Liver - Adverse Effects
Fluorinated and Fluoride Pesticides
beginning with
A-E F • G-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.
As time allows more information will be added.

Gliftor - Rodenticide - Rodenticide - CAS No. 8065-71-2

Abstract. Rats were subjected to the single inhalation effect of vapors of the zoocide gliftor (I; 50, 100, 350, 520, and 1100 mg/m-3). Morphological changes were noted beginning with a concentration of 350 mg/m-3. In a chronic experiment (4 mo.) the rats were subjected to I poisoning in a concentration of 10, 13, 64, and 110 mg/m-3. Distinct morphological changes in the organs were noted under the effect of concentrations 64 and 110 mg/m-3. Under the chronic effect of I there were considerable circulatory disorders and destructive changes of the interanl organs, especially in the liver, lungs, spleen, and kidneys.
Ref: Pathomorphological changes in internal organs of white rats under the inhalation effect of gliftor; by KNYSH VS, TKACH NZ, TSAREVSKII LP, MILOVANOVA VI. TR INST KRAEV PATOL AKAD NAUK KAZ SSR; 22 1971 23-28. [Abstract from Toxline at Toxnet.]

Haloxyfop - Herbicide - CAS No. 69806-34-4

The subchronic toxicity of haloxyfop (2-(4-((3-chloro-5-(trifluoromethyl)-2- pyridinyl)oxy)phenoxy)propanoic acid) herbicide, a peroxisome proliferator, was evaluated in rats, mice, dogs and monkeys. Male rats given 0.2 or 2.0 mg/kg/day and female rats given 2.0 mg/kg/day in feed for 16 weeks had peroxisome associated hepatocellular hypertrophy. Male and female rats given 2.0 mg/kg/day for 37 weeks also had increased renal tubular pigment. Mice given 2.0 mg/kg/day in feed for 13 weeks had peroxisome associated hepatocellular hypertrophy. Dogs fed 20 mg/kg/day and monkeys gavaged with 30 mg/kg/day for 13 weeks had hepatocellular hypertrophy, decreased size of thyroid follicles, and decreased red blood cell counts and serum cholesterol. Hepatocellular effects in dogs and monkeys were not associated with peroxisome proliferation. No-observed effect levels were between 0.02 and 0.2 mg/kg/day for rats, 0.2 mg/kg/day for mice, and 2 mg/kg/day for dogs and monkeys. There were no effects on reproduction in rats at dose levels up to 1.0 mg/kg/day or evidence of teratogenicity in rats or rabbits at dose levels up to 7.5 or 20 mg/kg/day, respectively.
Ref: Subchronic and reproductive toxicity and teratology of haloxyfop herbicide. Authors: Quast JF Yano BL Dietz FK Marler RM Hayes WC. Source: Toxicologist 1990 Feb;10(1):175. As cited at Toxnet.

Abstract: The potential of haloxyfop [2-(4-((3-chloro-5-(trifluoromethyl)-2- pyridinyl)oxy)phenoxy)propanoic acid; HAL] to induce the proliferation of hepatocellular peroxisomes (PP) was examined in rats, mice, dogs, and monkeys. Chemically induced PP is associated with the development of liver tumors in rodents via an apparent species-dependent, nongenotoxic mechanism of action. HAL is nongenotoxic yet has been shown to cause liver tumors in female B6C3F1 mice. Ingestion of HAL by rats and/or mice (0.1-14 mg/kg/day for 2 to 4 weeks) resulted in significant dose-related PP as evidenced by hepatocellular hypertrophy, increased peroxisome volume density (VD), and induction of peroxisomal enzymes and CYP4A1. Only a relatively weak induction of PP was noted at a carcinogenic dosage in female mice...
Ref: Fundam Appl Toxicol 1995 Nov;28(1):71-9. Species-dependent induction of peroxisome proliferation by haloxyfop, an aryloxyphenoxy herbicide. Stott WT, Yano BL, Williams DM, Barnard SD, Hannah MA, Cieszlak FS, Herman JR.

PubMed Abstract: The CoA esters of diclofop, haloxyfop and fluazifop are up to 425-fold more potent than the corresponding unconjugated herbicides as inhibitors of rat liver acetyl-CoA carboxylase (EC 6.4.1.2); the most potent inhibitor is (R)-fluazifopyl-CoA2 (Ki = 0.03 microM).
Ref: Life Sci 1992;50(7):533-40. Coenzyme A esters of 2-aryloxyphenoxypropionate herbicides and 2-arylpropionate antiinflammatory drugs are potent and stereoselective inhibitors of rat liver acetyl-CoA carboxylase. Kemal C, Casida JE.

Haloxyfop-methyl - Herbicide - CAS No. 69806-40-2

Group B2--Probable Human Carcinogen. Reviewed 9/ 18/ 89.
Ref: List of Chemicals Evaluated for Carcinogenic Potential. Science Information Management Branch, Health Effects Division, Office of Pesticide Programs, U. S. Environmental Protection Agency. March 15, 2002.
http://www.biomuncie.org/chemicals_evaluated_for_carcinog.htm

"There are eight diphenyl ethers that are structurally similar to diclofop-methyl. Of the chemicals, fomesafen sodium, haloxyfop-methyl (Verdict), oxyfluorfen, acifluorfen sodium, nitrofen, and lactofen were reviewed in the initial CPRC report. All of these chemicals induced liver adenomas and carcinomas in rats and/or mice..."
Ref: May 24, 2000 - Cancer Assessment Document. Evaluation of the Carcinogenic Potential of Diclofop-Methyl. (Second Review). Final Report. Cancer Assessment Review Committee, Health Effects Division, US EPA Office of Pesticide Programs.
http://www.fluoridealert.org/pesticides/Cancer.EPA.Assess.May.2000.pdf

-- 1) 2-Year Feeding (carcinogenicity) - mouse: Dietary levels tested: 0, 0.03, 0.065, and 0.6 mg/kg/day; B6C3F1 mice (50/sex/dose) were administered haloxyfop-methyl in the diet for 24 months. High-dose males exhibited a reduced body weight gain, elevated alkaline phosphatase levels, and an increase in relative liver weights. Histopathological observations of the livers from high-dose males and females were characterized by an alteration of the tinctorial staining properties of the hepatocytes. Based on the above effects the LEL for systemic toxicity is 0.6 mg/kg/day. The NOEL for systemic toxicity is 0.065 mg/kg/day.; core grade minimum (Dow Chemical U.S.A., 1985c)
-- 4) 16-Week Feeding - rat: Dietary levels tested: 0, 0.002, 0.02, 0.2, and 2 mg/kg/day; CDF Fischer 344 rats (15/sex/group) were administered haloxyfop- methyl in the diet for 16 weeks. A significant dose-related increase in relative liver weight was reported for male rats of the 0.002, 0.02, 0.2, and 2.0 mg/kg/day levels by 4, 5, 11, and 44%, respectively. Female relative liver weights were increased significantly (4%) at the 2.0 mg/kg/day levels. Males fed the 0.2 and 2.0 mg/kg/day levels showed enlarged hepatocytes and increased cytoplasmic homogeneity. An increase in hepatocellular cytoplasmic homogeneity was reported for females at 2.0 mg/kg/day. A significant decrease in relative testes weight (5%) accompanied by atrophy of the seminiferous tubules were reported for males fed the 2.0 mg/kg/day level. The LEL for systemic toxicity is 0.002 mg/kg/day, the lowest dose tested, based on a dose related increase in relative liver weight in males. A NOEL for systemic toxicity was not established.; core grade minimum (Dow Chemical U.S.A., 1982a)
-- 7) 36-Week Feeding - mouse: Dietary levels tested: 0, 0.02, and 2.0 mg/kg/day; B6C3F1 mice (10/sex/group) were administered haloxyfop-methyl in the diet for 9 months. A significant increase in serum alkaline phosphatase was reported for males at the 2.0 mg/kg/day level with a slight increase in serum alkaline phosphatase for females. The liver was slightly enlarged and darkened for both males and females at 2.0 mg/kg/day. A significant increase in the liver absolute weight and organ-to-body weight ratio of both males and females fed 2.0 mg/kg/day was observed. Males also exhibited a significant decrease in kidney and heart weights compared with the control organ weight. Livers of males and females at the 2.0 mg/kg/day dose exhibited an enlargement of centrilobular hepatocytes cells with an increase cytoplasmic homogenity and increased eosinophilia. Kidneys of males fed 2.0 mg/kg/day showed a decrease of cytoplasmic vacuolation of the proximal convoluted tubular cells. Based on the above effects, the LEL for systemic toxicity is 2.0 mg/kg/day. The NOEL for systemic toxicity is 0.02 mg/kg/day; core supplementary (Dow Chemical U.S.A., 1982d)
-- Critical Effect: Reduced relative kidney weights in F0, F1, and F2b adults; Reduced fertility in the F1/F2b generation. 3-Generation Rat Reproduction Study. Dow Chemical U.S.A.,1985a. NOEL: 0.005 mg/kg/day; LEL: 0.05 mg/kg/day.... Signs of toxicity in parental rats at 1 mg/kg/day level were reduced body weight gain and reduced food consumption without increased mortality or obvious toxicity to the offspring. In addition, a significant increase in relative liver weight and enlarged livers were observed, however this finding was more frequent in males than females. A significant decrease in relative kidney weight was observed at 0.05 and 1 mg/kg/day, but it again occurred more frequently in the F0, F1, and F2b adult male rats. Renal pigmentation was also reported at 1 mg/kg/day for male and female adult rats after the gross and histopathological examinations. Based on decreases in relative kidney weights, the LEL for systemic toxicity is 0.05 mg/kg/day. The NOEL for systemic toxicity is 0.005 mg/kg/day.

