Liver - Adverse Effects
Fluorinated and Fluoride Pesticides

beginning with
A-E • F-G H-P Q-Z
 
 
See some background information and definitions on liver

The use of high doses increases the likelihood that potentially significant toxic effects will be identified. Findings of adverse effects in any one species do not necessarily indicate such effects might be generated in humans. From a conservative risk assessment perspective however, adverse findings in animal species are assumed to represent potential effects in humans, unless convincing evidence of species specificity is available.

-- Food and Agricultural Organization of the United Nations

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

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 d
ogs, 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,
-- Sp
ecial 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 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: 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. The parent drug was selected as the marker residue. 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

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 female B6C3F1 mice. Equivocal results were obtained for male B6C3F1 mice which may have had an increased incidence of hepatocellular tumors. [DHEW/NCI; Bioassay of Fluometuron for Possible Carcinogenicity p.V (1980) Technical Rpt Series No. 195 DHEW Pub No. (NIH) 80-1751]
Ref: TOXNET profile from Hazardous Substances Data Base for FLUOMETURON.

http://www.fluoridealert.org/pesticides/FLUOMETURON.TOXNET.HSDB.htm

PubMed abstract: The experiments on the investigation of pesticide fluometuron (cotoran) influence on nuclease sensitivity and template activity of rat liver chromatin were carried out. Cotoran was found to bind specifically with non-histone proteins of chromatin. It was shown that this pesticide considerably decreases template activity of chromatin and its sensitivity to the action of nucleases. It suggests, that certain conformation changes occur in chromatin upon the action of cotoran.
Ref: Biull Eksp Biol Med 1992 Mar;113(3):261-3. [Effects of pesticide fluometuron (cotoran) on template synthesis of RNA] [Article in Russian] Khamidov DKh, Mirakhmedov AK, Sagatova GA, Azimova ShS. PMID: 1384777 [PubMed - indexed for MEDLINE]

-- 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).
-- CHRONIC TOXICITY. Rats were fed 7.5, 75, or 750 mg/kg/day for 90 days. At the 750 mg/kg dose, decreased body weight and congestion in the spleen, adrenals,
liver, and kidneys were evident. The NOAEL for this study was 7.5 mg/kg/day (100 ppm). When doses of 1.5, 15 or 150 mg/kg/day were fed to puppies for 90 days, congestion of the liver, kidneys and spleen occurred at the 150 mg/kg dose. No effects were seen at 15 mg/kg/day (400 ppm) (20).
Ref: Fluometuron. 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.

-- PubMed abstract: The experiments on the investigation of pesticide cotoran-effect on RNA synthesis and transport were carried out. Cotoran was shown to destroy considerably the processes of RNA biosynthesis in rat liver, that results in the decrease of RNA transport from nuclei into cytoplasm. By special experiments it was established that functional activity and the integrity of nuclear membrane (according to the alteration in the activity of nuclear membrane enzyme Mg2-dependent ATP-ase) was not destroyed.
Ref: Biull Eksp Biol Med 1992 Jan;113(1):40-2.
[RNA synthesis and transport in the rat liver under the effects of pesticide cotoran (fluometuron)]. [Article in Russian]; by Khamidov DKh, Marakhmedov AK, Sagatova GA, Azimova ShS.

Fluopicolide - Fungicide - CAS No. 239110-15-7

Chronic toxicity (page 4)
ii. Chronic toxicity/carcinogenicity was assessed in rats at dietary levels of 50, 200, 750 and 2500 ppm. The NOAEL was 200 ppm (8.4 mg/kg/day in males and 10.8 mg/kg/day in females) based on microscopic changes in the liver and kidneys similar to those observed in the 90-day rat study. No evidence of carcinogenicity was observed in rats up to 2500 ppm.
iii. The oncogenic potential of fluopicolide was investigated in C57BL/6 mice at dietary levels of 0, 50, 400, or 3200 ppm. Significantly lower body weight gain was seen at 3200 ppm in conjunction with a slight decrease in food consumption. Increased liver weight and centrilobular hepatocellular hypertrophy were observed at 400 and 3200 ppm in both sexes. In addition at 3200 ppm, an increased incidence of hepatocellular adenomas was noted in both sexes, but the incidence of hepatocellular carcinomas was not affected. The NOAEL was 50 ppm (equivalent to 7.9 and 11.5 mg/kg/day in males and females, respectively). Subsequent mechanistic work demonstrated a marked transient hepatocellular profileration, whch returned to control levels after 28 days of treatment. This was accompanied by a clear induction of total cytochrome P-450 and related enzymes. These results parallel findings with Phenobarbital, which has a well understood threshold-based mechanism of roden tumor formation commonly known to be of no relevance to humans.

Subchronic toxicity (pages 3-4)

Ninety-day feeding studies were conducted in dogs, mice and rats.
ii. In 90-day feeding studies in both CD-1 and C57BL/6 mice, liver was the only target organ identified with hepatocellular hypertrophy seen at dietary levels of 320 ppm and higher. The NOAEL in C57BL/6 mice was 200 ppm (equivalent to 37.8 and 52.8 mg/kg/day in males and females, respectively.)
iii. In a 90-day rat study with dietary levels of 100, 1400 and 20,000 ppm, the maximum tolerated dose (MTD) was exceeded at 20,000 ppm based on body weight gain of 30 to 40% below control. The target organs identified in rats were the liver (centrilobular hypertrophy) in both sexes and the kidneys in males (accumulation of hyaline droplets, single cell death at the proximal tubule epithelium, slight foci of basophilic tubules and granular casts) at 1400 ppm and 20,000 ppm. The NOAEL was 100 ppm, equivalent to 7.4 and 8.4 mg/kg/day, in males and females, respectively.

