Fludioxonil

248.19

248.18

603-476-3

ENS9J0YM16

DTXSID2032398

Colorless crystals|Yellow-ish crystals

29349990

58

4.12 at 25 deg C

1.54 at 20 deg C

199.8 °C

420.4±45.0 °C(Predicted)

208.0±28.7 °C

1.622

Solubility in: acetone 190; ethanol 44; toluene 2.7; n-octanol 20; hexane 0.1 (g/L at 25 deg C)

0-6°C

3.9 x 10 -7 Pa (25 °C)

LD50 in rats (mg/kg): >2000 orally; >2000 dermally; LC50 (4 hr) in rats: >2600 mg/m3 (Gehmann)

Odorless

Henry's Law constant = 5.3X10-10 atm-cu m/mol at 25 °C

pKa1: <0; pKa2: approx 14.1

165.7 Ų [M+Na]+ [CCS Type: DT, Method: stepped-field]|148.3 Ų [M-H]- [CCS Type: DT, Method: stepped-field]|146.13 Ų [M-H]-|147.8 Ų [M-H]-

log Kow = 2.6

III

9

3077

3

50/53

60-61

UX9347525

N

P273, P391, P501

H410

SRP: Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in air, soil or water; effects on animal, aquatic and plant life; and conformance with environmental and public health regulations. If it is possible or reasonable use an alternative chemical product with less inherent propensity for occupational harm/injury/toxicity or environmental contamination.

|Warning|H400 (98.54%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]|P273, P391, and P501|Aggregated GHS information provided by 206 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.|H400: Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]|H320: Causes eye irritation [Warning Serious eye damage/eye irritation]|P201, P202, P264, P273, P281, P305+P351+P338, P308+P313, P337+P313, P391, P405, and P501

Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166 (EU).|Handle with gloves. Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands.|Choose body protection in relation to its type, to the concentration and amount of dangerous substances, and to the specific work-place. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.|Respiratory protection is not required. Where protection from nuisance levels or dust are desired, use type N95 (US) or type P1 (EN 143) dust masks. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Use water spray, alcohol-resistand foam, dry chemical or carbon dioxide.|Wear self contained breathing apparatus for fire fighting if necessary.

Avoid dust formation. Avoid breathing vapors, mist, or gas. Ensure adequate ventilation. Evacuate personnel to safe area.|Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided.|Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal.

Provide appropriate exhaust ventilation at places where dust is formed. Normal measures for preventive fire protection.|SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

SOIL: Fludioxonil residues were reported at a maximum of 400 ug/kg in Ourense, Spain vineyard soils(1). Fludioxonil was not detected in 24 soil samples collected from around Yeongsan and Sumjin rivers in the Republic of Korea(2).

RURAL/REMOTE: Fludioxonil was detected in at least one of 38 air samples collected April to June 2010 in rural Spain(1).

The half-life of fludioxonil was 6.2-7.2 days on grapes at two experimental stations in China(1). Fourteen days after three low dosage applications the residual concentration was <1.0 mg/kg on grapes(1). The half-life of fludioxonil on emerald and jewel blueberries was 12.7 and 16.3 days, respectively; samples were collected in Concordia, Argentina(2).