Ref: Health Assessment. US EPA Integrated Risk Information System (IRIS).
http://www.fluoridealert.org/pesticides/Haloxyfop.Methyl.IRIS.htm

Hexafluoropropene, polymer with tetrafluoroethylene - EPA List 3 Inert - CAS No. 25067-11-2

Animal carcinogenicity data
Tetrafluoroethylene was tested for carcinogenicity in one study in mice and one study in rats by inhalation. In both sexes of mice, it increased the incidence of hepatocellular carcinomas, histiocytic sarcomas and haemangiosarcomas in the liver. In rats of both sexes, it increased the incidence of hepatocellular carcinomas and kidney tubule cell adenomas.
Evaluation
There is sufficient evidence in experimental animals for the carcinogenicity of tetrafluoroethylene.
Overall evaluation
Tetrafluoroethylene is possibly carcinogenic to humans (Group 2B).
Ref: International Agency for Cancer Research (IARC):
http://www-cie.iarc.fr/htdocs/monographs/vol71/048-tetrafluo.html

Hexaflumuron - Insecticide, Plant Growth Regulator - CAS No. 86479-06-3

In long-term (chronic) feeding tests, hexaflumuron increased the incidence and severity of a liver cell abnormality (U.S. EPA. Office of Pesticide Programs. 1994. Pesticide fact sheet: Hexaflumuron. Washington, D.C. Mar. 10).
Ref: Subterranean Termites. Part 2, by Caroline Cox. Journal of Pesticide Reform / Summer 1997. Vol. 17, No. 2

http://www.pesticide.org/subtermites2.pdf

Abstract: A toxicological evaluation of a new insecticide Sonet was realized. It was established that by its toxicity Sonet belongs to hazardous substances of class III. The main manifestations of its toxic effect on the body warm-blooded animals is its influence on the erythropoiesis and functional state of the liver.
Ref: Sviatnyi IM et al. (1992). [A hygienic evaluation of the insecticide Sonet and the characteristics of the mechanism of its toxic action in an experiment] [Article in Russian]. Lik Sprava. Jan;(1):84-7.

http://www.fluorideaction.org/pesticides/hexaflumuron.abstracts.htm
Definition: Erythropoiesis is the process of red blood cell production (which occurs in red bone marrow).

Indoxacarb - Insecticide - CAS No. 173584-44-6

COMBINED, RAT **52425-054 162226 "Combined Chronic Toxicity/Oncogenicity Study with DPX-JW062-106 (50% DPX-KN128, 50% DPX-KN127) Two-Year Feeding Study in Rats" (Frame, S. 835-E. I. du Pont de Nemours and Company, Haskell Laboratory, Elkton Road, Newark, Delaware, Study HLR 1174-96, 11/19/97). DPX-JW062-106 technical (Batch DPX-JW062-106, 47.5% DPX-KN128) was given in the diet daily to males at 0, 20, 40, 60, 125 or 250 ppm and females at 0, 10, 20, 40, 60 or 125 ppm for 24 months. Deaths of one female at 60 ppm and seven at 125 ppm during the first year were associated with bone marrow atrophy, splenic lymphoid depletion and thymic necrosis. Decreases in mean body weight/weight gain in males at 125 and 250 ppm and females at 60 and 125 ppm correlated with decreased food consumption. Hemolytic anemia at 60 ppm and above (males) and 40 ppm and above (females): RBC mass, hemoglobin and hematocrit were decreased and linked with increased reticulocyte counts and increased MCV. Bone marrow regenerative response was increased bone marrow hyperplasia in the one-year interim sacrifice 125 ppm females. Spleen weights were increased in both sexes at the respective high-dose levels and other non-neoplastic changes were secondary physiological responses to test substance-related hemolysis; increased pigment observed within the Kupffer cells of female livers (125 ppm) and the macrophages of the spleen (both sexes at 60 ppm and above) indicated increased RBC turnover. Increased hematopoiesis was reported in the spleen of interim sacrifice males at 125 ppm and above and in the bone marrow of high-dose males and females. After two years, secondary changes were seen in the liver, spleen, bone marrow, kidneys and thymus in high dose groups. Increased pigment was observed in the Kupffer cells of female livers at 40 ppm and above; in males, increases were noted at 250 ppm only. Increased splenic pigment was seen in all compound-treated male groups and in females at 60 ppm and above; a slight increase in splenic congestion was seen in 250 ppm males. No evidence of an oncogenic effect was reported. NOEL(M)= 40 ppm; (F)=20 ppm (M: 1.59 mg/kg/day; F: 1.04 mg/kg/day based on hemolytic anemia). Acceptable. Kellner, 1/29/99.
Ref: March 11, 1999: Summary of Toxicology Data - Indoxycarb. California EPA Department of Pesticide Regulation, Medical Toxicology Branch.
http://www.fluorideaction.org/pesticides/indoxacarb.ca.epa.1999.pdf

The haemosiderin deposits in spleen and liver, and spleen and bone marrow hyperplastic response should be considered to be secondary physiological responses to the increased RBC turn over. The very shallow dose-response curve also indicates that the compensatory mechanism of the haemopoietic system was not overcome (except at high doses in the dog) and the effect of indoxacarb in rats and dogs can be described as a compensated haemolytic effect.
July 18, 2002: Opinion of the Scientific Committee on Plants on specific questions from the Commission concerning the evaluation of Indoxacarb. European Commission. Health & Consumer Protection Directorate-General.
http://www.fluorideaction.org/pesticides/indoxacarb.eu.july.18.2002.pdf

Isoxaflutole - Herbicide - CAS No. 141112-29-0

Likely to be carcinogenic to Humans. Statistically significant increases in liver tumors in both sexes of CD-1 mice & Sprague-Dawley rats; statistically significant increases in thyroid tumors in male rats.
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

