Fluorinated and Fluoride Pesticides
Pesticides beginning with A-E F G-R S-Z

See FAN's summary of all the pesticides with Cancer effects.

Due to length, the Cancer effects section is now presented in 4 parts.

The most recent United States Cancer Statistics report was released in November 2003. This is the 2nd annual report prepared by the Centers for Disease Control and Prevention and the National Cancer Institute, in collaboration with the North American Association of Central Cancer Registries.

In 1998 I published the Citizens' Guide to 667 Chemicals Known to Cause Human Cancer in the newsletter Waste Not. The four top uses of these chemicals were in the manufacture of


Of the 667 known carcinogenic chemicals, 84 were identified by the US EPA in 1997 as "High Production Volume Chemicals" - produced in quantities greater than 1 million pounds a year.

If society wants to prevent cancer, the first step would be to ban the use, production and release of known and suspected carcinogens. - EC.

Towards what ultimate point is society tending by its industrial progress?
When the progress ceases, in what condition are we to expect
that it will leave mankind?
- John Stuart Mill, 1857 -

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

-- Food and Agricultural Organization of the United Nations

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

Fipronil - Acaracide, Insecticide - CAS No. 120068-37-3

Group C -- Possible Human Carcinogen. Thyroid follicular cell adenomas, carcinomas & combined adenomas/carcinomas (M); thyroid follicular cell adenomas and combined adenomas/carcinomas (F); Charles River CD rats.
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.

Group C--Possible Human Carcinogen. Reviewed 7/ 18/ 95.
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.

Cancer. The EPA's Health Effects Division Carcinogenicity Peer Review Committee classified fipronil in Group C - Possible Human Carcinogen, based on thyroid tumors observed in rats at 300 ppm (HDT). Mechanistic data indicate that these tumors are related to a disruption in the thyroid-pituitary status and are specific to the rat. In addition, there was no apparent concern for mutagenic activity. Thus, it was recommended that RfD methodology, i.e. non-linear or threshold, be used for the estimation of human risk.
Ref: August 24, 2005. Federal Register. Fipronil; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

-- Carcinogenic classification and risk quantification. EPA has classified this chemical as a Group C--Possible Human Carcinogen, based on increases in thyroid follicular-cell tumors in both sexes of the rat, which were statistically significant by both pair-wise and trend analyses. EPA has used the RfD methodology to estimate human risk because the thyroid tumors are due to a disruption in the thyroid-pituitary status. There was no apparent concern for mutagenicity.
Ref: Federal Register: July 17, 1998. Fipronil; Pesticide Tolerance. Final Rule.

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

Suggestive Evidence of Carcinogenicity, but not sufficient to assess human carcinogenic potential. Nasal lacrimal duct squamous cell carcinomas possibly treatment-related in female Wistar rats; Mitogenesis MOA accepted for lung tumors in CD-1 mice (both sexes).
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.