IDENTIFICATION AND USE: Fludioxonil comes in the form of odorless, yellowish or colorless crystals. It is a phenylpyrrole fungicide that interferes with glucose transport across fungal membranes. It is also used as an insecticide, and seed treatment/protectant. It is registered for pesticide use in the USA but approved pesticide uses may change periodically and so federal, state and local authorities must be consulted for currently approved uses. HUMAN EXPOSURE AND TOXICITY: Fludioxonil showed endocrine disruptor activity as antiandrogen in an androgen receptor reporter assay in engineered human breast cancer cells. Fludioxonil was also genotoxic in human HepG2 cells at concentrations of 4 uM. Treatment of human U251 (glial) and SH-SY5Y (neuronal) cells with fludioxinil significantly reduced cellular ATP at concentrations that were more than tenfold lower than those which significantly impaired cellular viability. The effects on energy metabolism were reflected in marked toxic effects on mitochondrial membrane potential. In addition, evidence of oxidative stress was seen. ANIMAL STUDIES: Fludioxonil has low acute toxicity in rats when administered by oral, dermal or inhalation routes, producing no deaths at 5000 and 2000 mg/kg bw and 2.6 mg/L of air, respectively, the highest doses tested. There were also no deaths in mice given fludioxonil at 5000 mg/kg bw by gavage. In other studies with repeated doses in mice and rats, the liver (necrosis, centrilobular hypertrophy, increased serum cholesterol and 5 'nucleotidase), the kidneys (nephropathy, inflammation, cysts) and hematopoietic system (mild anemia) were the principal targets. In mice, these effects were observed after 90 days of treatment at 450 mg/kg bw per day and at 590 mg/kg bw per day in one 18-month study, but not at 360 mg/kg bw per day in another such study. In rats, effects were seen at doses of > or = 400 mg/kg bw per day in short-term studies and at 110 mg/kg bw per day in a 2-year study; lower body-weight gains were also observed at these doses. Liver toxicity was generally manifested by increased concentrations of serum cholesterol and bilirubin and centrilobular hypertrophy and/or necrosis. Anemia was seen in mice (at > 590 mg/kg bw per day for 18 months) and rats (at 1300 mg/kg bw per day for 3 months). No hematological effects were observed in shorter studies in mice (at < or = 1050 mg/kg bw per day for 90 days) or rats (at < or = 2500 mg/kg bw per day for 20 days and at < or = 1000 mg/kg bw per day for 28 days). Blue discoloration of the urine, perineal fur, kidneys and gastrointestinal tract were common observations in all species. These effects were secondary to the formation of the blue metabolite in quantities that were sufficient, at high doses, to stain the various tissues. Fludioxonil is was not genotoxic, causing a negative result in assays for reverse mutation in S. typhimurium and E. coli, gene mutation in Chinese hamster V79 cells, unscheduled DNA synthesis in rat hepatocytes, micronucleus formation in bone marrow of rats and mice in vivo and chromosome aberration in Chinese hamsters in vivo. There was also no evidence of carcinogenic potential with fludioxonil in studies using rats. In a two-generation study of reproductive toxicity in rats, at a dose of 210 mg/kg bw per day, adult males had reduced body-weight gains and food consumption and pups had lower body-weight gains. ECOTOXICITY STUDIES: Data from concentrations of fludioxinil found in ponds collecting vineyard runoff water, suggest that the pesticide should not impair the establishment of vineyard pioneer plants.

Consumers may be simultaneously exposed to several pesticide residues in their diet. A previous study identified the seven most common pesticide mixtures to which the French population was exposed through food consumption in 2006. The aim of this study was to investigate if the seven mixtures are potentially cytotoxic and genotoxic and if so, whether compounds in a same mixture have a combined effect. The cytotoxicity and genotoxicity of the seven mixtures were investigated with a new assay (gamma-H2AX) using four human cell lines (ACHN, SH-SY5Y, LS-174T, and HepG2). Mixtures were tested at equimolar concentrations and also at concentrations reflecting their actual proportion in the diet. Irrespective of the cell line tested, parallel cytotoxicity of the seven mixtures was observed. /Only mixture 4 contained fludioxonil (cyprodinil, fludioxonil, k-cyhalothrin, procymidone, iprodione)./ /This was the/ only mixture /that/ was genotoxic for the HepG2 cells at concentrations = 3 uM in equimolar proportion and at 30 uM in actual proportion. Caspase 3/7 activity, the comet assay, and reactive oxygen species production were also investigated using the same mixture and HepG2 cells. /The genotoxicity and the cytotoxicity of mixture 4 containing each pesticide at the actual concentration observed in the French diet (procymidone 42%, iprodione 33%, cyprodinil 16%, fludioxonil 9%, and k-cyhalothrin 1%, were also tested. Five final concentrations of the mixture were tested (1, 3, 10, 30, and 100 lM). Clear genotoxic and cytotoxic effects were observed but at higher concentrations (30 vs. 3 lM) than in mixture 4 at equimolar concentration. The lower genotoxic and cytotoxic effects of the mixture in the real proportion compared to the equimolar concentrations concentrations could be partially explained by the fact that the proportion of the fludioxonil in the real proportion mixture was lower than in the equimolar mixture (9 vs. 20%)./ Our results suggest that pesticide metabolites from the mixture generated by HepG2 cells were responsible for the observed damage to DNA. Among the five compounds in the genotoxic mixture, only fludioxonil and cyprodinil were genotoxic for HepG2 cells alone at concentrations = 4 and 20 uM, respectively. Our data suggest a combined genotoxic effect of the mixture at low concentrations with a significantly higher effect of the mixture of pesticides than would be expected from the response to the individual compounds. /Mixture/|Many pesticides are used increasingly in combinations during crop protection and their stability ensures the presence of such combinations in foodstuffs. The effects of three fungicides, pyrimethanil, cyprodinil and fludioxonil, were investigated together and separately on U251 and SH-SY5Y cells, which can be representative of human CNS glial and neuronal cells respectively. Over 48 hr, all three agents showed significant reductions in cellular ATP, at concentrations that were more than tenfold lower than those which significantly impaired cellular viability. The effects on energy metabolism were reflected in their marked toxic effects on mitochondrial membrane potential. In addition, evidence of oxidative stress was seen in terms of a fall in cellular thiols coupled with increases in the expression of enzymes associated with reactive species formation, such as GSH peroxidase and superoxide dismutase. The glial cell line showed significant responsiveness to the toxin challenge in terms of changes in antioxidant gene expression, although the neuronal SH-SY5Y line exhibited greater vulnerability to toxicity, which was reflected in significant increases in caspase-3 expression, which is indicative of the initiation of apoptosis. Cyprodinil was the most toxic agent individually, although oxidative stress-related enzyme gene expression increases appeared to demonstrate some degree of synergy in the presence of the combination of agents... /Mixture/