-- Isoxaflutole demonstrates developmental toxicity and has been classified as a Group B2 carcinogen (probable human carcinogen).
-- In a combined chronic toxicity/carcinogenicity study in rats, evidence of systemic toxicity was observed at 500 mg/kg/day and included: abnormal gait, limited use of limbs, lower body weight gains and food consumption, decreased food efficiency during the first 14 weeks of the study, elevated cholesterol levels throughout the 104-week study, increased absolute and relative liver weights, and thyroid hyperplasia. Increased incidence of periacinar hepatocytic hypertrophy, portal tract (senile) bile duct changes, focal cystic degeneration of the liver was observed in males at 20 mg/kg/day and greater, females at 500 mg/kg/day. Eye opacity, gross necropsy changes in eyes, corneal lesions, degeneration of sciatic nerve and thigh muscles was observed in males at 20 mg/kg/day and higher doses and in females at 500 mg/kg/day. The chronic LOAEL is 20 mg/kg/day based on liver, thyroid, ocular, and nervous system toxicity in males and liver toxicity in females. The chronic NOEL is 2.0 mg/kg/day.
-- Under the conditions of this study, isoxaflutole induced benign and malignant tumors of the liver in both sexes at 500 mg/kg/day hepatocellular adenomas and hepatocellular carcinomas. Combined incidences of liver adenoma/carcinoma in males and females showed animals bearing carcinomas in the majority...
-- In a 78-week carcinogenicity study, isoxaflutole had no significant effect on the survival of animals. Systemic signs of toxicity in the treated groups included: decreased body weight gain in both sexes at 500 ppm and 7,000 ppm and for females at 25 ppm group; food consumption was unaffected except food efficiency was lower for both sexes at 7000 ppm during the first 14 weeks of the study; absolute and relative/body liver weights were significantly increased in both sexes at 7,000 ppm and at 500 ppm relative liver weight was increased in males at 52 weeks and in females at 78 weeks; gross necropsy at 78-week sacrifice revealed increased occurrences of liver masses in both sexes at 7,000 ppm; non-neoplastic lesions of the liver occurred at 52-week sacrifice in males at 500 ppm and in males and females at 7,000 ppm. At termination, the 500 ppm group males exhibited increased incidence of hepatocyte necrosis. At 7,000 ppm, significant increase in non-neoplastic lesions in both sexes included periacinar hepatocytic hypertrophy, necrosis, and erythrocyte-containing hepatocytes. In addition, males at the high dose had pigment-laden hepatocytes and Kupffer cells, basophilic foci, and increased ploidy; extramedullary hemopoiesis in the spleen was noted in both sexes; increase incidences of hepatocellular adenoma and carcinoma were observed in both sexes at 7,000 ppm in the 52-week and 78-week studies.
-- Among scheduled and unscheduled deaths in the 78-week study, there were significant occurrences of hepatocellular adenomas in 52% of the males and 29% of the females, and carcinomas in 33% of the males and 8% of the females (non-significant). The incidences of these tumors exceeded the corresponding historical incidence with this species in the laboratory. Combined adenoma and carcinoma incidences at 7,000 ppm were 73% for males and 35% for females. At 500 ppm, the incidences of 17% adenomas and 15% carcinomas in males and 2% adenomas in females were not statistically significant, but exceeded the means for historical controls. The 52- and 78-week studies revealed a dose-related decrease in the first occurrence of carcinomas in males; the earliest carcinomas were observed at 78, 71, 52, and 47 weeks at the 0 through 7,000 ppm doses. There were no carcinomas in females up to 78 weeks at 0, 25, or 500 ppm, although, the earliest finding at 7000 ppm was at 60 weeks. The LOAEL for this study is 64.4 mg/kg/day for males and 77.9 mg/kg/day for females (500 ppm), based on decreased body weight gains, increased liver weights, and increased incidences of histopathological liver changes. The NOEL is 3.2 mg/kg/day for males and 4.0 mg/kg/day for females (25 ppm). Although body weight was decreased marginally in females at 25 ppm, there were no corroborating findings of toxicity at this dose. Under conditions of this study, isoxaflutole appears to induce hepatocellular adenomas and carcinomas in male and female CD-1 mice. The chemical was tested at doses sufficient to measure its carcinogenic potential.
-- Reproductive Toxicity. In a 2-generation reproduction study in rats, evidence of toxicity was observed in the male and female parental rats of both generations: at 20 and 500 mg/kg/day, increased absolute and relative liver weights associated with liver hypertrophy was observed.. The Systemic LOAEL is 17.4 mg/kg/day for males and females, based upon increased liver weights and hypertrophy and the Systemic NOEL is 1.76 mg/kg/day for males and females...
Ref: US EPA. Pesticide Fact Sheet. Isoxaflutole Reason for Issuance: Conditional Registration Date Issued: September 15, 1998.

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

Lactofen - Herbicide - CAS No. 77501-63-4

Likely to be Carcinogenic to Humans at High Doses. Not Likely to be Carcinogenic to Humans at Low Doses. Hepatocellular carcinomas (M); Hepatocellular adenomas & carcinomas (M & F); CD-mice. Liver neoplastic nodules; Sprague-Dawley rats (M & F). MOE approach should be used for estimating human cancer risk, using a NOAEL of 2 ppm (0.3 mg/kg/day).
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

Lactofen acts via a peroxisome proliferation mechanism of action. Likely to be carcinogenic to humans at high enough doses to cause these biochemical and histopathological effects (peroxisome proliferation) in the livers of rodents but unlikely to be carcinogenic at doses below those causing these changes. Lactofen is considered to be a threshold carcinogen. NOAEL = 0.3 mg/kg/day based on increased activities of liver enzymes and increased incidence of liver histopathological findings at the LOAEL of 1.5 mg/kg/day.
Ref: Sept 24, 2004. Lactofen. Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluorideaction.org/pesticides/lactofen.fr.sept.24.2004.htm

Lactofen meets the criteria of an EPA Group B2 compound, i.e., a probable human carcinogen. This conclusion was based on an increased incidence of hepatocellular carcinomas in males and combined incidence of hepatocellular adenomas and carcinomas in both sexes of CD-1 mice following dietary administration of lactofen. In CD rats, there was increased incidence of liver neoplastic nodules in both sexes. Four structurally similar chemicals, acifluorfen, nitrofen, oxyfluorfen, and fomesafen, all produced hepatocellular tumors in rodents. Results of several subchronic and chronic studies indicated the liver and kidney as target organs for lactofen. Increased absolute and relative liver weight and hepatocytomegaly (the LOEL was 1.5 mg/kg/day; the NOEL was not determined) were observed in male mice fed lactofen for 78 weeks. At 37.5 mg/kg/day, there was also an increased incidence of cataracts and renal pigmentation. Based on the LOEL, an oral RfD of 0.002 mg/kg/day was derived. Renal dysfunction and decreased hemoglobin and hematocrit levels and red blood cell counts (the LOEL was 25/75 mg/ kg/day; the NOEL was 5 mg/kg/day) were observed in a 1-year feeding study in dogs. Increased renal and hepatic pigmentation (the LOEL was 50 mg/kg/day; the NOEL was 25 mg/kg/day) were noted in a 2-year feeding study in rats. In a 90-day mouse study, increased alkaline phosphatase, serum glutamate oxaloacetate transaminase (SGOT), and serum gleutanic pyruvic transaminase (SGPT) activities, increased liver weight, hepatic necrosis, biliary hyperplasia, decreased hematocrit and hemoglobin levels and red blood cell counts, extramedullary hematopoiesis, and kidney nephrosis and fibrosis (the LOEL was 26 mg/kg/day; the NOEL was not determined) were seen. Decreased hemoglobin and hematocrit levels, decreased red blood cell counts, and brown pigment in the kidney and liver (the LOEL was 50 mg/kg/day) were noted in a 90-day feeding study in rats. EPA believes that there is sufficient evidence for listing lactofen on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available carcinogenicity data and hepatic, renal, and hematological toxicity data for this chemical.
Ref: USEPA/OPP. Support Document for the Addition of Chemicals from Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) Active Ingredients to EPCRA Section 313. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.

Chronic/carcinogenicity feeding study-- Mouse-- 24-month. In a dietary 18-month oncogenicity study in mice at dosages of 10, 50 and 250 ppm Lactofen Technical, an increase in liver adenomas and carcinomas, cataracts and liver pigmentation was observed at 250 ppm. The lowest dose, 10 ppm, was the LOEL based on increased liver weight and hepatocytomegaly.
-- Chronic/carcinogenicity feeding study-- Rat-- 24-month. In a 2- year chronic feeding/oncogenicity study of Lactofen Technical in rats at dosages of 0, 500, 1,000 and 2,000 ppm in the diet, an increase in liver neoplastic nodules and foci of cellular alteration was observed in both sexes at 2,000 ppm. The NOEL for systemic toxicity is 500 ppm based on kidney and liver pigmentation.
-- Carcinogenicity. The Toxicology Branch Peer Review Committee has determined that lactofen meets the criterion for a B2 (possible human) carcinogen since it caused an increase in liver tumors (adenomas and/or carcinomas) in two species. Based on the mouse oncogenicity study, a human upper-bound potency estimate (Q1*) was calculated as 0.17 (mg/kg/day).
-- More importantly, evidence summarized above suggest that carcinogenic effects observed in rodent liver related to long term lactofen consumption are attributable to peroxisomal proliferation as opposed to a direct genotoxic effect. This mechanism of action would more appropriately be regulated as a threshold effect (similar to RfD comparisons) as opposed to a non-threshold effect with a quantitative potency factor derived from low dose extrapolations. This change in the hazard assessment process for lactofen would have a profound effect on the exposure and risk assessments for this chemical.
Ref: Federal Register: February 25, 1998 [Page 9532-9540]. Notice of Filing of Pesticide Petition.

http://www.fluoridealert.org/pesticides/Lactofen.FR.Feb.1998.htm

Lithium perfluorooctane sulfonate (LPOS) - Insecticide, Adjuvant - CAS No. 29457-72-5

In an unacceptable subchronic oral toxicity study in rats, the LOAEL was found to be 0.60 mg/kg/day in females, based on increased liver weight and 0.30 mg/kg/day in males, based on decreased triglycerides and hepatocytic vacuolization. The NOAEL is 0.20 mg/kg/day in females. No NOAEL was determined in males. It appears that LPOS suppresses hematopoiesis (blood production) in males as indicated by significant decreases in RBCs, hemoglobin, hematocrit, and the finding of extramedullary hematopoiesis. This study was classified as unacceptable for the following reasons: 1) a NOAEL was not determined in males; 2) an analysis of blood coagulation factors which is required for a subchronic study was not measured in the animals; 3) the mean food and water consumption calculated as g/week is not correct in the study (it is actually g/day) which raises the possibilities of potential errors in compound consumption, since the test substance was administered in drinking water; and 4) a range finding study was not performed in order to develop a rationale for the appropriate selection of doses in males and females.
Ref: US EPA. New Pesticide Fact Sheet. Lithium perfluorooctane sulfonate (LPOs). August 1999.