-- Cancer. Suggestive evidence of carcinogenic potential.
-- Carcinogenicity (mice).
NOAEL was not established. LOAEL is 250 ppm (equivalent to 29/38mg/kg/ day [M/F]), based on minimal to moderate centrilobular hepatocellular hypertrophy, minimal to severe extramedullary hematopoiesis, minimal to moderate pigment deposition in the sternal bone marrow, and increased incidence of tissue masses/nodules in the lungs in the males, and minimal to moderate decreased cellularity in the femoral bone marrow and hyperplasia/hypertrophy of the epithelial cells of the terminal bronchioles of the females At the doses tested, the carcinogenic potential of IKI-220 (flonicamid) is positive at 250 ppm in males and females based on the increased incidence of alveolar/bronchiolar adenomas, carcinomas, and combined adenomas/carcinomas. Dosing was considered adequate based on increased incidence of tissue masses/nodules in the lungs and microscopic findings in the liver, spleen, bone marrow, and lungs. However, data were provided suggesting this effect is specific to sensitive strains of mice. Carcinogenic in mice.
-- Combined Chronic/ carcinogenicity (rats). NOAEL is 200 ppm (equivalent to 7.32/8.92mg/ kg/day in males/females). LOAEL is 1,000 ppm (equivalent to 36.5/44.1mg/ kg/day in males/females) based on decreased body weights and body weight gains,and increased incidences of keratitis in males and striated muscle fiber atrophy in females. At the high dose there was an incidence (12%)of nasolacrimal duct* squamous cell carcinomas slightly outside the historical control range (0-10%) in male rats. A correlation between the incidence of inflammation and the fluctuating incidence of nasal tumors was made across dose groups. EPA did not consider the nasolacrimal duct tumors to be treatment-related. Female rats had a significant increasing trend in nasolacrimal duct squamous cell carcinomas at < 0.05, and at the high dose was slightly above the historical control mean (0.8%) and range (0-4%). EPA considered the nasolacrimal duct squamous cell carcinomas to be possibly treatment related, but that a clear association with treatment could not be made.
-- Aggregate cancer risk for U.S. population. In assessing the carcinogenic potential of flonicamid, EPA took into account the following weight-of-the-evidence considerations:
i. Flonicamid is not mutagenic.
ii. The treatment-related CD-1 mouse lung tumors (benign and malignant) which occurred in both sexes were due to an established mitogenic mode of action that occurred in a susceptible mouse strain with a high background. A clear species difference was
observed between mice and rats in the incidence of lung tumors and the BrdU Index studies. (Bromodeoxyuridine (BrdU) Index studies are used to quantify rates of cell proliferation). No tumors were seen in the lungs of rats. The flonicamid induced increase in the BrdU Index appears to be related to the different sensitivity of strains of mice, with the CD-1 mice being a relatively sensitive strain.
iii. The only other tumor response was nasolacrimal duct tumors which occurred in female rats at the high dose which were considered to be possibly treatment-related, but a clear association with treatment could not be made. Unlike male rats, the nasal tumor response in females could not be clearly associated with spontaneous inflammation related to malocclusion of incisor teeth, due to the low incidence of both the neoplastic and non-neoplastic lesions. Given these findings in the cancer and mutagenicity studies, EPA regards the carcinogenic potential of flonicamid as very low and concludes that it poses no greater than a negligible cancer risk to humans.
Ref: August 31, 2005. Flonicamid; Pesticide Tolerance. Final Rule. Federal Register.

-- In the 18-month mouse study... There were statistically significant increases in the incidence of alveolar/bronchiolar adenomas in both sexes of treated groups with hyperplasia/hypertrophy of epithelial cells in terminal bronchioles. There was a statistically significant increase in the incidence of alveolar/bronchiolar carcinomas in males at 750 ppm and 2,250 ppm and in females at 2,250 ppm only. These effects in the lungs of mice were not life threatening as most of effects were observed at the terminal sacrifice and there was no effect of treatment on mortality in the study. A NOAEL could not be determined from the dose levels administered. Mechanism-of-action studies have indicated that the lung effects are unique to the mouse and are not likely to translate to other species including the rat. Flonicamid technical was not carcinogenic in the rat.
Ref: Federal Register: May 23, 2003 (Volume 68, Number 100)] [Notices] [Page 28218-28222]. Flonicamid; Notice of Filing a Pesticide Petition to Establish a Tolerance for a Certain Pesticide Chemical in or on Food.

