394.ncp

TSCANEWCHEMICALSPROGRAM(NCP)CHEMICALCATEGORIESOfficeofPollutionPreventionandToxicsU.
S.
EnvironmentalProtectionAgency1200PennsylvaniaAve.
,NWWashington,D.
C.
20460Contacts:KennethMoss(moss.
kenneth@epa.
gov)RebeccaJones(jones.
rebecca@epa.
gov)KellyMayo-Bean(mayo.
kelly@epa.
gov)Lastrevised:August,2010iiINTRODUCTIONDisclaimerandPurposeofThisDocument:EPA'sOfficeofPollutionPreventionandToxics(OPPT)groupschemicalswithsharedchemicalandtoxicologicalpropertiesintocategoriessothatPMNreviewsarefacilitated.
PMNsubmittersandEPAreviewersbenefitfromtheaccumulateddataandpastdecisionsrepresentedbyacategory.
EPAconsidersallPMNs,includingnewchemicalsubstanceswhichfallwithinsuchcategories,onacase-by-casebasisandusesthemostappropriatestructuralanaloguetosupportanyconcernsforhealthorenvironmentaleffects.
Foranynewchemicalsubstance,ifEPAdetermines,underTSCAsection5(e),thatthesubstance"maypresentanunreasonableriskofinjurytohealthortheenvironment,"thePMNsubstancecanbesubjectedtoappropriatecontrolactionsand/ortestingunderTSCAsection5(e).
This"maypresent"findingisdevelopedthroughtheapplicationofcategory-basedorchemical-by-chemicalassessmentofhazardendpointsandcase-specificexposureassessment.
Thecategoriesincludedinthiscompilationrepresentchemicalsforwhichsufficientassessmentexperiencehasbeenaccumulatedsothathazardconcernsandtestingrecommendationsvarylittlefromchemicaltochemicalwithinthecategory.
Thus,thesecategoriesdonotnecessarilyrepresentthechemicalsofgreatestconcerntotheAgency.
Bythesametoken,thecategoriesarealsonotintendedtobeacomprehensivelistofallsubstancesthatmaybesubjecttofurtheractionintheNewChemicalsProgram.
IfanewchemicalsubstanceisstructurallysimilartoasubstanceforwhichEPAhaspositivetoxicitydataandthereissufficientexposure,EPAmayregulatethatsubstanceundersection5(e)oftheToxicSubstancesControlAct(TSCA)basedonitspotentialunreasonablerisk.
ThehazardpotentialofaPMNsubstanceisdependentonthemolecularweightofthecompound,thepresence/absenceofactivating/deactivatingsubstituents,otherphysical/chemicalproperties,andthelikelyrouteofexposure.
Typically,concernsareconfinedtochemicalswithmolecularweights1000willprobablybeexcludedinthefutureoncethisassumptionisconfirmedwithtoxicityinformation.
However,toxicityinformationisneededtoconfirmthisassumption.
HazardConcerns.
Acutetoxicityforthreemembersofthiscategoryareavailableandallhavebeenshowntobemoderatelytoxictoaquaticorganisms(i.
e.
,acutetoxicityvaluesbetween1and100mg/L):benzoylchloride,fish96-hLC50=35.
0mg/L,anaromaticdicarboxyldichloride,fish96-hLC50=6.
2mg/L,andbenzenesulfochloride,fish48-hLC50=3.
0mg/L.
Allofthesetestshavebeendonewiththestaticmethodusingnominalconcentrations.
Itisunclearjusthowacidchloridesaretoxictoaquaticorganisms.
Itisknownthatacidchlorideshydrolyzetothecarboxylic/sulfonicacidandHCl.
Itisnotknownifthetoxiceffectistheresultof(1)absorptionoftheacidchlorideandhydrolysiswithinthemembrane,or(2)theHClproducedfromthehydrolysis.
Itisknownthatthecarboxylic/sulfonic-acidhydrolysisproductsareoflowtoxicity.
Boundaries.
Therearenoknownlowerboundaries.
TheupperboundarieswillbebasedonKowandMWwhenenoughinformationisobtained.
Ingeneral,whenthelogKowvalueis8,testingwillberequesteduntilenoughinformationisobtainedtodeterminewhetherthesecompoundswillhavenotoxiceffectsatsaturation.
Generally,membersofthiscategorywillhaveMWsoflessthan1000,buttestingofmemberswithaMW>1000mayberequestedtoconfirmwhetheracidchlorideshavetobeabsorbedtobetoxic.
GeneralTestingStrategy.