/ACCIDENTAL POISONINGS/ Arthropod biological control agents (BCAs) are commonly released for greenhouse vegetable insect pest management. Nevertheless, chemicals remain a necessary control tactic for certain insect pests and diseases and they can have negative impacts on BCAs. The compatibility of some formulated reduced risk insecticides (abamectin, metaflumizone and chlorantraniliprole) and fungicides (myclobutanil, potassium bicarbonate and cyprodinil + fludioxonil) used, or with promise for use, in Canadian greenhouses with Orius insidiosus (Say), Amblyseius swirskii (Athias-Henriot) and Eretmocerus eremicus (Rose & Zolnerovich) was determined through laboratory and greenhouse bioassays. Overall, the insecticides and fungicides were harmless as residues to adult BCAs. However, abamectin was slightly to moderately harmful to O. insidiosus and A. swirskii in laboratory bioassays, whereas metaflumizone was slightly harmful to E. eremicus. In general, these products appear safe to use prior to establishment/release of these adult BCAs.|/OTHER TERRESTRIAL SPECIES/ Laboratory bioassays on detached soybean, Glycine max (L.) Merr., leaves were used to test 23 fungicides, five insecticides, two acaricides, one herbicide, and two adjuvants on a key Australian predatory mite species Euseius victoriensis (Womersley) in "worst-case scenario" direct overspray assays. Zero- to 48-hr-old juveniles, their initial food, and water supply were sprayed to runoff with a Potter tower; spinosad and wettable sulfur residues also were tested. Tests were standardized to deliver a pesticide dose comparable with commercial application of highest label rates at 1,000 L/ha. Cumulative mortality was assessed 48 hr, 4 days, and 7 days after spraying. Fecundity was assessed for 7 days from start of oviposition... Canola oil as acaricide (2 liter/100 liter) and wettable sulfur (200 g/100 liter) had some detrimental effect on survival and fecundity and cyprodinil/fludioxonil on survivor...|/PLANTS/ In Vitis vinifera L /grapevines/, photosynthesis and photosynthate partitioning are affected in the presence of fludioxonil and pyrimethanil, two fungicides commonly used in vineyards against Botrytis cinerea Pers. However, the effects were found to be different according to the model studied: plantlets (cv Chardonnay) grown in vitro, fruiting cuttings (cv Chardonnay) and plants grown in vineyards (cvs Chardonnay, Pinot noir and Pinot Meunier). In the plantlets grown in vitro, both fungicides decreased gas exchanges, photosynthetic pigment and starch concentrations in the leaves, whereas soluble carbohydrates transiently accumulated, suggesting that plantlets mobilised starch in response to photosynthesis inhibition caused by fungicides. In the fruiting cuttings, the fungicides did not affect photosynthesis, although fludioxonil caused starch decrease in parallel with sucrose accumulation, suggesting that the fungicide effects were of lower intensity than in vitro. Conversely, in vineyard, the two fungicides stimulated photosynthesis and increased pigment concentrations in the three vine cultivars tested. In the meantime, glucose, fructose and starch levels of the leaves declined after fungicide exposure, whereas sucrose accumulated, indicating that sucrose synthesis increased in the leaves following the fungicide treatment. Among the three varieties, Chardonnay was the most sensitive to the fungicides as revealed by the intensity of the responses and the longer period for recovery. In vineyard, the results suggested that the two fungicides, in addition to inhibiting B cinerea development, had a beneficial effect on vine physiology through the stimulation of leaf carbon nutrition, which may further enable the plant to rapidly make use of its defence reactions.|/PLANTS/ Procymidone, fludioxonil, and pyrimethanil are widely used to control the pathogenic fungus Botrytis cinerea in Champagne's vineyards. These fungicides may end up in surface waters and present potential risks for aquatic vascular plants and algae. Therefore, their toxicity was evaluated on Lemna minor /duckweed/ and Scenedesmus acutus /algae/ in six-day or 48-hr tests, respectively. Based on growth and chlorophyll (Chl) content of L. minor and S. acutus cultures, the results showed that the alga was the most sensitive to the fungicides. Among the fungicides, pyrimethanil was the most toxic for L. minor, its nominal IC50 was 46.16 mg/L and that of the other two was >100 mg/L. In contrast, pyrimethanil appeared the least toxic for S. acutus at low concentration, nominal IC50 were 22.81, 4.85, and 4.55 mg/L for pyrimethanil, fludioxonil, and procymidone, respectively. Fate of the fungicides in the media was also investigated and acute toxicity of the agrochemicals is discussed in regard to concentration in the culture media. Poor solubility of procymidone and fludioxonil appeared to be partly responsible for the low toxicity of these fungicides. Based on these toxicity data and the concentrations found in ponds collecting vineyard runoff water, these pesticides should not impair the establishment of pioneer plants.

