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

Acifluorfen, sodium - Herbicide - CAS No. 62476-59-9

Carcinogenicity. Acifluorfen has been classified as a Group B2 (probable human carcinogen) chemical by the OPP Cancer Peer Review Committee (CPRC), based on an increased number of liver tumors in both sexes of mice and a high incidence of uncommonly occurring stomach papillomas in male mice. The Committee recommended using the Q1* approach for quantification of human risk. The Q1* is 0.11 (mg/kg/day)-1.
Ref: Federal Register. July 25, 1997. Sodium Salt of Acifluorfen; Pesticide Tolerances for Emergency Exemptions. Final Rule.
http://www.epa.gov/fedrgstr/EPA-PEST/1997/July/Day-25/p19668.htm

Male mice had a significant increasing trend, and significant differences in the pair-wise comparisons of all dose groups with the controls, for liver adenoma and/or carcinoma tumors combined.
Ref: MEMORANDUM. November 8, 2001. SUBJECT: REVISED Sodium Salt of Aciflourfen (Tackle TM , Blazer TM ) Quantitative Risk Assessment (Q1 * ) Based On B6C3F1 Mouse Dietary Study Using mg/kg b.w.^ 3 /4 's/day Cross Species Scaling Factor. http://www.fluorideaction.org/pesticides/acifluorfen.na.cancer.nov01.pdf

Ammonium bifluoride - Wood Preservative - CAS No. 1341-49-7

PubMed Abstract: Male Wistar rats were exposed to NH4F in concentration corresponding to mean annual limit of fluoride compounds in the atmospheric air. After 3, 6 and 9 months a microsomal fraction was isolated from the liver, and the composition as well as the metabolic activity of this fraction was determined. The content of microsomal protein increased after 3-month-long period of experiment, and subsequently it dropped after the period of 9 months. The content of phospholipids decreased after 3 months. The content of microsomal cholesterol was particularly high after a 6-month-long experiment. There were also changes in the contents of individual phospholipid fractions, and fatty acids of phospholipids. The content of cytochrome P-450, cytochrome b5 and activity of NADH-cytochrome b5 reductase did not change. Activity of NADPH-dependent reductase of cytochrome c--decreased after the period of 9 months. Moreover, as consequence of changes in the activity of cytochrome P-450 system and the endoplasmic reticulum composition, alterations were observed in the metabolism of the tested substrates i.e. aniline and aminopyrine. The aniline turnover was inhibited after 6 and that of aminopyrine after 9 months experiment. The observed changes may prove that the detoxication capacity of the liver was impaired due to being exposed to ammonium fluoride.
Ref: Juzyszyn Z (1991). [Chronic effect of ammonium fluoride on selected parameters of microsomal fracture of the rat liver with special reference to the cytochrome P-450 system]. Ann Acad Med Stetin. 1991;37:49-64.

Benfluralin (Benefin) - Herbicide - CAS No. 1861-40-1

"Benefin: 13-Week Oral Toxicity Study in Beagle Dogs", (D.W. Dalgard, Hazleton Washington, HWA 174-135, 12/28/93). Benefin, purity 95.8%, administered via capsule at concentrations of 0, 5, 25, 125 mg/kg/day to 4 Beagle dogs/sex/group for 13 weeks. Emesis (compound colored) was slightly increased at all dose levels for females and for mid and high dose males. Liver weights was increased for high dose males; and the incidence of hepatocellular hypertrophy was increased for high dose males and females. Increased incidence of hemosiderin pigment was observed in the liver at the high dose and the spleen at mid and high dose levels. NOAEL = 5 mg/kg/day. Acceptable (Kishiyama, J., and P. Iyer, 5/12/98).
Ref: Summary of Toxicology Data for Benefin. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch
http://www.cdpr.ca.gov/docs/toxsums/pdfs/53.pdf

COMBINED, RAT **208-079 167288, :Benefin: Two-Year Dietary Chronic Toxicity/Oncogenicity Study in Fischer 344 Rats", (Michael R. Moore, Corning Hazleton Inc, Vienna, VA., Laboratory ID # CHV 174-133, Sponsor Report # DR-0097-3397-005, 1 July 1996). Fifty CDF ¨ (F-344)CrlBR rats per sex per group received benefin in the diet at 0, 10, 100, 2500, and 5000 ppm for 2 yr. An additional 10 per sex per group at the same dose levels were designated for 1-yr interim sacrifice. Estimated achieved dosages were 0, 0.5, 5.4, 136, and 275 mg/kg/day in males, and 0, 0.7, 6.8, 168, and 331 mg/kg/day in females, respectively over weeks 1-104. Chronic NOEL = 10 ppm (0.5 and 0.7 mg/kg/day in M and F), based on increased hyaline droplets in kidneys of both sexes at 100 ppm and above, increased and tubular cell karyomegaly and transitional cell hyperplasia in kidneys of males, hepatocellular hypertrophy and increased hepatocellular pigmentation in females, and calculus of renal pelvis in females. Substantial toxicity prompted investigators to determine that the two highest dose levels "exceeded the maximum tolerated dose and therefore should not be used for risk assessment". The study design, with no dose levels between 100 and 2500 ppm, gave no opportunity to characterize dose-response in this range of primary interest. These were major changes at the highest two dose levels (in both sexes, unless indicated), in addition to the findings for the NOEL (above) applying to both sexes. Body weights were reduced over time (in males, primarily in last few weeks of the study), so that at termination the deficits of 2500 and 5000 ppm groups compared to controls were 8 and 17% in males, and 18 and 28% in females, respectively. In females only, this was accompanied by approximately 10% food consumption reductions at each of the higher dose levels. There were reductions in the main hematology parameters (RBC counts, HCT, and Hb levels). Incidence and/or degree of chronic progressive nephropathy was increased. The majority of these rats had "slight" to "minimal" degeneration of sciatic nerve and skeletal muscle (thigh). Males had elevated incidence of single cell necrosis in liver. Chronic inflammation of the lungs was seen in the majority of these rats, whereas low incidences of congestion of the abdominal cavity, and urinary bladder hyperplasia were limited to these dose levels. Numerous clinical chemistry changes mirrored the above pathology in kidneys, liver, and perhaps other tissues at the higher two dose levels. Tumor incidence: thyroid follicular tumors (adenomas and carcinomas) increased in males (incidences of 1, 1, 1, 7, and 8 in controls through high dose, respectively) and females (incidences of 0, 0, 1, 5, and 4). Hepatocellular tumors (primarily adenomas) were increased in males (incidences of 2, 2, 1, 5, and 11 in controls through high dose, respectively). There were no statistically significant increases in epithelial cell tumors in kidneys nor urinary bladder, however the low incidences of transitional cell papilloma and tubule cell adenoma or carcinoma were predominantly found in 2500 and 5000 ppm groups (compare to the congener, trifluralin). Study is acceptable. Tumors are possible adverse effects, which should be evaluated in perspective of the many indications of excessive exposures at effective dose levels. Green and Aldous, 4/11/00.
Ref: Summary of Toxicological Data: Benefin. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch. Revised April 21, 2000.
http://www.fluorideaction.org/pesticides/benefin.ca.tox.rev.apr.2000.pdf

Benthiavalicarb-isopropyl - Fungicide - CAS No. 177406-68-7

• In a 2-generation reproduction study in Sprague Dawley rats receiving 0, 100, 1,000 or 10,000 ppm benthiavalicarb-isopropyl in the diet, the parental noobserved adverse effect level (NOAEL) was 100 ppm based on hepatocyte hypertrophy at the next higher dose level. The reproductive NOAEL was 10,000 ppm.
• In a developmental toxicity study in New Zealand White rabbits receiving 0, 10, 20 or 40 mg/kg/day benthiavalicarb-isopropyl from day 6 to 28 of gestation, the maternal NOAEL was 20 mg/kg/day based on abortion and increased liver weights at the 40 mg/kg/day dose.
• In a developmental toxicity study in Sprague Dawley rats receiving 0, 10, 100 or 1,000 mg/kg/day from day 7 to day 19 of
gestation, the maternal NOAEL was 10 mg/kg/day based on elevated liver and adrenal weights at 100 mg/kg/day. The NOAEL for developmental toxicity was 1,000 mg/kg/day.
• In the 13-week feeding study with mice, the dose levels were 0, 50, 200, 7,000, or 20,000 ppm. The NOAEL was 200 ppm (equivalent to 33.0 mg/kg/day and 45.2 mg/kg/day in males and females, respectively, based on systemic toxicity of decreased body weights, anemias, and generalized liver toxicity at 7,000 ppm.
• In the 3 month dog feeding study the dose levels were 0, 40, 200, or 1,000 mg/kg/day. The NOAEL was 40 mg/kg/day based on hematological and clinical chemistry changes, organ weight changes and the findings of hepatocyte hypertrophy and pigmentation in the spleen at 200 mg/kg/day.
.• In a chronic/oncogenicity study Fisher rats received 0, 50, 200, 5,000, or 10,000 ppm of benthiavalicarb- isopropyl for up to 104 weeks. The NOAEL was 200 ppm (9.9 mg/kg/day and 12.5 mg/kg/day in males and females respectively), based on a variety
of toxic effects, primarily in the liver and kidney, and adenocarcinomas of the uterus at 5,000 ppm.
• In an oncogenicity study in mice, the dietary doses were 0, 20, 100, 2,500 or 5,000 ppm. The NOAEL was 100 ppm (13.7 mg/kg/day and 18.6 mg/kg/day in males and females, respectively) based on a variety of toxic effects, primarily in the liver and kidney, and hepatocellular blastoma and carcinoma at 2,500 ppm.
• In a 52-week study with Beagle dogs, the dietary dose levels were 0, 4, 40, or 400 mg/kg/day. The NOAEL was 40 mg/kg/day based on increased liver weights in males and females at 400 mg/kg/day.
• Numerous supplemental mechanistic studies in the rodent were carried out to further elucidate the mechanisms involved in tumor formation in the lifetime rodent studies. These studies indicated that benthiavalicarb-isopropyl behaves like a promotor following initiation with diethylnitrosamine (DEN), and does not have initiating activity. The compound did not cause oxidative damage in studies on rat or mouse liver, was a slight enzyme inducer, and did not cause hepatocyte proliferation.
Ref: March 9, 2005. Petition for the establishment of Tolerances on Imported Grapes and Tomatoes. Federal Register: March 9, 2005.