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

PFOS is persistent, bioaccumulative and toxic to mammalian species. There are species differences in the elimination half-life of PFOS; the half-life is 100 days in rats, 200 days in monkeys, and years in humans. The toxicity profile of PFOS is similar among rats and monkeys. Repeated exposure results in hepatotoxicity and mortality; the dose-response curve is very steep for mortality. This occurs in animals of all ages, although the neonate may be more sensitive. In addition, a 2-year bioassay in rats has shown that exposure to PFOS results in hepatocellular adenomas and thyroid follicular cell adenomas; the hepatocellular adenomas do not appear to be related to peroxisome proliferation. Further work to elucidate the species differences in toxicokinetics and in the mode of action of PFOS will increase our ability to predict risk to humans.
Ref: November 21, 2002 report: Hazard Assessment of Perfluorooctane sulfonate (PFOS) and its salts. Organisation for Economic Co-operation and Development. ENV/JM/RD(2002)17/FINAL.
http://www.fluorideaction.org/pesticides/pfos.final.report.nov.2002.pdf

 Mefluidide and its potassium and diethanolamine salts - Herbicide, Plant growth regulator - CAS Nos. 53780-34-0, 53780-36-2, 83601-83-6)

"Lifetime Carcinogenicity Study in Mice", (International Research and Development Corporation, report no. 102-026, 5/14/1979). Mefluidide, purity 93%, fed at 0, 600, 1800 or 6000 ppm in diet to 60/sex/group for 18-19 months. Positive adverse chronic effect of liver toxicity. No evidence of oncogenicity. NOEL for hepatotoxicity is 600 ppm. UNACCEPTABLE. (J. Christopher, 7/1/85). Evaluated as possibly upgradeable with submission of pathology data adjusted according to time of death, complete histopathology for the mid dose group and organ weights. Rebuttal (#059987 in 034) discusses the requirements for an oncogenicity study as opposed to a combined and contains diet analyses. See Summary statement below. (Updated, Kishiyama and Gee, 7/14/88). ...Significant adverse effects consisted of increased mortality in the 6000 ppm (high) dose group and liver nodular hyperplasia in the 6000 and 1800 (intermediate) dose groups. The liver alterations were called "reparative or regenerative responses to toxic liver injury" and no oncogenic effect was claimed. Two consultant pathologist re-read the slides and generally agreed with the diagnoses of the IRDC pathologist. While no oncogenic effects were found, the reduced survival in the high dose group confounds interpretation. The pathology data need to be adjusted according to time of death rather than be lumped into singular incidence values irrespective of time of death or sacrifice. Appropriate statistics could then be performed. In any event, the report is still incomplete and unacceptable due to study conduct deficiencies originally outlined in Dr. Christopher’s review. F. Martz, 4/16/86.
Ref: Summary of Toxicology Data. 11-21-94 Revision. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/Mefluidide.CA.EPA.1986.pdf

21-Day Dermal toxicity - rabbit (4 rabbits/sex/dose). Acceptable/Non-guideline (NOAEL was not observed). Systemic LOAEL = 240 mg/kg/day, based on clinical chemistry (increased alkaline phosphatase and alanine aminotransferase) and organ weights (decreased spleen weight in females and increased liver weights in males). Edema and swelling with myelin loss in sciatic nerve was seen in 720 and 2400 mg/kg/day dose group. Dehydration observed at 2400 mg/kg/day dose. Dermal and systemic NOAELs were not established.
Ref: USEPA. Mefluidide - Toxicology section for the Reregistration Eligibility Decision Document (RED) (January 31, 2007)
http://www.fluoridealert.org/pesticides/docket/EPA-HQ-OPP-2007-0431-0009.pdf

Metaflumizone (BAS 320 I) - Insecticide - CAS No. 139968-49-3

-- Chronic toxicity. In the Sprague-Dawley rat, treatment by oral gavage with BAS 320 I for a 2-year chronic duration resulted in dose-related increased incidences of hepatocellular centrilobular hypertrophy in the livers of males and females at 60 mg/kg b.w./day and at 300/200 mg/kg b.w./day and hepatocellular basophilic alteration in males at 60 and 300 mg/kg b.w./day. (Note: Beginning the first day of Week 3, the dose level of the high-dose females was lowered from 300 to 200 mg/kg b.w./day, due to an adverse effect of -71% decreased body weight gain as compared to controls.)
Ref: October 27, 2004. Federal Register.
Pesticide tolerance petition.
http://www.fluorideaction.org/pesticides/metaflumizone.fr.oct.27.04.htm

Nissol (also known as MNFA) - Acaricide, Insecticide - CAS NO. 5903-13-9

Abstract. The effects of a single dose and repeated doses of N-methyl-N- ( 1- naphthyl ) monofluoroacetamide (MNFA) on the fluctuation of citrate in animals and the replationship between the activity of MNFA hydrolysis and the acute toxicity of MNFA in various species were investigated. MNFA was administered intraperitoneally at 25 mg/kg to male Wistar strain rats, 2.0 mg/kg to guinea pigs and 300 mg/kg to monkeys. At specified periods after dosing, the animals were sacrificed and the citrate content of heart, kidneys, liver and brain was determined. For the multiple dose study, MNFA was administered orally to male rats at doses of 0.625, 1.25, 2.5, 5.0 and 10.0 mg/kg/ day for 180 days and the citrate content was determined in the brain, heart, liver, kidney, testis and blood. In the rat, after a single dose of MNFA, the citrate level increased to 27, 10, 10 and negligible times the normal value in heart, kidneys, brain and liver, respectively. In the chronic toxicity experiment, the only increase (3 times the control value) was in the testes of rats receiving 10 mg/ kg/day of MNFA. In all other groups, the level in liver and kidney decreased significantly in comparison with the levels in animals receiving a single dose. It is suggested that this difference was due to metabolism and to the detoxification mechanism of the liver and kidney which may have been accelerated by the chronic administration of MNFA. The citrate level in the monkeys after a single dose was much lower than in the rat. In guinea pigs it increased to the maximum at 9 hr when it reached 30 times the control value in the kidney, 10 times in the heart, 6 times in the brain while no appreciable increase was found in the liver. The hydrolysis of MNFA by liver homogenates was closely related to the acute toxicity and the product of the hydrolysis was determined as N-methyl-1-naphthylamine. The enzyme activity in the guinea pig was about 35 times that of the rat or mouse. The LD50 of MNFA was 3.1 times that of N- ( 1-naphthyl ) monofluoroacetamide ( NFA ) and the amount hydrolyzed after 30 min incubation was about one- fifth.
Ref: Studies of the biochemical lesions caused by a new fluorine pesticide, N-methyl-N- ( 1-naphthyl ) monofluoroacetamide; by Noguchi T, Hashimoto Y, Miyata H. Toxicol. Appl. Pharmacol.; 13(2), 189-98, 1968.

Abstract. The accumulation of citrate was studied in spider-mites, house-flies and mice after treatment with the acaricide Nissol (5903139). Male Swiss-Webster-mice were injected with various concentrations of Nissol. House-flies were treated topically with Nissol at various concentrations or received thoracic injections. A slide/dip technique was used to dose two-spotted-spider mites with Nissol. Mortality was recorded at 24 hours after treatment and the median lethal dose (LD50) was calculated for each species. The citric-acid (77929) content was determined in homogenates of whole mice in brains, hearts, livers, and kidneys photospectrometrically. Citric-acid content was also determined in homogenates of flies and mites. The LD50 for intraperitoneal administration in mice was 200 milligrams per kilogram (mg/kg). The topical LD50 in house-flies was 525mg/kg and the injected LD50 was 14mg/kg. The LD50 for contact administration to spider mites was 250 parts per million. Citric-acid increased substantially in each species even by 3 hours after dosing. The maximum accumulation in mice occurred at 6 hours. Flies and mites continued to show increased accumulation through 12 hours. In the mouse citric-acid was accumulated in decreasing order in the heart, kidney, brain, and liver. The authors conclude that mites, flies and mice accumulate citrate when treated with Nissol. The toxicity of this acaricide may be related to inhibition of aconitase which catalyzes transformation of citric-acid.
Ref. Citrate Accumulation In Twospotted Spider Mites, House Flies, And Mice Following Treatment With The Acaricide 2-Fluoro-N-methyl-N-(1-naphthyl) Acetamide; by Johannsen FR. Knowles CO. Journal of Economic Entomology, Vol. 65, No. 6, pages 1754-1756, 14 references, 1972.