Reference: January 1, 2005, submission to US EPA from Valent U.S.A. Company. Federal Register Docket EPA-HQ-OPP-2006-0481-0002.
http://www.fluorideaction.org/pesticides/fluocopicolide.valent.june.2005.pdf

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

-- The pertinent study proposed for consumer risk assessment was the rat chronic study. However, 2 mouse chronic/oncongenicity studies were performed. The first showed liver neoplasia at <> 50 ppm, whilst histopatholical and organ weight effects were seen at all doses (10-250 ppm). Hence a NOEL could not be determined. The second sudy failed to find effects at up to 10 ppm. The mouse NOEL was therefore cncluded to be 10 ppm based on the second study, which allowed for the NOEL for neoplasia as seen in the first study. It should be noted that the second study employed technical material with lower levels of impurities. The technical fluoroglycofen-ethyl used in the initial mouse study was used in the rat chronic study without any treatment-related carcinogenicity. Peroxisome proliferation has been implicated by the applicant as the cause of hepatic neoplasia in mice. Subchronic studies in mice have shown peroxisome proliferation, along with biochemical and morphological changes in liver attributable to peroxisome proliferation, at similar doses to those which have caused hepatic neoplasia in the chronic study. It is important to note that this assessment is based only on fluoroglycofen-ethyl and its mammalian metabolites in which the diphenyl ether bond remains intact.
-- The pertinent no effect level from subacute/subchronic studies was 9 mg/kg bw/day (80 ppm) taken from the 14 day rat study, based primarily on enlarged livers and altered liver enzyme function at 800 ppm. This figure is above the no observed effect levels for the 3 month dietary mouse study and the 14 days perosxome prolifertion study. However, these figures were based on slight increases in hepatocellular hypertrophy at the next dose, which in the 3 month mouse study were shown to be reversible, especially at the lower dose. Hence the no adverse effect level for mice was concluded to be 9.6 mg/kg bw/day. The rat 8 mg/kg bw/day NEL is also lower than the dog 52 week study NEL (9.9-9.9 mg/kg bw/day) which was based on increased liver and kidney weights at higher doses.
-- The chronic toxicity and oncongenicity of fluoroglycofen-ethyl was investigated in mice (2 studies) and rats. In both species, the systemic toxicity was much the same as had been seen in the sub-acute studies, the main effects being on the liver and kidneys. In the first mouse study, carcinogenicity, as seen by primary liver neoplasms, was increased at 50 and 250 pm but not at 10 ppm...
-- A satellite group which was treated for 14 weeks and then given a 13 week recovery period showed that the compound related effects were at least partially reversible. The NOEL for chronic oral exposure to fluoroglycofen-ethyl was 0.95 mg/kg bw/da (20 ppm) based on the hepatic and renal effects at 100 ppm.
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/evallist_alphabet.htm

Fluoxastrobin - Fungicide - CAS No. 193740-76-0

2.3 SHORT TERM TOXICITY. The short-term toxicity of fluoxastrobin has been investigated in dietary studies in rats (28-day and 90-day studies), mice (2-week and 90-day studies) and dogs (90-day and 1-year studies). A 28-day dermal toxicity study in rats has also been conducted. The liver is the main target organ in all tested species (rats, mice and dogs). Histological changes were seen in the urinary system of rats (high doses) and dogs. Male rats were more sensitive than females to the effects of fluoxastrobin/HEC 5725 on the liver and urinary tract. Other target organs were adrenals, erythrocytes and thyroid. Reduced body weight gain was a key finding in dog studies. (page 12).
Ref: Conclusion regarding the peer review of the pesticide risk assessment of the active substance fluoxastrobin finalised: August 10, 2005. European Food Safety Authority.
http://www.fluorideaction.org/pesticides/fluoxastrobin.eu.review.2005.pdf

-- Subchronic toxicity. A subchronic toxicity feeding study with rats over 90 days demonstrated a NOAEL of 7.3 and 18.3 mg/kg bwt/day for males and females, respectively, based on reduced body weights and alterations in several urinary tract-related clinical chemistry parameters, at the higher dose levels. In a subchronic feeding study in mice over 14 weeks, a NOAEL was not established based on decreased alanine aminotransferase (ALAT) and increased absolute and relative liver weights at the low dose level (21.7 and 35.3 mg/kg bwt/day for males and females respectively). A 14-week feeding study in dogs demonstrated a NOAEL of 3.0 mg/kg bwt/day based on decreased body weights and food consumption, and liver effects (enzyme induction, increased liver weights, cytoplasmic change), and thyroid effects (decreased T3)
-- Chronic toxicity. A 24-month chronic/oncogenicity feeding study in rats demonstrated a NOAEL of 53.0 and 35.2 mg/kg bwt/day for males and females, respectively. An oncogenicity study in the mouse revealed a NOAEL of 18.5 and 29.5 mg/kg bwt/day for males and females, respectively based on liver effects. There was no indication in the rat or mouse for an oncogenic effect of fluoxastrobin. A 1-year feeding study with dogs demonstrated a NOAEL of 1.7 and 1.5 mg/kg bwt/day for males and females, respectively based on decreased body weights and slight liver effects (increased alkaline phosphatase (Aph) and liver weights).
Ref: Federal Register: April 23, 2003. Fluoxastrobin; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Fluoxastrobin.FR.Apr23.2003.htm

• Chronic toxicity-dogs. LOAEL was 8.1 mg/kg/day for males and 7.7 mg/kg/day for females based on body weight reductions and hepatocytomegaly [see definition below] and cytoplasmic changes associated with increased serum liver alkaline phosphatase indicative of cholestasis.
• 90-Day oral toxicity-dogs.
dose-related reductions in net body weight gain and food efficiency in addition to toxicity findings in the liver in both sexes (cholestasis) and in kidneys (increased relative weights in females and degeneration of the proximal tubular epithelium in males).
• 90-Day oral toxicity-mice. There was a dose related increase in liver weight in both sexes and in kidney weight in females, in addition to other effects whose toxicological relevance was considered uncertain. Among these effects were increased hepatocellular hypertrophy [see definition below] with cytoplasmic changes in the high-dose males and minimal to moderate kidney tubular hypertrophy in mid- and high-dose females.
90-Day Subchronic Oral Toxicology-Dog. dose-related reductions in net body weight gain and food efficiency; toxicity findings in the liver (cholestasis) in both sexes; and toxicity findings in the kidneys (increased relative weights in females and degeneration of the proximal tubular epithelium in males).
Ref: Federal Register. September 16, 2005. Fluoxastrobin; Pesticide Tolerances. Final Rule.