Benzotrifluoride - (also known as Trifluoromethylbenzene) - Insecticide - CAS No. 98-08-8

-- Trifluoromethylbenzene was studied for oral toxicity in Crj:CD (SD) rats in an OECD combined repeat dose and reproductive/developmental toxicity screening test at doses of 0, 20, 100 and 500 mg/kg/day. With regard to repeated dose toxicity, effects on liver and kidney were observed in both sexes given more than 100 mg/kg, indicating a NOEL is of 20 mg/kg/day for both sexes...
-- Test Results: ... As necropsy findings, renal hypertrophy and discoloration were observed in males of the 500 mg/kg group. Increase kidney weights in males given more than 100 mg/kg and in females of the 500 mg/kg group, and increased liver weights in males given more than 100 mg/kg were observed. On histopathological examination, centrilobular hepatocyte hypertrophy in both sexes, and hyaline droplets, necrosis, basophilic change and dilatation of renal proximal tubules in males were noted in the 100 and 500 mg/kg groups. Therefore, the NOEL is considered to be 20 mg/kg/day for both sexes.
Ref: 1988. GINC: Global Information Network on Chemicals. The Databases of Chemicals. http://www.fluorideaction.org/pesticides/benzotrifluoride.toxicity.htm

Bifenthrin - Acaricide, Insecticide - CAS Numbers: 82657-04-3 (Cis); 83322-02-5 (Trans)

A chronic/carcinogenicity study in mice fed at doses of 0, 50, 200, 500, or 600 ppm (0, 2.5, 10, 25, or 30 mg/kg/day) in the diet for 87 weeks (males) or 92 weeks (females). Chronic LOEL is 10 mg/kg/day based on the incidence of tremors in both sexes. Chronic NOEL is 2.5 mg/kg/day. Carcinogenic potential was evidenced by a statistically significant increased trend for hemangiopericytomas in the urinary bladders of males, a significant dose-related trend for combined hepatocellular adenomas and carcinomas in males, and a significantly higher incidence of combined lung adenomas and carcinomas in females.
Ref: Federal Register: November 26, 1997. Bifenthrin; Pesticide Tolerances. Final Rule.
http://www.fluoridealert.org/pesticides/Bifenthrin.FR.Nov.1997.htm

-- Category C (possible human) carcinogen, primarily on the basis of the mouse carcinogenicity study in which the high-dose males (81.3 mg/kg/day) showed a highly significant increased incidence of urinary bladder tumors. Other findings in the mouse study included a dose-related trend of increased combined incidences of adenoma and adenocarcinoma of the liver (males only), and increased incidences of bronchioalveolar adenomas and adenocarcinomas of the lung in females at some, but not all, doses relative to their controls.
Ref. Federal Register. April 30, 2003. Bifenthrin; Pesticide Tolerance.
http://www.fluorideaction.org/pesticides/bifenthrin.fr.apr.30.2003.htm

Butafenacil - Herbicide - CAS No. 134605-64-4

-- The most susceptible species in long term studies was the mouse. A NOEL for butafenacil-allyl of 0.36 mg/kg bw/day was found for males in an 18 month study, essentially based on haematological effects mostly in males and liver toxicity in animals of both sexes. A rat 2-year study revealed a NOEL of 1.14 mg/kg bw/day for males, based on liver toxicity in animals of both sexes. A safety factor of 100 is considered appropriate for the ADI, due to the extensive toxicology database for butafenacil-allyl. This results in an ADI of 0.004 mg/kg bw/day (p 10).
Long-Term Studies. Mice received butafenacil in the diet at concentrations of 0, 1, 3, 10 and 60 ppm over 18 months. Haematological effects included lower mean values for erythrocyte count, haemoglobin concentration and haematocrit in males at 60 ppm at weeks 53 and 79, respectively, and for erythrocyte count, haemoglobin and haematocrit at week 79 in males at 10 ppm. Males also had slightly increased neutrophil and monocyte counts at 60 ppm, and a slight thrombocytosis. Mean absolute and relative liver weights were increased in both sexes at 60 ppm. The incidence of enlarged liver was increased in males at 60 ppm and in females at 10 and 60 ppm. Microscopic examination revealed an increased incidence of hepatocyte necrosis and hyperplasia of Kupffer cells in the liver of males at 10 and 60 ppm, and of females at 60 ppm. In addition, an increased incidence of lipofuscin deposition, and inflammatory cell infiltration was seen in males at 60 ppm. There was no treatment-related increase in the incidence of neoplasms at any dose. Butafenacil was not carcinogenic in mice. The NOEL was 3 ppm in males and 10 ppm in females, equivalent to 0.36 and 1.20 mg/kg bw/day for males and females, respectively (p7-8).... Rats were administered butafenacil in the diet at doses of 0, 10, 30, 100 and 300 ppm for 24 months. At interim sacrifice, the incidence and/or severity of liver necrosis was increased in both sexes at 100 and 300 ppm. In addition, increased incidence of hepatocellular single cell necrosis (300 ppm) and increased incidence (100 and 300 ppm) and severity (300 ppm) of cholangiofibrosis were noted in females. At the end of the study, higher incidences and slightly increased severity of fatty change in the liver, and slightly higher incidences of increased mitotic activity of hepatocytes were observed in females at 300 ppm. There was no treatment-related increase in the incidence of neoplasms at any dose. Butafenacil was not carcinogenic in rats. The NOEL was 30 ppm, equivalent to 1.14 mg/kg bw/day for males and 1.30 mg/kg bw/day in females, respectively... Butafenacil was administered to rats in the diet at concentrations of 0, 100, 300 and 1,000 ppm for a period of 90 days. Observations and functional tests conducted during the Functional Observation Battery did not show any effects of toxicological significance. No morphological changes in the central or peripheral nervous system were revealed at neuropathological examination. Microscopic examination of the liver showed inflammatory cell infiltration, cholangiofibrosis of the intrahepatic bile ducts, pigments within Kupffer cells, necrosis of single hepatocytes, cytoplasmic vacuolation, hypertrophy of centrilobular hepatocytes, and an increased mitotic activity of hepatocytes of males at 1,000 ppm. Slight effects were seen at 300 ppm, indicating the beginning of liver necrosis.
Ref: Public Release Summary on Evaluation of the new active BUTAFENACIL in the products LOGRAN B-POWER HERBICIDE & TOUCHDOWN B-POWER HERBICIDE. National Registration Authority for Agricultural and Veterinary Chemicals. Australia. February 2002.
http://www.nra.gov.au/publications/prsbuta.pdf

Carfentrazone-ethyl - Herbicide - CAS No. 128639-02-1

-- A 2-year rat chronic toxicity/carcinogenicity study was conducted in rats at intake levels of 0, 2, 9, 37 and 188 mg/kg/day for males and 0, 3, 12, 49 and 242 mg/kg/day for females. The study found the compound to be noncarcinogenic to rats under the conditions of the study. The no-observed- effect level (NOEL) was 200 ppm (9 mg/kg/day ) for males and 50 ppm (3 mg/kg/day) for females respectively and the lowest-observed-effect-level (LOEL) was 800 ppm (37 mg/kg/day) for males and 200 ppm (12 mg/kg/day) for females, based on liver histopathology and total urinary porphyrin.
-- Chronic Toxicity. An 18-month mouse carcinogenicity study was conducted in mice at dietary intake doses of 0, 10, 110 and 1090 mg/kg/day for males and 0, 12, 119 and 1296 mg/kg/day for females). The study found the compound to be noncarcinogenic to mice under the conditions of the study. The systemic NOEL was 70 ppm (equivalent to 10 mg/kg/day for males and 12 mg/kg/day for females), and the systemic LOEL was 700 ppm (equivalent to 110 mg/kg/day for males and 119 mg/kg/day for females) based on increased mortality and microscopic signs of hepatotoxicity.
Ref: US EPA Pesticide Fact Sheet for Carfentrazone-ethyl. September 30, 1998.
http://www.fluorideaction.org/pesticides/carfentrazone.epa.fact.1998.pdf

