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Abstracts

Activity: Fungicide (pyrrole)
Structure:

Adverse Effects:
Body Weight Decrease
Cancer: "currently unclassifiable" - statistically significant trend for malignant LYMPHOMAS in female mice; statistically significant increases in LIVER tumors in female rats
Cholesterol
Endocrine: Ovary
Endocrine: Thymus
Genotoxic
Kidney
Liver
Spleen
Environmental

-- 1 Year chronic toxicity study - dog. NOAEL = 3.3 mg/kg/day. LOAEL = 35.5 mg/kg/day based on decreased weight gain in female dogs.
-- 13 Week Oral Feeding Study - rat. Systemic. NOAEL= 64 mg/kg/day. LOAEL = 428 mg/kg/day based on decreased body weight gain in both sexes, chronic nephropathy in males, and centrilobular hepatocyte hypertrophy in females.
Ref: Federal Register: September 12, 2001. Fludioxonil; Pesticide Tolerances for Emergency Exemptions. Final Rule. http://www.fluoridealert.org/pesticides/Fludioxonil.FR.Sept.12.2001.htm

A chronic oral toxicity study in dogs dosed for 52 weeks at 0, 100, 1,000, and 8,000 ppm in the diet (0, 3.1, 33.1, and 297.8 mg/kg/ day in males; 3.3, 35.5, and 330.7 mg/kg/day in females. The LEL is 297.8 mg/kg/day for male dogs based on decreased body weight, hematology alterations (increase in platelets and fibrin), clinical chemistry alterations (increase in cholesterol and alkaline phosphatase) and increased liver weight. The LEL is 35.5 mg/kg/day for female dogs based on a marked decrease in body weight gain for weeks 1 - 13 and weeks 1 - 52 of the study. The NOEL is 33.1 mg/kg/day for male dogs and 3.3 mg/kg/day in female dogs.
Ref: Federal Register: October 29, 1997 [Page 56075-56082]. 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fludioxonil.FR.Oct.29.1997.htm

Cancer: "currently unclassifiable" - statistically significant trend for malignant LYMPHOMAS in female mice; and statistically significant increases in LIVER tumors in female rats (click on for all fluorinated pesticides)

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

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

Cholesterol (click on for all fluorinated pesticides)

A chronic oral toxicity study in dogs dosed for 52 weeks at 0, 100, 1,000, and 8,000 ppm in the diet (0, 3.1, 33.1, and 297.8 mg/kg/ day in males; 3.3, 35.5, and 330.7 mg/kg/day in females. The LEL is 297.8 mg/kg/day for male dogs based on decreased body weight, hematology alterations (increase in platelets and fibrin), clinical chemistry alterations (increase in cholesterol and alkaline phosphatase) and increased liver weight. The LEL is 35.5 mg/kg/day for female dogs based on a marked decrease in body weight gain for weeks 1 - 13 and weeks 1 - 52 of the study. The NOEL is 33.1 mg/kg/day for male dogs and 3.3 mg/kg/day in female dogs.
Ref: Federal Register: October 29, 1997 [Page 56075-56082]. 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fludioxonil.FR.Oct.29.1997.htm

Endocrine: Ovary (click on for all fluorinated pesticides)

-- Gene mutation and other genotoxic effects were studied using fludioxonil technical: ... iii. Chromosome aberrations assay (in vitro) in Chinese hamster ovary (CHO) cells with and without S9 activation provided convincing evidence that fludioxonil is a clastogen and polyploidy inducer.
Ref: Federal Register. October 7, 1998. Fludioxonil; Pesticide Tolerance. Final Rule. http://www.fluoridealert.org/pesticides/Fludioxonil.FR.Oct.1998.htm