http://www.fluorideaction.org/pesticides/fluoxastrobin.fr.sept16.05.html

Definitions:
Hepatocytomegaly is an enlargement of the hepatocytes and is generally classified into three types: hepatocellular hypertrophy, megalocytosis, and hepatocellular vacuolation. Hepatocellular hypertrophy is an enlargement of cellular diameter without accompanying nuclear changes, leading to a net gain in the dry mass of the liver. A common cause of hepatocellular hypertrophy is proliferation of endoplasmic reticulum, indicating induction of cytochrome P450, that is, exposure to cytochrome P450-inducing compounds. Megalocytosis is characterized by enlargement of both the cell and the nucleus, and hepatocellular vacuolation is characterized by vacuolation, or formation of pockets of fluid within the hepatocytes. Little is known about the mechanism of the latter two types of hepatocytomegaly, but all three types are associated with exposure to genotoxic contaminants.
Ref: Environmental Effects of Dredging Technical Notes. Methods for the Assessment of the Genotoxic Effects of Environmental Contaminants; Cellular and Organ/Organism Effects. US Army Engineer Waterways Experiment Station. EEDP-04-25. July 1995.
http://www.fluorideaction.org/pesticides/genotoxic.army.1995.report.pdf

Flupyrsulfuron-methyl - Herbicide - CAS No. 144740-54-5

-- Long term toxicity and carcinogenicity. Target / critical effect: Indications of liver toxicity. 18-month oral mouse : 25 ppm ( 3.51 mg/kg bw/day). Carcinogenicity: (Liver tumours in mice).
Ref: FINAL European Commission Review report for the active substance flupyrsulfuron-methyl. Finalised in the Standing Committee on Plant Health at its meeting on 27 April 2001 in view of the inclusion of flupyrsulfuron-methyl in Annex I of Directive 91/414/EEC.

http://europa.eu.int/comm/food/fs/ph_ps/pro/eva/newactive/list2_flupyrsulfi_en.pdf

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... Mortalities over the 24-month period were 24/50, 28/50, 28/50 and 31/50 in males and in females 33/50, 36/50 and 39/50 at dose levels of 0, 1, 20 and 100 ppm... Post-mortem examinations showed the most probable cause of deaths in males to be pituitary tumors followed by chronic progressive nephropathy and urinary tract infections. In females mammmary tumors followed by pituitary tumors were considered the most probable cause of morbidity... At the interim-kill, organ weights showed moderate significant treatment-related increase in the absolute liver and kidney weights in males and females at the 100 ppm dose level compared with controls. The relative liver and kidney weights were significantly increased in males at the 100 ppm dose level and in females at 10 ppm. A significant increase in the incidence of hyaline droplet deposition in the proximal tubular epithelium occurred in the kidneys of males (15/20 compared with 6/20 controls) at the 100 ppm dose level. Minimal to moderate hypertrophy of centrilobular hepatocytes was observed in the liver of all top dose animals and at the 10 ppm dose level (10/20 males and 3/20 females). In the thyroid, an increase int he follicular epithelial height in both sexes was noted at the 100 ppm dose level. At the terminal-kill, the absoloute and relative liver and kidney weights of males and females were slightly to moderately increased at 100 ppm dose level. Necropsy revealed slightly increased incidence of liver masses in top dose females (0/50, 0/50 and 6/50 at dose levels of 0. 1, 10 and 100 ppm respectively). Microscopic findings at 24 months were slight increases in the incidence and severity of chronic progressive nephropathy in males and females at the 100 ppm dose level. Slight to severe centrilobular cellular hypertrophy, bile duct hyperplasia (51/100 compared with 21/100 for controls in both sexes) and significant increase in the incidence of malignant liver tumors (8/50 compared with 0/50 in males) in females occurred at the top dose level...
-- For liver tumours, no clearcut identifiable preneoplastic lesions were identified (No data requirement for this to be demonstrated has previously been requested). Liver tumors in both sexes at 100 ppm were associated with increased liver weight, increased incidence and severity of hepatocyte hypertrophy (both of which were observed in shorter term studies and responded to changes in dose), and bile duct hyperplasia and a slight increase in eosinophilic foci in females seen in the chronic study of the rat at 24 months only. Clear NOELs for liver tumors and the induction of associated liver effects were determined in rats and mice.