-- Subchronic oral toxicity study in the dog. LOAEL = 150 mg/kg/day based on decreased body weight gain and increased porphyrin levels. -- -- Chronic toxicity study in rats. LOAEL = 12 mg/kg/day based on liver histopathology and increased urinary porphyrin levels.
Ref: Federal Register: June 12, 2002. Carfentrazone-ethyl; Pesticide Tolerances for Emergency Exemptions. Final Rule.
http://www.fluoridealert.org/pesticides/Carfentrazone-E.FR.June2002.htm

--- Repeat-dose studies indicate that the primary targets for carfentrazone-ethyl toxicity are the liver, kidney, and the red blood cell forming system. Liver toxicity in all tested species was characterised by increased liver weight, microscopic changes in liver cells and increases in plasma levels of liver enzymes...
--- NOEL/ADI The lowest overall NOEL for carfentrazone-ethyl was 3 mg/kg bw/day. This NOEL was established in the 2-year rat study, based on pigment deposition, red fluorescence and histopathological changes in the liver of rats at the next highest dose. A safety factor of 100 is considered appropriate for the ADI, due to the extensive, high quality toxicology database for carfentrazone-ethyl. This results in an ADI of 0.03 mg/kg bw/day.
Ref: April 2000 - Australia. Evaluation of the new active CARFENTRAZONE-ETHYL in the product AFFINITY 400 DF HERBICIDE. National Registration Authority for Agricultural and Veterinary Chemicals. NRA Ref. 51555.
http://www.fluorideaction.org/pesticides/carfentrazone-e.aus.2000rpt.pdf
Also available at http://www.apvma.gov.au/publications/prscar.pdf

Chlorfenapyr - Acaricide, Insecticide - CAS No. 122453-73-0

The 100-fold margin of safety is adequate to assure a reasonable certainty of no harm to infants and children from the proposed use. As stated earlier, the NOAEL is based on the effects observed in the rat and mouse chronic oncogenicity studies, (reduced bwt gains, increased globulin and cholesterol values and increased liver weights in the rat and reduced bwt gains and vacuolation of white matter of the mouse brain)...
Ref: Federal Register: August 26, 1999 [Page 46677-46680]. Notice of Filing; Pesticide Petition. http://www.fluoridealert.org/pesticides/Chlorfenapyr.FR.Aug.26.1999.htm

-- The no observed adverse effect level from the 28-day dermal toxicity study of 100 mg/kg/day for short- and intermediate-term occupational or residential risk assessments is based on increased cholesterol, relative liver weights and cytoplasmic vacuolation of the liver in male and females rabbits at the lowest observed adverse effect level of 400 mg/kg.
Ref: US EPA. Summary of Chlorfenapyr Risk Benefit Assessment.
http://www.fluorideaction.org/chlor-summ.pdf

-- Subchronic Studies... A 28-Day Rat Feeding Study", J.E. Fischer; Non-guideline; Rat; American Cyanamid Company, Toxicology Department, Princeton, NJ; Report No. T-0221; 8/30/91; AC 303,630 Technical (purity: 98.4%); 5 animals/sex/group; Doses: 0, 600, 900, 1200, 1600, 2000 ppm (males-0, 68.3, 106.3, 134.2, 176.8, 243.0 mg/kg/day, females-0, 71.6, 108.4, 138.5, 184.8, 245.5 mg/kg/day), in the diet, 4 weeks... Necropsy: increased absolute liver weight (M-1600, F-900, 1200, 1600, 2000 ppm)... Target organ: liver; NOEL: (M/F) 1200 ppm (based on increased SGPT activity, incidence of hepatocellular hypertrophy and increased relative liver weight in 1600 ppm treatment group); Study supplemental. (Moore, 1/30/95)
Ref: Summary of Toxicological Data for Chlorfenapyr. California EPA. Department of Pesticide Regulation. Medical Toxicology Branch. August 24, 2001.
http://www.fluorideaction.org/pesticides/chlorfenapyr.ca.epa.aug2001.pdf

-- MRID No. 42770219 (1993)-- 90-Day oral toxicity rats. NOAEL = 24.1 mg/kg/day. LOAEL = 48.4, based on spongiform myelopathy in the brain and spinal cord of male rats, decreased body weight gain and increased relative liver weight in males and females, increased absolute liver weight in females, and decreased hemoglobin in females.
- MRID No. 43492831 (1993). 21/28-Day dermal toxicity rabbit. NOAEL = 100 mg/kg/day. LOAEL = 400 mg/kg/day, for both sexes, based on changes in liver chemistry and morphology.
-- Classification: ``Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential'' based on significant trends in liver tumors (adenomas and combined adenomas/ carcinomas), malignant histiocytic sarcomas, and testicular cell tumors in male rats and uterine polyps in female rats seen at the highest dose.
Ref: Federal Register: September 26, 2003. Chlorfenapyr; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/chlorfenapyr.fr.sept26.2003.htm

Chlorflurazole - Herbicide - CAS No. 3615-21-2

Animal Toxicity Studies: Non-Human Toxicity Excerpts: ... AN UNCOUPLER OF OXIDATIVE PHOSPHORYLATION CAUSING 50% UNCOUPLING OF RAT LIVER MITOCHONDRIAL OXIDATIVE PHOSPHORYLATION AT 6X10-7 MOLAR ALSO STIMULATING ATPASE ACTIVITY & CELL RESPIRATION. [Spencer, E. Y. Guide to the Chemicals Used in Crop Protection. 7th ed. Publication 1093. Research Institute, Agriculture Canada, Ottawa, Canada: Information Canada, 1982. 107]
Ref: TOXNET profile from Hazardous Substances Data Bank for CHLOROFLUORAZOLE.
http://www.fluoridealert.org/pesticides/Chlorfluorazole.TOXNET.HSDB.htm

Chlorfluazuron - Insecticide - CAS No. 71422-67-8

Abstract: [Chlorfluazuron, 71422- 67-8] was evaluated for reproductive toxicity. The test material was administered at dietary concentrations of 0, 2000, or 10000 ppm to 11-13 male and 11-13 female CRJ:CD rats per test group for 13 weeks before pairing and through 2 cycles of mating, gestation, and lactation periods. Body weights of treated animals were comparable to controls. A statistically significant increase of liver/body weight ratio was seen in treated females. A slight reduction was observed in parameters of reproductive performance in the second (F1B) mating, including mating index, fecundity index, and male and female fertility index. A statistically significant increase in fetal liver/body weight ratio was observed at all treatment levels. No other parameters were examined.
Ref: 1992 - INITIAL SUBMISSION: IKI-7899: PRELIMINARY REPRODUCTION STUDY IN RATS BY DIETARY ADMINISTRATION (FINAL REPORT) WITH COVER LETTER DATED 03-27-92; from ISHIHARA SANGYO KAISHA LTD. Report available from The National Technical Information Service; Order No. NTIS/OTS0535939. EPA/OTS; Doc #88-920001555. [From Toxline at Toxnet]

Chlorodifluoromethane - Insecticide, Fungicide, Propellant - CAS No. 75-45-6

Animal Data - INHALATION: 4 hour, LC50, rat: 220,000 ppm. The compound is a skin irritant and a slight eye irritant, but is not a skin sensitizer in animals. Effects from single high exposures include central nervous system depression, anesthesia, rapid breathing, lung congestion and microscopic liver changes...
Ref: Material Safety Data Sheet for Freon 22. DuPont. 1996.

