductive NOEL = 20 ppm [1.3 mg/kg/day] Reproductive LOEL = 100 ppm [6.9 mg/kg/day] based on increased pup death in early lactation (including cannibalism) for F1 litters and the same effects in both F1 and F2 pups at the high dose level of 500 ppm [37.2 mg/kg/day in F1 males and 41.5 mg/kg/day in F1 females, respectively].
Ref: US EPA. Pesticide Fact Sheet. Flufenacet Reason for Issuance: Conditional Registration Date Issued: April 1998.
http://www.epa.gov/opprd001/factsheets/flufenacet.pdf

- Reproductive and developmental toxicity--
---- A 2-generation rat reproduction study with a parental systemic no observed adverse effect level (NOAEL) of 20 ppm (1.4 mg/kg/day in males and 1.5 mg/kg/day in females) and a reproductive NOAEL of 20 ppm (1.3 mg/kg/day) and a parental systemic lowest observed adverse effect level (LOAEL) of 100 ppm (7.4 mg/kg/day in males and 8.2 mg/kg/day in females), based on increased liver weight in F1 females and hepatocytomegaly in F1 males, and a reproductive LOAEL of 100 ppm (6.9 mg/kg/ day) based on increased pup death in early lactation (including cannibalism) for F1 litters and the same effects in both F1 and F2 pups at the high dose level of 500 ppm (37.2 mg/kg/day in males and 41.5 mg/kg/day in females), respectively.
---- A rabbit developmental study with a maternal NOAEL of 5 mg/kg/ day and a maternal LOAEL of 25 mg/kg/day based on histopathological finds in the liver and a developmental NOAEL of 25 mg/kg/day and a developmental LOAEL of 125 mg/kg/day based on increased skeletal variations.
Subchronic toxicity:
----- A 13-week mouse feeding study with a NOAEL of 100 ppm (18.2 mg/ kg/day for males and 24.5 mg/kg/day for females), and a LOAEL of 400 ppm (64.2 mg/kg/day for males and 91.3 mg/kg/day for females) based on histopathology of the liver, spleen and thyroid.
---- A 13-week dog dietary study with a NOAEL of 50 ppm (1.70 mg/ kg/day for males and 1.67 mg/kg/day for females), and a LOAEL of 200 ppm (6.90 mg/kg/day for males and 7.20 mg/kg/day for females), based on evidence that the bio-transformation capacity of the liver has been exceeded (as indicated by increase in LDH, liver weight, ALK and hepatomegaly), globulin and spleen pigment in females, decreased T4 and ALT values in both sexes, decreased albumin in males, and decreased serum glucose in females.
- Chronic toxicity
---- A 1-year dog chronic feeding study with a NOAEL was 40 ppm (1.29 mg/kg/day in males and 1.14 mg/kg/day in females), and a LOAEL of 800 ppm (27.75 mg/kg/day in males and 26.82 mg/kg/day in females) based on increased alkaline phosphatase, kidney, and liver weight in both sexes, increased cholesterol in males, decreased T2, T4 and ALT values in both sexes, and increased incidences of microscopic lesions in the brain, eye, kidney, spinal cord, sciatic nerve, and liver.
Ref: Federal Register. March 29, 2000. Notice of Filing a Pesticide Petition to Establish a Tolerance for Certain Pesticide Chemicals in or on Food.
http://www.fluoridealert.org/pesticides/Flufenacet.FR.Mar.29.2000.htm

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

Carcinogenicity data. Adequately conducted carcinogenicity studies in the rat and mouse have been reported. Flufenoxuron was not carcinogenic in the rat. The NOEL for non-neoplastic effects (body weight and relative spleen weight changes) was 25 mg-1.kg-1.d-1. In the mouse there was an increased incidence of haemangiosarcoma in the liver (males) and spleen (females) at 50000 ppm, and an apparent increase in hepatocellular carcinoma in males at all dose levels. The apparent increase in liver tumors was due to an abnormally low control incidence, and therefore flufenoxuron had no significant carcinogenic activity in the mouse. No NEL was established in this study.
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/evallist_alphabet.htm

