FLUTRIAFOL (248)
Flutriafol501FLUTRIAFOL (248)First draft prepared by Mr M Irie, Ministry of Agriculture, Forestry and Fisheries, Tokyo, JapanEXPLANATIONResidue and analytical aspects of flutriafol were considered for the first time by the present Meeting.The residue evaluation was scheduled for the 2011 JMPR by the Forty-second Session of the CCPR.Flutriafol is a triazole fungicide used in many crops for control of a broad spectrum of leafand ear cereal diseases, particularly embryo borne diseases e.g., bunts and smuts. The Meetingreceived information on identity, animal and plant metabolism, environmental fate in soil, rotationalcrops, analytical methods, storage stability, use patterns, supervised trials, farm animal feeding studiesand fates of residues in processing.IDENTITYCommon nameChemical nameIUPAC:CAS:CAS Registry No:CIPAC No:Synonyms:Structural formula:Molecular formula:Molecular -triazol-1-ylmethyl)benzhydryl alcohol( 3O301.3Physical and chemical propertiesPure active ingredientPropertyAppearanceResultsWhite solidMelting point130.5 C (99.0% purity)Relative density1.17 103 kg/m3 at 19.8 C (99.0% purity)Vapour pressure 0.01 10-3 Pa at 25 C (95.1% purity)Volatility (Henry’s law constant)Solubility in waterNo data submitted95 mg/L in distilled water at 20 C (99.0% purity)Partition coefficientLog Pow 2.32 0.004 at 20 C (95.1% purity)ReferenceComb, 2006 (1358FLU)Comb, 2006 (1358FLU)Tognucci, 2003(1097 FLU)Piasentini deCampos, 2007 (1513FLU)Tognucci, 2004(1103 FLU)Piasentini de
sisFlutriafol was stable to hydrolysis at pH5, 7 and 9 at50 C over 30 days.Flutriafol was hydrolytically stable in buffered solution atpH5, 7, and 9 at 25 C up to 30 days.PhotolysisFlutriafol was photolytically stable in aqueous buffersolution (pH7) at 25 C for periods up to the equivalentof 66 days Florida summer sunlight.Photolysis of flutriafol by the direct absorption ofsunlight (in the absence of photosensitisers) is not asignificant degradation process in the environment.No data submittedDissociation constantReferenceCampos, 2007 (1511FLU)Snow and Cavell,1982 (212 FLU)Hawkins, Elsom andJackson, 1987 (213FLU)Skidmore, 1987 (214FLU)Moffatt, 1994 (215FLU)Technical materialPropertyMinimum concentrationAppearanceResults93.6%Fine white powderOdourodourless at room temperature(wet paste: 77.2% purity)Acetone:114 - 133 g/L at 21 CEthyl acetate:29 - 33 g/L at 21 Cn-heptane: 10 g/L at 21 CXylene: 10 g/L at 21 C1,2-dichloroethane:20 - 25 g/L at 21 CMethanol:114 -133 g/L at 21 CSolubility in organic solventsFormulations: Suspension concentrate (SC)ReferenceKusk, 2006(1359 FLU)SØndergaar, 2006(1367 FLU)Tognucci, 2004(1104 FLU)250 g ai/L or 125 g ai/LMETABOLISM AND ENVIRONMENTAL FATEThe metabolism of flutriafol has been investigated in animals and plants. The fate and behaviour offlutriafol in animals, plants and the environment was investigated using the [14C] labelled testmaterials shown in Figures Figure 1 [14C]-Labelled test materials used in animals, plants metabolism studies, and theenvironmental fate studiesThe chemical structures of the major degradation compounds from the metabolism offlutriafol are provided below.