Thetestingstrategyforacidchlorideswillconsistoftwosteps.
(1)Hydrolysis(HarmonizedTestGuideline835.
2120)willberecommended.
Dependingontheoutcomeofthisenvironmentalfatetestingandreassessment,(2)theaquaticbasesetofenvironmentaltoxicitytestswillberecommendedforaquaticexposureswiththefishacutetoxicitytestdoneonceortwice.
Chronictoxicitytestingforaquaticorganismsinclude:thefishearlylifestatetoxicitytest,thedaphnidpartiallifecycletoxicitytestandthealgaltoxicitytest.
Theterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedinggrowthtest,theearthwormacutetoxicitytestandthesoilmicrobialcommunitybioassay)willberecommendedforterrestrialexposures.
Chronictoxicitytestingforterrestrialorganismsinclude:theplantwholelifecycletest,theplantuptaketest,andthesoilmicrobialcommunitybioassay.
October,19902Category:AcidDyesandAmphotericDyesEnvironmentalToxicityDefinition.
Organicdyesaredividedintofourclassesdependingonthetypeofelectronicchargeofthedye:nonionic(neutraldyes);anionic(negativechargeoraciddyes);cationic(positivecharge)dyes;andamphoteric(mixtureofpositiveandnegativechargesonsamemolecule)dyes.
Nonionicorneutraldyesareassessedasneutralorganicchemicalsforwhichthereisaseparatecategorydescription,andcationicdyesalsohaveaseparatecategorydescription.
Amphotericdyesareassessedeitherascationicoranionicdyesdependingondominantnetcharge.
HazardConcerns.
Analysisofover200aciddyes(Aueretal.
1990,Nabholz1990,Sigmanetal.
1983,Tonogaietal.
1979,LittleandLamb1972,ADMI1974)haveindicatedthatsomemonoacidanddiaciddyescanshowmoderatetohightoxicity(i.
e.
,acutevalues100mg/L)towardsfishandinvertebrates.
Somemetalchelateddyes,i.
e.
,Al,Co,Cr,Fe,haveshownmoderatetoxicitytowardsfishanddaphnidsandthetoxicityhasnotbeenexplainedbytheresidualfree(un-chelated)metalioninthedyeproduct.
Allaciddyesshowedmoderatetoxicitytowardsgreenalgae.
Analysisofavailabledata(Aueretal.
1990,Nabholz1990)hassuggestedthateffectstoalgaewerenottheresultofdirecttoxicitybutrepresentedanindirecteffectduetoshading.
Seniorregulatorydecision-makersinOPPT(thenOTS)decidedin1988thattherisktoalgaefromindirect(shading)toxicitywasnotanunreasonableriskfortwomainreasons:(1)algaegrewquicklyassoonasthedyewasdiluted,and(2)thereleaseofcoloredeffluentsintheU.
S.
generallyresultsinimmediatecomplaintsbycitizenstotheirlocalauthorities,e.
g.
,countyandstategovernments.
Therapidresponsebythepublicgenerallyresultsinquickregulatoryactionbylocalofficials.
SincethereisnoSARforaciddyes(Aueretal.
1990),hazardprofilesformonoaciddyesaredevelopedusingmeasureddataordataforthenearestanalog(s).
Boundaries.
Acidsdyesmusthavesomewatersolubilityandmolecularweightsgenerallyneedtobenearorbelow1000.
GeneralTestingStrategy.
I.
ReleasetoAquaticEcosystems:Tier1.
Becauseoftheaboveboundaryconditions,andtheneedtoassesshumanexposureaswellasenvironmentaltoxicity,ifthereisinsufficientknowledgeaboutthewatersolubilityofthedye,thenitshouldbemeasured(HarmonizedTestGuideline830.
7860).
Thefishanddaphnidacutetoxicitytestsfromtheaquaticbasesetofenvironmentaltoxicitytestswillberecommendedforaquaticexposures.
Theacutetoxicitytestsforfish(HarmonizedTestGuideline850.
1075)anddaphnids(HarmonizedTestGuideline850.
1010)willbedoneusingtheflow-throughmethodwithmeasuredconcentrations,andeffectiveconcentrationswillbebasedon100%activeingredients(AI)andmeanmeasuredconcentrations.
3IfthereisnosignificantriskfromthePMNaftertheresultsofthefishanddaphnidacutetoxicitytestshavebeenintegratedintotheriskassessment,thennofurthertestingisrecommended.
However,ifthereisasignificantrisk,thengotoTier2.
Tier2.
PhototransformationofChemicalsinWater—IndirectPhotolysisScreeningTest(HarmonizedTestGuideline835.