Abstract: Flufenoxuron (Benzoylphenyl urea derivative) - antimoulting insecticide Ð is recently used for controlling insect reproduction in cultivated areas. The study determined the hazardous effects of the applied dose-treatment during the critical period of rat embryonic development and the induction of growth retardation. In the present work, flufenoxuron was intragastrically administered by stomach intubation to pregnant rats at concentration levels 0 & 20 mg/kg b.wt. in saline solution every other day on gestation day 7 till parturition. Experimental and control pregnant rats were sacrificed on days 13 & 16 of gestation and the foetuses were fixed in 10 percent formol saline. Histological abnormalities of thyroid, liver and kidneys of mothers as well as of skeletal axial and appendicular regions of foetuses were investigated. Foetuses maternally treated with flufenoxuron exhibited delayed differentiation of chondrification and ossification of axial and appendicular regions. The observed defects in foetuses may be attributed to the histological abnormalities of thyroid, liver and kidneys of maternal tissues as well as to the direct effect of the parents as a result of the insecticide or its metabolites on the affected structures during early morphogenesis and differentiation.
Ref: J. Egypt. Ger. Soc. Zool., Vol. 25(B), 65-81, 1998. PATTERNS OF DEVELOPMENTAL DEFECTS OF RAT FOETUSES MATERNALLY TREATED WITH AN ENVIRONMENTAL ANTIMOULTING INSECTICIDE FLUFENOXURON; by Karim, S.A.
http://www.egsz.org/BiologicalCurrentContent/Zoology/Comparative%20Physiology/TOXICOLOGY.htm

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

Carcinogenicity rodents (mouse) - [870.4200]. NOAEL = 39.9 - 43.7 mg/kg/day M/F LOAEL = 401.8 - 447.9 mg/kg/day M/F, based on liver toxicity in both sexes and mild anemia in males. No evidence of carcinogenicity.
Ref: Federal Register: September 19, 2003. Flufenpyr-Ethyl; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/flufenpyr-ethyl.fr.sept2003.htm

-- The kidney and liver appear to be the target organs of flufenpyr-ethyl. EPA has not had the opportunity to review the toxicity studies on flufenpyr-ethyl and has not established toxic endpoints.
-- Reproduction. In the rat reproduction study, flufenpyr-ethyl technical was administered in the diet at levels of 0, 200, 2,000, and 20,000 ppm for 2-generations. Parental toxicity was observed at all dose levels, although the effects at the low dose were minimal. Parental toxicity was exhibited by dose-related microscopic changes in the kidney in high dose F0 animals, in all treated F1 males, and in high dose F1 females. There were also 2 high dose F1 males that died possibly as a result of treatment. Midzonal cytoplasmic vacuolation of the hepatocytes was also observed in the liver of all groups of treated animals in both generations. Based on the results of this study, the NOAEL for parental toxicity was considered to be less than 200 ppm. The NOAEL for reproductive and neonatal toxicity was considered to be 20,000 ppm.
-- 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, decreased spleen weights, an increase in the incidence and severity of basophilic tubules of the kidneys and slight to mild diffusely distributed vacuolation in the liver. Based on these results, the NOAEL was 2,000 ppm (134.2 mg/kg/day) for the males and 20,000 ppm (1,509.6 mg/kg/day) for the females.
-- 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. Thymus weights were slightly increased. Diffusely distributed hepatic vacuolation was seen in the high dose males. Based on these findings, the NOAEL was 10,000 ppm (595.2 mg/kg/ day) in the males and 20,000 ppm (1,377.5 mg/kg/day) in the females.
-- 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, increased liver and thymus weights, and enlarged liver. Centrilobular hepatocellular hypertrophy and vacuolation and increases in the severity and incidence of hepatic focal and single cell necrosis were observed. Based on these findings, the NOAEL was 300 ppm (44.9 mg/kg/day) for males and 1,000 (210.5 mg/kg/day) for females.
-- 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. Liver weights were increased and ovary weights were decreased. Histopathological findings included: Hepatocellular fatty vacuolation. The NOAEL for this study in both sexes was [[Page 37818]] 1,000 ppm (128.4 mg/kg/day for males and 155.7 mg/kg/day for females).
-- 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). Slight to moderate hepatocellular fatty vacuolation and necrosis were observed. There were no increases in incidence of pre-neoplastic or neoplastic lesions. Based on these results, the NOAEL was 350 ppm for both sexes (39.9 mg/ kg/day for males and 43.7 mg/kg/day for females).
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. The results of long-term studies of toxicity that were evaluated by the Committee at its forty-second meeting showed that flumequine had no carcinogenic effects in rats, whereas in CD-1 mice an increase in the incidence of liver tumours was observed at oral doses of flumequine of ≥400mg/kg bw per day (the lowest dose tested) in an 18-month study. The incidence of tumours in male mice was significantly higher than that in female mice. In male mice, the incidence of liver tumours increased in a dose-related and time-dependent manner, and was paralleled by an increase in the incidence of hepatotoxic changes. The present Committee re-evaluated the three short-term studies in mice, which used a two-stage hepatocarcinogenesis protocol, that were presented to the Committee at its sixtieth meeting. In these studies, treatment with flumequine caused the development of basophilic liver foci, which could suggest that flumequine has tumour initiating potential. However, the Committee also noted that concurrent hepatotoxicity (evidenced by pale, vacuolated hepatocytes with fatty droplets, inflammatory cell infiltration, increased mitotic figures and/or necrosis) was observed, as well as a regenerative response to these toxic changes and indications of oxidative stress.
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