FlutriafolCompound nameStructure503M1B4-HydroxyflutriafolFound inmetabolismstudiesLivestocks, RatsM1D4-Hydroxy-5-methoxyflutriafolLivestocks, RatsM2BFlutriafol-(trans)-dihydrodiolLivestocks, RatsM5Mixture of two isomerichydroxyflutriafol derivativesLivestocksR5aHexose conjugated flutriafolPlantsC6Defluorinated flutriafolPlants
Flutriafol504Compound nameTriazolealanine1,2,4-triazoyl-3-alanineFound inmetabolismstudiesPlantsTriazoleacetic acid1H-1,2,4-triazol-1-ylacetic ivestocks, SoilTriazole lactic acidPlants imal metabolismThe Meeting received studies on the metabolism of flutriafol in rats, lactating cows and laying hens.The study on rats was evaluated by the WHO Core Assessment Group of the 2011 JMPR. A summaryof the rat metabolism is given in this section.RatsIn rat, flutriafol was extensively absorbed following single oral administration of 5 or 250 mg/kgdose. Bile was shown to be the major route of elimination of administered radioactivity excreted viathis route over three days. Excretion of the dose was rapid at both dose levels and urinary excretionwas the major route, accounting for 50–68% daily dose in the repeat dose animals and 61–68% for thesingle dose animals. The remaining radioactivity was excreted in the faeces (29–55%) with less than6% dose remaining in the tissues 168 hours after the final repeat dose was administered and lessthan.8% 168 hours after the single dose. Only a minor amount of cleavage of the triazole moiety fromthe flutriafol molecule occurred. Furthermore, no metabolism was detected in the triazole group or inthe 4-fluorophenyl ring of molecule. All identified metabolites were shown to be hydroxylatedderivatives of the 2-fluorophenyl ring. Three of the major urinary metabolites were identified as a 3,4(cis)- and the two M2B isomers of flutriafol. The bulk of remainder of urinary radioactivity wasattributable to glucuronide conjugates, the two main aglycones of which were identified as M1B andM1D.Lactating cowThe metabolism of flutriafol in the lactating cow has been studied using flutriafol labelled with 14C inthe triazole positions (Figure 1) (Hignett, 1985: 85 FLU). After a 7 days settling in period, the cowwas dosed twice daily, for a period of 7 days, with gelatine capsules containing 14C-triazole flutriafolabsorbed onto powdered maize. Capsules were introduced directly into the stomach via a stomachtube. The cow received mean daily doses of 40 mg of flutriafol per day, equivalent to a daily intake oftotal diet (20 kg) containing flutriafol at a level of approximately 2 ppm in the diet.
Flutriafol505Urine and faeces were collected, starting two days before dosing, every 12 hours until the last36 hours, then four hourly. Milk samples were collected twice daily starting two days before dosing.The cow was sacrificed approximately four hours after administration of the last dose, the followingtissues were collected: subcutaneous, omental and perirenal fat, muscle, liver, kidneys and heart.Radioactivity in these compartments as well as in faeces and urine was measured by liquidscintillation counting (LSC) after combustion to determine the total radioactive residues (TRR).In order to characterise and identify the radioactive residue components, samples of urine,milk, liver and kidney were subjected to extensive extractions and further treatment. Characterisationof radioactive residues covered the fractionation into organosoluble and watersoluble/polarcomponents. Solvent extraction was conducted using water, acetonitrile, methanol, as well as ether,acetone, dichloromethane and hexane. The polar fraction of urine, milk, liver and kidney as well asthe unextractable fraction of liver was subjected to enzyme and acid/base hydrolysis. The mainmethod for the identification of metabolites was thin layer chromatography (TLC). The metaboliteswere characterised by co-chromatography with reference substances in two dissimilar solventsystems. Extracts were analysed using HPLC with subsequent LSC quantification and gaschromatography/mass spectrometry (GC/MS) to determine the metabolic profile by comparison withreference substances.Most of the administered radioactivity was excreted