5270)Ift1/22days,gotoTier4.
Tier3a.
Ift1/25,000arepresumednottoposeahazardunderanyconditions.
Typically,concernsareconfinedtothosespecieswithmolecularweights5and5,butdisplayexcesstoxicityatlowerlogKowvalues.
ThetoxicityofacrylatesandmethacrylatescanbepredictedbyaQSAR(quantitativestructure-activityrelationship),althoughtherearesomemembersoftheclasssuchasallylmethacrylatethataresignificantlymoretoxicthanpredictedbytheQSAR.
Boundaries.
Typically,environmentaltoxicityconcernsareconfinedtothosechemicalswithmolecularweights1000willbeexcludedfromthiscategory.
Acutetoxicityforaldehydesisknowntobelimitedbytheoctanol/waterpartitioncoefficient(Kow).
AbovealogKowvalueof>6.
0,aldehydesshownoeffectsatsaturationforacuteeffectsduring96-hexposurestofish.
AldehydeswhicharesolidsatroomtemperaturemayshownotoxicityatsaturationatlowerKowvaluesdependingonthemeltingpoint,i.
e.
,thehigherthemeltingpointatagivenKow,thegreaterthelikelihoodthatnotoxicitywillbeobservedatsaturation.
Forsolids,thenoeffectsatsaturationhastobedeterminedonacase-by-casebasis.
TherearenomeasuredupperKowlimitsforchronictoxicityatthistime,butitmaynotbemuchabovealogKow=8.
FuturetestingwilldetermineKowlimits.
TheaquatictoxicityforaldehydesmaybedeterminedthroughSARanalysisbyEPAusingECOSAR–ahazardestimationtoolthatuseschemicalstructuredescriptorstoestimatetheacuteandchronictoxicityofasubstancetoaquaticorganisms.
[LinkforECOSAR:http://www.
epa.
gov/opptintr/newchems/tools/21ecosar.
htm]EnvironmentalFate:Boundaries:MW5,000andnomorethan25%ofspecieshavemolecularweightslessthan1,000andnomorethan10%ofspecieshavemolecularweightslessthan500.
Foralkoxysilaneswithalkylsubstituentslargerthanpropylgroups,theequivalentweightcutoffis1,000.
Thedegreeofconcerndependsontherelativeabundanceoflowermolecularweightspecies,butthereisnomolecularweightthresholdabovewhichtherewouldbenoconcern.
Tobetterdefinetheboundariesofthecategory,EPAseekstestingonalimitednumberofalkoxysilanesthatfocuseson(1)therelationshipbetweenmolecularweight(oralkoxysilyl16equivalentweight)andinhalationtoxicityand(2)theimportanceofincreasingalkoxychainlengthinlimitingtoxicity.
GeneralTestingStrategyTheAgencyrecommendsthefollowingtestingasappropriatetoaddresshealthandenvironmentaltoxicityconcernsforthiscategory:1.
90-daysubchronictestinrodentsbytheinhalationroute(HarmonizedTestGuideline870.
3100).
2.
Hydrolysis(HarmonizedTestGuideline835.
2120).
Ift1/2islessthanonehour,basesetecotoxicitytesting(see"3,"below)isconductedwiththehydrolysisproductsonly.
Ift1/2isgreaterthanonehour,basesetecotoxicitytestingisconductedwiththeparentmaterial;thePMNsubmitterhastheoptionofalsotestingwiththehydrolysisproducts.
3.
Base-setecotoxicitytestingtoincludefish(HarmonizedTestGuideline850.
1075)usingthestaticmethod,daphnids(HarmonizedTestGuideline850.
1010)usingthestaticmethodandalgae(HarmonizedTestGuideline850.
5400)usingthestaticmethod,allnominalconcentrations.
Directdilutionofthetestalkoxysilaneandorganismsisaddedwithin10minutes.
Thestatic-renewalmethodisusedforfishanddaphnidtest,plusanadditionalfishtestusingagedstocksolution.
Resultsoftheacuteecotoxicitytestingmaytriggerchronicfish(HarmonizedTestGuideline850.
1400)anddaphnid(HarmonizedTestGuideline850.
1300)testing.
4.
Physical-chemicalorenvironmentalfatetestingincluding,asappropriate:-Meltingpoint(HarmonizedTestGuideline830.
7200)orboilingpoint(HarmonizedTestGuideline830.
7220)-Watersolubility(HarmonizedTestGuideline830.
7840or830.
7860)-LogKow(HarmonizedTestGuideline830.
7550,830.
7560or830.
7570;orOECD123,PartitionCoefficient(1-Octanol/Water):Slow-StirringMethod)-Vaporpressure(HarmonizedTestGuideline830.
7950)-PhototransformationofChemicalsinWater—DirectPhotolysis(OECD316)orIndirectPhotolysisScreeningTest(HarmonizedTestGuideline835.
5270).
Needforwatersolubility,logKow,andphotolysistestingdeterminedbyoutcomeofabovehydrolysistesting.
September,1988;revisedJune,199417Category:AluminumCompoundsRiskManagementStatement.
Greatestconcernisforsolubleformsofaluminum(Al).
Ifwatersolubilityisgreaterthan1partperbillion(1ppb),theAgencywillprohibitreleasesofthePMNsubstancetowaterpendingthesubmissionofenvironmentaltoxicitytesting.
Definition.
ThiscategoryincludesinorganicsaltsofAl,complexesbetweenAlandorganicacidsorchelatesofAlbypolyanionicmonomers,andorganoAlcompounds,i.
e.
,Alcovalently-bondedwithcarbon.
Forexample,someinorganicAlsaltsinclude:Alhydroxide,Alchloride,Alfluoride,Alnitrate,Alphosphate,andAlsulfate.
NotincludedinthiscategoryaredyescomplexedwithAl(seedyecategoriesaddressedelsewherewithinthisATSCANewChemicalsProgramChemicalCategories@document).
HazardConcerns.
SolublesaltsofAlareknowntobehighlytoxictogreenalgaeandmoderatelytoxictofishandaquaticinvertebratesatpHvaluesbetween6.
5to9.
0andintermsofsolubleAlinmgAl/L.
ToxicityinformationisavailableforAlchloride,Alsulfate,andNaaluminate.
TheOfficeofWater(USEPA,1988,EPA440/5-86-008)citedSeiptetal.
(1984,WaterAirSoilPollut.
23:81-95)whoconcludedthat"thesimplehydroxides(Al(OH)2+andAl(OH)2+)areregardedasthemostdangerousformswhileorganicallyboundAlandpolymericformsarelesstoxicoressentiallyharmless.
"TheOfficeofWater(USEPA,1988)alsoconcludedthatsolutionsofAlinwaterapproachchemicalequilibriumratherslowlyandthatAlcanformstrongcomplexeswithfulvicandhumicacids.
ThetoxicityprofileforsolubleAlsalts,listedbelow,isbasedon(1)availablemeasured(M)toxicitydata,(2)mgAl/L(ppmAl),(3)pHbetween6.
5and9.
0,and(4)moderatehardness(about150.
0mg/LasCaCO3).
fish(FHM)96-hLC50=35.
0M,pH7.
3,H220fish(RT)96-hLC50=8.
6M,pH7.
5,H47fish(RT)96-hLC50=7.
4M,pH6.
6,H47fish(RT)96-hLC50=14.
6M,pH7.
3,H47meanRT96-hLC50=10.
0Predicted,n3fish(BT)96-hLC50=3.
6M,pH6.
5,Hmeanfish96-hLC50=11.
0Predicted,n3daphnid(Cd)48-hLC50=1.
9M,pH7.
4,H50daphnid(Cd)48-hLC50=3.
7M,pH7.
7,H47meanCd48-hLC50=2.
7Predicted,n2daphnid(Dm)48-hLC50=3.
9M,pH7.
0,H45daphnid(Dm)48-hLC50=38.
0M,pH7.
1,H220meanDm48-hLC50=12.
0Predicted,n2meandaphnid48-hLC50=5.
7Predicted,n218OWFWAcuteWQC=1.
5greenalgal96-hEC50=0.
570,Measured,pH7.
6,H15greenalgal96-hEC50=0.
460,Measured,pH8.
2,H15meanalgal96-hEC50=0.
510Predicted,n2fish(FHM)ChV=3.
3Measured,pH7.
7,H220fish(FHM)ACR=11.
0Measureddaphnid(Dm)ChV=0.
742Measured,pH8.
3,H220daphnid(Dm)ChV=0.
320Measured,pH7.
7,H45meanDmChV=0.
490Predicted,n2DmACR=24.
0Measureddaphnid(Cd)ChV=1.
9Measured,pH7.
2,H50CdACR=1.
4MeasuredmeandaphnidChV=0.
970Predicted,n2meandaphnidACR=5.
9MeasuredOWFWChronicWQC=0.
087algalChV=0.
100Predicted,EC50/4BiologicalFateFish(BT-eyedembryo)30-dBCF(wb)=50.