-- Short Term Toxicity. Oral route. Rat. (b)... Groups of 5 male and 5 female outbred 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...Organ weights showed a dose-related increase in the relative liver weight at dose levels of 20 ppm in males (15-44%) and at 100 ppm and 10 mg/kg bw/day dose levels (25-27%). The relative kidney weight was increased in males only (11-21%) compared with controls at dose levels of 20 ppm. Gross examination at necropsy revealed accentuation of the lobular pattern of the liver at dose levels of 5 ppm in females and at 20 ppm in males. Pale kidneys were observed in males at dose levels of 5 ppm... Histopathology showed significant treatment-related centrilobular hepatocyte hypertrophy in males and females at dose levels of 100 ppm. In the kidney, slight to moderate hyaline droplet mephropathy was observed in males at 20 ppm. In the thyroid, the incidence and severity of thyroid effects including colloid depletion, follicular cell hyperplasia and hypertrophy did not show a clear treatment-relationship (statistically significant compared with controls at 100 and 200 ppm but not at 400 ppm and 10 mg/kg bw/day dose levels). The NOEl was 5 ppm (0.45 mg/kg bw/day) based on increased liver and kidney weights and histopathological changes in the liver, kidney and thyroid at the higher dose level of 20 ppm... The liver, thyroid and kidneys were noted to be the target organs of the test compound and significant changes in these organs indicative of significant hepatic enzyme induction were considered to be relevant for risk assessment.
-- Haematology, clinical chemistry and urinalysis parameters showed incidences of statistically significant changes which were considred to be of limited toxicological significance because they were eithe not dose-related or were reported to be withing the range of historical data. There was an increase in the absolute liver (35%) and adrenal (36.4%) weights in females at the 100 ppm dose level. The relative kidney (14%) and liver (21%) weights in males and the relative kidney (6.9%) and adrenal (30%) weights in females were significantly increased at the 100 ppm dose level. In females, the relative liver weight was increased at dose levels of 15 ppm (14%) and 100 ppm (32%). At the end of the withdrawal period, the relative kidney weight in males and the relative liver weight in females were still siginficantly elevated compared with controls. Gross examination of organs revealed accentuated lobular pattern of the liver in males and females at the 15 ppm (on male only) and 100 ppm (3 males and 6 females) dose levels but a significant reduction in the incidence of lobulation of the liver (1 male only) was observed at the end of the withdrawal period.
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

Fluridone - Herbicide - CAS No. 59756-60-4

CHRONIC EXPOSURE (Fluridone Technical). The following effects were reported in chronic, teratogenic, and reproductive toxicity studies in laboratory animals where experimental dosage levels and durations of exposure were far in excess of those likely to occur in humans.
-- Chronic Toxicity - Decreased survival in lifetime feeding study. Increased liver enzyme activity, liver weight, liver cell size, and microscopic liver cell changes. Increased kidney weights, and microscopic kidney cell changes. Increased serum enzyme levels...
Ref: Material Safety Data Sheet for Sonar SRP Herbicide. SePro Corporation.

http://www.fluoridealert.org/pesticides/Fluridone.MSDS.Sepro.1994.PDF

REPRODUCTION, RAT ** 018, 042; 44095, 138394; "One-Generation Reproduction Bridging Study of Fluridone (EL-171, compound 112371) Administered in the Diet to Fischer 344 Rats (Studies R04090 and R21890)" submitted to support "A Multigeneration Reproduction Study with EL-171 in Rat (Studies R-338, R-888 and R-19)" (J. A. Hoyt, Toxicology Research Lab., Lilly Research Laboratories, Greenfield, IN, Study #s R04090 and R21890, 5/24/95); Dietary concentrations of fluridone (Lot# 117AS8, 99.5% purity): 0, 0.02, 0.065 or 0.2% administered daily to 30 rats/sex/dose in the F7 generation for 10 weeks during premating, mating, gestation and lactation and in the F7 generation throughout a 10 week postweaning growth period; two deaths in the F7 generation (one male from the 0.065% group and one female from the 0.2% group) attributing to failure to adjust to ventilated caging were reported; no treatment-related effects on reproduction parameters; however, the live birth index was slightly depressed (92.74% of control, p < 0.05) in the 0.2% group as compared to control group; at 0.2%, 8/23 litters contained one or more offspring which were considered stillborn; in the F7 and F7 generations, males and females treated at the 0.2% level exhibited increased absolute kidney weight; minimal to slight bilateral chronic multifocal nephrosis detected in F7 males of the 0.065% and 0.2% dose groups and in F7 males and females of the 0.2% dose group; although dose related increases in absolute liver weight occurred in F7 and F7 generations in both sexes in the 0.065% and 0.2% dose groups, the liver weight increases were not accompanied by histopathological changes; no adverse effects; parental NOEL = 0.02% (based on bilateral chronic multifocal nephrosis and increased liver weight), developmental NOEL = 0.065% (depressed liver birth index); originally unacceptable and not upgradeable (Van Way and Parker, 7/18/86) and subsequently upgraded to acceptable (Leung, 8/3/95).
Ref: Summary of Toxicology Data. Fluridone. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch, Revised: 2/9/00.

http://www.fluoridealert.org/pesticides/Fluridone.CA.EPA.Tox.Data.pdf

Flurprimidol - Plant Growth Regulator - CAS No. 56425-91-3

Summary Science Statement:
-- Chronic feeding/oncogenicity studies were conducted in both the rat and mouse. Hepatocellular changes in the males including enzyme induction, fatty change, hepatocellular eosinophilic change and focal atypia were observed in the rat study. A core- supplementary mouse study showed increased absolute and relative liver weight in females. Although both the rat and mouse study are core-supplementary for oncogenicity due to inadequate dose selection, they both satisfy the requirement for oncogenicity testing in one species for the requested non-food uses. No oncogenic potential was observed at any dose level in either of these two studies. New rat and mouse studies (which achieve the Maximum Tolerated Dose - MTD) will be required for any food use registrations.
-- The requirements for a 90-day feeding study have been satisfied. A subchronic oral rat study showed an increased hepatic enzyme induction in males (significant and dose increases in p-nitroanisol o-demethylase activity). The subchronic oral mouse study indicated an increased incidence of hepatocellular hypertrophy in the males.