-- 52964 - 0068, 0069 & 0070 216042, 216043, 216044 “Vol 0068: Dietary Carcinogenicity of IKI-220 Technical in Mice; Vol 0069: Pathology Sub-Report (Supplemental) for Dietary Carcinogenicity of IKI220 Technical in Mice; Vol 0070: Historical Data for Dietary Carcinogenicity of IKI-220 Technical in Mice,” (Nagaoka, T., Nakashima, N.; Shin Nippon Biomedical Laboratories, Ltd., Kagoshima, Japan; The Institute of Environmental Toxicology, Ibaraki, Japan; 1/22/04, 3/30/04, 1/22/04 for volumes 0068, 0069 & 0070, respectively). Flonicamid technical (IKI-220: 98.7% pure) was fed in diet to Charles River Crj:CD-1®(ICR)BR mice (50/sex/dose) at 0, 10, 25, 80 and 250 ppm (equivalent doses: M = 1.20, 3.14, 10, 30.3 mg/kg/day; F = 1.42, 3.67, 11.8, 36.3 mg/kg/day) for 78 weeks. Systemic NOEL = 80 ppm (There was an increase in lung hyperplasia and hypertrophy (both sexes) and liver fatty change in centrilobular hepatocytes (F) at 250 ppm. There was a statistically significant decrease in absolute kidney weights in females at 250 ppm. There was a statistically significant increase in lung masses--pulmonary adenomas and carcinomas in males at 250 ppm.) Not acceptable (There were numerous deficiencies in this study (see A., above). There were no interim kills, nor were all target organs examined and weighed as recommended by FIFRA Guidelines.), not upgradeable. Possible adverse effect indicated (There was a statistically significant increase in pulmonary adenomas and carcinomas in males at 250 ppm. Silva, 4/29/05
-- Rationale for Regulation by Reference Dose,” (Cohen, S.M., Hardisty, J.F., McCarty, J.D.; FMC Corporation, Agricultural Products Group, Princeton, NJ; Document #: flonicamid 04-04, 8/31/04). This report contains a complete discussion (along with a presentation of summary data) on the mechanism and potential for oncogenicity of flonicamid. All studies discussed in this report were presented for review to DPR. Many of the potential adverse effects, primarily regarding the incidence of nasal and lung cancer in rats and mice, respectively, were initially noted in worksheets provided by USEPA. Upon re-evaluation of the noted effects, the nasal cancers in rats were found to originate in the nasal-lacrimal duct, which is more common than the squamous cell carcinomas. The nasolacrimal duct tumors were determined to be unilateral and not bilateral which indicated they were spontaneous and not due to treatment. Based on the low spontaneous incidence of these tumors in humans versus rats, the potential for their initiation in humans after flonicamid exposure, were negligible. Lung tumors (observed only in mice) appeared to be due to mitogenesis, non-linear, non-genotoxic mode of action for which a threshold dose has been established. Historical controls were presented for all potential adverse effects. Included also were complete discussions of all questions raised by USEPA. This information is supplemental. No worksheet was performed for this data volume. Silva, 2/2/05.
Reference: April 28, 2005 - Summary of toxicology data. California EPA, Department of Pesticide Regulation, Medical Toxicology Branch.

* Note: The nasolacrimal duct carries tears from the lacrimal sac into the nasal cavity.

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

Suggestive Evidence of Carcinogenicity to Humans. An increase in thyroid gland follicular cell tumors in male rats, and an increased incidence of hepatocellular tumors observed in the male mice was treatment-related.
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.

-- Carcinogenicity mice NOAEL = Males:1.1 mg/kg/day; Females: 1.2 mg/kg/day. LOAEL = Males: 10.7 mg/kg/day; Females: 11.7 mg/kg/day based on increased incidences of brown macrophages in the liver of both sexes, eosinophilic vacuolated hepatocytes in males, and increased liver weight in females. Clear evidence of carcinogenicity (hepatocellular tumors) in male mice, but not in females.
-- Combined chronictoxicity/ NOAEL = Males: 0.38 mg/kg/day; carcinogenicity rats Females: 0.47 mg/kg/day LOAEL = Males: 3.8 mg/kg/day; Females: 4.9 mg/kg/day based on liver toxicity in both sexes, pancreatic exocrine atrophy in females and testicular atrophy in males. Some evidence of carcinogenicity (thyroid gland follicular cell tumors) in male rats, but not in females.
-- Carcinogenicity mice NOAEL = Males:<126 mg/kg/day, Females: <162 mg/kg/day LOAEL = Males: 126 mg/kg/day; Females: 162 mg/kg/day based on increased liver weights and liver and brain histopathology in both sexes Equivocal/some evidence of carcinogenicity (hepatocellular tumors) in male mice, but not in females,
Ref: Federal Register. September 7, 2001. Fluazinam; Pesticide Tolerance. Final Rule.