CTFT: Chlorotrifluorotoluene, 4-,Alpha,Alpha,Alpha- Intermediate used in herbicides - CAS No. 98-56-6

In 14-day toxicity studies, 1 of 10 female rats given the top dose of 1000 mg/kg CTFT in corn oil died on day 8; no deaths of male rats or of mice of either sex were attributable to the administration of CTFT. Body weight gains in all groups of rats and mice were similar with the exception of the top dose (1000 mg/kg) groups of male and female rats, which lost weight during the first week and resumed weight gain during the second. CTFT was found to accumulate in the kidneys of male rats, and there was a linear relationship between the kidney CTFT concentrations and the kidney levels of a2u-globulin, as determined by an ELISA assay. Microscopic changes in male rats included a dose-related toxic nephropathy consistent with that previously described as "hyaline droplet nephropathy." Dosed male and female rats also had hepatocyte hypertrophy and cytoplasmic vacuolization of the adrenal cortex. Clinical pathology findings suggested a mild anemia and cholestasis in rats. In contrast to rats, mice did not show appreciable CTFT concentrations in any tissue evaluated, suggesting a more rapid elimination of the chemical. However, hepatocellular hypertrophy, and clinical pathology findings consistent with cholestasis and mild liver injury, were noted in mice in the 400 and 1000 mg/kg dose groups. These studies demonstrated that oral doses of CTFT of 400 mg/kg or higher caused liver hypertrophy in rats and mice and adrenal changes in rats. Doses of 50 mg/kg or higher caused "hyaline droplet nephropathy" in male rats. The results were similar with CTFT administered either in corn oil or in -CD (although absorption of CTFT was somewhat more rapid with -CD), suggesting that -CD may be an appropriate vehicle for toxicity studies with other chemicals.
Ref: National Toxicology Program. July 1992. Toxicity Studies of p-Chloro-,,Trifluorotoluene (CAS NO: 98-56-6) Administered in Corn Oil and -Cyclodextrin to F344/N Rats and B6C3F1 Mice in 14-Day Comparative Gavage Studies.
http://www.fluoridealert.org/pesticides/CTFT.NTP.ToxicityStudy.1992.htm

Clodinafop-propargyl - Herbicide - CAS No. 105512-06-9

Suggestive Evidence of Carcinogenic Potential. Prostate gland adenomas in male Tif:RAIf(SPF) rats at the high dose only cannot be discounted; Peroxisome Proliferator-Activated Receptor Agonism MOA for liver tumors in 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

-- Carcinogenicity. In accordance with the EPA Proposed EPA Weight-of-the-Evidence Categories, August 1999, the Agency's Cancer Assessment Review Committee (CARC) classified clodinafop-propargyl as "likely to be carcinogenic to humans" by the oral route based on the occurrence of prostate tumors in male rats, ovarian tumors in female rats, and liver tumors in both sexes of mice, as well as blood vessel tumors in female mice. For the quantification of human cancer risk, the CARC recommended a linear low-dose extrapolation approach based on the most potent of these tumor types. This approach is supported by possible genotoxic potential and the lack of confirmation of the mode of action of clodinafop-propargyl. The most potent unit risk, Q1 * (mg/kg/day) -1 , of those calculated for clodinafop-propargyl is that for male mouse liver benign hepatoma and/or carcinoma combined tumor rates at 0.129 (mg/kg/day) -1 in human equivalents.
SUBCHRONIC AND CHRONIC TOXICITY
-- 870.3100/ 28-Day Oral Gavage in Rats NOAEL < 5 mg/kg LOAEL = 5 mg/kg for M and F based on liver toxicity (enzyme changes),
-- 870.3100/ 13 Week Oral Toxicity in Rodent NOAEL = M: 0.9 mg/kg; F: 8.2 mg/kg/day LOAEL = M: 120 ppm (8.2 mg/kg/day); F: 1000 ppm (71.1 mg/kg/day) decreased body weight; based on increased liver weights and enzymes (AlPtase); decreased thymus weight (atrophy). Reversed after 28 day recovery period.
-- 870.3100/ 13 Week Oral Toxicity in Mice NOAEL = M: 0.9mg/kg/day; F: 1.1mg/kg/day LOAEL = M: 7.3 mg/kg/day ; F: 8.6 mg/kg/day based on clinical chemistry; glucose, sodium, and chloride increases and hepatocellular hypertrophy in males and females.
-- 870.3200 28-Day Dermal Toxicity in Rats. Systemic NOAEL = 50 mg/kg/day Systemic LOAEL = 200 mg/kg based on dose-related increases in liver weights and clinical signs (piloerection and hunched posture) in male rats. Dermal NOAEL = 1000 mg/kg/day.
-- 870.3800 Two Generation Rat Reproduction Study Parental/Systemic NOAEL= 3.2 mg/kg/day. Parental/Systemic LOAEL = 31.7 mg/kg/day based on decrease in body weight gain, reduced food consumption, increased liver and kidney weights and histopathological changes in the liver and renal tubules...
-- 870.4200b Carcinogenicity -Mice NOAEL = M: 1.10 mg/kg/day; F: 1.25 mg/kg/day LOAEL =M: 11.0 mg/kg/day; F: 12.6 mg/kg/day based on increase in liver enzyme activity and liver weights. Under the conditions of this study, clodinafop-propargyl induced hepatocellular tumors at 29.6 mg/kg. The chemical was tested at doses sufficient to measure its carcinogenic potential.
-- 870.4300 Chronic/ Oncogenicity in the Rat. NOAEL = M:0.03 mg/kg/day ; F: 0.03 mg/kg/day LOAEL = M: 0.3 mg/kg/day; F: 0.4 mg/kg/day based on hepatocytic hypertrophy, chronic progressive nephropathy, and tubular pigmentation. Under the conditions of this study, treatment with clodinafop-propargyl increased the incidence of prostate and ovarian tumors in rats at 750 ppm. For males, an increased incidence of prostate adenoma was seen in the high-dose group. The chemical was administered at a dose sufficient to test its carcinogenic potential.
-- Special Study: The Effect Of CGA 184927 On Selected Biochemical Parameters In The Rat Liver. Following Subchronic Administration. The effects of clodinafop-propargyl on selected liver enzymes in the rat were similar to the effects seen after subchronic treatment with known peroxisome proliferators (hypolipidemic compounds, phenoxyacetic acid derivatives). Hence, clodinafop-propargyl was considered to most likely be a peroxisome proliferator in the rat liver.
-- Special Study: Trendelenburg, C. Effects on Selected Plasma Concentrations and Biochemical Parameters in the Liver upon Subchronic Administration to Male Adult Rats. Clodinafop-propargyl may act as a peroxisomal proliferating agent and alters monooxygenase activity in subfamilies of cytochrome P450 which are known to be involved in the synthesis or catabolism of steroid hormones.
Ref: US EPA Pesticide Fact Sheet. Reason for Issuance: Conditional Registration. June 6, 2000.
http://www.epa.gov/opprd001/factsheets/clodinafop.pdf

Dietary treatment of rats with concentrations over 2 years resulted in initial inappetence in males and reduced body weight development in both sexes treated at 750 ppm. The main target organ of toxicity was the liver. Changes in plasma protein and lipid levels, strongly enhanced serum activities of liver enzymes, increased liver weights, and severe liver necroses were observed at dietary doses of 300 and 750 ppm in males and at 750 ppm in females. The degenerative lesions provide strong evidence that these dose levels exceeded a maximum tolerated dose (MTD). Top dose group males showed a higher incidence of prostate adenoma, while prostate hyperplasia was reduced. However, the total incidence of proliferative changes in the prostate remained unchanged indicating a progression from prostate hyperplasia to adenoma. Females treated at the same high dose had higher incidences of ovary tubular adenoma. The slightly enhanced incidences of these lesions are likely a consequence of the severe disturbance of the general metabolic balance due to excessive liver toxicity. In fact, male rats fed 750 ppm exhibited a marked increase in peroxisomal oxidation, and an increase in cytochrome P450 4A1/ A3 and 4A2 in their livers. Further, a decrease in cytochrome P450 isoenzymes including CYP 2A, CYP 3A, and male-specific CYP 2C11 was observed. The total oxidation rate of testosterone, aromatase (CYP 19A1) activity plasma estradiol concentration and plasma-- dihydrotestosterone are altered at this level of treatment. Clodinafop- propargyl is a potent peroxisome proliferator in the rat liver and this peroxisomal prolifering activity manifests itself by altering Cytochrome P450-dependent monooxygenses which are involved in steroid hormone homeostasis. The NOAEL of 10 ppm was equivalent to a mean daily dose of 0.32 mg/kg in males and 0.37 mg/kg in females. The EPA HIARC concluded that based on hepatocellular hypertrophy and kidney findings, the NOAEL was 1 ppm (0.031 in males and 0.034 in females. Carcinogenicity. The EPA HIARC recommended, based on the increased incidence of prostate and ovarian tumors in rats and hepatocellular tumors in mice, that the Cancer Assessment Review Committee review clodinafop-propargyl... The scientific evidence available amply demonstrates that exposure to substances that produce tumors by a peroxisome proliferator mode of action does not represent a risk of tumor development in man. Novartis, therefore, has concluded that clodinafop-propargyl is not a carcinogen of relevance to humans.
Ref: Federal Register. April 26, 2000. [PF-938; FRL-6554-2]
http://www.epa.gov/fedrgstr/EPA-PEST/2000/April/Day-26/p10432.htm