0Measured,pH7.
2,H242Fish(BT-fry)30-dBCF(wb)=136.
0Measured,pH7.
2,H242meanfishBCF=93.
0Predicted,n2ThetoxicityprofileforsolubleinorganiccomplexesofAlcanbepredictedviaMWadjustmentofthetoxicityforAltothetoxicityofthecomplex.
CaAlhydroxyphosphites[141728-04-3]CaxAl2(OH)2(x+3-y)(HPO3)y@mH2Owithx=2to12,(2x+5))2>y>0,andm=0to12;typicalcomposition=31%Ca,9.
5%Al,&8.
0%P;solidwithmp>250EC(dec);S=680mg/L;pH11.
5;Concentration(mg/L)EffectComplexAlNotesfish96-hLC50120.
011.
0Predictedfish96-hLC50409.
06.
0Measureddaphnid48-hLC5060.
05.
7Predicteddaphnid48-hLC5024.
0nmMeasured19greenalgal96-hEC505.
40.
510PredictedfishChV35.
03.
3PredicteddaphnidChV10.
00.
970PredictedalgalChV1.
00.
100PredictedNaAlfluoride[15096-52-3]sodiumfluoaluminate;sodiumfluoridealuminum;cryolite;kryolith;M12,2673;Na3AlF6;MW210;composition:13%Al;solidwithmp1000EC;S=610mg/LwithpH6.
2;usedasaninsecticidesince1929;Concentration(mg/L)EffectComplexAlNotesfish96-hLC5085.
011.
0Predictedfish96-hLC5021.
02.
8Measureddaphnid48-hLC5044.
05.
7Predictedgreenalgal96-hEC503.
90.
510PredictedfishChV25.
03.
3PredicteddaphnidChV7.
50.
970PredictedalgalChV0.
7700.
100PredictedThetoxicityprofileforchelatesofAlwithpolyanionicmonomerscanbepredictedviaMWadjustmentofthetoxicityforAltothetoxicityofthechelate.
ThetoxicityprofilefororganoAlcompoundsaredevelopedforonlythehydrolysisproduct(s)ofAl.
OrganoAlcompoundsareunstableinairandwater.
MethylAlandethylAlarepyrophoricanddodecylAlslowlyhydrolysesinwater.
Boundaries.
ThetoxicityofAlcompoundsdependsontheirwatersolubility,thebioavailabilityofAl,andtheirstability.
ThemostimportantpropertydeterminingthetoxicityofAlcompoundsiswatersolubility.
Watersolubilitycannotbepredictedaccuratelyandhastobemeasured.
Molecularweight(MW)isonlyimportantwhenAlcomplexesarewatersolubleandstable.
StablecomplexesofAlwithMWs>1000arenotexpectedtobeabsorbedbyaquaticorganismsandAlisnotexpectedtobebioavailableeveniftheyarewatersoluble.
Therefore,onlyunstableAlcompoundswithMWs5,000arepresumednottoposeahazardunderanyconditions.
Typically,concernsforhealtheffectsareconfinedtothosespecieswithmolecularweights1000willbeexcludedfromthiscategory.
Acutetoxicityforanilineswhichareliquidsatroomtemperatureisknowntobelimitedbytheoctanol/waterpartitioncoefficient(Kow).
AbovealogKowvalueof≥7.
38,anilinesshownoeffectsatsaturationduring96-hexposures(VeithandBroderius(1987).
AnilineswhicharesolidsatroomtemperaturemayshownotoxicityatsaturationatlowerKowvaluesdependingonthemeltingpoint,i.
e.
,thehigherthemeltingpointatagivenKow,thegreaterthelikelihoodthatnotoxicitywillbeobservedatsaturation.
Forsolids,noeffectsatsaturationshouldbedeterminedonacase-by-casebasis.
TherearenoknownKowlimitsforchronictoxicityatthistime,butitmaynotbemuchabovealogKow=8forliquidanilines.
HazardConcerns.
AnalysisoftheaquatictoxicityforanilineshasbeenreviewedinvariouspublicationsandhasbeendeterminedthroughSARAnalysisbyEPAusingECOSAR–ahazardestimationtoolthatuseschemicalstructuredescriptorstoestimatetheacuteandchronictoxicityofasubstancetoaquaticorganisms.
[LinkforECOSAR:http://www.
epa.
gov/opptintr/newchems/tools/21ecosar.
htm].
Publications.
Fish96-hLC50(VeithandBroderius1987);fish14-dLC50(Deneeretal1987);fish14-dLC50(Hermensetal1984);daphnids48-hLC100(NendzaandSeydel1988aand1988b);andgreenalgal96-hEC50(NendzaandSeydel1988aand1988b).