-- Cancer (oral, dermal, inhalation). `Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential'' 2 . Quantification of human cancer risk not required. 2 Increases in thyroid gland follicular cell tumors in male rats; increases in hepatocellular (liver) tumors in male mice.2 (Ref 2: 2Cancer Assessment Document - Evaluation of the Carcinogenic Potential of Fluazinam, March 29, 2001, HED Doc. No. 014512.)
-- Cancer. Since fluazinam has been classified as ``Suggestive evidence of carcinogenicity, but not sufficient to assess human carcinogenic potential,'' an exposure assessment was not performed.
Ref: Federal Register: April 18, 2002. Fluazinam; Pesticide Tolerance. Final Rule.

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

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

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

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

-- The EPA classified Fludioxonil as a Group D - not classifiable as to human carcinogenicity. The evidence is inadequate and cannot be interpreted as showing either the presence or absence of a carcinogenic effect. In one mouse study, there was a significant trend for malignant lymphomas in female mice up to 3,000 ppm. However, in a second study up to 7,000 ppm, the limit dose, there was no evidence of carcinogenicity for either sex. In rats, fludioxonil produced a significant trend and pair- wise increase in hepatocellular tumors, combined, in female rats at doses adequate to assess carcinogenicity. The EPA determined that based on the increase in liver tumors in female rats that was statistically significant for combined adenoma/carcinoma only, the lack of tumorogenic response in male rats or in either sex of mice, and the need for additional mutagenicity studies, a Group D classification was appropriate. However, the Agency has since received the additional mutagenicity studies and based on the negative preliminary findings of the studies, the fact that the statistical increase in liver tumors in female rats occurred only at the highest dose, the lack of tumorigenic response in male rats and mice, the Agency has concluded that fludioxonil does not pose a significant cancer risk.
Ref: Federal Register: September 12, 2001. Fludioxonil; Pesticide Tolerances for Emergency Exemptions. Final Rule.

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

Group C -- Possible Human Carcinogen. Statistically significant increases in combined adenomas/carcinomas of the lung (M); Malignant lymphocytic lymphomas (F); CD-1 mice.
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.

Group C--Possible Human Carcinogen. Reviewed 8/ 28/ 96.
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.

The significant cancer risk contributors have been identified as drinking water (direct and indirect, all sources), and several rotational crops with wheat (flour), soybean (oil), and rice (white) having the highest contributions. (page 7)
• A re-examination and statistical analysis of the rates of all lymphocytic lymphomas in female mice and all alveolarhronchiolar hyperplasia, adenomas, and carcinomas in male mice from the carcinogenicity study in mice (0, 10,500, or 2000 ppm [83-2b]) indicated that male mice had a significant increasing trend in alveolar/bronchiolar adenomas andor carcinomas combined at p < 0.05. There were no significant differences in the pair-wise comparisons of the dosed groups with the controls. The male alveolarhonchiolar tumor rates were 15/56, 16/59, 19/56, and 24/58, respectively (L. Taylor Memorandum 9/13/95, TXR 012742). Female mice had a significant increasing trend and a significant difference in pair-wise comparison of the high-dose group (2000 ppm) with the controls for lymphocytic lymphomas at p < 0.05. The lymphatic tissue tumor rates were 4/5 1, 10124, 6/17, and 12/53, respectively (L. Taylor Memorandum 9/13/95, TXR 012742).(page 9)
• D. Classification of Carcinogenic Potential.
The Health Effects Division Carcinogenicity Peer Review Committee (CPRC) met on Oct. 11, 1995 to discuss and evaluate the weight-of-the-evidence on fluometuron with particular reference to its carcinogenic potential. The consensus of the CPRC was that fluometuron should be classified as Group C -possible human carcinogen and for the purpose of risk characterization, both a low dose extrapolation model (Q,’) applied to the animal data (lung tumors in male mice) and the Reference Dose (RfD) approach should be used. This was based on statistically significant increases in combined adenomadcarcinomas of the lungs in male mice and malignant lymphocytic lymphomas in female mice, at a dose which was less than adequate for fully assessing the carcinogenic potential of fluometuron ( L. Taylor Memorandum 8/28/96, TXR 012049).
A quantitative risk assessment-Q,* was performed for fluometuron (B. Fisher Memorandum 12/24/96, TXR 012809). The unit risk, QI*(mg/kg/day)-’of fluometuron, based upon male mouse combined lung (adenomas and/or carcinomas) tumor rates is 1.80 x lo-*in human equivalents (converted from animals to humans by use of the 314‘s scaling factor-1994, Tox Risk, 3.5-K. Crump) (Ref. 1). The dose levels used from this 2-year study were 0, 10,500, and 2000 ppm of fluometuron. The corresponding tumor rates (from re-read slide data, 7/92) for the male mice were 15/56, 16/59, 19/56, and 24/58 respectively.
The estimate of unit risk, Q1*was based upon lung (adenoma and/or carcinoma) tumor rates in male mice. Since male mice had statistically significant increases in mortality with dose increments of fluometuron, the estimate of the unit risk, Q1*,was obtained by the application of the time-to-tumor Weibull model (Tox-Risk program, version 3.5-K. Cnunp). The resulting estimate of unit risk, Q1*,was converted to human equivalents by the use of weights of 0.03 kg for the mice and 70 kg for the humans and the 3/4’s scaling factor for interspecies extrapolation. It is to be noted that Q,* (mg/kg/day)-’ is an estimate of the upper bound on risk and that (as stated in the EPA Risk Assessment Guidelines) “the true value of the risk is unknown, and may be as low as zero. (page 11-12).
(1). See memo-Deriving Q,*s Using the Unified Interspecies Scaling Factor, P.A. Fenner-Crisp. Director-HED, 7/1/94.
Ref. February 1, 2005. US EPA: Fluometuron: Revised HED Risk Assessment for Phase III of the Reregistration Eligibility Decision. Docket Identification Number: OPP-2004-0372-0008.