Cloransulam-methyl - Herbicide - CAS No. 147150-35-4

-- In a 90-day mouse feeding study the NOEL was 50 mg/kg/day males. In a 21-day rabbit dermal study the dermal irritation NOEL was equal or greater than 1000 mg/kg/day and the systemic NOEL was equal to 500 mg/kg/day. In a 1-year dog chronic feeding study the NOEL was 10 mg/kg/day and the LOEL was 50 mg/kg/day based on hepatocellular hypertrophy and accumulation of pigment, and increased activity of alkaline phosphatase and alanine aminotransferase liver enzymes and decrease in albumin and total bilirubin.
-- In the rat Chronic Feeding / Carcinogenicity study the NOEL was equal to 75 mg/kg/day and the Lowest Observed Effect Level (LOEL) was 325 mg/kg/day based on significant increase in hemoglobin, hematocrit, and red cell count in males, activities of the liver enzymes aspartate and alanine aminotransferase as well as alkaline phosphatase were decreased in males, cholesterol was decreased in females, specific gravity of urine was decreased in females, increased relative wight in liver and relative weight of testes in males, males exhibited an increased incidence of collecting duct hypertrophy and females exhibited increased incidence of vacuolation in the kidney. There was no evidence of carcinogenicity for cloransulam-methyl in this study. In the mouse carcinogenicity study the NOEL was 10 mg/kg/day and the LOEL was 108 mg/kg/day based on based on a decrease in renal tubule vacuolation in male mice, increased size of centrilobular and midzonal hepatocytes accompanied by altered tinctorial properties in females and centrilobular hepatocyte hypertrophy in males. Total tumor incidence (adenoma + carcinoma) was not increased by dosing with cloransulam-methyl.
-- 90-day dietary (mice): NOEL = 50 mg/kg/day (males) LOEL = 100 mg/kg/day for males based on increased levels of alkaline phosphatase and increased liver weights and an increase in the size of hepatocytes.
-- 1 Year Chronic Feeding (dog): NOEL = 10 mg/kg/day LOEL = 50 mg/kg/day based on hepatocellular hypertrophy and accumulation of pigment, and increased activity of alkaline phosphatase and alanine aminotransferase liver enzymes and decrease in albumin and total bilirubin.
-- Chronic Feeding/ Carcinogenicity (rat): NOEL = 75 mg/kg/day LOEL = 325 mg/kg/day based on significant increase in hemoglobin, hematocrit, and red cell count in males, activities of the liver enzymes aspartate and alanine aminotransferase as well as alkaline phosphatase were decreased in males, cholesterol was decreased in females, specific gravity of urine was decreased in females, increased relative weight in liver and relative weight of testes in males, males exhibited an increased incidence of collecting duct hypertrophy and females exhibited increased incidence of vacuolation in the kidney. There was no evidence of carcinogenicity for cloransulam-methyl in this study.
-- Carcinogenicity (mouse): NOEL = 10 mg/kg/day LOEL = 108 mg/kg/day based on a decrease in renal tubule vacuolation in male mice, increased size of centrilobular and midzonal hepatocytes accompanied by altered tinctorial properties in females and centrilobular hepatocyte hypertrophy in males. Total tumor incidence (adenoma + carcinoma) was not increased by dosing with cloransulam-methyl.
Ref: USEPA. Pesticide Fact sheet. Cloransulam-methyl. Reason for Issuance: Conditional Registration Date Issued: October 29, 1997.
http://www.epa.gov/opprd001/factsheets/cloransulam.pdf

... Cloransulam-methyl 84% DF was not found to be carcinogenic, teratogenic or to cause reproductive effects. In-vitro and animal mutagenicity studies were negative. Target organ effects have been reported in the blood, kidney, liver, testes and thyroid gland...
Ref: Material Safety Data Sheet for Gauntlet Herbicide. MSDS Ref. No: F18-20-2. Date Approved: 09/25/2000. Revision No. 1. FMC Corporation, Agricultural Products Group, 1735 Market Street, Philadelphia, PA 19103, USA. http://www.fluoridealert.org/pesticides/Gauntlet.HerbicideMSDS.2000.pdf.
Also available at http://www.cdms.net/ldat/mp48J001.pdf

Cyhalofop-butyl - Herbicide - CAS No. 122008-85-9

5. Subchronic and chronic toxicity, and oncogenicity. Cyhalofop- butyl caused increases in liver and kidney weights, microscopic hepatocellular hypertrophy, renal tubular microscopic effects, and distended gallbladders when given at sufficiently high dose levels to the appropriate species for 13 weeks. Similar increases in liver and kidney weights, hepatocellular hypertrophy, and renal effects were also observed in chronic toxicity studies in rodents. In addition, mice had liver inflammation (microgranulomas). Chronic toxicity in dogs was limited to decreased body weight and the occurrence of concretions in the gallbladder. Using the Guidelines for Carcinogen Risk Assessment published September 24, 1986 (51 FR 33992), it is proposed that cyhalofop and cyhalofop-butyl be classified as Group E for carcinogenicity (no evidence of carcinogenicity) based on the results of carcinogenicity studies in two species. Dow AgroSciences LLC believes that there was no evidence of carcinogenicity in an 18-mouse feeding study and a 24-month rat feeding study at all dosages tested.
Ref: Federal Register. April 25, 2001. [PF-1009; FRL-6774-7]
http://www.fluoridealert.org/pesticides/Cyhalofop-butyl.FR.Apr.2001.htm

Cyhalothrin - Acaricide, Insecticide - CAS No. 68085-85-8

Long term toxicity and carcinogenicity Target / critical effect: Liver Lowest relevant NOAEL: NOEL 1.7 mg/kg bw/d, 2 y rat (cyhalothrin) Carcinogenicity: Negative
Ref: European Commission. Review report for the active substance lambda-cyhalothrin. Finalised in the Standing Committee on Plant Health at its meeting on 19 October 2000 in view of the inclusion of lambda-cyhalothrin in Annex I of Directive 91/414/EEC. 7572/VI/97-final. 25 January 2001.
http://europa.eu.int/comm/food/fs/ph_ps/pro/eva/existing/list1-24_en.pdf

Cyhalothrin, lambda - Insecticide - CAS No. 91465-08-6

-- Short term toxicity. Target / critical effect: Organs: Liver, CNS. Lowest relevant oral NOAEL / NOEL: 0.5 mg/kg bw/d, oral, 1 y dog.
Ref: European Commission. Review report for the active substance lambda-cyhalothrin. Finalised in the Standing Committee on Plant Health at its meeting on 19 October 2000 in view of the inclusion of lambda-cyhalothrin in Annex I of Directive 91/414/EEC. 7572/VI/97-final. 25 January 2001.
http://europa.eu.int/comm/food/fs/ph_ps/pro/eva/existing/list1-24_en.pdf

Dichlofluanid - Wood Preservative, Antifoulant, Fungicide, Acaricide - CAS No. 1085-98-9

-- In the chronic studies, the most consistent findings were cranial osteosclerosis in the rat, and findings consistent with fluorosis in a 2-year mouse study. Clinical chemistry findings with supportive histopathology were observed in a 1-year study in the dog which were indicative of renal and liver damage. A detailed assessment of cranial osteosclerosis was performed in a 2-year study in the rat; a LOEL was established at 10-14 mg kg -1 d -1..
-- A detailed assessment of cranial osteosclerosis was performed in a rat 2-year study (summarised in section 3.3.5.1) in which a LOEL was established at 10-14 mg kg -1 d -1 . A clear increase in the incidence of cranial osteosclerosis was observed in the low- and middle-dose groups, with almost all animals affected at the top dose. These findings are likely to be secondary to fluorosis in these animals. In terms of interspecies comparisons, in a mouse 2- year study, thickening of both the appositional bone of the cranial vault and nasal turbinates, and tooth alveolitis were observed at the top dose of 1,731-1,873 mg kg -1 d -1 . These findings are also considered to be a secondary consequence of fluorosis in these animals. No evidence of fluorosis was observed in the dog studies. It is considered that these findings are likely to represent a fluoride mediated perturbation of bone metabolism but are not considered to be of concern for human health. It is considered that the observed liver and renal damage is of concern to human health.
-- In a 1-year dog study clinical chemistry findings with supportive histopathology, indicative of nephrotoxicity and liver damage, were observed. In this study a NOAEL of 2.5 mg kg -1 d -1 was established.
Ref: January 2003 - Evaluation on: Booster biocides in antifouling products. Full review of Dichlofluanid. No. 206. Evaluation of Fully Approved or Provisionally Approved Products. Prepared by : The Health and Safety Executive Biocides & Pesticides Assessment Unit, Magdalen House, Stanley Precinct Bootle Merseyside L20 3QZ Available from: Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX, UK.
Also available at: http://www.pesticides.gov.uk/citizen/Evaluations/206_dichlofluanid.pdf