-- In vitro Chromosome aberration. Chinese hamster ovary cells were tested with and without metabolic activation from 1.37 to 700 g/mL. Positive for nondisjunction of chromosomes both in the presence and absence of activation.
-- Fludioxonil was not mutagenic in the tests for gene mutations. However, because of the powerful induction of polyploidy in the in vitro Chinese hamster ovary cell cytogenetic assay and the suggestive evidence of micronuclei induction in rat hepatocytes in vivo, additional mutagenicity testing was performed in an in vivo study specifically designed for aneuploidy analysis.
Ref: Federal Register: December 29, 2000. Fludioxonil; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fludioxonil.FR.Dec.2000.htm

Genotoxicity. Mutagenicity potential of fludioxonil was tested in several studies. In the Chinese hamster ovary (CHO) cell assay, some clastogenic and polyploidogenic effects were seen at or near the precipitating concentration of the test substance. However, results were negative in the Ames assay, CHO V79 cell assay, hepatocyte DNA repair assay, rat hepatocyte micronucleus test, mouse bone marrow test, and Chinese hamster bone marrow test. A dominant lethal test conducted in the mouse was also negative.
Ref: Federal Register. March 29, 2000. [Page 16602-16608]. Notice of Filing a Pesticide Petition to Establish a Tolerance for Certain Pesticide Chemicals in or on Food.
http://www.fluoridealert.org/pesticides/Fludioxonil.FR.March29.2000.htm

Endocrine: Thymus (click on for all fluorinated pesticides)

-- A carcinogenicity study in mice administered technical fludioxonil in the diet at 0, 10, 100, 1,000, and 3,000 ppm (0, 1.1, 11.3, 112, and 360 mg/kg/day for males and 0, 1.4, 13.5, 133, and 417 mg/kg/day for females)... Other macroscopic changes in female mice were an increased incidence of enlarged thymus, spleen, mediastinal lymph node, and liver and an increased incidence of lymphoma in these organs. The LOAEL is 112 mg/ kg/day for male mice, based on the increased incidence of clinical toxicity and 417 mg/kg/day for female mice, based on the increased liver weight and the increased incidence of macroscopic pathology.
Ref: Federal Register. October 7, 1998. Fludioxonil; Pesticide Tolerance. Final Rule. http://www.fluoridealert.org/pesticides/Fludioxonil.FR.Oct.1998.htm

-- In a 4 week dermal toxicity study, where the animals were treated 5 days per week, there were no signs of skin irritation at up to 1000 mg/kg bw/day. The NOAEl was 200 mg/kg bw/day, based on the presence of enlarged macrophages in the thymic cortices of all females at 1000 mg/kg bw/day. This finding is unexpected since it has not been reproduced in any other study where the animals have been systemically exposed to high doses of fludioxonil for long periods. It may be a phenomenon of high dose exposure via the dermal route.
-- The plant metabolites CGA 192155, CGA 265378, CGA 308103, and the chicken metabolite CGA 309565, were of low acute oral toxicity to the rate with LD50's of >2000 mg/kg bw, except for CGA 309103 where the LD50 was >1000 mg/kg bw. At gross necropsy, spotted thymuses were noted in all females (all of which died within one day of dosing) treated at 2000 mg/kg bw CGA 308103, but not at the lower dose levels, 200, 500 and 1000 mg/kg bw. The significance of the findings in the thymuses of the animals which died was not investigated further. In Salmonella typhimurium reverse mutation assays, the 4 above mentioned plant metabolites showed no evidence of mutagenic potential. The above results give further assurance that consumer risk from exposure to these metabolites is acceptable.
Ref: Evaluation of Fludioxonil. UK Department for Environment, Food and Rural Affairs, Pesticides Safety Directorate, Mallard House, Kings Pool, 3 Peasholme Green, York YO1 7PX. March 1995.
Note: this pdf document is large with no search engine.
Available at: http://www.pesticides.gov.uk/PSD_PDFs/Evaluations/126_fludioxonil.pdf

Genotoxic (click on for all fluorinated pesticides)