Aromaticdiamines(i.
e.
,twoaminesononebenzene)anddinitroanilinesareknowntobemoretoxicthanpredictedbytheseSARs.
Membersofthiscategoryexhibittoxicityrangingfromlowtoxicity(i.
e.
,>100mg/L)tohightoxicity(i.
e.
,2days,gotoTier4.
Tier3a.
Ift1/25.
3timeswhentheNOECswerecompared(seeTableVIIinVanLeeuwen).
Daphnidchronictoxicitytesting(HarmonizedTestGuideline850.
1300),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,and21;measuredTOCofdilutionwaterinthecontrol;thehighesttreatmentconcentrationonanominal-basisshouldbesetattheaqueoussolubilitylimit;solventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthePMNbeyonditsaqueoussolubilitylimit;andthe7-ddaphnidchronictoxicitytestcannotbesubstitutedforthe21-dtoxicitytestbecauseVanLeeuwenetal(1990)havedemonstratedthatthefish7-dELStoxicitytestunderestimatedthechronictoxicityofanilinesmeasuredbythefish28-dELStoxicitytestby>5.
3timeswhentheNOECswerecompared(seeTableVIIinVanLeeuwen).
Aerobicbiodegradabilityaccordingtoeitherofthefollowingtestguidelines:-ReadyBiodegradability(sixmethods;chooseanyone)(HarmonizedTestGuideline835.
3110)-ReadyBiodegradability–CO2inSealedVessels(HeadspaceTest)(HarmonizedTestGuideline835.
3140)II.
ReleasetoTerrestrialEcosystems:Theterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedlinggrowthtest[HarmonizedTestGuideline850.
4230],theearthwormtoxicitytest[HarmonizedTestGuideline850.
6200]andthesoilmicrobialcommunitybioassay[HarmonizedTestGuideline850.
5100])willberecommendedforterrestrialexposures.
Chronictoxicitytestingforterrestrialorganismsinclude:theplantwholelifecycletest(HarmonizedTestGuideline850.
4150),theplantuptaketest(HarmonizedTestGuideline850.
4800),andthesoilmicrobialcommunitybioassay(HarmonizedTestGuideline850.
5100).
29References.
DeneerJW,SinnigeTL,SeinenWandHermensJLM.
1987.
Quantitativestructure-activityrelationshipsforthetoxicityandbioconcentrationfactorofnitrobenzenederivativestowardstheguppy(Poeciliareticulata).
AquaticToxicology10:115-129.
HermensJ,LeeuwanghP,andMuschA.
1984.
Quantitativestructure-activityrelationshipsandmixturetoxicitystudiesofchloro-andalkylanilinesatanacutelethaltoxicityleveltotheguppy,Poeciliareticulata.
EcotoxicologyandEnvironmentalSafety8:388-394.
LeiferA.
1990(14Dec).
ReviewofSection5testdataforo-phenylenediamine,m-phenyldiamine,andp-phenylenediamine.
Memorandum.
Washington,DC:ExposureAssessmentBranch,ExposureEvaluationDivision(TS-798),OfficeofToxicSubstances,UnitedStatedEnvironmentalProtectionAgency,401MSt,SW,20460-0001.
NendzaMandSeydelJK.
1988a.
Multivariatedataanalysisofvariousbiologicaltestsystemsusedforthequantificationofecotoxiccompounds.
QuantitativeStructure-ActivityRelationships7:165-174.
NendzaMandSeydelJK.
1988b.
Quantitativestructure-activityrelationshipsforecotoxicologicallyrelevantbiotestsystemsandchemicals.
Chemosphere17:1585-1602.
VanLeeuwenCJ,AdemaDMM,andHermensJ.
1990.
Quantitativestructure-activityrelationshipsforfishearlylifestagetoxicity.
AquaticToxicology16:321-334.
VeithGDandBroderiusSJ.
1987.
Structure-toxicityrelationshipsforindustrialchemicalscausingtype(II)narcosissyndrome.
InKaiserKLE(ed),QSARInEnvironmentalToxicology-II,pp.
385-391.
ReidelPublishingCompany.
May,1991;revisedJune201030SubcategoryofAnilines:DianilinesHumanHealthEnvironmentalToxicityDefinition.
APMNmusthavethefollowingminimumstructuralrequirementstobeconsideredamemberofthiscategory:1.
Thestructuremusthaveatleasttwophenylringswithabridgingcarbon,oxygen,nitrogen,orsulfur2.
