UNITEDSTATESENVIRONMENTALPROTECTIONAGENCYWASHINGTON,D.C.2046026MAR2014MEMORANDUMSUBJECT:Flazasulfuron:ImmunotoxicityDataReviewPCCode:119011DPBarcode:OFFICEOFCHEMICALSAFETYANDPOLLUTIONPREVENTIOND403650DecisionNo.:467010RegistrationNo.:71512-11PetitionNo.:NARegulatoryAction:Section3RiskAssessmentType:NACaseNo.:NATXRNo.:0056922CASNo.:104040-78-0MRIDNo.:SeeSummaryTable40CFR:180.655FROM:VincentChen,ToxicologistRiskAssessmentBranch3HealthEffectsDivision,7509PTHROUGH:ChristineOlinger,BranchChi(J,f./</RiskAssessmentBranch3'f_._.:.J'HealthEffectsDivision,7509TO:DanielKenny,BranchChiefHerbicideBranchRegistrationDivision,7505PPage1of2I.CONCLUSIONSRAB3hascompleteditsreviewofthetoxicologystudysubmitted(seeDER)inaccordancewiththerevised40CFRPart158Guidelines.ThisstudyisclassifiedasAcceptableIGuidelineandsatisfiestheguidelinerequirementforanimmunotoxicitystudy(OPPTS870.7800).II.ACTIONREQUESTEDTheRegistrationDivision(RD)requestedthatHealthEffectsDivision(HED)reviewtheimmunotoxicitystudythatwassubmitted.III.BACKGROUNDNotApplicableIV.RESULTSffiiSCUSSIONThefollowingtablesummarizesthestudythatwassubmittedforreviewandforwhichtheattachedDERhasbeenprepared.DataSubmissionsMRIDCommentsImmunotoxici48870301NewDERPage2of228-DayImmunotoxicityStudyinMice(2012)Page1of9FLAZASULFURONI119011OPPTS870.7800IDACO4.8IOECDNoneEPAReviewer:VincentChen,M.S.RiskAssessmentBranchIII,HealthEffectsDivision(7509P)Date:26MAR2014EPASecondaryReviewer:YungG.Yang,Ph.D.Signature:'==RiskAssessmentBranchVI,HealthEffectsDivision(7509P)Date:6MAR14TXR:0056922STUDYTYPE:IDATAEVALUATIONRECORDI28-DayDietaryIrnmunotoxicityStudy-MouseOPPTS870.7800PCCODE:119011TESTMATERIAL(PURITY):Flazasulfuron(98.95%a.i.)SYNONYMS:TechnicalFlazasulfuron;SL-160Templateversion02106DPBARCODE:D403650IUPAC:1-(4,6-dimethoxypyrimidin-2-y1)-3-(3-trifluoromethyl-2-pyridylsulfony!)ureaCAS:N-[[(4,6-dimethoxy-2-pyrimidinyl)amino]carbonyl]-3-(trifluoromethyl)-2-pyridinesulfonamideCITATION:SetserJJ.(2012).A28-DayOral(Dietary)ImmunotoxicityStudyofTechnicalFlazasulfuroninFemaleCD-IMice.WILResearchLaboratories,LLC[1407GeorgeRoad,Ashland,OH44805-8946,USA].StudyID:WIL-282033.25April2012.MRID48870301.Unpublished.SPONSOR:IshiharaSangyoKaisha,Ltd.3-15,Edobori1-Chome,Nishi-ku,Osaka,550-0002,JapanEXECUTIVESUMMARY:Inanirnmunotoxicitystudy(MRID48870301),flazasulfuron(98.95%a.i.)wasadministeredtofemaleCrl:CD-1(ICR)mice(10/dose)viadietatdoselevelsofO,600,3000,or6000ppm(0,122.5,662.9,or1198.3mg!kg/day)forT-celldependentantigenresponse(TDAR)evaluation.Thepositivecontrolgroupconsistedof10femaleCrl:CD-l(ICR)micethatwereadministered50mg!kgcyclophosphamidemonohydrateviaintraperitonealinjectiononDays24-27.OnDay24,allTDARanimalswereimmunizedvia0.2mLintravenousinjectionwith1x108sheepredbloodcells(SRBC).OnDay28,TDARanimals'spleenswereextractedandsingle-cellsuspensionswereprepared;thelevelofanti-SRBCIgMproducedinresponseSRBCantigenadministrationwasdeterminedthroughanantibody-formingcell(AFC)assay.Otherparametersevaluatedwere:clinicalsignsoftoxicity,mortality,bodyweight,bodyweightgain,foodconsumption,andselectorganweights(i.e.spleenandthymus).Therewerenounscheduledmortalitiesinanytreatmentgroup.Inthetreatedanimalstherewerenotestsubstance-relatedeffectsonbodyweightororganweights(spleenandthymus);andtherewerenotestsubstance-relatedfindingsformacroscopicpathology.Inthetreatedanimals,therewerenoadversetestsubstance-relatedeffectsonfoodconsumption;therewerenoadversefindingsforclinicalsignsoftoxicity.Foodefficiency,waterconsumptionandmicroscopicpathologywerenotevaluated.ThesystemictoxicityNOAELis6000ppm(1198.3mglkglday)andtheLOAELis>6000ppm(1198.3mglkglday).Theanti-SRBCAFCassayresultsshowedthattherewerenostatisticaldifferencesinanti-SRBCFLAZASULFURON/11901128-DayImmunotoxicityStudyinMice(2012)Page2of9OPPTS870.7800IDACO4.8/OECDNoneAFCresponsesinspecificactivityandtotalactivityofanytreatmentgroupwhencomparedwiththevehiclecontrols.Ahighinter-individualvariabilitywasnotedinallthetreatmentgroupsaswellasinthecontrolgroup.Evaluationofindividualanimaldatadidnotshowanytrendordistributionthatwoulddemonstratesignificantsuppressionofanti-SRBCAFCresponse.TheNaturalKiller(NK)cellsactivitywasnotevaluatedinthisstudy.Thetoxicologydatabaseforthischemicaldoesnotrevealanyevidenceofimmunotoxicity.Theoverallweightofevidencesuggeststhatthechemicaldoesnotdirectlytargettheimmunesystem.UnderHEDguidanceaNKcellactivityassayisnotrequiredatthistime.BasedonTDARresults,theimmunotoxicityNOAELis6000ppm(1198.3mglkg/day)andtheLOAELis>6000ppm(1198.3mglkg/day).ThisstudyisclassifiedasAcceptableIGuidelineandsatisfiestheguidelinerequirementforanimmunotoxicitystudy(OPPTS870.7800).COMPLIANCE:SignedanddatedGLP,QualityAssurance,andDataConfidentialitystatementswereprovided.FLAZASULFURON111901128-DayImmunotoxicityStudyinMice(2012)Page3of9OPPTS870.7800IDACO4.81OECDNoneI.MATERIALSANDMETHODS.A.MATERIALS:1.TestMaterial:l)escription:Lot/Batch#:Purity:CompoundStability:CAS#ofTGAI:Structure:FlazasulfuronOff-whitepowder0208(Exp:11Dec2012)98.95%a.i.Stablewhilefrozen(-30to-10°C)andprotectedfromlight104040-78-02.VehicleandPositiveControl:Antibody-FormingCell(AFC)AssayVehicle:TreatedandNegativeControlAnimals:BasalDietPositiveControl:Cyclophosphamide(100.6%a.i.,lotnumber:120M1253V).3.TestAnimals:Species:Strain:AtStudyInitiation:Source:Housing:Diet:Water:EnvironmentalConditions:AcclimationPeriod:B.STUDYDESIGN:Source:Sigma-Aldrich,Inc.