-- Gene mutation and other genotoxic effects were studied using fludioxonil technical: ... iii. Chromosome aberrations assay (in vitro) in Chinese hamster ovary (CHO) cells with and without S9 activation provided convincing evidence that fludioxonil is a clastogen and polyploidy inducer.
Ref: Federal Register. October 7, 1998. Fludioxonil; Pesticide Tolerance. Final Rule. http://www.fluoridealert.org/pesticides/Fludioxonil.FR.Oct.1998.htm

Kidney (click on for all fluorinated pesticides)

Fludioxonil safety. a. Ciba has submitted over 25 separate toxicology studies in support of tolerances for fludioxonil. According to Ciba, fludioxonil has a low order of acute toxicity by the oral, dermal, and inhalation exposure routes. The compound is slightly irritating to the eye, non-irritating to skin, and is not a dermal sensitizer. It is not a teratogen and does not affect reproduction or fertility. The kidney and liver have been identified as target organs in subchronic and chronic toxicity studies. No mutagenic activity has been seen in vivo.
Ref: Federal Register. February 5, 1997. [PF-695; FRL-5584-1]
http://www.fluoridealert.org/pesticides/Fludioxonil.FR.Feb.5.1997.htm

A combined chronic toxicity/carcinogenicity study in rats fed 0, 10, 30, 100, 1,000 and 3,000 ppm for either 12 or 24 months (males: 0, 0.37, 1.1, 3.7, 37 and 113 mg/kg/day, respectively; females: 0, 0.44, 1.3, 4.4, 44 and 141 mg/kg/day respectively)... At necropsy, [[Page 56078]] males at the 3,000 ppm dose level exhibited an increased incidence of enlarged livers, and kidneys with discolored foci or general discoloration and an increased severity of progressive nephropathy; kidneys with cysts were reported at both the 1,000 and 3,000 ppm dose levels. For females in the 1,000 and 3,000 ppm dose levels there was an increase incidence of general discoloration of the the kidneys.
Ref: Federal Register.October 29, 1997. 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fludioxonil.FR.Oct.29.1997.htm

-- 13 Week Oral Feeding Study - rat. Systemic. NOAEL= 64 mg/kg/day. LOAEL = 428 mg/kg/day based on decreased body weight gain in both sexes, chronic nephropathy in males, and centrilobular hepatocyte hypertrophy in females.
Ref: Federal Register: September 12, 2001. Fludioxonil; Pesticide Tolerances for Emergency Exemptions. Final Rule.
http://www.fluoridealert.org/pesticides/Fludioxonil.FR.Sept.12.2001.htm

Liver (click on for all fluorinated pesticides)

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

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

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

Spleen (click on for all fluorinated pesticides)

A carcinogenicity study in mice administered in the diet nominal dose levels at 0, 10, 100, 1,000, and 3,000 ppm (0, 1.1, 11.3, 112, and 360 mg/kg/day for male mice; 0, 1.4, 13.5, 133, and 417 mg/kg/day for female mice). Male mice at the 3,000 ppm level exhibited clinical toxicity in the form of an incidence of male mice which ``convulsed'' when handled. No significant effects on body weight, weight gain, food consumption, hematology, or microscopic non-neoplastic pathology was reported in either sex. Increased liver weight (9%) and spleen weight (34%) were observed in male mice at the 3,000 ppm dose level, which correlated with the macroscopic observations of enlarged spleen and raised foci of their liver. Female mice showed a statistically significant increase in liver weight at the 3,000 ppm dose level, and this is also supported by the macroscopic observation of enlarged liver at the 3,000 ppm dose level in female mice. Other macroscopic changes in female mice were an increased incidence of enlarged thymus, spleen, mediastinal lymph node, and liver, and an increased incidence of lymphoma in these organs.
Ref: Federal Register: October 29, 1997 (Volume 62, Number 209) [Rules and Regulations] [Page 56075-56082]. 4-(2,2-difluoro-1,3-benzodioxol-4-yl)-1H-pyrrole-3-carbonitrile; Pesticide Tolerance. Final Rule.
http://www.fluoridealert.org/pesticides/Fludioxonil.FR.Oct.29.1997.htm