Fludioxonil's production may result in its release to the environment through various waste streams; its use as a fungicide(1) will result in its direct release to the environment(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), Koc values of 991-5785(2-3), indicate that fludioxonil is expected to have low to no mobility in soil(SRC). Volatilization of fludioxonil from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 5.3X10-10 atm-cu m/mole(SRC), based upon its vapor pressure, 2.93X10-9 mm Hg(4), and water solubility, 1.80 mg/L(4). Fludioxonil is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(4). Soil dissipation half-lives have been reported as 140-350 days; the half-life is decreased when non-UV light is applied(5). Field dissipation half-lives of 87-228 days were reported(2). The half-life of fludioxonil was 6.0-12.1 days on soil at two experimental stations in China(6). The photodegradation half-life of fludioxonil from near-surface soil was 1.6 days(2).|AQUATIC FATE: Based on a classification scheme(1), Koc values of 991-5785(2-3), indicate that fludioxonil is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(4) based upon an estimated Henry's Law constant of 5.3X10-10 atm-cu m/mole(SRC), derived from its vapor pressure, 2.93X10-9 mm Hg(5), and water solubility, 1.80 mg/L(5). Fludioxonil is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(4). According to a classification scheme(6), an estimated BCF of 240(SRC), from its log Kow of 4.12(5) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is high(SRC). Fludioxonil is expected to be essentially stable in aquatic environments, based on laboratory aerobic aquatic half-lives of 473-718 days(2). Near-surface photodegradation half-life was reported as 8.7 days in water(2).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), fludioxonil, which has a vapor pressure of 2.93X10-9 mm Hg at 25 °C(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase fludioxonil may be removed from the air by wet and dry deposition(SRC).

Fludioxonil is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(1). Photodegradation was determined to be the main route of dissipation from tomatoes in a greenhouse(2). Near-surface soil and aqueous photodegradation half-lives were reported as 1.6 and 8.7 days, respectively(3). Extractable fludioxonil concentrations were 45.6 and 71.6% of the amount applied 69 days after soil treatment using non-UV light and dark conditions, respectively(4). Respective fludioxonil percent degraded was 14.1 and 11.5 with 32.3 and 10.2% non-extractable from the soil(4).

An estimated BCF of 240 was calculated in fish for fludioxonil(SRC), using a log Kow of 4.12(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC).

Koc values of 1671-5785 have been reported in soil(1). Other Koc values of 991-2440 have been reported(2). According to a classification scheme(3), these Koc values suggest that fludioxonil is expected to have low to no mobility in soil.|The Koc of soil from four vineyards (8 samples) in Contevedra, Spain was determined for fludioxonil. The mean and range Koc values were 3544 and 1671-5785, respectively. The mean and range Kd were 187 and 62-213 mL/g, respectively(1).[Table#8239]

The Henry's Law constant for fludioxonil is estimated as 5.3X10-10 atm-cu m/mole(SRC) derived from its vapor pressure, 2.93X10-9 mm Hg(1), and water solubility, 1.80 mg/L(1). This Henry's Law constant indicates that fludioxonil is expected to be essentially nonvolatile from moist soil and water surfaces(2). Fludioxonil is not expected to volatilize from dry soil surfaces(SRC) based upon its vapor pressure(1).