Twelve of the 26 most widely used pesticides in the U.S. are classified as possible or probable carcinogens by the EPA based on studies of laboratory animals, with an annual use that totals 380 million pounds. (atrazine (C=possible), metolachlor (C), metarn sodium (B2=probable), dichloropropene (B2), cyanazine (C), pendimethalin (C), trifluralin (C), acetochlor (B2), chlorothalonil (likely), mancozeb (B2), fluometuron (C), and parathion (C). Four frequently used pesticides have been associated with increased risk of cancer for exposed humans in epidemiological studies. 190 million pounds of these four pesticides are used annually in the U.S., including 120 million household applications every year. (atrazine, 2,4 D, glyphosate, diazinon). (Journal of Pesticide Reform, Summer 1999, at 5). Last year, the EPA moved under the Food Quality Protection Act to phase out residential uses of diazinon, but agricultural uses remain legal.
Ref: Testimony of the Maine Organic Farmers and Gardeners Association In support of L.D. 1540. March 29, 2001.

1980 Abstract: ... A bioassay of the phenylurea herbicide fluometuron for possible carcinogenicity was conducted by administering the test chemical in feed to F344 rats and B6C3F1 mice. Groups of 50 rats of each sex were fed diets containing 125 or 250 ppm of fluometuron for 103 weeks, and groups of 50 mice of each sex were fed diets containing 500 or 1,000 ppm of fluometuron for 103 weeks. Matched controls consisted of groups of 50 untreated rats and 25 untreated mice of each sex. All surviving animals were killed at 103 to 105 weeks. Splenomegaly observed in rats in the subchronic studies influenced selection of the doses for the chronic study; however, no splenic effects were observed in the chronic study. Mean body weights of the dosed groups of male and female rats and mice were essentially the same as those of the corresponding control groups. Survival of dosed groups of rats and mice was similar to that of the corresponding control groups. Similarities between mean body weights and survival between dosed and control animals in the chronic study suggest that these animals could have tolerated higher doses. The only possible carcinogenic effects from compound administration were in male mice. Incidences of hepatocellular carcinomas or adenomas in male mice were dose related, and the incidence in the high-dose group was marginally higher than that in the corresponding matched controls or pooled controls from concurrent studies. Under the conditions of this bioassay, fluometuron was not carcinogenic for F344 rats or for female B6C3F1 mice. Equivocal results were obtained for male B6C3F1 mice which may have had an increased incidence of hepatocellular tumors. Because of the equivocal findings and because both rats and mice may have been able to tolerate higher doses, it is concluded that additional testing of fluometuron for carcinogenicity is warranted. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Equivocal Female Mice: Negative Synonym: 1,1-dimethyl-3-(a,a,a-trifluoro-m-tolyl) urea
Ref: Bioassay of Fluometuron for Possible Carcinogenicity (CAS No. 2164-17-2). National Toxicology Program. Natl Toxicol Program Tech Rep Ser. 1980 Aug;195:1-99.