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

-- 1999 PubMed Abstract: It has been reported that flumequine (FLU) induces hepatic tumors in mice when given orally for 18 months. We investigated possible underlying mechanisms using a two-stage mouse hepatocarcinogenesis model. After initiation with a single intraperitoneal injection of 100 mg/kg body weight diethylnitrosamine (DEN) or saline, male CD-1 mice were given 4000 ppm FLU in the diet or 500 ppm phenobarbital (PB) in drinking water for 9, 19, 24 or 30 weeks. Toxicity, evidenced by centrilobular swollen and polar hepatocytes with fatty droplets, infiltration of inflammatory cells and increased numbers of mitosis in hepatocytes, was apparent in the livers of mice treated with FLU at all time points, but its severity declined towards the termination. FLU did not induce cytochrome P-450 enzymes such as 1A1, 2B1 and 3A2 as assessed immunohistochemically, while positive expression of 8-hydroxy-2'-deoxyguanosine (8-OHdG) was increased in hepatocytes of both DEN + FLU and FLU groups compared with the relevant controls. In animals given PB, eosinophilic swelling of hepatocytes was prominent, and the hepatocytes showed strongly positive reactions for CYP 1A1 and 3A2. Altered cell foci were induced in the livers of FLU-treated animals both with and without DEN initiation, especially the former, and their development paralleled the degree of hepatic toxicity. These results suggest that FLU hepatocarcinogenicity in mice is dependent on hepatotoxic damage and consequently increased cell proliferation. Oxidative damage to DNA may also be a crucial factor.
Ref: Cancer Lett 1999 Jul 1;141(1-2):99-107. Hepatotoxicity and consequently increased cell proliferation are associated with flumequine hepatocarcinogenesis in mice. Yoshida M et al.

-- Maximum Residue Limits. In calculating MRL values for flumequine, the following factors were considered: á An ADI of 0-30 m g/kg, based on a toxicological end-point, was established by JECFA. This will yield a daily intake of 0-1800 m g/kg for a 60-kg person. á The parent drug was selected as the marker residue. á Muscle and kidney were proposed as target tissues. For practical reasons, however, liver is the proposed target tissue for chickens in place of kidney.
Ref: Flumequine.
http://www.fao.org/docrep/W8338E/w8338e0a.htm#TopOfPage

-- In the 90-day subchronic toxicity carried out on CD-1 mice, flumequine was administered to at level doses of 0, 25, 50, 100, 400 and 800 mg/kg bw/day for males and dosages of 1, 100, 400 and 800 mg/kg bw/day for females. In the two high doses groups, the histopathological examination of the livers revealed, in both males and females, periacinar single cell necrosis and inflammation, periacinar pigment laden macrophages, increased ploidy of hepatocytes, hepatocytic intranuclear inclusions, increased periacinar hepatocytic fatty vacuolation. However, a periacinar hepatocytic hypertrophy was only observed in males : in 7 of 12 animals of the 800 and 400 mg/kg bw dose group, in 5 of 12 animals in the 100 mg/kg bw dose group and in 1 animal in the 50 mg/kg bw dose group and these lesions were dosage-related. In addition, an inhibition of the activity of NADPH-cytochrome P450 for females of the two highest dose grop and of UDP-glucuronosyltranferase for males at 50 mg/kg bw was also reported... 25 mg/kg bw/day was considered as the NOEL for hepatotoxicity in mice.
-- In an 18-month carcinogeniciy study in mice, flumequine was administered in the feed at 0, 400 or 800 mg/kg bw. The combined incidence of benign and malignant liver tumours was dose related : 37 % in the 400 mg/kg bw dose group, 88 % in the high dose group vs. 9 % in the control group for males and 13 % in the high dose females vs. 0 % for the contrl and the low dose groups. Dose related changes in the hepatocytes which paralleled the liver tumour incidence occurred in the low dose males and in the high dose males and females.
-- There is evidence of compound-related tumorigenic efffects in the liver of mice. In order to explain the mechanism of liver tmour induction, the dosage of a preneoplastic markter yGT and of a detoxification enzymes, GSH S-transferase, were performed on liver samples collected in the 90-toxicity study carried out in mice. No variations of yGT were noted whatever the dosage used. However, an increase of the GSH S-transferase activity in females dosed at 400 and 800 mg/kg bw and in males dosed at 800 mg/kg bw showed that flllumequine induced detoxification phenomena, showing cells hepatotoxicity. However, this phenomena was not correlated with the number of tumours incidence. As the tumorigenicity is considered to be a consequence of hepatotoxiciity, it was concluded that the NOEL of 25 mg/kg bw/day covered both end-points.
Ref: Committee for Veterinary Medicinal Products. Flumequine. Summary Report. EMEA/MRL/104/96-FINAL. June 1996. Study performed by EMEA, London UK for the European Agency for the Evaluation of Medicinal Products. Veterinary Medicines Evaluation Unit.
http://www.fluoridealert.org/pesticides/Flumequine.Report.1996.pdf