Fludioxonil was not detected in 228 fresh potato samples collected from 34 farmers markets located in Calgary and Edmonton, Canada; detection limit and sample dates were not reported(1). Of 173 agricultural products analyzed in 2006 from Japan, two were reported to contain fludioxonil at 6.2 and 203 ng/g(2). Fludioxonil was detected in 18 of 47 wine grape (Vitis vinifera L.) samples collected from the 2006 harvest in Slovenia at a maximum concentration of 0.03 mg/kg(3).

/A feeding study was conducted in which three groups of three dairy cows received 0.55 ppm, 1.6 ppm or 5.5 ppm fludioxonil in the diet for 28-30 days. Residues of fludioxonil and metabolites, determined as CGA-192155 (2,2-difluorobenzo[1,1]dioxole-4-carboxylic acid), were quantifiable only at the highest feeding level (5.5 ppm). Residues were found in the milk of two of three cows, with maximum values of 0.019 mg/kg and 0.014 mg/kg on days 14 and 21, respectively. At the lowest feeding level, residues were detected in milk on days 3-21 at levels of 0.001-0.004 mg/kg, with maximum detection on day 3.

Occupational exposure to fludioxonil may occur through inhalation and dermal contact with this compound at workplaces where fludioxonil is produced or used. Monitoring and use data indicate that the general population may be exposed to fludioxonil via ingestion of fruits, vegetables and wines that have residual concentrations of fludioxonil. (SRC)

The metabolism of (14)C-pyrrole-labelled fludioxonil was studied in goats... Two goats were given radiolabelled fludioxonil orally at a level equivalent to 100 ppm in the feed for 4 consecutive days. The levels of radioactive residue, calculated as fludioxonil, were: 0.07 mg/kg in tenderloin muscle, 0.19 mg/kg in fat, 5.8 mg/kg in liver, 2.9 mg/kg in kidney and 2.2 mg/kg in milk on day 4. Organic solvents released 35% of the TRR in liver, 76% in muscle, 50% in kidney, 35% in liver, 87% in fat and 90% in milk. Protease treatment of the solid residues from solvent extraction of liver, kidney and muscle released 75-91% of the remaining activity. Less than half of this released activity was characterized as proteins by derivatization with 2,4-dinitrofluorobenzene.|Five laying hens were given gelatin capsules containing [(14)C-pyrrole]fludioxonil for 8 consecutive days at a rate equivalent to about 89 ppm in the feed. The vast majority of the radiolabelled residue was eliminated in the excreta (88-102% of the total administered dose). The levels of radioactive residues, calculated as fludioxonil, in the tissues and eggs were as follows: liver, 8.9 mg/kg; muscle, 0.12 mg/kg; skin with fat, 0.25 mg/kg; peritoneal fat, 0.17 mg/kg; egg yolk, 1.8 mg/kg (day 7); egg white, 0.054 mg/kg (day 7). A series of organic solvent extractions released 61% TRR in liver, 33% in kidney, 62% in muscle, 42% in skin with fat, 74% in egg white and 83% in egg yolk. The solids remaining after solvent extraction of liver (33% TRR), kidney (54%) and muscle (34%) were solubilized with protease and characterized by treatment with 2,4-dinitrofluorobenzene. Protease solubilized 54% of the unextracted activity in liver, 63% of that in kidney and 67% of that in muscle. About 25% of the released radioactivity (< 10% TRR) was derivatized by 2,4-dinitrofluorobenzene at pH 2, indicating the terminal amino group of amino acids. Alkaline hydrolysis (15% KOH, 95 oC) released all the remaining radioactivity from the solvent-extracted liver (33% TRR), but it could be characterized only as acidic, polar compounds. About 69% of the TRR in eggs, 24% in liver, 14% in kidney, 44% in muscle and 29% in skin with fat were identified...|A feeding study was conducted in which three groups of three dairy cows received 0.55 ppm, 1.6 ppm or 5.5 ppm fludioxonil in the diet for 28-30 days. Residues of fludioxonil and metabolites, determined as CGA-192155 (2,2-difluorobenzo[1,1]dioxole-4-carboxylic acid), were quantifiable only at the highest feeding level (5.5 ppm)... No quantifiable residue was found in the tissues of ruminants at levels 60 times (cows) and 80 times (beef cattle) the calculated dietary burden. Fludioxonil and metabolites were detected in liver and kidney at concentrations of 0.014-0.017 mg/kg and 0.022-0.025 mg/kg, respectively, at the 5.5 ppm feeding level. None was detected in fat or muscle.|The dermal absorption of fludioxonil, excluding material bound to the skin, is low in rats in vivo (< 5%) and in human skin in vitro (< 0.5%). In a study of dermal penetration in rats in vitro, values for dermal absorption at low levels of application were comparable to those obtained in a study performed in vivo (< 2%), but at higher levels significantly overestimated absorption in vivo (38%).