[St.Louis,MO,USA]FemaleOnlyMouseCrl:CDI(ICR)Age:7weeksWeight:21.4-27.5gCharlesRiverLaboratories[Raleigh,NC]Individuallyhousedinstainlesssteelwire-meshcagesuspendedabovecage-boardCertifiedRodentLabDiet®5002(PMINutritionInternational,LLC)adlibitumReverseosmosistreatedwateradlibitumviaautomaticwateringsystemTemperature:Humidity:AirChanges:Photoperiod:13days21.5-22.0°C42.4-50.6%10freshairchangesIhour12hrsdarkI12hrslight1.InLifeDates:19December2011-16January20122.AnimalAssignment:AnimalswereassignedrandomlytothetestgroupsnotedinTable1.Table1:StudyDesie;n•Dose(m:fkg!day)NumberofAnimalsPrimaryDietaryConcentration(ppm)MaleFemaleMaleFemaleControl0-0-10Low600-122.5-10Mid3000-662.9-10High6000-1198.3-10PositiveControl00- - -10InformatiOnwasobtamedfrompages9-10ofthestudyreportDosedwith50mg/kg/daycyclophosphamidemonohydrate(CPS)viaintraperitonealinjectiononDays24-27.3.SpeciesandGenderSelection:ThereportstatesthatfemaleCrl:CD-1(1CR)micewereusedduetothetestingfacility'sFLAZASULFURON/11901128-DaylmmunotoxicityStudyinMice(2012)Page4of9OPPTS870.7800IDACO4.8/OECDNonefamiliaritywiththespecies;onlyfemalewereusedbecausetheywerethoughttobemoreconsistentrespondersthanmales.4.DoseSelection:Thedoseswereselectedsothatthehighestdosetestedwouldbe1000mg/kg/dayandthelowerdosestoevaluateanydoseresponse.5.DietPreparationandAnalysis:DietwaspreparedweeklybymixingappropriateamountsoftestsubstancewithCertifiedRodentLabDiet®5002andwasstoredatroomtemperature.Priortodietadministration,homogeneitywastested(600and6000ppmdoses).Stabilitywasevaluatedbystoringasamplesofthe600and6000ppmdietformulationfor7and11daysatroomtemperature.Concentrationwasevaluatedbycollectingamiddlestratasampleofeachdietformulationfromthefirstandlastadmixpreparations.Theanalyticaldataindicatedthatthemixingprocedurewasadequateandthevariationbetweennominalandactualdosageswasacceptable(Table2).Table2:ResultsofDietAnalysis"ParameterResultHomogeneity(%RSD)1.7-3.6%Stability(%RSD)0.83-19%Concentration(%RSD)0.57-6.2%Informationwasobtamedfrompages117-122ofthestudyreport6.Statistics:Statisticalsignificancewasjudgedatand1.SpecificanalyseswereperformedonthedatacollectedaslistedinTable3.Table3:StatisticalAnalysis"ParameterStatisticalAlgorithmBodyweightIfparametricone-wayANOVA(SnedecorandCochran,1980)wassignificantforintergroupBodyweightchangedifferencesFoodconsumptionThenDunnett'stest(Dunnett,1964)wasusedtocomparetestsubstance-treatedgroupsStudent'st-TestwasusedtoevaluatepositivecontroldataagainstvehiclecontroldataTerminalbodyweightDatawastestedforhomogeneityofvariancesusingBartlett'sChiSquareTest(Bartlett,1937)OrganweightHomogenousdatawasevaluatedusingparametricone-wayANOVA(KruskalandWallis,1932)AbsoluteIfresultsweresignificant,RelativeThentreatmentgroupswerecomparedtothevehiclecontrolgroupusingDunnett'stestAFCdata(Dunnett,1955;Dunnett,1964)INonhomogenousdatawasevaluatedusinganonpararnetricANOVA(Wilson,1956)Ifresultsweresignificant,ThentreatmentgroupswerecomparedtothevehiclecontrolgroupusingGehan-WilcoxonTest(GrossandClark,1973)Dose-relatedtrendswereevaluatedacrossvehicle andtreatmentgroupsusingJonckheere'sTest(HollanderandWolfe,1973)Student'st-Test(SokalandRohlf,1981)wasusedtoevaluatepositivecontroldataagainstvehiclecontroldata;statisticalsignificancewasp::=;0.05.InformatiOnwasobtamedfrompage28ofthestudyreportFLAZASULFURON/119011C.METHODS:1.Observations:28-DayImmunotoxicityStudyInMice(2012)Page5of9OPPTS870.7800IDACO4.8/OECDNoneAnimalswereobservedtwicedailyformortalityandmorbundity.Clinicalexaminationswereperformeddaily.Detailedphysicalexamswereconductedweeklyonallanimals;examsbeganoneweekpriortorandomizationandcontinuedtonecropsy.2.BodyWeight:Animalswereweighedtwiceweekly;recordsbeganoneweekpriortorandomizationandcontinuedtonecropsy.3.FoodConsumptionandCompoundIntake:Individualfoodconsumptionwasrecordedtwiceweeklythroughoutthestudy;recordsbeganoneweekpriortorandomizationandcontinuedtonecropsy.Foodintakewascalculatedasg/animal/dayforeachinterval.Whenfoodconsumptioncouldnotbe measureforagiveninterval(duetospillage,weighingerror,obviouserroneousvalue,etc.);thenthevaluewas"NA."Themeanamountofconsumed(mglkg/day)perdosegroupwascalculatedfromthemeanfoodconsumption(glkg/day)andtheconcentrationinthefood(ppm).4.WaterConsumption:Parameterwasnotevaluated.5.SacrificeandPathology:OnDay28,animals(not-fasted)wereeuthanizedbycarbondioxideinhalationfollowedbyexsanguinations.Thenecropsiesincluded,butwerenotlimitedto,examinationoftheexternalsurface,allorifices,andthecranial,thoracic,abdominal,andpelviccavities,includingviscera.Thespleenandthymuswerecollected.6.OrganWeights:Thespleenandthymusweightswererecorded.7.Immunotoxicity:a.Anti-SRBCIgMAntibody-FormingCellAssay(AFC):OnDay24,animalswereimmunizedintravenouslyviatailveinwith1x108SRBCsin0.2mLEBSSwith15mMHEPES.Spleensampleswereprocessedintosingle-cellsuspensionsbymashingthespleensbetweenthefrostedendsoftwoglassslides.CellsuspensionswerethencentrifugedandresuspendedinEBSSwithHEPES(3mL).Theviabilityofsplenocyteswasdeterminedusingpropidiumiodide(PI)andtheCoulter®EPICS®XL-MCLTMFlowCytometer.Theanti-SRBCIgMresponsetosheeperythrocyteswasmeasuredusingamodificationoftheoriginalhemolyticplaqueassayofJeme(JemeandNordin,1963;Jemeetal.,1974)andasdescribedbyWhiteetal.,2010.Afterisolationandresuspensionofthespleencells,1:30and1:120dilutionswereprepared.A0.1mLaliquotofspleencellsfromeachsuspensionwasaddedtoseparatetesttubes,eachcontaining25JlLofguineapigcomplement,25JlLofFLAZASULFURON/11901128-DayImmunotoxicityStudyinMice(2012)Page6of9OPPTS870.7800IDACO4.8/OECDNonesRBC,and0.5mLofwarmagar(0.5%).Afterthoroughlymixing,eachtesttubemixturewasplatedontoaseparatepetridish,coveredwithamicroscopecoverslip,andincubatedat36-380Cfor3hours.Spleencellcountswereperformedon3mLsamplesusingaModelZ1CoulterCounter.Thecells/spleen,AFC/106SpleenCells,andAFC/Spleenweredetermined.TheplaquesthatdevelopedwerecountedusingaBellcoplaqueviewer.Aplaque,occurringfromthelysisofsRBC,iselicitedasaresultoftheinteractionofcomplementandantibodies(producedinresponsetotheIBimmunizationoftheanimals)directedagainstsRBC.EachplaqueisgeneratedfromasingleIgMantibody-producingBcell(plasmacell),permittingthenumberofAFCpresentinthewholespleentobecalculated.b.NaturalKiller(NK)CellActivityAssay:Notperformed.II.RESULTS:A.OBSERVATIONS:1.ClinicalSignsofToxicity:Therewerenofindingsobserved.2.Mortality:Therewerenounscheduledmortalities.B.BODYWEIGHTANDBODYWEIGHTGAIN:Therewerenotestsubstance-relatedeffectsonbodyweightandbodyweightgain(Table5).Table5:MeanBodyWeightandBodyWeightGain"DoseGroup(ppm);n=10060030006000TimePointMeanBodyWeights(g)±SD(%differencefromnegativecontrol)DayOO23.2±1.1823.5±1.59(1.3)23.4 ±0.91(0.9)23.9±1.54(3.0)Day0723.9±1.3923.7 ±2.11(-0.8)23.5±1.61(-1.7)24.3±1.57(1.7)Day1424.9±1.5725.2±2.23(1.2).24.4±1.95(-2.0)25.1±1.91(0.8)Day2126.1±1.9026.3±2.34(0.8)25.3±2.33(-3.1)25.8 ±2.17(-1.1)Day2826.6±1.8727.1±2.89(1.9)26.3±2.48(-1.1)26.5±2.09(-0.4)IntervalMeanBodyWeightGains(g)±SD(%differencefromnegativecontrol)Days00-070.7±0.620.3±0.950.1±1.08Days00-141.6±1.011.7±1.061.0±1.30Days00-212.9±1.582.9±1.271.9±1.69Days00-283.4±1.553.6±1.792.9±1.80InformatiOnwasobtamedfrompages48-50and54-55ofthestudyreportp:S:0.05p:S:0.01C.FOODCONSUMPTIONANDCOMPOUNDINTAKE:1.FoodConsumption:0.4±0.471.2±0.561.8±0.882.6±0.75PositiveControl23.5±1.07(1.3)24.3±1.83(1.7)25.5±2.25(2.4)27.1±2.93(3.8)27.0±2.67(1.5)0.8±0.972.0±1.343.6±2.053.5±1.83Therewerenoadversetestsubstance-relatedeffectsonfoodconsumption(Table6).Therewasadecreaseinfoodconsumptionondays21-24forthe6000ppmdosegroup,howevernoadversedecreaseinbodyweightwasobserved.FLAZASULFURONI11901128-DayImmunotoxicityStudyinMice(2012)Page7of9OPPTS870.7800IDACO4.8IOECDNoneTable6:MeanFoodConsumption•DoseGroup_(t>p_m}in=-10060030006000PositiveControlIntervalMeanFoodConsumption(g/animallday)±SD'%differencefromnegativecontrol)Days00-035.3±0.864.7±0.86(-11.3)5.3±1.05(0.0)Days03-075.4±0.785.0±0.65(-7.4)5.0±0.53(-7.4)Days07-105.1±0.544.8±0.57(-5.9)5.0±0.72(-2.0)Days10-145.7±1.455.2 ±0.71(-8.8)5.4 ±0.84(-5.3)Days14-176.1±1.135.1±0.52(-16.4)6.2±1.35(1.6)Days17-216.0±0.915.4 ±0.78(-10.0)5.6±0.69(-6.7)Days21-245.6±0.705.5±0.68(-1.8)5.4±0.68(-3.6)Days24-285.4±0.595.5±1.18(1.9)5.4 ±0.58(0.0)InformatiOnwasobta.medfrompages56-57ofthestudyreportp::S0.05p::S0.014.8±0.59(-9.4)6.0±1.49(13.2)5.1±0.46(-5.6)5.4±0.73(0.0)4.8±0.37(-5.9)5.2±0.90(2.0)5.2±0.84(-8.8)5.7±0.98(0.0)5.4±0.78(-11.5)6.3±1.38(3.3)5.5±0.61(-8.3)5.5±0.84(-8.3)4.1±0.97(-26.8)"5.9±1.12(5.4)5.2±0.68(-3.7)5.1±0.86(-5.6)2.Compound Intake:TheachieveddosagesinthetestgroupsarereportedinTable1.3.FoodEfficiency:Parameterwasnotevaluated.D.WATERCONSUMPTION:Parameterwasnotevaluated.E.ORGANWEIGHTS:Therewerenotestsubstancerelatedeffectsobservedonthespleenandthymus(Table7).Table7:MeanTerminalBodyWeightsandOrganWeights•DoseGroup(ppm);n=lO01600I3000I6000PositiveControlMeanTerminal Weight(g)±SD(%differencefromcontrol)BodyWeight26.6±1.9I27.1 ±2.9(1.9)I26.3± 2.5(-1.1)I26.5±2.1(-Q.4)27.0±2.7(1.5)..MeanTerminalWeight(mg)±SD(%differencefromcontrolSpleen123.4±34.8I136.o±54.2c1o.2)I122.4 ±42.2c-o.8)I122.5±27.6c-o.1)58.5±15.8(-52.6)''Thymus44.o±11.1I39.9±14.3(-9.3I47.8 ±17.5(8.6I44.5±15.5(1.115.1±5.3(-65.7)'MeanRelativeOrganWeight(%BodyWeight)±SD(%differencefromcontrol)Spleeno.46±0.11Io.5o±o.2oC8.7)I0.46±0.14(0.0)Thymuso.t7±o.o4Io.15±o.o4(-1L8)I0.18±0.06(5.9)Informationwasobtamedfrompage159ofthestudyreportp::S0.05p:::;0.01F.IMMUNOTOXICITYTESTS:1.Anti-SRBCAntibody-FormingCellAssay(AFC):I0.46±0.08(0.0)0.22±0.05(-52.2)..I0.17±0.05(0.0)0.06±0.02(-64.7)"Theresultsoftheanti-SRBCAFCdidnotindicateanytreatment-relatedimmunosuppressiveeffects(Table8).Therewerenostatisticaldifferencesinanti-SRBCAFCresponsesinspecificactivity(AFC/106spleencells)andtotalactivity(AFC/spleen)ofanytreatmentgroupwhencomparedwiththevehiclecontrols.Ahighinter-individualvariabilitywasnotedinallthetreatmentgroupsaswellasinthecontrolgroup.Evaluationofindividualanimaldatadidnotshowanytrendordistributionthatwoulddemonstratesignificantsuppressionofanti-SRBCAFCresponse(Figure1).ThepositivecontrolgroupdemonstratedastatisticaldecreaseinAFCresponseascomparedtothevehiclecontrols.FLAZASULFURON111901128-DayImmunotoxicityStudyinMice(2012)Page8of9OPPTS870.7800IDACO4.81OECDNoneTable8:Anti-SRBCAFCResults•PrimarybParameter±SD(%differencefromnegativecontrol)DoseGroup(ppm)10SpleenCellsISpleen12MAFC1106SpleenCells017.40±4.60608±34960019.94± 7.42(14.6)1353±1318(122.5)300017.49±5.20(0.5)1138±805(87.2)600018.06±4.40(3.8)774±539(27.3)PositiveControl5.76±1.62(-66.9)0±0(-42.7)Informattonwasobtamedfrompage160ofthestudyreportp::50.05p::50.01Figure1.Anti-SRBClgMAFCDistributionsofIndividualAnimalData•10'SpleenCellsISpleenIlgMAFC1106SpleenCells5000BOO:i!..1..)4000a4a.!!600•.!!...."'