Flumethrin - Acaricide - CAS No. 69770-45-2

Abstract: The effects of repeated exposure to the pyrethroid insecticide flumethrin (40 mg/kg intraperitoneally once a day for 6 days) on the activity of cytochrome P450-dependent monooxygenases and UDP-glucuronosyltransferase as well as on antipyrine disposition were investigated in male Wistar rats. Pretreatment with flumethrin decreased the activities of NADPH-cytochrome c reductase (38%), aniline hydroxylase (53%), aminopyrine N-demethylase (54%), and UDP-glucuronosyltransferase (34%), and the content of cytochrome P450 (36%) in hepatic microsomes. Total plasma clearance of antipyrine was decreased by flumethrin pretreatment (54%), while the elimination half-life at beta phase and the mean residence time of antipyrine were increased (96 and 88%, respectively). Urinary excretion of norantipyrine, 4-hydroxyantipyrine, and 3-hydroxymethylantipyrine was decreased by 60, 38, and 33%, respectively, in the 96 hr after flumethrin treatment. In addition, the rate constants for formation of each of these metabolites were decreased by an average of approximately 74%. These findings provide evidence that flumethrin exposure diminishes hepatic enzyme levels and catalytic activities of monooxygenase systems as well as oxidative metabolism of antipyrine.
Ref: Effects of flumethrin on hepatic drug-metabolizing enzymes and antipyrine disposition in rats; by A Anadon et al. Toxicol Appl Pharmacol 1995 May;132(1):14-8.

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.fluoridealert.org/pesticides/Flumiclorac-pentyl.MSDS.htm

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

Subchronic, Chronic, and Other Toxicity
-- 870.3100 90-Day oral toxicity -mouse NOAEL = mg/kg/day: 429 (M & F) LOAEL = mg/kg/day: 1429 (M & F) based on increased liver weight in males
-- 870. 3100 4-Week oral toxicity -mouse NOAEL = mg/kg/day: 151.5 (M), 164.5 (F) LOAEL = mg/kg/day: 419.9 (M), 481.6 (F) based on increased absolute &/or relative liver weights in M & F
-- 870.4100 12-Month capsule -dog NOAEL = 100 mg/kg/day (M & F) LOAEL = 1000 mg/kg/day (M &F), (LIMIT DOSE) based on the following for males and females: increased absolute and relative liver weights; 300% increase in alkaline phosphatase values
Ref: US EPA Pesticide Fact Sheet. April 12, 2001.
http://www.epa.gov/opprd001/factsheets/flumioxazin.pdf

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

The spleen, kidney, and liver appear to be the organs consistently affected following exposure to moderate doses of fluometuron in rats and dogs in subchronic, chronic, developmental, and reproductive studies. (page 8)
Ref. February 1, 2005. US EPA: Fluometuron: Revised HED Risk Assessment for Phase III of the Reregistration Eligibility Decision. Docket Identification Number: OPP-2004-0372-0008. 
http://www.fluorideaction.org/pesticides/fluometuron.opp-2004-0372-0008.pdf

Groups of 50 /B6C3F1/ mice of each sex were fed diets containing 500 or 1,000 ppm of fluometuron for 103 weeks. Matched controls consisted of groups of 25 untreated mice of each sex. All surviving animals were killed at 103 to 105 weeks. Mean body weights of the dosed groups of male and female mice were essentially the same as those of the corresponding control groups. Survival of dosed groups of mice were similar to that of the corresponding control groups. Similarities between mean body weights and survival between dosed and control animals in the chronic study suggest that these animals could have tolerated higher doses. The only possible carcinogenic effects from compound administration were in male mice. Incidences of hepatocellular carcinomas or adenomas in male mice were dose related, and the incidence in the high-dose group was marginally higher than that in the corresponding matched controls or pooled controls from concurrent studies. Under the conditions of this bioassay, fluometuron was not carcinogenic for F344 rats or for female B6C3F1 mice. Equivocal results were obtained for male B6C3F1 mice which may have had an increased incidence of hepatocellular tumors. Because of the equivocal findings and because both rats and mice may have been able to tolerate higher doses, it is concluded that additional testing of fluometuron for carcinogenicity is warranted. (Summary page v)
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