Eachterminalphenylringmusthaveaprimaryaminogroup(oragroupthatcanbereadilymetabolizedtoaprimaryaminogroup)eithermeta-orpara-tothebridgingatomCompoundswithoneormoreadditionalphenylring(s),withorwithoutringsubstituents,andoneormorebridgingatomsarealsoincludedinthecategory.
MinimumStructureforDianilineCategoryThecompoundsofgreatestconcernarethosehavingX=C,N,orOandn=0or1.
HazardConcerns.
Membersoftheclassareconsideredtobepotentialcarcinogensandmutagensbyanalogyto4,4'-methylendianiline,4,4'-methylenebis(o-toluidine),and4,4'-oxydianiline.
Classmembersarepotentialretinotoxicagentsbyanalogyto4,4'-methylenedianiline,4,4'-oxydianiline,andthediaminodiphenylalkanedrugsandarealsopotentialreproductiveandsystemictoxicantsbyanalogyto4,4'-methylenedianiline.
31GeneralTestingStrategyTheNewChemicalsProgramhasconsideredthefollowingtoxicityteststobethemostappropriatefordianilinesfoundtoposeanunreasonablerisk:I.
ExposuretoHumans-Ratacuteoralretinopathyscreeningstudy(protocoltobeapprovedbyEPA)-Pigmentedrat90-daysubchronictoxicitystudybytheoralroute(HarmonizedTestGuideline870.
3100)orinhalationroute(HarmonizedTestGuideline870.
3465)toincludehistopathologicalexaminationoftheeyesandreproductiveorgans(eyestobeexaminedbybothlightandelectronmicroscopy)-2-yearcarcinogenicitybioassay(HarmonizedTestGuideline870.
4200)inratsandmiceInthe90-daysubchronictoxicitystudy,thecompanymayopttocarryagroupofanimalsateachdoselevelfora90-dayrecoveryperiodtodeterminewhetherpotentialretinopathyisreversible.
Forsomecompoundsinthisclass,short-termmutagenicitytestingmaybeappropriate.
Whenappropriate,specifictestingwillbedeterminedbyEPAmutagenicityassessorsonacasebycasebasisbyreferralto"shortquestion.
"Wherethegeneralpopulationisatasignificantriskfromdrinkingwaterexposure(viasurfacewaterreleases)toPMNchemicalsofthisclass,thefollowingfatetestingmaybeappropriate:-PhototransformationofChemicalsinWater—IndirectPhotolysisScreeningTest(HarmonizedTestGuideline835.
5270)-Aerobicbiodegradabilityaccordingtoeitherofthefollowingtestguidelines:-ReadyBiodegradability(sixmethods;chooseanyone)(HarmonizedTestGuideline835.
3110)-ReadyBiodegradability–CO2inSealedVessels(HeadspaceTest)(HarmonizedTestGuideline835.
3140)(Seeanilinecategorydescriptionfordetails)ResultsoftheabovefatetestsmaymitigateconcernfordrinkingwaterexposuretoPMNofthisclass.
However,fatetestresultsWILLNOTCHANGEAGENCYCONCERNSFOROCCUPATIONALEXPOSUREtoPMNsofthiscategory.
32II.
ReleasetoAquaticEcosystemsTier1.
Becauseoftheaboveboundaryconditions,andtheneedtoassesshumanexposureaswellasenvironmentaltoxicity,ifthereisinsufficientknowledgeaboutthewatersolubilityofthedye,thenitshouldbemeasured(HarmonizedTestGuideline830.
7860).
Thefishanddaphnidacutetoxicitytestsfromtheaquaticbasesetofenvironmentaltoxicitytestswillberecommendedforaquaticexposures.
Theacutetoxicitytestsforfish(HarmonizedTestGuideline850.
1075)anddaphnids(HarmonizedTestGuideline850.
1010)willbedoneusingtheflow-throughmethodwithmeasuredconcentrations,andeffectiveconcentrationswillbebasedon100%activeingredients(AI)andmeanmeasuredconcentrations.
IfthereisnosignificantriskfromthePMNaftertheresultsofthefishanddaphnidacutetoxicitytestshavebeenintegratedintotheriskassessment,thennofurthertestingisrecommended.
However,ifthereisasignificantrisk,thengotoTier2.
Tier2.
PhototransformationofChemicalsinWater—IndirectPhotolysisScreeningTest(HarmonizedTestGuideline835.
5270).
Ift1/22days,gotoTier4.
Tier3a.
Ift1/21000arestilltoxic.