Ref: TOXNET profile from Hazardous Substances Data Bank for 1-Chloro-1,1-Difluoroethane.,1,-difluo.toxnet.htm

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

Likely to be carcinogenic to humans. Reviewed 12/ 8/ 98.
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.

-- Fluthiacet-methyl is classified as a "likely to be a human carcinogen" based on the presence of pancreatic tumors (exocrine adenomas, islet cell adenomas and combined islet cell adenomas + carcinomas) in male rats and liver tumors (adenomas and combined adenomas + carcinomas) in male and female mice.
Ref: US EPA. Pesticide Fact Sheet. Fluthiacet-methyl Reason for Issuance: Conditional Registration Date Issued: April 1999.

-- Carcinogenicity rats. NOAEL in males = 2.1 mg/kg/day LOAEL in males = 130 mg/kg/day NOAEL in females = 2.5 mg/kg/day LOAEL in females = 154 mg/kg/dayIn males there were decreased body weight, liver toxicity, pancreatic toxicity and microcytic anemia. In females there were liver toxicity, uterine toxicity and slight microcytic anemia. In males only at 130 and 219 mg/kg/day there was respectively, an increase in the trend toward pancreatic exocrine adenomas and pancreatic islet cell adenomas.
-- Carcinogenicity mice. NOAEL in males and females = 0.1 mg/ kg/day LOAEL in males and females = 0.1 and 1.2 mg/kg/day, respectively, based on non- neoplastic liver findings. In males, and possibly females, at 10 mg/kg/day for males and 12 mg/kg/day for females; and at 32 gm/kg/day for males and 37 mg/ kg/day for females, there was an increase in the number of mice with hepatocellular adenomas, carcinomos and or adenomas/ carcinomas.
-- Chronic Dietary General population. 18-month carcinogenicity in the mouse. NOAEL = 0.1 mg/kg/day Non-neoplastic liver findings (increase in absolute and relative liver
weights, fatty changes, chronic inflammation, karyomegaly, single cell necrosis and ceroid/lipofuscin pigmentation).
-- Cancer. Fluthiacet-methyl has been classified as ``likely to be a human carcinogen'' by EPA. The Office of Pesticide Programs, Heath Effects Division, Cancer Assessment Review Committee recommended a linear low-dose approach (Q1*) for human risk assessment. The Q1* is 0.207 (mg/kg/day)-1 in human equivalents and is based upon the combined hepatocellular tumors (adenomas and carcinomas) in male mice. EPA conducted a cancer assessment analysis (food) using DEEM software and Tier 2 chronic dietary exposure assumptions. The assumptions of this Tier 2 chronic dietary analysis are as specified above. The cancer risk estimate (food only) for the U.S. population (total) is 3.93 x 10-8. This risk estimate translates to a dietary exposure of 1.90 x 10-7 mg/kg/day. This dietary exposure value was back-calculated based upon the cancer risk estimate and the Q1*. As cancer risk = Exposure x Q1 * Thus, Exposure = cancer risk estimate/ Q1 * or Exposure = 3.93 x 10-8/0.207.
Ref: Federal Register: December 21, 2001. Fluthiacet-methyl; Pesticide Tolerance. Final Rule.

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

Group C--Possible Human Carcinogen. Reviewed 8/ 27/ 86.
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.