Dichlorodifluoromethane - Insecticide, Fungicide Propellant, EPA List 2 Inert - CAS No. 75-71-8

-- Pathologic liver changes were reported in guinea pigs chronically exposed (continued for 90 days; or eight hr daily, 5 days weekly, for six wk) to F 12 at levels of about 4,000 mg/cu m (0.08 % by vol). [USEPA; Ambient Water Quality Criteria Doc: Halomethanes p.C-52-5 (1980) EPA 440/5-80-051]
-- Short-term inhalation studies have been reported for CFC-11, CFC-12, CFC-112, CFC-113, CFC-114, and CFC-115. The results showed low toxicity, and the effects observed were related mainly to the CNS, respiratory tract, and the liver. Oral toxicity studies have confirmed the low toxicity. [WHO; Environmental Health Criteria 113: Fully Halogenated Chlorofluorocarbons p.18 (1990)]
Ref: TOXNET profile from Hazardous Substances Data Bank for Dichlorodifluoromethane.
http://www.fluoridealert.org/pesticides/Dichlorodifluorometh.TOXNET.htm

Dichlorofluoromethane (CFC-21) - Propellant, EPA List 2 Inert - CAS No. 75-43-4

-- Repeated exposures have produced marked hepatic damage or failure. Ten rats exposed at 10,000 ppm CFC-21, 6 hours per day, 5 days per week for 2 weeks, all survived, but their livers were grossly pale and heavy. Histopathologic examination showed centrilobular necrosis with related changes. In comparable 90-day series of exposure at 5000 and 1000 ppm levels, rats showed bilateral hair loss and excessive mortality (20 of 54 died at 1000 ppm, 15 of 54 at 5000 ppm). Four dogs exposed at both levels showed weight loss. Cirrhosis was evident in rats exposed at both levels, but with dogs histopathologic changes in the liver were mild and evident only at the 5000 ppm. [American Conference of Governmental Industrial Hygienists, Inc. Documentation of the Threshold Limit Values and Biological Exposure Indices. 6th ed. Volumes I,II, III. Cincinnati, OH: ACGIH, 1991. 434]**PEER REVIEWED**
-- /GUINEA PIGS/ ... EXPOSED /UP TO 2 HR/ @ CONCN OF 10.2% DIED &, ON AUTOPSY, CONGESTED LUNGS, CONGESTED KIDNEYS, CONGESTED LIVER, DISCOLORED SPLEEN, & HIGHLY CONTRACTED HEART WERE FOUND. [American Conference of Governmental Industrial Hygienists. Documentation of the Threshold Limit Values for Substances in Workroom Air. Third Edition, 1971. Cincinnati, Ohio: AmericanConference of Governmental Industrial Hygienists, 1971. (Plus supplements to 1979) 81]**PEER REVIEWED**
-- TSCA Test Submissions: A subchronic inhalation toxicity study was conducted with groups of male (35) and female (35) albino rats (strain not reported) receiving whole body exposure to dichloromonofluoromethane at a nominal concentration of 0, 50, 150 or 500ppm in a dynamic air flow chamber for 6 hours per day, five days per week for approximately 90 days. On day 45 and day 90, 5 animals per sex and 20 animals per sex, respectively were sacrificed. The remaining animals were observed for an additional 30 days and then sacrificed. Four high dose males were found dead during the exposure period and one female and six males from the high dose group were found dead during the recovery period. High dose rats were observed to have statistically significant (p < 0.01) lower body weights than controls during the exposure period, but were comparable after the 30 day recovery period. Hematology, clinical chemistry and urine analysis values were similar between all dosed animals and control animals, with the exception of a slightly higher total blood leukocytes counts and elevated mean SAP and SGPT values for high dose animals at approximately 45, 90 and 120 days. A dose related increase in urine fluoride levels was also observed. Histopathology evaluation of treated animals revealed portal cirrhosis of the liver, interstitial edema of the pancreas and degeneration of the seminiferous epithelium [the sperm producing part of the testicle - EC]. Three cases of leukemia were observed in high dose male rats. [Industrial Bio-Test Laboratories; Subacute Inhalation Toxicity Study with Genetron 21 in Albino Rats, (1979), EPA Document No. FYI-OTS-0779-0045, Fiche No. OTS0000045-0 ]
Ref: TOXNET profile from Hazardous Substances Data Base for DICHLOROFLUOROMETHANE.
http://www.fluoridealert.org/pesticides/Dichlorofluoromethan.TOXNET.htm

Diclosulam - Herbicide - CAS No. 145701-21-9

Based on oral feeding studies, the primary target organs are the liver and kidney. In a subchronic rat feeding study, the primary target organ is the liver including increased relative organ weight, hepatocellular hypertrophy, and slight multifocal necrosis. Decreased body weight and kidney lesions were also noted. Liver effects were also noted in a subchronic dog study and included increased relative liver weight, centrilobular hepatocellular changes, and hepatocellular necrosis accompanied by elevated ALP, AST, and ALT.
Ref: Federal Register. March 8, 2000. Diclosulam; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Diclosulam.FR.March8.2000.htm

Diflubenzuron - Chemosterilant, Insecticide - CAS No. 35367-38-5

Chloroaniline, p (or 4-chloraniline) is a metabolite of Diflubenzuron. In 2006, USEPA classified chloroaniline, p as a "Group B2 -- Probable Human Carcinogen." "Spleen (fibrosarcomas, hemangiosarcomas & osteosarcomas) (M); Adrenal (pheochromocytomas (M & F); F344/N rats. Hepatocellular adenomas/carcinomas (M); Hemangiosarcomas in spleen and/or liver (M) in B6C3F1 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

At all dose levels, histopathological examinations indicated dose related increases of hemosiderosis and congestion of the spleen, hemosiderosis and chronic hepatitis of the liver, and mild erythroid hyperplasia of the bone marrow... Male rats at 6 and 18 mg/kg/day and female rats at 18 mg/kg/day had blue extremities indicative of cyanosis. Histopathological examinations indicated non-neoplastic treatment-related effects in the spleen, liver, bone marrow and adrenal gland... (National Toxicology Program (NTP) Report No. 351; July, 1989)..."
Ref: US EPA RED. August 1997.
http://www.fluoridealert.org/pesticides/Diflubenzuron.RED.pdf

-- Chronic toxicity. Diflubenzuron was given by capsule to male and female Beagle dogs for 1 year at dose levels of 0, 2, 10, 50, and 250 mg/kg/day. Body weight (bwt) gain was slightly reduced in females at 250 mg/kg/day. Absolute liver and spleen weights were increased in males given 50 and 250 mg/kg/day. A reduction in hemoglobin and mean corpuscular hemoglobin concentration, with an elevation in reticulocyte count, was seen at 50 and 250 mg/kg/day. Methemoglobin and sulfhemoglobin values were increased at doses of 10 mg/kg/day and greater. Histopathological findings were limited to pigmented macrophages and Kupffer cells in the liver at doses of 50 and 250 mg/ kg/day. The NOAEL for chronic toxicity in dogs was 2 mg/kg/day.
-- A 91-week carcinogenicity study in CFLP mice was conducted at doses of 0, 16, 80, 400, 2,000, and 10,000 ppm. There was no increase in tumor incidence as a result of diflubenzuron administration. Target organ effects included: Increased methemoglobin and sulfhemoglobin values, Heinz bodies, increased liver and spleen weight, hepatocyte enlargement, and vacuolation, extramedullary hemopoiesis in the liver and spleen, siderocytosis in the spleen and pigmented Kupffer cells. A NOAEL for these effects was 16 ppm (2 mg/kg/day).
-- Diflubenzuron was fed to male and female Sprague Dawley rats for 2 years at dose levels of 0, 156, 625, 2,500, and 10,000 ppm. Methemoglobin values were elevated in female rats at all dose levels and in male rats at the two highest dose levels. Blood sulfhemoglobin was elevated in females, only, at dose levels of 2,500, and 10,000 ppm. MCV and reticulocyte counts were increased in high dose females. Spleen and liver weights were elevated at the two highest doses. Histopathological examination demonstrated an increase in hemosiderosis of the liver and spleen, bone marrow and erythroid hyperplasia, and areas of cellular alteration in the liver. There was no increase in tumor formation...
-- PCA [p-chloroaniline; a metabolite of Diflubenzuron] hydrochloride was administered 5 days/week by oral gavage to male and female B6C3F1 mice at doses of 0, 3, 10, or 30 mg/kg/day. Mean body weights of high dose male and female mice were generally within 5% of those of controls throughout the study. The incidence of hepatocellular adenomas or carcinomas (combined) was increased in a non-dose-dependent manner in treated male mice. Metastasis of carcinoma to the lung was seen in the high dose group. An increased incidence of hemangiosarcomas of the liver or spleen was seen in high dose male mice. It was concluded that, under the conditions of this 2-year gavage study, there was some evidence of carcinogenic activity of PCA hydrochloride for male B6C3F1 mice and no evidence of carcinogenic activity of PCA hydrochloride for female B6C3F1 mice.
Ref: Federal Register: December 14, 2001. (Volume 66, Number 241)] [Notices] [Page 64823-64828]. Notice of Filing Pesticide Petitions to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.
http://www.fluoridealert.org/pesticides/Diflubenzuron.FR.Dec14.2001.htm