Two goats were given radiolabelled fludioxonil orally at a level equivalent to 100 ppm in the feed for 4 consecutive days....The main component identified in muscle was fludioxonil, representing 24% and 43% of the TRR in the two goats. Likewise, fludioxonil was the main component of the residue in omental fat, representing 83% TRR. The main identified metabolite in muscle was the sulfate conjugate of the 2-hydroxy or 5-hydroxy derivative of fludioxonil (22% or 2% TRR). Minor metabolites identified in muscle (< 10% TRR) included the 2-O-glucuronide derivative of fludioxonil and the 5-O-glucuronide derivative of fludioxonil. (The position numbers refer to the pyrrole ring.) About 50% of the residue in muscle and 83% of the residue in fat were identified. Multiple components were found in kidney and liver. The following were identified in kidney: 2-Oglucuronide derivative of fludioxonil (23% TRR); 7prime-O-glucuronide derivative (8% TRR); 5-O-glucuronide derivative (15% TRR); fludioxonil (2% TRR); and 2- or 5-O-sulfate ester (0.7% TRR), for a total identification of 48%. In liver, only fludioxonil was identified (14% TRR). Two labile compounds (24% TRR) were also encountered. No compounds without the pyrrole-phenyl linkage were identified.|Five laying hens were given gelatin capsules containing [(14)C-pyrrole]fludioxonil for 8 consecutive days at a rate equivalent to about 89 ppm in the feed... The main metabolites identified in eggs were the sulfate conjugate of the 1-hydroxy derivative of fludioxonil (40% TRR) , the succinamic acid derivative (10% TRR) and the sulfate conjugate of the 2-hydroxy or 5-hydroxy derivative (13% TRR). Fludioxonil was a minor component (2.1% TRR) in eggs. The succinamic acid derivative was the only significant metabolite identified in liver, at about 6% TRR. The metabolites identified in kidney were the glucuronide conjugate of the 2-hydroxy or 5-hydroxy derivative (4.7% TRR), fludioxonil (2.6% TRR) and the 7prime-hydroxy derivative (2.8% TRR). The main components identified in breast muscle were fludioxonil (29% TRR) and the sulfate conjugate of the 1-hydroxy derivative. A similar situation existed for skin with attached fat, which contained fludioxonil (9.8%) and the sulfate conjugate of the 1-hydroxy derivative (14%). On the basis of the characterizations and identifications made in the study of metabolism in hens, .../it was/concluded that metabolism in poultry involves oxidation at the C-2, C-5 and N-1 positions in the pyrrole ring and at the C-7prime of the benzodioxol ring. This is followed by the formation of sulfate or glucuronide conjugates. The C-2 hydroxypyrrole further oxidizes to the 2,5-dioxo-2,5-dihydro pyrrole and succinamic acid derivatives. The last two compounds are unique to poultry. The remaining metabolites found in the hen and all the metabolites in ruminants were also found in rats.|fludioxonil and metabolites, determined as 2,2-difluoro-1,3- benzodioxole-4-carboxylic acid, are stable for at least 12 months in frozen muscle and for at least 18 months in frozen liver, milk and eggs.|After oral administration of radiolabelled fludioxonil, the radiolabel is rapidly and extensively (approximately 80% of the administered dose) absorbed, widely distributed, extensively metabolized and rapidly excreted, primarily in the feces (approximately 80%) via the bile (approximately 70%), with a small amount being excreted in the urine (approximately 20%). The maximum blood concentration is reached within 1 hr after administration. Elimination is biphasic, with half-lives of between 2 and 5 hr for the first phase and between 30 and 60 h for the second phase. Fludioxonil is rapidly cleared from the blood and tissues, and there is consequently negligible potential for accumulation. The metabolism of fludioxonil proceeds primarily through oxidation of the pyrrole ring, leading to one major (57% of the administered dose) and one minor (4% of the administered dose) oxo-pyrrole metabolite. Hydroxylation of the phenyl ring yields the corresponding phenol metabolite, which represents 2% of the administered dose. These phase I metabolites are subsequently excreted as glucuronyl and sulfate conjugates and, together with unabsorbed and unchanged fludioxonil excreted in feces, account for approximately 75% of the administered dose. The dimerization of the hydroxy pyrole metabolite produces a metabolite of an intense blue color.|A feeding study was conducted in which three groups of three dairy cows received 0.55 ppm, 1.6 ppm or 5.5 ppm fludioxonil in the diet for 28-30 days. Residues of fludioxonil and metabolites, determined as CGA-192155 (2,2-difluorobenzo[1,1]dioxole-4-carboxylic acid), were quantifiable only at the highest feeding level (5.5 ppm)... Only tissue samples from cows fed the 5.5 ppm diet were analyzed. No residues of fludioxonil or metabolites were found. The LOQ was 0.01 mg/kg in muscle and 0.05 mg/kg in liver, kidney and fat (perirenal and omental).