-- Decreased plasma cholesterol and triglycerides and increased liver weights (reversible at 7 days post-treatment) were observed at 50 mg/kg/day (only dose tested) when administered in the diet of rats for 4 weeks. In a 90-day rat study, dietary administration of 5 mg/kg/day (LOEL) produced alterations in lipid metabolism and increases in liver weight. The NOEL was 0.25 mg/kg/day. In a 26-week dog study, dietary administration of 25 mg/kg/day (LOEL) produced alterations in lipid metabolism and liver changes (changes not defined). The NOEL was 1 mg/ kg/day. Liver toxicity (increased liver masses, discolored hepatocytes, and pigmented Kupffer cells) was observed in a 2-year rat feeding study at 50 mg/kg/day (LOEL). The NOEL was 5 mg/kg/day. Metabolism studies have shown that fomesafen accumulates in the liver. EPA believes that there is sufficient evidence for listing fomesafen on EPCRA section 313 pursuant to EPCRA section 313(d)(2)(B) based on the available hepatic toxicity data for this chemical.
Ref: USEPA/OPP. Support Document for the Addition of Chemicals from Federal Insecticide, Fungicide, Rodenticide Act (FIFRA) Active Ingredients to EPCRA Section 313. U. S. Environmental Protection Agency, Washington, DC (1993). As cited by US EPA in: Federal Register: January 12, 1994. Part IV. 40 CFR Part 372. Addition of Certain Chemicals; Toxic Chemical Release Reporting; Community Right-to-Know; Proposed Rule.

-- 4. Carcinogenicity. Fomesafen is classified as a Group C carcinogen with a Q* of 1.9 x 10-1 (mg/kg/ day)-1. This classification was based on: (i) Increases in both adenomas and carcinomas at several dose levels in both sexes of mice; (ii) some evidence of reduced latency for the time of tumor appearance; (iii) limited evidence of mutagenic effects; and, (iv) the structural similarity of fomesafen to other biphenyl ether herbicides which have been shown to be carcinogenic.
-- iii. Cancer risk. Based on exposure levels for drinking water, as given above, the estimate of cancer risk is 2.7 x 10-6. This figure is an overestimate, as it was arrived at based on several very conservative assumptions. Estimates used were calculated based on data from only one small scale study conducted in NC, for use of fomesafen on soybeans at a vulnerable site. This represents a worst case scenario, so is not representative of the ``average'' conditions of use. Additionally, there is language on the product label warning of the potential of fomesafen to leach to ground water in vulnerable areas. Vulnerable areas in this case refers to areas where soils are permeable (sand and silt loams) and the water table is shallow. The majority of areas of soybean production, and potential use of fomesafen, will not likely be vulnerable sites, thus the data used from the one small scale study greatly overestimates levels which could actually occur. Further, it is assumed that this exaggerated level will occur in all drinking water throughout the US, and that each individual consumes 2 liters of drinking water per day.
-- When considering structural similarities with other chemicals, fomesafen falls into the class of ``biphenyl ether'' chemical compounds; this means that this group of chemicals have structural similarities, including a biphenyl ether group, in common. This is used as a piece of supporting evidence for the classification of fomesafen as a Group C carcinogen, since other chemicals of this group (with similar structure) have been found to be carcinogens. However, other indications of the carcinogenicity of fomesafen (i.e., increases of adenomas and carcinomas in a mouse study, limited evidence of mutagenic effects) were also used in deciding this cancer classification. At this time, the Agency does not have sufficient understanding of the structural relationship to the mechanism of toxicity of these chemicals to conclude that they may be combined for the purposes of conducting a risk assessment. Although fomesafen contains some chemical structures in common with other chemicals that have been found to be carcinogens, EPA does not yet fully understand the implications of such a relationship, nor how, or if, these structures relate to the toxicological activity of the chemical. For the purposes of this tolerance action, therefore, EPA has not assumed that fomesafen has a common mechanism of toxicity with other substances.
Ref: Federal Register. November 19, 1997. Fomesafen; Pesticide Tolerances for Emergency Exemptions. Final Rule.

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

Fomesafen sodium - Herbicide - CAS No. 108731-70-0

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. Except for haloxyfop-methyl, all of the other chemicals produced positive results in at least one of the mutagenicity assays... For fomesafen (P.C.Code 123802) the data included, a 4-week feeding study in the mouse (MRID 40786709), a 28-day feeding study in the hamster (MRID 40910801) and an in vitro study (MRID 40910802, Elcombe et al., Annals NY Acad Sci. 804: 628-635 [1996]) with rat, mouse, guinea pig and human hepatocytes...
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.
Note: Except for Nitrofen, all the pesticides cited above are fluorinated.

Possible Carcinogen [Liver - see Fomesafen above]
Ref: PAN Pesticides Database.

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