-- The requirements for a 2 generation reproductive study have been satisfied. The Parental Systemic Toxicity in a 2 generation reproduction study showed increased incidence of non-neoplastic hepatocellular alteration including fatty change and vacuolation (males) and increased susceptibility to stress factors. Decreased mating, fertility, fetal survival (stillbirths), neonatal survival and neonatal body weight in both sexes and in both generations were observed at the Reproductive NOEL. other parental signs of toxicity included increased susceptibility to stress (pregnant females) resulting in death, increased relative liver weight (males and females), depressed body weight, weight gain and food consumption (males and females).
-- Subchronic Studies. A 90-day feeding study in rats treated to 0, 1.68, 6.04, 20.39, 68.34 mg/kg/day (males) and 0, 1.98, 7.13, 24.37, 78.47 mg/kg/day (females) of flurprimidol. The systemic No-Observable- Effect-Level (NOEL) was 1.68 mg/kg/day and the Lowest-Effect- Level (LEL) was 6.04 mg/kg/day based on increased hepatic enzyme induction in males (significant and dose increases in p- nitroanisol O-demthylase activity). At 24.37 mg/kg/day there was increased relative and absolute ovarian (female) and relative liver (male) weight. At 68.34 mg/kg/day, there was increased absolute liver weight (males).
-- A 90-day feeding study in the mouse, treated with 0, 15, 67.5 and 300 mg/kg/day of technical flurprimidol. The NOEL was 15 mg/kg/day and the LEL was 67.5 mg/kg/day based on increased incidence of hepatocellular hypertrophy in the males. At 300 mg/kg/day, there was evidence of enzyme induction, increased liver weight and hepatocellular hypertrophy in females.
-- Chronic Studies - Rodent Feeding Studies. A 2-year study in rats treated with either 0, 1.0, 3.6, 12.1 and 41.2 mg/kg/day of flurprimidol technical for males and 0, 1.2, 4.4, 14.5, and 49.3 mg/kg/day for females the NOEL was 3.6 mg/kg/day and the LEL was 12.1 mg/kg/day based upon hepatocellular changes in males including enzyme induction, fatty change, hepatocellular eosinophilic change and focal atypia. At 41.2 mg/kg/day there was also a transient body weight and weight gain decrease (males), increased cholesterol and triglycerides (males and females) increased hepatic enzyme induction and liver weight, fatty change and hepatocellular eosinophilic change (females). No oncogenic potential was observed at any dose level.
-- A 2-year core-supplementary study in mice treated with either 0, 1.4, 10.5 or 79.9 mg/kg/day of flurprimidol, the systemic NOEl was 1.4 mg/kg/day. The LEL was 10.5 mg/kg/day based on increased absolute and relative liver weight in the males. No oncogenic potential was observed at any dose level.
-- Reproduction Study, A 2 generation reproduction study in the rat treated with (time weighted average) 0, 1.8, 7.3, and 74 mg/kg/day of flurprimidol had a Parental Systemic Toxicity NOEL of 1.8 mg/kg/day and a LEL of 7.3 mg/kg/day based on increased incidence of non-neoplastic hepatocellular alterations including fatty change and vacuolation (males) and increased susceptibility to stress factors. The Reproductive NOEL was 7.3 mg/kg/ and the LEL was 74 mg/kg/day based on decreased mating, fertility, fetal survival (stillbirths), neonatal survival and neonatal body weight in both sexes and in both generations. There was an increased incidence of persistent vaginal estrous and no corpora lutea. Additional parental signs of toxicity at 74 mg/kg/day included increased susceptibility to stress (pregnant females) resulting in death, increased relative liver weight (males and females), depressed body weight, weight gain and food consumption (males and females).
Ref: EPA Pesticide Fact Sheet for Flurprimidol. Reason for Issuance: New Chemical Registration. Date Issued: FEB 22 1989. Fact Sheet Number: 202.

http://www.fluoridealert.org/pesticides/Flurprimidol.EPA.Facts.1989.htm

Flurtamone - Herbicide - CAS No. 96525-23-4

Flurtamone: Table 5.31 Incidence of centrilobular hypertrophy of the liver
Ref: December 2000 . Evaluation on: Flurtamone. No. 196. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK. http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm 
Dose FO adults F1 adults
ppm Male Female Male Female
0 2/30 0/30 6/30 0/30
75 6/30 1/30 10/30 0/30
500 18/30 5/30 26/30 0/30
2000 28/30 17/30 29/30 22/30
5000 28/30 27/30 28/30 27/30

-- Short term toxicity. Target / critical effect: Liver: Hepatomegaly, centrilobular hypertrophy. Lowest relevant oral NOAEL / NOEL: 5 mg/kg bw (1 year dog study). Lowest relevant dermal NOAEL / NOEL: 1000 mg/kg bw (21 day study in rat)
-- Long term toxicity and carcinogenicity. Target / critical effect: Liver: hypertrophy, centrilobular hypertrophy. Kidney: increased amyloidosis in mice. Lowest relevant NOAEL: 2.8 mg/kg bw (2 year rat study) Carcinogenicity: No carcinogenic potential

Ref: July3, 2003. Flurtamone. Sanco/10162/2003-Final. Review report for the active substance flurtamone. Finalised in the [EU] Standing Committee on the Food Chain and Animal Health at its meeting on 4 July 2003 in view of the inclusion of flurtamone in Annex I of Directive 91/414/EEC.
http://www.fluorideaction.org/pesticides/flurtamone.eu.july.2003.pdf