After oral administration of radiolabelled fludioxonil, the radiolabel is rapidly and extensively (approximately 80% of the administered dose) absorbed, widely distributed, extensively metabolized and rapidly excreted, primarily in the feces (approximately 80%) via the bile (approximately 70%), with a small amount being excreted in the urine (approximately 20%). The maximum blood concentration is reached within 1 hr after administration. Elimination is biphasic, with half-lives of between 2 and 5 hr for the first phase and between 30 and 60 h for the second phase. ...

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/ENDOCRINE MODULATION/ Fenhexamid and fludioxonil are antifungal agents used in agricultural applications, which are present at measurable amounts in fruits and vegetables. Fenhexamid and fludioxonil showed endocrine disruptor activity as antiandrogens in an androgen receptor reporter assay in engineered human breast cancer cells. Little is known about how environmental chemicals regulate microRNA (miRNA) expression. This study examined the effect of fenhexamid and fludioxonil on the expression of the oncomiR miR-21 in MCF-7, T47D, and MDA-MB-231 human breast cancer cells and downstream targets of miR-21 in MCF-7 cells. Fenhexamid and fludioxonil stimulated miR-21 expression in a concentration-dependent manner and reduced the expression of miR-21 target Pdcd4 protein. Antisense to miR-21 blocked the increase in Pdcd4 protein by fenhexamid and fludioxonil. Fenhexamid and fludioxonil reduced miR-125b and miR-181a, demonstrating specificity of miRNA regulation. Induction of miR-21 was inhibited by the estrogen receptor antagonist fulvestrant, by androgen receptor antagonist bicalutamide, by actinomycin D and cycloheximide, and by inhibitors of the mitogen-activated protein kinases and phosphoinositide 3-kinase pathways. Fenhexamid activation was inhibited by the arylhydrocarbon receptor antagonist alpha-napthoflavone. Fenhexamid and fludioxonil did not affect dihydrotestosterone-induced miR-21 expression. Fludioxonil, but not fenhexamid, inhibited MCF-7 cell viability, and both inhibited estradiol-induced cell proliferation and reduced cell motility. Together these data indicate that fenhexamid and fludioxonil use similar and distinct mechanisms to increase miR-21 expression with downstream antiestrogenic activity.|/ALTERNATIVE and IN VITRO TESTS/ Consumers may be simultaneously exposed to several pesticide residues in their diet. A previous study identified the seven most common pesticide mixtures to which the French population was exposed through food consumption in 2006. The aim of this study was to investigate if the seven mixtures are potentially cytotoxic and genotoxic and if so, whether compounds in a same mixture have a combined effect. The cytotoxicity and genotoxicity of the seven mixtures were investigated with a new assay (gamma-H2AX) using four human cell lines (ACHN, SH-SY5Y, LS-174T, and HepG2). Mixtures were tested at equimolar concentrations and also at concentrations reflecting their actual proportion in the diet. Irrespective of the cell line tested, parallel cytotoxicity of the seven mixtures was observed. /Only mixture 4 (cyprodinil, fludioxonil, k-cyhalothrin, procymidone, iprodione) contained fludioxonil./ /This was the/ only mixture /that/ was genotoxic for the HepG2 cells at concentrations = 3 uM in equimolar proportion and at 30 uM in actual proportion. Caspase 3/7 activity, the comet assay, and reactive oxygen species production were also investigated using the same mixture and HepG2 cells. /The genotoxicity and the cytotoxicity of mixture 4 containing each pesticide at the actual concentration observed in the French diet (procymidone 42%, iprodione 33%, cyprodinil 16%, fludioxonil 9%, and k-cyhalothrin 1%, were also tested. Five final concentrations of the mixture were tested (1, 3, 10, 30, and 100 uM). Clear genotoxic and cytotoxic effects were observed but at higher concentrations (30 vs. 3 uM) than in mixture 4 at equimolar concentration. The lower genotoxic and cytotoxic effects of the mixture in the real proportion compared to the equimolar concentrations concentrations could be partially explained by the fact that the proportion of the fludioxonil in the real proportion mixture was lower than in the equimolar mixture (9 vs. 20%)./ Our results suggest that pesticide metabolites from the mixture generated by HepG2 cells were responsible for the observed damage to DNA. Among the five compounds in the genotoxic mixture, only fludioxonil and cyprodinil were genotoxic for HepG2 cells alone at concentrations = 4 and 20 uM, respectively. Our data suggest a combined genotoxic effect of the mixture at low concentrations with a significantly higher effect of the mixture of pesticides than would be expected from the response to the individual compounds. /Mixture/|/ALTERNATIVE and IN VITRO TESTS/ Many pesticides are used increasingly in combinations during crop protection and their stability ensures the presence of such combinations in foodstuffs. The effects of three fungicides, pyrimethanil, cyprodinil and fludioxonil, were investigated together and separately on U251 and SH-SY5Y cells, which can be representative of human CNS glial and neuronal cells respectively. Over 48 hr, all three agents showed significant reductions in cellular ATP, at concentrations that were more than tenfold lower than those which significantly impaired cellular viability. The effects on energy metabolism were reflected in their marked toxic effects on mitochondrial membrane potential. In addition, evidence of oxidative stress was seen in terms of a fall in cellular thiols coupled with increases in the expression of enzymes associated with reactive species formation, such as GSH peroxidase and superoxide dismutase. The glial cell line showed significant responsiveness to the toxin challenge in terms of changes in antioxidant gene expression, although the neuronal SH-SY5Y line exhibited greater vulnerability to toxicity, which was reflected in significant increases in caspase-3 expression, which is indicative of the initiation of apoptosis. Cyprodinil was the most toxic agent individually, although oxidative stress-related enzyme gene expression increases appeared to demonstrate some degree of synergy in the presence of the combination of agents... /Mixture/