in the urine and faeces. The total quantityof radioactivity excreted in the urine and faeces was 45% and 33% of the dose, respectively.Radioactive residues in muscle and fat (subcutaneous, omental and perirenal) were insignificant( 0.01 mg/kg equivalent to flutriafol). The liver, kidney and heart contained residues of 0.291, 0.061and 0.011 mg/kg equivalent to flutriafol. Table 1 summarizes the results from administration ofradiolabelled compound.Table 1 Excretion and retention of radioactivity by cow after oral administration oflabeled flutriafol at a nominal dietary administration of 40 mg for 7 daysSampleUrineFaecesMilkMuscleLiverKidneyHeartFat (subcutaneous)Fat (omental)Fat (perirenal)% of administered dose45.133.40.114C-triazoleTRR (mg flutriafol equivalent/kg)0.0080.2910.0610.0110.002 0.0010.003A total of 0.1% of the radioactivity administered to the cow was collected in the milk over the7 day dosing period. The radioactive residue in the milk gradually increased to 0.007 mg/L (flutriafolequivalent) by Day 4 of the study, and maintained this level until the end of the study. Theconcentration of radioactive residues in milk is summarized in Table 2.Table 2 Concentration of total radioactive residues (TRR) in milk (12 hours sampling) and amount ofmilk collected during administration of 14C-flutriafol (40 mg/day)Time .TRR, mg flutriafol 0070.007Volume, L8.5210.139.599.319.93
506FlutriafolTime (days)TRR, mg flutriafol 7p.m.: sample of evening milking; a.m.: sample of morning milkingVolume, L9.8810.90In the urine, no parent flutriafol was observed by TLC analysis. Most of the radioactivity wasassociated with polar materials, although traces of 4-hydroxyflutriafol (M1B) and flutriafol-(trans)dihydrodiol (M2B) were seen. Hydrolysis of the polar metabolites with enzyme and acid liberatedseveral organosoluble compounds, including M1B and another compound with very similarchromatographic properties (Compound Y).A small amount of parent flutriafol and M1B were contained in the ether fraction of the milk.No compound in this fraction accounted for more than 6% of TRR in the milk. Most of theradioactivity in the milk (75%) was associated with polar, water soluble metabolites which wereconverted to oraganosoluble fractions by extensive hydrolysis conditions. One radioactive compoundwas present, which cochromatographed with M1B.Half of the radioactivity extracted from the liver was organosoluble. Parent flutriafol (27%)dominated this fraction. The more polar, water soluble extracted radioactivity was hydrolysed withenzyme, acid and alkali. These combined procedures liberated an organosoluble fraction whichcontained flutriafol (2%), 4-hydroxy-5-methoxyflutriafol (M1D, 2%), M1B (1%) and at least twoother minor radioactive compounds. Most of the radioactivity from a non-extracted fraction wassolubilised enzymatically. Two compounds, flutriafol and M1D, were identified and no individualcompound accounted for more than 10% of TRR in the liver.Most of the radioactivity (81%) found in the kidneys was extracted with the aqueousacetonitrile. Only a small amount of the radioactivity in the aqueous acetonitrile extract waspartitioned into dichloromethane. This organosoluble fraction contained a mixture of at least sixminor radioactive compounds, including flutriafol (1%) and M1B ( 1%). Water soluble radioactivityaccounted for 66% of the radioactive residue. Hydrolysis with a sequence of enzyme, acid and baserendered most of this fraction organosoluble (38%). M1B (22%) dominated this fraction, which alsocontained flutriafol (6%).Table 3 Flutriafol and related residues identified in urine, milk and tissuesCompoundFlutriafol*4-Hydroxyflutriafol* (M1B)4-Hydroxy-5-methoxyflutriafol* (M1D)Compound YFlutriafol-(trans)-dihydrodiol (M2B)* including conjugatesUrineMilk% of sample TRRLiverKidney237traces2912-723-13-