-- Two-year dietary study in mice. In a carcinogenicity study, groups CD-1 mice (60/sex/dose) were fed diets containing 0, 30, 300, 3500 and 7000 ppm flurtamone (91.9% purity) for at least 78 weeks... The mean intake of flurtamone for males and females was estimated to be 4.5, 45, 525 and 1050 mg/kg bwday at 30, 300, 3500 and 7000 ppm, respectively. After 78 weeks of treatment, the mortality rate for the 7000 ppm female mice was significantly higher than controls and a significant negative survival trend was found in both sexes. The test laboratory pathologist considered systemic amyloidosis to be the major cause of death (Table 5.34) [page 102]. Gross necropsy revealed an increased incidence of enlarged livers and liver masses at dose levels 3500 and of irregular shaped kidneys at 7000 ppm. Significant increases in mean liver weight (absolute and relative) were observed in 3500 and 7000 ppm animals (not statistically significant in 3500 ppm males) at both the interim and terminal sacrifices (Table 5.26). Significant decreases in mean absolute kidney weights were observed in males at 7000 ppm at the interim and terminal sacrifices [page 103]. Microscopic examinations revealed an increased incidence of systemic amyloidosis (most severe in the kidneys) in the 3500 and 7000 ppm animals and the 300 ppm females that died or were sacrificed in extremis. The incidence and severity of renal amyloidosis is given in Table 5.27. An increase in the incidence of centrilobular hypertrophy was observed in both sexes at dose levels 3500 ppm. The incidence of hepatic pigment (primarily in the reticuloendothelial cells) was increased in males at dose levels 3500 ppm and in females at 7000 ppm... [page 105]. Significant increases in mean relative liver weight were observed in males and females in both generations at dose-levels 2000 ppm. Mean absolute liver weights were significantly increased in F0 males, F0 females and F1 mates at 5000 ppm, and in F0 males and F1 females at 2000 ppm... The only microscopic finding which could be attributed to compound administration was centrilobular hypertrophy of the liver. Dose-related increases in the incidence of centrilobular hypertrophy were observed in F0 and F1 animals at dose levels 500 ppm (Table 5.31). This centrilobular hypertrophy was considered to be an adaptive biological response [page 108]
Ref: December 2000 . Evaluation on: Flurtamone. No. 196. Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK. Available online at:
http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm

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

-- Oral RfD Summary: Critical Effect Experimental Doses. Liver cell enlargement. 1-Year Dog Feeding Study. du Pont, 1985. NOEL: 5 ppm (0.2 mg/kg/day) LEL: 20 ppm (0.7 mg/kg/day).
-- Nustar was administered in the diet at 0, 5, 20, or 75 ppm (0, 0.2, 0.7, or 2.5 mg/kg bw/day) to 5 dogs/sex/dose for 1 year. Hypertrophy of the centrilobular hepatocytes was noted in both sexes at the mid- and high-dose levels. Changes observed only at the high dose were consistent with hepatotoxicity and inflammation. In males these included: increased WBC counts due to increased neutrophils, monocytes and eosinophils; increased alkaline phosphatase and decreased cholesterol and total protein; and hepatocytic vacuolation. Increased liver weight and centrilobular inflammation of the liver occurred in both males and females. Thus, the NOEL and LEL for systemic toxicity are 5 ppm (0.2 mg/kg/day) and 20 ppm (0.7 mg/kg/day), respectively. [E.I. du Pont de Nemours and Company. 1985. MRID No. 40042113. Available from EPA. Write to FOI, EPA, Washington, DC 20460.]
-- 2-Year Feeding (oncogenic) - rat: No increase in neoplastic lesions at any dose; Systemic NOEL=0.46 mg/kg/day; Systemic LEL=2.3 mg/kg/day (hepatic changes in females at 1 year, including increased relative liver weight and hepatocellular hypertrophy); core grade minimum (E.I. du Pont de Nemours & Co., Inc., 1986a)
-- Teratology - rat: Maternal NOEL=10 mg/kg/day; Maternal LEL=100 mg/kg/day (increased mortality after day 23 of gestation, prolonged gestation, decreased food consumption and weight gain, increased relative and absolute liver weight); Developmental NOEL (pre and post natal)=2 mg/kg/day; Developmental LEL=10 mg/kg/day (increased incidence of small renal papilla, distended ureter, dilated renal pelvis, decreased pup survival); core grade minimum (E.I. du Pont de Nemours & Co., Inc., 1985b)
-- 2-Year Feeding (oncogenic) - mouse: Systemic NOEL=3.4 mg/kg/day; Systemic LEL=27 mg/kg/day (increased absolute and relative liver weight and increased hepatocellular fatty change in male and females); core grade supplementary (E.I. du Pont de Nemours & Co., Inc., 1985d)
-- 90-Day Feeding - dog: NOEL=25 ppm (0.625 mg/kg/day); LEL=125 ppm (3.13 mg/kg/day) (bladder hyperplasia, elevated alanine aminotransferase/serum glutamate pyruvate transaminase, uric acid, decreased total protein Ca albumen, cholesterol, increased liver weight); core grade minimum (E.I. du Pont de Nemours & Co., Inc., 1983b)
Ref: US EPA IRIS. NuStar CASRN: 85509-19-9. Available October 6, 2003, at Toxnet.

-- 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

Likely to be Carcinogenic to Humans. Pancreatic cell tumors (exocrine adenomas, islet cell adenomas, and combined islet cell tumors); Sprague-Dawley rats (M). Hepatocellular tumors (adenomas and combined adenoma/carcinoma); CD-1 mice (M & F). CD-1 mice (M & F).
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

A chronic reference dose (RfD) (0.001 mg/kg/day) was identified for fluthiacet-methyl, based on non-neoplastic liver findings (increase in absolute and relative liver weights, fatty changes, chronic inflammation, karyomegaly, single cell necrosis and ceroid/lipofuscin pigmentation).
Ref. Federal Register. December 21, 2001. Fluthiacet-methyl; Pesticide Tolerance. Final Rule.