fludioxonil

The National Pesticide Information Retrieval System (NPIRS) identifies 11 companies with active labels for products containing the chemical fludioxonil. To view the complete list of companies, product names and percent fludioxonil in formulated products click the following url and enter the CAS Registry number in the Active Ingredient field.|Fludioxonil Technical (Syngenta Crop Protection, LLC): Active ingredient: Fludioxonil 98.0%.|Medallion Fungicide (Syngenta Crop Protection, LLC): Active ingredient: Fludioxonil 50.0%.|Maxim XL Fungicide (Syngenta Crop Protection, LLC): Active ingredient: Fludioxonil 21.0%; Metalaxyl-M 8.4%.|For more Formulations/Preparations (Complete) data for Fludioxonil (32 total), please visit the HSDB record page.

The WHO Recommended Classification of Pesticides by Hazard identifies fludioxonil as unlikely to present an acute hazard in normal use; Main Use: fungicide, other than for seed treatment.|Fludioxonil (announced in 1991) is used as seed treatment for control of Gibberella in rice and to control Fusarium, Rhizoctonia, Tilletia, Helminthosporium, and Septoria in cereal and noncereal crops.

Analytical Enforcement Methodology: Adequate high-performance liquid chromatography/ultraviolet light detector (HPLC/UV) methods (Syngenta Methods AG-597 and AG-597B) are available for enforcing tolerances for residues of fludioxonil in or on plant commodities. An adequate liquid chromatography, tandem mass spectrometry (LC-MS/MS) method (Analytical Method GRM025.03A) is available for enforcing tolerances for residues of fludioxonil in or on livestock commodities.

Agrochemicals -> Fungicides|Fungicides|Environmental transformation -> Pesticides (parent, predecessor)

Fludioxonil has known environmental transformation products that include (2,2-difluoro-benzo(1,3)dioxol-4-carbocyclic acid and 3-carbamoyl-2-cyano-3-(2,2-difluoro-benzo(1,3)dioxol-4-yl)-oxirane-2-carbocyclic acid.|Fludioxonil has known environmental transformation products that include CGA 192155, CGA 265378, and CGA 339833.