Norflurazon - Herbicide - CAS No. 27314-13-2

Group C -- Possible Human Carcinogen. Statistically significant increase in comparison to controls in liver adenomas & combined liver adenomas & carcinomas, as well as the statistically significant positive trend for these hepatocellular adenomas & combined adenomas & carcinomas; CD-1 mice (M).
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 two-year carcinogenicity study was conducted in male and female CD-1 HaM/ICR Swiss mice in which 125 mice/sex/dose were administered technical norflurazon in the diet at dose levels of 0, 85, 340, or 1360 ppm (0, 12.8, 58.7, or 218.8 mg/kg/day) for 100-104 weeks... Liver weight was increased by 9% and 15% in male and female mice at the 340 ppm dose level, and by 27% and 21% at the 1360 ppm dose level, respectively. The liver to body weight ratio was increased by 19% and 4% in male and female mice at the 340 ppm dose level, and by 43% and 19% at the 1360 ppm dose level, respectively. Increased incidences of enlarged spleen, nephritis, swollen/enlarged liver, and nodular enlargement of the liver were observed in high dose male mice, while increased incidences of pyelonephritis, enlarged liver, and cystic ovaries were observed in high dose female mice. Carcinogenic potential was evidenced by an increased incidence of hepatic adenoma and combined adenoma/carcinoma in high dose male mice. The systemic NOEL was determined to be 12.8 mg/kg/day (85 ppm) for male mice, and 58.7 mg/kg/day (340 ppm) for female mice. The systemic LEL was determined to be 58.7 mg/kg/day (340 ppm) for male mice, based on the increased incidence of enlarged spleen, increased absolute and relative liver weight, and increased incidence of nephritis. The systemic LEL was determined to be 218.8 mg/kg/day (1360 ppm) for female mice, based on the increased incidence of enlarged liver and cystic ovaries, the increased absolute and relative liver weight, and the increased incidence of pyelonephritis (guideline 83-2; MRID 00111649).
-- As a result of the July 18, 1990 meeting of the OPP/Health Effects Division Carcinogenicity Peer Review Committee, norflurazon was classified as a non quantifiable Group C - possible human carcinogen - based upon statistically significant pair-wise comparisons of the incidence of liver adenomas and combined liver adenomas/ carcinomas as well as statistically positive trends for these lesions in male CD-1 mice receiving 218.8 mg/kg/day norflurazon technical in the diet for up to 104 weeks (MRID 00111649).
-- A 2-generation reproductive toxicity study was conducted in male and female Wistar rats. In this study, norflurazon technical was administered in the diet at dose levels of 0, 150, 750, or 1500 ppm over 2 generations (0, 10.2, 50.8, or 102.5 mg/kg/day for F males; 0, 12.1, 0 62.0, or 129.7 mg/kg/day for F females; 0, 13.2, 67.8, or 138.6 0 mg/kg/day for F males; 17.1, 81.7, and 173.0 mg/kg/day for F1 1 females). The NOEL for systemic toxicity was determined to be 150 ppm (10.2 mg/kg/day for males and 12.1 mg/kg/day for females), and the systemic toxicity LEL was determined to be 750 ppm (50.8 mg/kg/day for males and 62.0 mg/kg/day for females), based on significant increases in liver and kidney weights observed in both generations of parental rats and the increased incidence of hepatocellular hypertrophy in both generations of parental rats...
Ref: US EPA REREGISTRATION ELIGIBILITY DECISION NORFLURAZON. LIST A. CASE 0229.

http://www.fluoridealert.org/PESTICIDES/Norflurazon.RED.EPA.pdf

Congestion of the liver, hepatocyte swelling and increased liver weights, and increase in colloid vacuole in the thyroid were observed in dogs fed 450 ppm (10.25 mg/kg/day) norflurazon for 6 months. The NOEL was 150 ppm (3.75 mg/kg/day). An oral RfD of 0.04 mg/ kg/day has been determined. Increased relative liver weight and hypertrophy of the thyroid with depletion of colloid were seen in rats fed 2,500 ppm (125 mg/kg/day) norflurazon for 90 days. The NOEL was 500 ppm (25 mg/kg/day). Hepatic hyperplasia and hypertrophy and increased relative liver weight were noted in a 28-day feeding study in rats. The LOEL was 1,000 ppm (50 mg/kg/day) and the NOEL was 500 ppm (25 mg/kg/ day). Increased relative liver weight and diffuse and smooth granular livers were seen in a 28-day feeding study in mice. The LOEL was 2,520 ppm (328 mg/kg/day) and the NOEL was 420 ppm (55 mg/kg/day). EPA believes that there is sufficient evidence for listing norflurazon on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available hepatic and thyroid toxicity data.
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.

The chronic NOAEL of 1.5 mg/kg/day was established based on increased absolute and relative liver weight and increased cholesterol in both sexes in a 6-month feeding study in dogs at the LOAEL of 4.77 mg/kg/day... The acute and chronic dietary exposure analyses are based on the Dietary Exposure Evaluation Model (DEEM TM .) The acute dietary exposure estimates used the entire distribution of single day food consumption. The chronic dietary exposure estimates the three day average consumption for each population subgroup. The DEEM TM analysis was conducted using consumption data from the USDA 1989-92 Continuing Surveys for Food Intake by Individuals (CSFII).
Ref: US EPA May 31, 2002. Tolerance Reassessment Progress and Risk Management Decision.

http://www.fluoridealert.org/pesticides/Norflurazon.TRED.May31.2002.pdf

Novaluron - Insecticide - CAS No. 116714-46-6

Toxicology Summary... The main toxicological effect noted in the animal database was oxidative stress and destruction of red blood cells (RBCs), most likely due to the action of an aniline metabolite (3-chloro-4-(1,1,2-trifluoromethoxy) aniline). As a result of erythrocyte destruction, secondary effects were observed in associated blood tissues/organs and included pigmentation in Kupffer cells in the liver as well as macrophages in the spleen... (page 10)
Ref: Proposed Registration Decision. PRD2006-05. Health Canada Pest Management Regulatory Agency. December 22, 2006.
http://www.fluorideaction.org/pesticides/novaluron.canada.12-22-06.pdf

-- Short-term incidental oral (1-30 days); Intermediate-term incidental oral (1-6 months); and Intermediate-term inhalation (1 to 6 months): 90-day feeding study in rat. LOAEL = 8.64 mg/kg/day based on clinical chemistry (decreased hemoglobin, hematocrit and RBC counts) and histopathology (increased hematopoiesis and hemosiderosis in spleen and liver).
-- Chronic toxicity - dog
. NOAEL= 10 mg/kg/day. LOAEL=100 mg/kg/day
based on hemat
ologic changes associated with histopathological changes in liver
and spleen.
-- Short-term, Intermediate-term and Long-term inhalation: LOAEL = 8.64 mg/kg/day based on clinical chemistry (decreased hemoglobin, hematocrit and RBC counts) and histopathology (increased hematopoiesis and hemosiderosis in spleen and liver)
Re: June 2, 2004. Novaluron; Pesticide Tolerance. Final Rule. Federal Register.
http://www.fluoridealert.org/pesticides/novaluron.fr.june.2.2004.htm

Noviflumuron -Insecticide - CAS No. 121451-02-3

“XDE-007: 18-Month Oncogenicity Study in CD-1 Mice,” (Johnson, K.A.; Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, MI; 4/25/05). XDE-007 technical (N-[3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3hexafluoropropoxy)phenyl]-N’-(2,6-difluorobenzoyl)urea), 97.9% pure) was fed in diet to CD-1 mice (50/sex/dose) at 0, 0.5, 3 (males only), 30 and 100 (females only) mg/kg/day for up to 18 months. Systemic NOEL = 3 mg/kg/day (males) and 30 mg/kg/day (females) There was an increase in mortality for females at 100 mg/kg/day (M: 56% vs 32%). There was an increased incidence in tonoclonic convulsions (primarily in females) at the high dose. There was an increase in relative and absolute liver weights in females at > 30 mg/kg/day. Males had an absolute liver weight increase at 30 mg/kg/day and a relative increase at > 3 mg/kg/day. Both sexes showed an increase in all severities of liver hypertrophy (hepatocytic, centrilobular/midzonal, diffuse) at 30 mg/kg/day (male) and at 100 mg/kg/day (female)... Possible adverse effect indicated: There was an increased incidence in hepatocytic adenomas and in hepatocytic adenomas plus carcinomas (slight in males, statistically significant in females) at 30 mg/kg/day (5, 7, 4, 12 of 50) and 100 mg/kg/day (F: 0, 1, 0, 4** of 50 by Peto’s mortality adjusted statistics ). Females showed an increased incidence in lung carcinomas (non-metastatic) at 100 mg/kg/day (0, 0, 1, 2** by Peto’s statistics).
-- “XDE-007: Two-Generation Dietary Reproduction Toxicity Study in CD Rats,” (Carney, E.W., Zablotny, C.L., Liberacki, A.B., Yano, B.L.;Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, MI; 3/22/04). XDE -007 (97.9% pure) was fed in diet to Crl:CD (SD) IGS BR rats (30/sex/dose/generation) at 0, 0.5, 5 or 25 mg/kg/day continuously from pre-mating of parental generation 1 (P1) through weaning of offspring through 2 generations (2 matings for P2 generation) to F2b weaning. Parental Systemic NOEL = 5.0 mg/kg/day (There were increased absolute and relative liver weights in both sexes of P1 and P2 adults at 25 mg/kg and in P1 female liver weights at 5.0 mg/kg...
Ref: August 2005 - Summary of toxicological data. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.
http://www.fluorideaction.org/pesticides/noviflumuron.ca.epa.2005.pdf