Flutriafol507This study shows that the residue in ruminants resulting from the use of flutriafol will be low.Traces of metabolite shown to be present are the same compounds identified in rat metabolismstudies. The proposed metabolic pathway is shown in Figure HM2BCH3OOHM1DFigure 2 Proposed Metabolic Pathway of Flutriafol in Lactating CowLaying henThe nature of the residue in laying hens (Gallus gallus) was conducted with two radiolabeled forms offlutriafol (14C-triazole-flutriafol and 14C-carbinol-flutriafol) (Dohn, 2006: 1464 FLU). Eachradiolabelled test material was administered orally in cellulose-filled gelatin capsules to single combbrown laying hens once daily for 7 consecutive days. The average dietary dose was equivalent to13.9 ppm for the [14C-triazole]-flutriafol, and 11.6 ppm for the [14C-carbinol]-flutriafol. Excreta werecollected once daily (in the morning, before dose administration) from the treated hens only. Eggswere collected twice daily (morning and evening) from treated and control hens. The hens weresacrificed approximately 24 hours after the last dose was administered. The following tissues werecollected at necropsy from treated and control hens: muscle (composite of breast and thigh),abdominal fat, liver and gastrointestinal tracts.Portions of each excreta sample and homogenized gastrointestinal tracts were subjected tocombustion analysis. The radioactive residue in egg, liver, muscle and fat samples were measured bydigestion of subsamples with tissue solubilizer. The 14C contents of the samples were measured byliquid scintillation counting. The characterization of the residues in eggs, liver, muscle and fat wasconducted by solvent extraction with acetonitrile/water, followed by HPLC and TLC analysis. The
508Flutriafolidentification of the metabolites was done with available reference standards, and also by purifyingmetabolites from excreta followed by identification by LC/MS analysis where possible.Most of the administered doses (91.6% for triazole label and 92.6% for the carbinol label)were recovered in the excreta and gastrointestinal tracts at sacrifice. Each daily dose was almostcompletely excreted within 24 hours.The total radioactive residue (TRR) values were the highest for liver (0.36–0.41 mg/kg),followed by muscle (0.01–0.06 mg/kg) and fat (0.02–0.04 mg/kg). The distribution of the radioactiveresidues is summarized in Table 4.Table 4 Recovery of administered 14C in excreta and gastrointestinal tracts and concentration of theTRR in tissuesMatrixTotal excretaGastrointestinal tractTotalTissue matrixLiverMuscleFat[14C-triazol]flutriafol% Total administered 14C89.71.991.6[14C-triazol]flutriafol, mg/kg0.4110.0640.035[14C-carbinol]flutriafol% Total administered 14C91.21.492.6[14C-carbinol]flutriafol, mg/kg0.3590.0110.016The radioactive residues in egg appeared to reach plateau concentrations by the end of thestudy, and ranged from 0.134 mg/kg (carbinol label) to 0.204 mg/kg (triazole label). The samplesselected were taken from the evening collection on Day 6 (these samples had the largest residue inboth groups) and the last collection (morning of Day 8). The concentration of 14C-flutriafol derivedradioactivity in the egg samples are summarized in Table 5.Table 5 Concentration of the TRR in eggsTime point[14C-triazol]flutriafol, mg/kgDay 1 (pre dose)0.0005Day 1 pm0.001Day 2 am0.041Day 2 pm0.089Day 3 am0.088Day 3 pm0.135Day 4 am0.129Day 4 pmNEDay 5 am0.145Day 5 pm0.184Day 6 am0.167Day 6 pm0.206 a (0.205b)Day 7 am0.190Day 7 pm0.204Day 8 am (sacrifice)0.184 a (0.204b)NE: No eggs were produced.aValues determined using tissue solubilizerbValue determined by extraction analysis of PES[14C-carbinol]flutriafol, 170.160 a (0.159b)0.1260.1210.133 a (0.134b)Parent flutriafol was the most abundant component of the residue in all egg samples extracted(present at 0.088–0.119 mg/kg). Free 1,2,4-triazole was detected in the eggs (0.056–0.060 mg/kg). Inaddition, a mixture of two isomeric hydroxyflutriafol derivatives (referred to as M5) was present in allegg samples examined (0.009–0.010 mg/kg). The most abundant compound was 1,2,4-triazole(0.048 mg/kg) in muscle treated with [14C-triazole] flutriafol. Other components in the muscle werepresent at 0.01 mg/kg. The primary component of the fat residue was flutriafol (0.012–0.028 mg/kg,75–80% of TRR). Free 1,2,4-triazole was detected in fat (0.004 mg/kg). The distribution of 14Cresidue components in egg and tissue samples is presented in Table 6.