http://www.epa.gov/fedrgstr/EPA-PEST/2001/December/Day-21/p31497.htm

-- 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.
-- Carcinogenicity mice. NOAEL in males and females = 0.1 mg/ kg/day LOAEL in males and females = 0.1 and 1.2 mg/kg/day, respectively, based on non- neoplastic liver findings. In males, and possibly females, at 10 mg/kg/day for males and 12 mg/kg/day for females; and at 32 gm/kg/day for males and 37 mg/ kg/day for females, there was an increase in the number of mice with hepatocellular adenomas, carcinomos and or adenomas/ carcinomas.
-- Chronic Dietary General population. 18-month carcinogenicity in the mouse. NOAEL = 0.1 mg/kg/day Non-neoplastic liver findings (increase in absolute and relative liver
weights, fatty changes, chronic inflammation, karyomegaly, single cell necrosis and ceroid/lipofuscin pigmentation).
-- Cancer. Fluthiacet-methyl has been classified as ``likely to be a human carcinogen'' by EPA. The Office of Pesticide Programs, Heath Effects Division, Cancer Assessment Review Committee recommended a linear low-dose approach (Q1*) for human risk assessment. The Q1* is 0.207 (mg/kg/day)-1 in human equivalents and is based upon the combined hepatocellular tumors (adenomas and carcinomas) in male mice. EPA conducted a cancer assessment analysis (food) using DEEM software and Tier 2 chronic dietary exposure assumptions. The assumptions of this Tier 2 chronic dietary analysis are as specified above. The cancer risk estimate (food only) for the U.S. population (total) is 3.93 x 10-8. This risk estimate translates to a dietary exposure of 1.90 x 10-7 mg/kg/day. This dietary exposure value was back-calculated based upon the cancer risk estimate and the Q1*. As cancer risk = Exposure x Q1 * Thus, Exposure = cancer risk estimate/ Q1 * or Exposure = 3.93 x 10-8/0.207.
Ref: Federal Register: December 21, 2001. Fluthiacet-methyl; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fluthiacet.M.FR.Dec.21.2001.htm

Flutolanil - Fungicide - CAS No. 66332-96-5

A rabbit developmental study with a maternal NOEL of 5 mg/kg/day and a maternal LOEL of 25 mg/kg/day based on histopathological finds in the liver and a developmental NOEL of 25 mg/kg/day and a developmental LOEL of 125 mg/kg/day based on increased skeletal variations.
Ref: Federal Register. June 23, 1998. [PF-813; FRL-5795-1]

http://www.fluoridealert.org/pesticides/Flutolanil.FR.June.23.1998.htm

Subchronic toxicity. A 84-day rat feeding study with a No Observed Effect Level ( NOEL) less than 100 ppm [6.0 mg/kg/day] for males and a NOEL of 100 ppm [7.2 mg/kg/day] for females and with a Lowest Observed Effect Level (LOEL) of 100 ppm [6.8 mg/kg/day] for males based on suppression of thyroxine (T4) level and a LOEL of 400 ppm [28.8 mg/kg/day] for females based on hematology and clinical chemistry findings. A 13-week mouse feeding study with a NOEL of 100 ppm [18.2 mg/kg/day for males and 24.5 mg/kg/day for females] and a LOEL 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 NOEL of 50 ppm [1.70 mg/kg/day for males and 1.67 mg/kg/day for females] and a LOEL 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 [[Page 34180]] ALT values in both sexes, decreased albumin in males, and decreased serum glucose in females. A 21-day rabbit dermal study with the dermal irritation NOEL of 1,000 mg/kg/day for males and females and a systemic NOEL of 20 mg/kg/day for males and 150 mg/kg/day for females and a systemic LOEL of 150 mg/kg/day for males and 1,000 mg/kg/day for females based on clinical chemistry data (decreased T4 and FT4 levels in both sexes) and centrilobular hepatocytomegaly in females.
Ref
: Federal Register: June 23, 1998 [Page 34176-34184]. Notice of Filing of Pesticide Petitions.
http://www.fluoridealert.org/pesticides/Flutolanil.FR.June.23.1998.htm

Flutriafol - Fungicide - CAS No. 76674-21-0

-- 7.2 Subacute toxicity. a) In a 90-day feeding study, rats were fed diet containing 0, 20, 200 or 2,000 ppm flutriafol. At the highest does, reduced body weight and food intake, haemotological and biochemical changes, increased liver weight, centrilobular hypertrophy, proliferation of SER, elevated hepatic aminopyrine-N-demethylase (APDM) activity were noted. In females fed 200 ppm, only adaptive responses (liver enlargement and elevated APDM) were seen, whereas minimal fatty change was evident in some males. A NEL of 20 ppm (approx. 1 mg/kg bw/day) was established by the SSC (April 1983).
--b) In a 90-day study, dogs were administered oral doses (capsules) of 0, 1, 5 or 15 mg flutriafol/kg bw/day. Reduced body weight gain, increased liver weight, elevated hepatic APDM and plasma ALP activity, were observed in the 15 mg/kg bw/ dosage group. At the 5 mg/kg dosage level, APDM activity was elevated in both sexes. Slight increases in liver weight were seen in females at the low and intermediate dosage levels. A NEL of 5 mg/kg bw/day was established by the SSC [Scientific Subcommittee on Pesticides] (April 1983).
-- 7.7 Assessment a)... Although the incidence of hepatocellular tumours was higher than the historical control data predicted, the increased incidence of individual tumours was not significant, only the combined incidence of hepatocellular carcinoma and adenoma achieved statistical significance. The available evidence suggested that the increase in hepatocellular tumors involved an epigenetic mechanism, all in vitro and in vivo mutagenicity assays were negative and changes in clinical chemistry suggested altered liver metabolism and liver injury. In addition, adaptive responses (increased liver weight, centrilobular hypertrophy, proliferatin of SER and enzyme induction) were evident at low doses in the subacutre rat and dog studies. This evidence suggested that flutriafol was possibly a weak tumour promoter at high dose levels and this effect was possibly secondary to the liver injury. The NOEL for the study was determined to be 20 ppm flutriafol (about 1 mg/kg bw/day). (b) In the multigeneration study, dietary administration of 1,000 ppm flutriafol during the premating period induced a reduction in bodyweight gain and food consumption in F0 parents, and reduced bodyweight gain in F1 females. Increased liver weight, centrilobular hypertrophy (males only) and fatty change were found in F0 and F1 parents fed 1,000 ppm flutriafol. Fatty change in the liver was also evident in F1 males fed 240 ppm flutriafol.... In the high dosage group, the proportion of pups born alive in the second generation litters was significantly reduced. Mean litter size was significantly reduced in F1B and F2A litters. In the high dosage groups, fatty change of the liver was evident in F1B, F2A and F2B pups.. The NEL for reproductive performance in rats was 240 ppm flutriafol (equivalent to approx 12 mg/kg bw/day).
Evaluation on: Flutriafol. October 1996. Issue No. 158, UK Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX.
http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm

Fluxofenim - Herbicide safener - CAS No. 88485-37-4

Chronic/Subchronic Toxicity Studies. Fluxofenim: Liver and kidney effects; Thyroid effects at high doses (dogs).
Target Organs Active Ingredients Fluxofenim: Liver, kidney, and thyroid.
Ref: Ciba-Geigy Material Safety Data Sheet for Concep-III.

http://www.fluoridealert.org/pesticides/Fluxofenim.MSDS.Ciba.1996.htm

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

-- 4. Carcinogenicity. Fomesafen is classified as a Group C carcinogen with a Q* of 1.9 x 10-1 (mg/kg/ day)-1. This classification was based on: (i) Increases in both adenomas and carcinomas at several dose levels in both sexes of mice; (ii) some evidence of reduced latency for the time of tumor appearance; (iii) limited evidence of mutagenic effects; and, (iv) the structural similarity of fomesafen to other biphenyl ether herbicides which have been shown to be carcinogenic.
-- When considering structural similarities with other chemicals, fomesafen falls into the class of ``biphenyl ether'' chemical compounds; this means that this group of chemicals have structural similarities, including a biphenyl ether group, in common. This is used as a piece of supporting evidence for the classification of fomesafen as a Group C carcinogen, since other chemicals of this group (with similar structure) have been found to be carcinogens. However, other indications of the carcinogenicity of fomesafen (i.e., increases of adenomas and carcinomas in a mouse study, limited evidence of mutagenic effects) were also used in deciding this cancer classification. At this time, the Agency does not have sufficient understanding of the structural relationship to the mechanism of toxicity of these chemicals to conclude that they may be combined for the purposes of conducting a risk assessment. Although fomesafen contains some chemical structures in common with other chemicals that have been found to be carcinogens, EPA does not yet fully understand the implications of such a relationship, nor how, or if, these structures relate to the toxicological activity of the chemical. For the purposes of this tolerance action, therefore, EPA has not assumed that fomesafen has a common mechanism of toxicity with other substances.
Ref: Federal Register. November 19, 1997. Fomesafen; Pesticide Tolerances for Emergency Exemptions. Final Rule.
http://www.fluoridealert.org/pesticides/Fomesafen.FR.Nov.19.1997.htm

-- 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. In a 90-day rat study, dietary administration of 5 mg/kg/day (LOEL) produced alterations in lipid metabolism and increases in liver weight. The NOEL was 0.25 mg/kg/day. In a 26-week dog study, dietary administration of 25 mg/kg/day (LOEL) produced alterations in lipid metabolism and liver changes (changes not defined). The NOEL was 1 mg/ kg/day. Liver toxicity (increased liver masses, discolored hepatocytes, and pigmented Kupffer cells) was observed in a 2-year rat feeding study at 50 mg/kg/day (LOEL). The NOEL was 5 mg/kg/day. Metabolism studies have shown that fomesafen accumulates in the liver. EPA believes that there is sufficient evidence for listing fomesafen on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available hepatic 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.

-- Classification -- C; possible human carcinogen.
-- Animal Carcinogenicity Data. Limited. Sixty-four Charles River CD-1 mice/sex/dose group were dosed for 2 years with fomesafen at 0, 1, 5, 100 and 1000 ppm by dietary incorporation. A double-size control group was used. At 12 months, 24 mice/sex from the controls and 12 mice/sex from the treated groups were killed. In male mice at termination, the incidence of liver adenomas was significantly increased at 1, 100 and 1000 ppm when compared with controls. The incidences of liver carcinomas and a combination of liver adenomas and carcinomas were significantly increased at 1000 ppm. In the females, the incidence of adenomas was increased at 100 and 1000 ppm and carcinomas were increased at 1000 ppm when compared with controls. The incidence of adenomas and carcinomas combined was significantly increased at 100 and 1000 ppm. Both sexes, therefore, showed a progression from benign to malignant tumors with increased dose. Some liver tumors (adenomas and carcinomas) were apparent at the 52-week interval kill. There was increased mortality in the males at 100 and 1000 ppm and in the females at 1000 ppm, due to liver toxicity forcing termination of the study. The 1000 ppm animals were killed at 79 weeks (males) or 89 weeks (females). The MTD appeared to be exceeded at 100 ppm in the males and 1000 ppm in the females. The tumor increases occurred at dose levels of fomesafen that were both below and above the MTD (Huntingdon, 1985).
Ref: US EPA. Fomesafen (CASRN 72178-02-0). IRIS (Integrated Risk Information System).

-- PubMed Abstract: Administration of herbicide fomesafen and of fomesafen combined with one dose of iron to 44 mice during 3 to 14 months caused hyperplastic and preneoplastic changes in the liver tissue which had been described in experimental carcinogenesis* small groups of altered hepatocytes storing glycogen or lipids and foci of small basophilic liver cells occurred as early as after 3 months. Altered hepatocytes were found more frequently in mice getting fomesafen and iron. Later nodular hyperplasia of liver cells developed with nodes 3-20 mm in diameter which mostly consisted of altered hepatocytes with plenty of glycogen. After 12 and 14 month-lasting administration of fomesafen and fomesafen with iron, the hepatocellular carcinoma was proved in 5 mice. In 4 mice, the preneoplastic changes in liver tissue were accompanied by micronodular hyperplasia of liver cells which did not participate on the development of big nodes and hepatocellular carcinoma.
Ref: Cesk Patol 1998. Apr;34(2):67-71. [Morphologic findings in liver tissue in mice after long-term administration of the herbicide fomesafan] by Chlumska A, Fakan F, Krijt J.

http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query_old?uid=9624829&form=6&db=m&Dopt=b

 
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