-- (Oral) 008; 186500; "XR-007: 4-Week Dietary Toxicity Study in Fischer Rats" (Lick, S.J. et al., Health & Environmental Research Laboratories, The Dow Chemical Company, Midland, MI, Laboratory Project Study ID 971106, 10/9/97). XR-007 (Lot # DECO-615-112, purity = 99.6%) was admixed to the feed and fed to 5 Fischer 344 rats per sex per dose at dose levels of 0, 1, 10, 100, 500, or 1000 mg/kg/day (0, 1.0, 10.4, 101.4, 512.6, 1029.1 mg/kg/day, respectively for males and 0, 1.1, 10.9, 105.1, 520.6, 1055.6 mg/kg/day, respectively for females) for 4 weeks... A treatment-related increase in mean relative liver weight was observed in both sexes at 500 and 1000 mg/kg/day. Microscopic examination revealed treatment-related hepatocellular hypertrophy (centrilobular) in males at 1000 mg/kg/day and in females at 500 and 1000 mg/kg/day. No adverse effects. NOEL (M) = 101.4 mg/kg/day and NOEL (F) = 105.1 mg/kg/day (based on an increase in mean relative liver weight and hepatocellular hypertrophy). Supplemental (because only 5 animals per sex per dose were used, the animals were treated for only 4 weeks, no ophthalmological examinations were conducted, and no analysis of the dosing material was conducted). (Corlett, 10/3/02)
-- 007; 186499; "XDE-007: 28-Day Dietary Toxicity Study in CD-1 Mice" (Yano, B.L. and Day, S.J., Toxicology & Environmental Research and Consulting, The Dow Chemical Company, Midland, MI, Laboratory Project Study ID 001248, 6/12/01). XDE-007 (Lot, Reference No. F0031-148, TSN102332, purity = 98.4%) was admixed to the feed and fed to 5 CD-1 mice per sex per dose at dose levels of 0, 10, 100, 500, or 1000 mg/kg/day (0, 10.8, 110, 538, 1060 mg/kg/day, respectively for males and 0, 11.2, 113, 504, 1140 mg/kg/day, respectively for females) for 28 days. No mortalities occurred. No treatment-related clinical signs were observed. Treatment-related increases in mean platelet level and mean cholesterol level were observed in both sexes at 100, 500, and 1000 mg/kg/day. A treatment-related increase in mean relative liver weight was observed at in males at 100, 500, and 1000 mg/kg/day and in females at 500 and 1000 mg/kg/day. Microscopic examination revealed treatment-related hepatocellular hypertrophy with altered tinctorial properties (centrilobular/midzonal to panlobular) in males at 500 and 1000 mg/kg/day and very slight vacuolation (consistent with fatty change) of the periportal hepatocytes in males at 500 and 1000 mg/kg/day and in females at 1000 mg/kg/day. No adverse effects. NOEL (M) = 10.8 mg/kg/day and NOEL (F) = 11.2 mg/kg/day (based on increases in mean platelet and mean cholesterol levels). Supplemental (because only 5 animals per sex per dose were used and because the animals were treated for only 28 days). (Corlett, 9/30/02)

Ref: September 26, 2002. Summary of Toxicology Data for Noviflumuron ((XDE-007) or N-(((3,5-dichloro-2-fluoro-4-(1,1,2,3,3,3-hexafluoropropoxy)phenyl)amino)carbonyl)-2,6- diflurobenzamide. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.
http://www.fluoridealert.org/pesticides/Noviflumuron.CA.EPA.2002.pdf

Nuarimol - Fungicide - CAS No. 63284-71-9

Abstract: Early hepatic changes induced by nuarimol (63284719) were studied in rats. Male Wistar-rats were administered 0, 31.5, 62.5, or 125mg/kg nuarimol orally daily for up to 5 days. Selected rats were killed after 1, 3, or 5 days of exposure or 10 days after the last dose and weighed. The livers were removed and weighed and liver tissues were assayed for p-nitroanisole-O-demethylase (PNAD). The DNA was isolated and the effects of nuarimol on DNA synthesis were evaluated by measuring uptake of tritiated thymidine. Fragments of liver tissue were examined for histopathological changes. The number of hepatocytes undergoing mitosis was determined. Nuarimol did not affect body weight. Administration of three doses of 62.5 and 125mg/kg nuarimol significantly increased relative liver weight. The 31.5mg/kg dose did not affect liver weight. PNAD activity was significantly increased after the first doses of 62.5 and 125mg/kg nuarimol. Three doses of 31.5mg/kg nuarimol were required to induce a significant increase in PNAD activity. Single doses of nuarimol caused a dose dependent increase in DNA synthesis and the mitotic index. After three and five doses, the level of DNA synthesis decreased, returning to the control level after five doses. After five doses of 31.5, 62.5, and 125mg/kg nuarimol mitotic activity returned to the control value. Nuarimol caused time dependent increases in the number of binucleated hepatocytes. One and three administrations caused a dose related increase in cytoplasmic vacuolization and focal destruction of centrilobular hepatocytes. These changes partially disappeared after five doses. The authors conclude that the early hepatic effects of nuarimol include increases in PNAD activity and cellular hyperplasia, as manifested by increases in the level of DNA synthesis and mitotic activity. The increase in the number of binucleated hepatocytes and signs of necrosis suggest that the hepatomitogenic effect of nuarimol may reflect a regeneration response.
Ref: Kostka G et al (1994). Early Hepatic Changes Induced by Nuarimol in Rats. Journal of Applied Toxicology, Vol. 14, No. 5, pages 337-342. As cited at Toxnet.

Exposure to nuarimol causes both acute and chronic effects. It is moderately acutely toxic, with a WHO classification of Class III, or "slightly hazardous" and a rat oral LD50 of 1250 mg/kg. (24) DowElanco data indicates a single oral as well as inhalation exposure of the product caused laboratory rats to exhibit reduced activity, clonic convulsion (muscle contraction), ataxia (loss of balance and coordination), labored breathing, reduced weight gain, and coma. Laboratory animals exhibited increases in liver weight and enzyme activity and microscopic liver cell changes when repeatedly exposed to the product. (8) The product is also an eye irritant. (8,16,21) As mentioned above, EPA has concerns over the product's ability to cause cancer and birth defects in lab animals. (10)
Ref: NEVER-REGISTERED PESTICIDES: Rejected Toxics Join the "Circle of Poison." Greenpeace USA Pesticide Campaign report. By Sandra Marquardt, Laura Glassman and Elizabeth Sheldon. February 1992.

http://www.fluoridealert.org/pesticides/Nuarimol.Greenpeace.1992.htm

Oxyfluorfen - Herbicide - CAS No. 42874-03-3

Group C -- Possible Human Carcinogen. Liver (adenomas, carcinomas 7 combined adenomas and/or carcinomas); CD-1 mice (M).
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

Oxyfluorfen is a phenoxyphenyl-type herbicide. Several chronic oral toxicity studies suggest that oxyfluorfen may be hepatotoxic. Hepatic effects (e.g. increased absolute liver weight, necrosis, regeneration, and hyperplastic nodules) were observed in mice fed diets containing greater than 3 mg/kg/day oxyfluorfen for 20 months (the NOEL was 0.3 mg/kg/day). Based on these findings, an oral RfD value of 0.003 mg/kg/ day was derived. This study was supported by other chronic feeding studies that demonstrated increases in liver weight, alkaline phosphatase activity, and bile pigmented hepatocytes (the LOEL was 15 mg/kg/day; the NOEL was 2.5 mg/kg/day) in dogs, and minimal hypertrophy of centrilobular hepatocytes (the LOEL was 40 mg/kg/day; the NOEL was 2 mg/kg/day) in rats. EPA believes that there is sufficient evidence for listing oxyfluorfen on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the hepatotoxic effects of this chemical.
Ref: USEPA/OPPT. Support Document for the Health and Ecological Toxicity Review of TRI Expansion Chemicals. 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.