Abstract: Diflubenzuron (DFB), a potent inhibitor of insect chitin synthesis, was administered to Swiss Webster mice in a 30-day oral intubation study. Animal groups received either no treatment, vehicle control (Polyethylene glycol 400), or DFB suspensions at doses of 125, 500, and 2,000 mg/kg body weight. Hepatic glutathione S-transferase activity as well as morphological characteristics were studied. DFB was shown to elicit hepatocellular changes at all dose levels. The activities of three glutathione S-transferases (S-aryl, S-aralkyl, and S-epoxide) were all altered after DFB administration. Light microscopy revealed radial arrays of hepatocellular vacuolization between the portal and central vein areas. Electron-microscopic examination, verified by morphometric analysis, revealed degenerative changes as well as an increased volume density of the endoplasmic reticulum.
Ref: J Appl Toxicol. 1986 Oct;6(5):343-8. Effects of diflubenzuron on the mouse liver. Young MF, Trombetta LD, Carson S.

Diflufenican - Herbicide - CAS No. 83164-33-4

-- Subchronic/chronic toxicity studies... The NOAEL in the 104-week mouse study was 500 ppm (approximately 60 - 70 mg/kg bw/day) based on minimal reduction in body weight gain at the 500 ppm dose level and significant reduction in body weight gain and increase in the absolute and relative liver weight in females at the higher dose level. Diflufenican was not tumourigenic in the mouse. The NOEL in the 52-week oral study in the dog was 100 mg/kg bw/day based on significant increase in liver weight at the higher dose level.
Ref: September 1995. Evaluation on Diflufenican. 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 7PX, UK. Available at:
http://www.pesticides.gov.uk/citizen/evaluations/evallist_alphabet.htm

Dithiopyr - Herbicide - CAS No. 97886-45-8

... In a 13-week dog feeding study, increased alkaline phosphatase, discolored livers, and cholestasis was observed at 10 mg/kg/day (LOEL). The NOEL was 1 mg/kg/day. In addition, at 30 mg/kg/day, increased serum glutamic-pyruvic transaminase and serum glutamic oxaloacetic transaminase, increased liver and kidney weights, and decreased cholesterol and albumin were observed. EPA believes that there is sufficient evidence for listing dithiopyr on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available hepatic and renal 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 following results were presented by a Monsanto scientist.
-- Four-week Feeding Study in Mice. Dithiopyr was administered via the diet to groups of 6 male and 6 female CD-1 mice for 4 weeks at concentrations of 0, 300, 1000, 3000, 10,000 and 30,000 ppm... Liver enlargement and discoloration, adrenal enlargement, and atrophy of the thymus, spleen, seminal vesicles, ovaries and uterus were noted on gross post-mortem examination... (The Institute of Environmental Toxicology, 1987)
-- Thirteen-week Feeding Study in Mice Dithiopyr was administered via the diet to groups of 12 male and 12 female CD-1 mice for 13 weeks at concentrations of 0, 10, 100, 1000 and 5000 ppm. Mortality, decreased body weight gain, reduced feed efficiency, and mild anemia were observed at the higher dose level. By study termination many high dose animals appeared jaundiced, emaciated and had distended abdomens. Postmortem examination revealed primarily liver and kidney toxicity. Elevated plasma AP, alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea nitrogen and cholesterol levels were indicative of cholestasis and liver toxicity. These biochemical changes were accompanied by a significant increase in liver weight, hepatocellular swelling, vacuolation and necrosis, dissociation of hepatocellular cords, and bile duct proliferation... The subchronic NOEL in mice is considered to be 10 ppm. (The Institute of Environmental Toxicology, 1989)
-- Two-week Oral Study in Dogs ¥Dithiopyr was administered orally via gelatin capsule to 1 male and 1 female beagle dog for 2 weeks at dose levels of 0, 10, 30, 60, 100 and 200 mg/kg/day. Emesis and decreased body weight were observed at the higher dose levels. Biochemical and histopathological evidence of liver toxicity, manifest as increased AP, AST, and g-GT levels in plasma, along with hepatocellular swelling, pigment deposition, and focal necrosis, were apparent on postmortem examination. The NOEL is considered to be 10 mg/kg/day. (The Institute of Environmental Toxicology, 1988)
-- Thirteen-week Oral Study in Dogs ¥Dithiopyr was administered orally via gelatin capsule to groups of 6 male and 6 female beagle dogs for 13 weeks at dose levels of 0, 1, 10 and 30 mg/kg/day. Postmortem examination revealed liver toxicity and moderate to severe cholestasis at the higher dose levels. Specific findings included : increased liver weights, increased AP, AST and g-GT levels in plasma, along with liver swelling, distended gallbladders with sandy stones, pigment deposition in bile canaliculi and Kupffer cells, and mononuclear cell infiltration of the liver. The subchronic NOEL in dogs is considered to be 1 mg/kg/day. (The Institute of Environmental Toxicology, 1988)
-- Eighteen-month Feeding Study in Mice ¥In an oncogenicity study, dithiopyr was administered via the diet to groups of 70 male and 70 female CD-1 mice for 78 weeks at concentrations of 0, 3, 30 and 300 ppm... Postmortem examination revealed primarily liver toxicity. There were no statistically significant or biologically significant increases in neoplastic lesions. ¥Liver enlargement and discoloration, hepatocellular swelling, bile duct proliferation, and pigment deposition in hepatocytes, Kupffer cells and the bile canaliculi were indicative of mild liver toxicity and cholestasis... The chronic NOEL in mice is considered to be 3 ppm (equivalent to a daily intake of 0.31 mg/kg b.w. in males and 0.37 mg/kg b.w. in females). (The Institute of Environmental Toxicology, 1989)
-- Twelve-month Oral Study in Dogs ¥Dithiopyr was administered orally via gelatin capsule to groups of 6 male and 6 female beagle dogs for 52 weeks at dose levels of 0, 0.5, 5 and 25 mg/kg/day... Postmortem examination revealed liver toxicity and cholestasis. Specific findings included : increased AP levels in plasma, liver enlargement and discoloration, the presence of black sandy materials in the gallbladder, hepatocellular necrosis and fibrosis, pseudo-bile duct formation, bile duct proliferation, and increased mucoidal secretion in the gallbladder. Brown pigment deposition was also found in the bile canaliculi, Kupffer cells and the kidneys. The chronic NOEL in dogs is considered to be 0.5 mg/kg/day. (The Institute of Environmental Toxicology, 1989)
-- REPRODUCTION AND DEVELOPMENTAL TOXICITY STUDIES 1. Two-generation Reproduction Study in Rats ¥Dithiopyr was administered via the diet to groups of 24 male and 24 female S-D rats over 2 consecutive generations at concentrations of 0, 25, 250 and 2500 ppm... Postmortem examination of parental animals revealed primarily liver toxicity, consisting of organ enlargement and discoloration, hepatocellular swelling and necrosis, and bile stasis. Other findings included : increased kidney weight, focal renal tubular atrophy, thyroid follicular hypertrophy, and adrenal cortical hypertrophy. Postmortem examination of the offspring revealed liver enlargement and the appearance of white spots at the periphery of the liver lobes. These findings were accompanied by histopathological evidence of hepatocellular swelling and localized areas of hepatocellular necrosis, fibrosis and mineralization. The white liver spots are considered a reversible lesion due to their declining incidence with increasing animal age and their complete absence in adults... (The Institute of Environmental Toxicology, 1989)
Ref: Summary of Toxicology Studies With Dithiopyr Dennis P. WARD. Toxicology Department, The Agricultural GroUp, A Unit of Monsanto Company (Received February 20, 1993) -
http://wwwsoc.nii.ac.jp/pssj2/tec_info/dithiopy.pdf

Epoxiconazole - Fungicide - CAS No. 135319-73-2 (formerly 106325-08-0)

"Likely to be Carcinogenic to Humans." Combined hepatocellular tumors in male or female 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