.'!..•4.•<..i•I<tooo•I•II•••a.•II.IIIl.0•00I23450I2 34TreatmentGroup•Oroup2:""'....•arac.':l'olibftc-1•Clreup2:600..-•a-..'r.ilinc-alear.,..]:)OQ(IPJIIII5I700io"'iJiota,Tbo00103laMAFCISpleen121±83249±223(105.8)203±172(67.8)142±107(17.4)0±0(-100.0)103lgMAFCISpleen•.•••lIIl.iIt•4.I234•Onup2:10DI'P"'•o,..,:ra.itincCIIIVcllFtguresweregeneratedbytherevtewerusmgmformattonobtamedfrompage163ofthestudy2.NaturalKiller<NK)CellActivityAssay:Thisparameterwasnotevaluated.G.SACRIFICEANDPATHOLOGY:Therewerenotestsubstance-relatedmacroscopic pathologicalfindings.Microscopicpathologywasnotevaluated.III.DISCUSSIONANDCONCLUSIONS:A.INVESTIGATORS'CONCLUSIONS:5TreatmentoffemaleCD-1mice with600,3000,and6000ppmofTechnicalFlazasulfuroninthe dietfor28dayswaswelltoleratedanddidnotsuppressthehumoralcomponentoftheimmunesystemwhenevaluatedusingtheAFCassay.Therefore,basedontheweightofevidenceinthisstudy,theno-observed-effectlevel(NOEL)forsuppressionofthehumoralimmuneresponsewas6000ppm(equivalentto1198.3mg/kg/day),thehighestdietaryconcentrationadministered.B.REVIEWERCOMMENTS:Therewerenounscheduledmortalitiesinanytreatmentgroup.Inthetreatedanimalstherewerenotestsubstance-relatedeffectsonbodyweightororganweights(spleenandthymus);andtherewerenotestsubstance-relatedfindingsformacroscopicpathology.Inthetreatedanimals,therewerenoadversetestsubstance-relatedeffectsonfoodconsumption;therewerenoadversefindingsforclinicalsignsoftoxicity.Foodefficiency,waterconsumptionandmicroscopicpathologywerenotevaluated.ThesystemictoxicityNOAELis6000ppm(1198.3mglkglday)andtheLOAELis>6000ppm(1198.3mglkglday).FLAZASULFURON/11901128-DayImmunotoxicityStudyinMice(2012)Page9of9OPPTS870.7800IDACO4.8/OECDNoneTheanti-SRBCAFCassayresultsshowedthattherewerenostatisticaldifferencesinantiSRBCAFCresponsesinspecificactivityandtotalactivityofanytreatmentgroupwhencomparedwiththevehiclecontrols.Ahighinter-individual variabilitywasnotedinallthetreatmentgroupsaswellasinthecontrolgroup.Evaluationofindividualanimaldatadidnotshowanytrendordistributionthatwoulddemonstratesignificantsuppressionofanti-SRBCAFCresponse.TheNaturalKiller(NK)cellsactivitywasnotevaluatedinthisstudy.Thetoxicologydatabaseforthischemicaldoesnotrevealanyevidenceofimmunotoxicity.Theoverallweightofevidencesuggeststhatthechemicaldoesnotdirectlytargettheimmunesystem.UnderHEDguidanceaNKcellactivityassayisnotrequiredatthistime.BasedonTDARresults,theimmunotoxicityNOAELis6000ppm(1198.3mglkg/day)andtheLOAELis>6000ppm(1198.3mglkg/day).C.STUDYDEFICIENCIES:Therewerenomajordeficienciesfoundineitherstudyandthedeficienciesthatwerenoteddonotimpacttheinterpretationofthestudyresults.