Microscopic changes observed at 12 months included binucleate hepatocytes (6/10), central lobular hepatocyte hypertrophy (7/10), and enlarged hepatocyte nuclei (6/10) in high dose females compared to 0/5 for controls. Similar changes were not seen at the terminal sacrifice, despite the fact that the animals received higher doses during the last 12 months of the study. Therefore the findings at 12 months may be an adaptive effect... The microscopic liver and kidney lesions were generally classified slight in mid-dose animals and slight to moderate in high-dose animals... The only treatment-related histopathological lesion in the liver was slight to moderate bile pigmented hepatocytes in both sexes after 104 weeks (n.s.) and hepatocellular vacuolization was seen in high-dose females.
Ref: US EPA. Toxicology Chapter for RED. August 8, 2001.

http://www.epa.gov/oppsrrd1/reregistration/oxyfluorfen/oxytoxchapter.pdf

Penoxsulam - Herbicide - CAS No. 219714-96-2

-- Subchronic toxicity. Dietary exposure to penoxsulam identified the liver and/or urinary tract (kidneys and bladder) as target organs in rats, mice, and dogs following a 4-week and 13-week administration. Effects on the liver were reflected in increased liver weights and hepatocellular hypertrophy, but these effects were not associated with increases in mixed function oxidase (MFO) enzyme activity... Other than the crystal deposition in the kidneys, all effects following subchronic exposure to rats appeared to be reversible. Very high doses were associated with significant decreases in body weight, weight gain, and feed consumption.
-- Reproductive and developmental toxicity. Penoxsulam did not have any effect on reproductive parameters at dose levels that induced treatment-related effects in parental rats. At the highest dosage tested (HDT) (300 mg/kg/day), body weights and weight gains in both males and females were depressed, liver and/or kidney weights were increased, and histologic changes were noted in the liver (males) and kidneys (females). At 100 mg/kg/day, increased liver weights were recorded in males, with no histologic correlate, and histologic changes noted in the kidneys of females...
Ref: August 6, 2003. Federal Register: August 6, 2003 (Volume 68, Number 151)] [Notices] [Page 46609-46613]. Penoxsulam; Notice of Filing a Pesticide Petition To Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

http://www.fluorideaction.org/pesticides/penoxsulam.fr.aug.6.2003.htm

Perfluidone - Herbicide - CAS No. 37924-13-3

-- Subchronic toxicology effects of perfluidone are as follows: - A 90-day dog feeding study showed liver disorders (hepatic lesions, hepatocyte vacuolation, hyaline degeneration, and biliary stasis) at the two highest dose levels (400 and 800 ppm).
-- The Agency (US EPA) is not conducting a tolerance reassessment on perfluidone, because the only use is on flue-cured tobacco. This use is a nonfood and non-feed use which does not require a tolerance. Therefore, the Agency will not require residue chemistry data on the metabolism of perfluidone and related metabolite(s) in crops and animals.
Ref: Chemical Fast Sheet for Perfluidone. Number 74. Date Issued: September 30, 1985.

http://www.fluoridealert.org/pesticides/Perfluidone.Fact.Sheet.1985.htm

Abstract: The influence of perfluidone (37924133) on oligomycin inhibited mitochondrial respiration was investigated in-vitro. Mitochondria were prepared from albino Wistar-rats and incubated with pyruvate-malate, succinate, or ascorbate N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD) as substrate. Aliquots of 50 nanomolar adenosine-diphosphate, oligomycin, and perfluidone at concentrations from 0 to 160 millimolar (mM), or carbonylcyanide-p-trifluoromethoxyphenyl-hydrazone (FCCP), a classic protonophore, were added at specific time intervals. Oxygen consumption was measured polarographically. The effect of varying concentrations of perfluidone on oligomycin sensitive mitochondrial adenosine-triphosphatase (ATPase) was also determined. With succinate as substrate, respiratory rates increased from 29.5 nanogram atoms oxygen/milligram mitochondrial protein/minute (ng/mg/minute) to 85.4ng/mg/minute after adding 40mM perfluidone. The extent of respiration stimulation by perfluidone increased with increasing concentrations. After adding FCCP at 1microM, the oligomycin inhibited respiratory rate of 31.4ng/mg/minute was increased to 151.3ng/mg/minute. The respiratory rate was increased in a dose dependent fashion at perfluidone concentrations up to 80microM which gave a maximum stimulation of about 5 fold. At higher concentrations of perfluidone the extent of stimulation of respiration decreased. Similar results were obtained when respiration was supported by pyruvate-malate. Maximum sensitivity to perfluidone, about 5 fold stimulation, was obtained at 100microM and decreased at higher concentrations. When ascorbate TMPD was used as the substrate, a 2 fold stimulatory effect was obtained at 20microM perfluidone; maximum effect was apparent at 80microM perfluidone and respiration was decreased at higher concentrations. The authors conclude that perfluidone probably increases the permeability of the inner mitochondrial membrane to protons, as does FCCP, and acts as a classic protonophore.
Ref: Olorunsogo OO et al. (1985). Sensitivity Of Oligomycin-Inhibited Respiration Of Isolated Rat Liver Mitochondria To Perfluidone, A Fluorinated Arylalkylsulfonamide. Toxicology, Vol. 35, No. 3, pages 231-240

PFOS - PFOS - Insecticide, US EPA List 3 Inert

Due to length, click here for effects page


Picolinafen - Herbicide - CAS No. 137641-05-5

-- Fat, liver and kidneys contained the highest amounts of picolinafen metabolites labelled on the pyridine ring, whereas the blood, liver, spleen and lungs contained the highest amounts of picolinafen metabolites labelled on the aniline ring.
-- Short-Term Studies All mice fed picolinafen at dietary concentrations of 0, 100, 1000, 2000, 3500 or 7000 ppm for 28 days... Discolouration of the extremities, discoloured organs (kidney, liver, lungs, testes and heart) and haematological changes (increased MCH, MCHC, reticulocyte and Heinz bodies numbers) were observed at 3500 and 7000 ppm. Spleen and liver weights were increased at 2000 ppm and the breakdown products of blood cells accumulated in the liver and spleen and the production of blood cells in the spleen were increased in males at 1000 ppm and females at 2000 ppm. The severity of these histopathological changes increased in a dose-related manner.
-- In a study in which groups of two dogs per sex were fed picolinafen at dietary concentrations of 0, 100, 1000, 2000, or 10000 ppm for 28 days, ... Livers were enlarged, liver weights and liver glycogen increased and serum cholesterol was increased in males at 1000 ppm and females at 2000 ppm.
-- In mice fed picolinafen at dietary concentrations of 0, 50, 500, 1000 or 2000 ppm for 13 week... Liver weight and pigment deposition were increased at 2000 ppm with other histopathological changes observed in the liver of males at 500 ppm and females at 1000 ppm. The spleens of some mice were enlarged and spleen weights were increased in females at 1000 ppm...
- In rats fed picolinafen at dietary concentrations of 0, 80, 400 or 800 ppm ... Liver to body weight ratios were increased in males at 800 ppm and females at 400 and 800 ppm. Pigment deposition was increased in the liver and spleen at 400 and 800 ppm. The NOEL in this study was 80 ppm, equal to 6.4 mg/kg bw/day in males and 6.8 mg/kg bw/day in females.
-- Long-Term Studies In mice fed picolinafen at dietary concentrations of 0, 40, 400 or 800 ppm for 18 months, there was no increase in the incidence of neoplasms... Increased liver weights and histopathological changes were observed in females at 800 ppm with histopathological changes observed in the livers of males at 400 and 800 ppm.
Ref: Public Release Summary on Evaluation of the new active PICOLINAFEN in the products SNIPER HERBICIDE & PARAGON HERBICIDE. Australia. National Registration Authority for Agricultural and Veterinary Chemicals November 2000.

http://www.nra.gov.au/publications/prspic.pdf

Following subchronic and chronic administration, mice also exhibited treatment-related findings in the liver, including centrilobular hepatocellular hypertrophy and hepatocellular vacuolation. These were noted following 28-day, 90-day and 78-week dietary administration. The NOAELs for mice were 23.4, 10.2, and 6.9 mg/kg bw/d following 28-day, 90-day, and 78-week dietary administration, respectively.
Ref: February 17, 2003 - Canada. Picolinafen. Regulatory Note REG2003-02. Alternative Strategies and Regulatory Affairs Division, Pest Management Regulatory Agency.
http://www.fluorideaction.org/pesticides/picolinafen.canada.feb.2003.pdf

Primisulfuron-methyl - Fungicide, Herbicide- CAS No. 86209-51-0

-- Chronic toxicity: Doses of 125 mg/kg/day administered in the diet to dogs over a 1-year period produced decreased body weight gain, anemia, increased liver weight, and thyroid hyperplasia (abnormal growth) [15]...
-- Reproductive effects: Changes in the function of the testes were noted in rats fed high doses (250 mg/kg/day) of primisulfuron-methyl over two generations. There was also a decrease in the body weight of the offspring. No compound-related effects on reproduction were noted at doses below 50 mg/kg/day [15]. Testicular atrophy was seen in rats in chronic studies (see above),
which could result in reproductive effects. The available data suggest that reproductive effects in humans due to primisulfuron are not likely under normal circumstances.
-- Organ toxicity: Target organs identified in animal studies include the liver, kidneys, spleen, and testes
, as well as the skeleton.
Ref: E X T O X N E T Extension Toxicology Network Pesticide Information Profiles. Revised June 1996.