Flutriafol509Table 6 Distribution of metabolites in egg and tissue sampleComponentEgg, Day 6 PMEgg, Day .0094.40.0011,2,4-Triazolea 5PESc0.0052.40.0062.90.004Total 0.0107.50.0011,2,4-Triazolea ESc0.0042.50.0086.00.004Total (TRR)0.15999.90.134100.10.011aComponents extracted with acetonitrile/waterbM5 is a mixture of two isomeric hydroxyflutriafol derivativescPost extracted 015.366.9100.0Extraction of the liver samples released 33.1 to 41.4% of the TRR. Flutriafol was detected inliver at low concentrations (0.007–0.013 mg/kg, 1.9–3.2% TRR). Free 1,2,4-triazole was present inliver at 0.057 mg/kg (13.9% TRR), and the mixture of hydroxyflutriafols (M5) was present at 0.006 to0.007 mg/kg. A significant amount of the residue (58.6–66.9% TRR) was not extracted withacetonitrile/water. The residue remaining in the post-acetonitrile/water –extracted solids wassubjected to a variety of enzymatic and chemical treatments, which resulted in the gradual release ofmost of the residue. Sequential treatments with two proteases (pepsin and pancreatin) released thelargest portion of the residue (21.2–25.3% of TRR). However, the radioactivity released was complexin nature when examined by HPLC and TLC.Table 7 Characterisation of radioactive residues in PES fraction of 7041.40.10425.30.0174.1Subtotal in primary extractaSolubilised by enzyme treatmentb,cSolubilized by 1N HCl(ambient temp. x24h) bSolubilized by 1N NH4OH0.0368.8(ambient temp. x22h) bSolubilized by 6N HCl0.0030.7(reflux. x19h)dichloromethane soluble bSolubilized by 6N HCl0.04611.2(reflux. x19h)aqueous soluble bRemaining (by difference) b0.0358.5Sub total PEScb0.24158.6Total (TRR)0.411100.0aComponents extracted with acetonitrile/water.bAssociated with solids remaining after extraction with acetonitrile/watercSolubilised with successive treatments with pepsin and pancreatin bile .3591.466.9100.0
Flutriafol510The major metabolic processes were formation of two hydroxyl flutriafol derivatives byhydroxylation, and formation of free 1,2,4-triazole. Based on the findings, the proposed metabolicpathway of flutriafol in hens is shown in Figure 3.FlutriafolBinding to proteinTM5Figure 3 Proposed Metabolic Pathway of Flutriafol in Laying HensSummary of animal metabolismMetabolism of 14C labelled flutriafol has been studied in lactating cow and laying hens. In bothstudies, flutriafol was metabolized to several metabolites. All metabolites detected in the metabolismof lactating cow were also found in the metabolism of rats. The major metabolic processes in layinghens were the binding of flutriafol to liver proteins, the formation of hydroxyl flutriafol derivatives(fluorophenyl moiety), and the formation of free 1,2,4-triazole.Plant metabolismPlant metabolism studies were performed on apples, cereals (wheat a
Moffatt, 1994 (215 FLU) Dissociation constant . No data submitted : Technical material . Property Results Reference Minimum concentration 93.6% Appearance Fine white powder Kusk, 2006 (1359 FLU) Odour odourless at room temperature (wet paste: 77.2% purity) .
248 IN NATURE AND IN MAN – PART 1 . from Harav Yitzchak Ginsburgh Introduction In this lecture, we will discuss the significance of the number 248. Many of us are probably aware that the number 248 has tremendous significance in Torah. First,
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