-- Dose levels 23 mg/kg/day resulted in maternal death, clinical signs, clinical chemical effects, liver effects (i.e., damage), histopathology, and limited number of pregnancy and pups with reduced body weights which increased in severity to the upper dose levels, this also indicated that doses above 23 mg/kg/day were considered to be beyond the maximum tolerated dose (MTD) for pregnant rats.
--Chronic toxicity. i. A series of two 1-year dog studies (study A dose levels were 0, 1.6, 15, and 49 mg/kg/day for which a NOAEL was established in females, and study B dose levels were 0, 0.3, 0.6, 0.9, and 1.1 mg/kg/day to determine a NOAEL in males. The NOAEL was established as 1.1 mg/kg/day based on the following effects: a. Mortality in the 49.0 mg/kg/day dose group with severe clinical signs and evidence of liver damage in those dogs which were sacrificed for humane reasons.
-- Separate chronic feeding and oncogenicity studies in rats were performed to assess the chronic toxicity and oncogenic potential of epoxiconazole. The chronic toxicity study was conducted at dose levels of 0 and approximately 2, 8, 38, and 78 mg/ [[Page 57341]] kg/day. The oncogenicity study was conducted at dose levels of 0 and approximately 2, 7, 40, and 80 mg/kg/day. The results from the 2 studies are combined and summarized as follows: c. Increased absolute and relative liver weights were seen for males and/or females at dose levels 38 mg/kg/day. d. Microscopic findings were observed in the liver for male and/or female rats at dose levels 38 mg/kg/day, in female adrenals at the highest dose test, and in the ovaries at dose levels 38 mg/kg/day.
-- It has been determined that liver tumor effects observed at the 70.4 and 205.4 mg/ kg/day dose levels clearly exceeded the MTD. The liver necrosis observed in the male and female mice, further support the finding that the MTD was exceeded in the 70.4 and 205.4 mg/kg/day dose levels. A series of mechanistic studies were performed to elucidate and define the liver promotion properties of epoxiconazole. The following conclusions can be drawn from the data: The material is a potent inducer of the hepatic cytocrome P-450 enzyme system, similar to the drug-phenobarbital. The material induced proliferation of the smooth endoplasmatic reticulum in the liver centrolobular hypertrophy and induction of phase 1 and phase 2 enzymes of the xenobiotic metabolism. The material was determined not to be an initiator of the carcinogenic process, but a promoter of initiated cells in the tumorgenesis as has been similarly shown with drug--phenobarbital.
Ref: September 22, 2000. Federal Register. [Notices] [Page 57338-57344]. Notice of Filing Pesticide Petitions to Establish Tolerances for Certain Pesticide Chemicals in or on Food.
http://www.fluorideaction.org/pesticides/epoxiconazole.fr.sept.2000.htm

Ethalfluralin - Herbicide - CAS No. 55283-68-6

Beagle dogs were given 0, 4, 20, or 80 mg/kg/day orally, by capsule, for 1-year. The NOAEL was 4 mg/kg/day. The LOAEL was 20 mg/kg/ day, based on increased urinary bilirubin, variations in erythrocyte morphology, increased thrombocyte count, and increased erythroid series of the bone marrow. Elevated alkaline phosphatase levels were found at the two higher doses and siderosis of the liver at the high dose.
Ref: Federal Register. November 14, 2001. [PF-1052; FRL-6808-9]
http://www.fluoridealert.org/pesticides/Ethalfluralin.FR.Nov14.2001.htm

-- Subchronic toxicity studies using mice and rats resulted in changes in liver and kidney weights, decreased weight gain, and changes in blood and enzyme activity. A study using beagle dogs resulted in changes in the liver, blood and cholesterol..
-- A chronic toxicity and carcinogenicity study using rats resulted in mammary gland tumors in female rats at mid and high doses. EPA concluded on June 8, 1994, that ethalfluralin should be classified as a Group C, possible human carcinogen, based on the results of that study. A second study in mice caused liver cell, blood and enzyme changes, as well as increased liver, kidney and heart weights in females, and decreased body weight gain. A study using beagle dogs resulted in changes in the blood, bone marrow, enzymes and liver.
Ref: January 1995. US EPA R.E.D. FACTS Ethalfluralin.
http://www.fluorideaction.org/pesticides/ethalfluralin.red.epa.1995.pdf

Etoxazole - Miticide, Ovicide - CAS No. 153233-91-1

-- 90-Day oral toxicity rodents (rat). NOAEL = 61.8/69.0 milligrams/kilogram/ day (mg/kg/day) Male/Female (M/F) LOAEL = 183.7/204.8 mg/kg/day (M/F), based upon increases in hepatic enzyme levels, increased liver weights and centrilobular hepatocellular swelling in both sexes and liver enlargement in females only
-- 90-Day oral toxicity rodents (mouse). NOAEL = 213.6/250.5 mg/kg/day (M/F) LOAEL = 878.4/994.5 mg/kg/day (M/F), based upon periportal hepatocellular necrosis, increased alkaline phosphatase levels, accompanied by increased relative liver weight, liver enlargement, and centrilobular hepatocellular swelling
-- 90-Day oral toxicity nonrodents (dog). NOAEL = 5.33/5.42 mg/ kg/day (M/F) LOAEL = 53.7/55.9 mg/ kg/day (M/F), based upon clinical signs (vomiting foamy fluid and mucous stool), clinical chemistry, increased liver weights, and centrilobular swelling in the liver and acinar cell atrophy in the prostate.
-- Prenatal developmental toxicity in nonrodents (rabbit). Maternal NOAEL = 200 mg/kg/day LOAEL = 1,000 mg/kg/day based upon liver enlargement and decreased body weight gains and food consumption. Developmental NOAEL = 200 mg/kg/day LOAEL = 1,000 mg/kg/ day based upon increased incidences of 27 presacral vertebrae and 27 presacral vertebrae with 13th ribs in the fetuses.
-- Reproduction and fertility effects (rat). Parental/Systemic NOAEL = 20 mg/kg/ day LOAEL = 100 mg/kg/ day (M/F), based upon increased liver weights in the P and F1 males and increased adrenal weights in the P females Offspring/Systemic NOAEL = 20 mg/kg/ day LOAEL = 100 mg/kg/ day (M/F), based upon pup mortality Reproductive NOAEL = 100 mg/kg/day LOAEL = not determined.
-- Combined chronic toxicity/ carcinogenicity rodents (rat). NOAEL = 64 mg/kg/day (M/F). LOAEL = not determined Equivocal evidence of carcinogenicity.
-- Chronic toxicity nonrodents (dog). NOAEL = 4.62/4.79 mg/kg/day (M/F). LOAEL = 23.5/23.8 mg/ kg/day (M/F), based upon increased alkaline phosphatase activity, increased liver weights, liver enlargement (females), and incidences of centrilobular hepatocellular swelling in the liver.
-- 78-Week carcinogenic mouse. NOAEL = 242/243 (M/ F). LOAEL = 484/482 (M/ F), based on a slight increase in the incidence of a fatty change in the centrilobular hepatocytes in males.
-- The weight-of- the-evidence from the 28-day, 90-day, 52- week interim chronic toxicity/ carcinogenicity and the 2-year chronic toxicity/ carcinogenicity rat studies shows that the systemic effects (mainly in the liver) occur around the same dose levels from short- term through long-term exposure without increasing in severity. Therefore, results of the 28-day dermal toxicity study can be applicable to long-term exposure.
Ref: Federal Register: September 26, 2003. Etoxazole; Pesticide Tolerance. Final Rule.
http://www.fluorideaction.org/pesticides/etoxazole.fr.sept.26.2003.htm

Subchronic/Chronic Toxicity
-- 870.3100 90-Day Feeding Rat NOAEL = not determined LOAEL = 300.4/336.6 (M/F), based on clinical signs, clinical chemistry, increased liver weights, and histopathology
-- 870.3100 90-Day Feeding Rat NOAEL = 18.3/20.5 (M/F) LOAEL = 183.7/204.8 (M/F) based on increase in hepatic enzyme levels, increased liver weights and centrilobular hepatocellular swelling in both sexes and liver enlargement in females only
-- 870.3150 90-Day Feeding Mouse NOAEL = 213.6/250.5 (M/F) LOAEL = 878.4/994.5 (M/F), based on periportal hepatocellular necrosis, increased alkaline phosphatase levels, accompanied by increased relative liver weight, liver enlargement, and centrilobular hepatocellular swelling
-- 870.3150 90-Day Feeding Dog NOAEL = 5.33/5.42(M/F) LOAEL = 53.7/55.9 (M/F), based on clinical signs (vomiting foamy fluid and mucous stool), clinical chemistry, increased liver weights, and on centrilobular hepatocellular swelling in the liver and acinar cell atrophy in the prostate.
-- 870.3200 21-Day Dermal Tox Rat NOAEL = 1000 LOAEL > 1000, no effects noted. 870.3700 Developmental Tox Rabbit NOAEL = Maternal: 200 Developmental: 200 LOAEL = Maternal: 1000, based on liver enlargement and decreased body weight gains and food consumption Developmental: 1000, based on increased incidences of 27 presacral vertebrae and 27 presacral vertebrae with 13 ribs (skeletal variations) in the fetuses
Ref: US EPA Pesticide Fact Sheet. August 2002.
http://www.epa.gov/opprd001/factsheets/etoxazole.pdf