http://ace.ace.orst.edu/info/extoxnet/pips/primisul.htm

-- Chronic toxicity. EPA has established the RfD for primisulfuron- methyl at 0.006 milligrams/kilogram/day (mg/kg/day). This RfD is based on an 80-week mouse feeding study with a LOEL of 1.7 mg/kg/day based on increased absolute and relative liver weights. An uncertainty factor of 300 was used because a NOEL was not achieved.Carcinogenicity. Primisulfuron-methyl has been classified as a Group D chemical incomplete evidence based on liver tumors in mice.
Ref: Federal Register: December 17, 1997.Primisulfuron-methyl; Pesticide Tolerances for Emergency Exemptions. Final Rule.

http://www.fluoridealert.org/pesticides/Primisulfuron-methyl.FR.97.htm


In a 1-year dog study, dietary administration of 250/125 mg/kg/day (LOEL: the dose was changed after week 10 in the study) produced thyroid hyperplasia, anemia, increased platelet levels, vacuolar changes, and increased absolute and relative liver weights. The NOEL was 25 mg/kg/day. In an 18-month study in mice, dietary administration of 1.7 mg/kg/day produced increased absolute and relative liver weights in females. No NOEL was established. Based on this study, an oral RfD of 0.006 mg/kg/day was derived. In a 2-year mouse study, increases in absolute and relative liver weights were observed at 408 mg/kg/day in males and 1.7 mg/kg/day in females. The systemic LOEL and NOEL in males was 408 mg/kg/day and 40.2 mg/kg/day, respectively. The systemic LOEL in females was 1.7 mg/kg/day and a NOEL could not be established. EPA believes that there is sufficient evidence for listing primisulfuron on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available thyroid and liver 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.

Prodiamine - Herbicide - CAS No. 29091-21-2

-- Chronic/Subchronic Toxicity Studies. Prodiamine: Liver (alteration and enlargement) and thyroid effects (hormone imbalances) at high dose levels (rats); decreased body weight gains.
-- Carcinogenic Potential. Prodiamine: Benign thyroid tumors (rat). None observed (mouse).
-- Target Organs. Prodiamine: Liver and Thyroid.
Ref: Material Safety Data Sheet for Barricade 65WG Herbicide. Novartis. February 28, 2000.

http://www.fluoridealert.org/pesticides/Prodiamine.MSDS.2000.pdf

Profluralin - Herbicide - CAS No. 26399-36-0

(FAN NOTE: Very little Tox data available)
-- Lifetime feeding studies with high dose levels of profluralin technical have produced an increased incidence of hepatic tumors in mice.
Ref: March 1985. Profile of Herbicide (Tolban). Pesticide Management Education Program at Cornell Univeristy.

http://www.fluoridealert.org/pesticides/Profluralin.Tolban.1985.fct.htm

Prosulfuron - Herbicide - CAS No. 94125-34-5

-- Short term toxicity Target / critical effect: Liver (hepatocyte hypertrophy), heart (myocardial degeneration), hematopoietic system (red blood cells decreased) Lowest relevant oral NOAEL / NOEL: NOAEL = 6 mg/kg b.w./day (90-day, dog)
-- Long term toxicity and carcinogenicity Target / critical effect: Liver (hepatocellular hypertrophy in mice), indication of hormonal disruption (uterus and mammalian gland in rats) at high dose levels Lowest relevant NOAEL: NOAEL = 1,7 mg/kg bw/day (18-month, mouse) Carcinogenicity: No carcinogenic potential
Ref: July 2, 2002 - Review report for the active substance prosulfuron. European Commission Health & Consumer Protection Directorate-General.

http://www.fluoridealert.org/pesticides/Prosulfuron.EU.July.2002.pdf

-- In an 18-month mouse carcinogenicity study, prosulfuron was administered at dose levels of 0, 1.71, 81.4, 410 or 832 mg/kg/day (males), and 0, 2.11, 100, 508 or 1,062 mg/kg/day (females). There was no evidence of carcinogenic effects up to 1,062 mg/kg/day, the HDT. The NOAEL was 1.71 mg/kg/day in males, and 100 mg/kg/day in females based on increased incidence/severity of centrilobular hepatocellular hypertrophy.
-- Chronic toxicity. Prosulfuron was fed to dogs at dosages of 0, 0.33, 1.95, 18.6 or 41.0 mg/kg/day (males) and 0, 0.31, 1.84, 20.2, or 48.8 mg/kg/day (females) for 1-year. The NOAEL was 1.84 mg/kg/day based on hematologic and clinical chemistry effects and incidence of lipofuscin accumulation in the liver at 18.6 mg/kg/day.
Ref: Federal Register: August 25, 1999. [PF-882; FRL-6093-7]. Notice of Filing a Pesticide Petition to Establish a Tolerance for Certain Pesticide Chemicals in or on Food.

http://www.fluorideaction.org/pesticides/prosulfuron.fr.aug.25.1999.htm

Pyraflufen-ethyl - Herbicide - CAS No. 129630-19-9

Likely to be Carcinogenic to Humans. Hepatocellular adenomas and combined adenomas, carcinomas and/or hepatoblastomas in male and female (SPF) ICR (Crj:CD-1) mice.
Ref:
April 26, 2006 . Chemicals Evaluated for Carcinogenic Potential by the Office of Pesticide Programs. From: Jess Rowland, Chief Science Information Management Branch Health Effect Division (7509C) Office of Pesticide Programs, USEPA.
http://www.fluorideaction.org/pesticides/pesticides.cancer.potential.2006.pdf

-- Short term toxicity Target / critical effect: Liver, kidney, red blood cells. Lowest relevant oral NOAEL / NOEL: 200 ppm (20 mg/kg bw/d) 90 day mouse (satellite group in 78 wk study)
-- Long term toxicity and carcinogenicity Target / critical effect: Red blood cells and liver in mice, urinary and biliary tract in rats.Lowest relevant NOAEL: 200 ppm (20 mg/kg bw/d ) 2 year mice study 400 ppm ( 20 mg/kg bw/d) 2 year rat study. Carcinogenicity: Increased incidence of hepatocellular adenomas in mice at hepatotoxic doses, not carcinogenic in rats. Classification and labelling not appropriate.
-- Other toxicological studies. Accumulation of porphyrins in all organs except skin and Harderian glands. Inhibitor of some liver P450 dependent activities; inhibitor of catalase. Induction of liver single cell necrosis followed by mitosis.
Ref: July 2, 2002 - Review report for the active substance pyraflufen-ethyl. European Commission Health & Consumer Protection Directorate-General.

http://www.fluoridealert.org/pesticides/Pyraflufen-eth.EU.July.2002.pdf

Pyridalyl - Insecticide - CAS No. 179101-81-6

Subchronic toxicity.
-- Pyridalyl technical was tested in rats in a 3-month feeding study. Effects included decreased body weight gain, altered blood biochemistry,
increased relative liver weight and histopathological changes in the liver, ovary, adrenal and lung. The NOAEL is 100 ppm (5.56 mg/kg/day in males and 6.45 mg/kg/day in females).
-- A 13-week feeding study in mice was conducted. Effects included decreased body weight gain, hematological and blood biochemical effects, increased liver weight, decreased kidney and ovary weights and histopathological changes in liver, kidney, ovary and adrenal. The NOAEL is 70 ppm in males (8.169 mg/kg/day) and 700 ppm in females (86.78 mg/kg/day).
-- A 13-week oral (capsule) toxicity study was conducted in
dogs. Effects included decreased body weight gain, clinical signs indicative of respiratory distress, hematological and blood biochemistry effects, increased liver, lung and kidney weights and histopathological alterations of the lung, kidney, adrenal and liver. The NOAEL was 10 mg/kg/day.
Chronic toxicity.
-- Pyridalyl was administered in the diet to mice for 78-weeks. Effects included decreased body weight gain and food consumption/efficiency, and increased liver and kidney weights. The NOAEL of the study was 50 ppm (5.04 mg/kg/day in males and 4.78 mg/kg/day in females)
-- Pyridalyl was administered for 12-months by capsule to
dogs. There were alterations in blood biochemistry (alkaline phosphatase and alanine aminotransaminase) and increased liver weights. The NOAEL of the study was 20 mg/kg/day.
Ref: Federal Register: December 5, 2003. Pyridalyl; Notice of Filing a Pesticide Petition.
http://www.fluorideaction.org/pesticides/pyridalyl.fr.dec.5.2003.htm

 
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