Acutetoxicitymaybelow,i.
e.
,>100mg/L,ifastrongcationicsurfactantcounterionandtheanionicsurfactantformatightionpair.
Testing.
Toaddressecotoxicityconcerns,basesetacuteaquatictoxicitytesting(greenalgae:staticmethod,daphnidandfish:flow-throughmethod,allmeasuredconcentrations).
Tier1.
Theacuteaquaticbasesetofenvironmentaltoxicitytestswillberecommendedforaquaticexposuresandtheterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedlinggrowthtest,theearthwormacutetoxicitytestandthesoilmicrobialcommunitybioassay)willberecommendedforanyterrestrialexposures.
AcutefishtoxicitytestHarmonizedTestGuideline850.
1075AcutedaphnidtoxicitytestHarmonizedTestGuideline850.
1010GreenalgaetoxicitytestHarmonizedTestGuideline850.
540035EarlyseedlinggrowthtestHarmonizedTestGuideline850.
4230EarthwormacutetoxicitytestHarmonizedTestGuideline850.
6200SoilmicrobialcommunitybioassayHarmonizedTestGuideline850.
5100Tier2.
Ifacutetoxicitytestingindicatesasignificantrisk,thenenvironmentalfatetestingintheformofaerobicbiodegradationtestingisrecommendedaccordingtoeitherofthefollowingtestguidelines:-ReadyBiodegradability(sixmethods;chooseanyone)(HarmonizedTestGuideline835.
3110)-ReadyBiodegradability–CO2inSealedVessels(HeadspaceTest)(HarmonizedTestGuideline835.
3140)Tier3.
Inaddition,ifacutetoxicitytestingindicatesasignificantrisk,thenchronicaquatictoxicitytestingwithfishandaquaticinvertebrateswillberecommended.
FishearlylifestagetestHarmonizedTestGuideline850.
1400DaphnidchronictoxicitytestingHarmonizedTestGuideline850.
1300September1988;revisedSeptember,1996;revisedJune201036Category:AzidesEnvironmentalToxicityDefinition.
AzidesareaclassofchemicalsconsistingofbothinorganicandorganiccompoundsandcharacterizedbythefunctionalgroupN=N=N.
Substitutionsmaybeeithermetalsororganiccompounds,e.
g.
,aceticacidandbenzene.
Sofar,onlymonomericaromaticazidecompoundshavebeensubmittedasPMNs.
Noaliphaticazides,e.
g.
,alkylazides,havebeensubmittedasPMNs.
Aliphaticazidesmaybetooexplosivetoisolate,however,diazidoaceticacidesterisknowntoexistandhasbeentestedinrats.
HazardConcerns.
Itisassumedthatazideshavetobeabsorbedtobetoxic,therefore,azideswithMW>1000willbeexcludedfromthiscategory.
Acutetoxicityformonomericazidesisassumedtobecorrelatedandlimitedbytheoctanol/waterpartitioncoefficient(Kow).
AbovealogKowvalueof>5.
0,azidesareassumedtoshownoeffectsatsaturationduring96-hourexposurestofish.
OrganicazideswhicharesolidsatroomtemperaturemayshownotoxicityatsaturationatlowerKowvaluesdependingontheirmeltingpointand/ortheirwatersolubility.
Forexample,fororganicazides,thehigherthemeltingpointatagivenKow,thegreaterthelikelihoodthatnotoxicitywillbeoccuratsaturation.
Forsolids,noeffectsatsaturationhastobedeterminedonacase-by-casebasis.
TheupperKowlimitsforchronictoxicityareapproximatelylogKow=8.
ThetoxicityforinorganicazideshastobedeterminedbyintegratingthetoxicityofNaazidewiththetoxicityofanyotherinorganicelement,e.
g.
,Pb,withaMWadjustmentfordifferencesintoxicitybetweenNaazideandtheotherinorganicelement.
Naazide[26628-22-8]hasbeentestedbytheUSEPAERL-Duluth:fatheadminnow96-hLC50=5.
46mg/Lbasedonaflow-throughmethodwithnominalconcentrations.
TheSARfororganicazidesisbasedon(1)sodiumazidevalue,(2)acalculatedlogKow,and(3)noacuteeffectstofishatsaturationassumedtooccuratalogKow>5.
0whichisequivalenttoalogfish96-hLC50=-2.
5inmillimolesperliter.
EnvironmentalFate:Naazideisknowntohydrolyzeinwatertoformhydrazoicacid(orhydrogenazide,NH3,[7782-79-8],MW43,M12,4815).
HydrogenazideisextremelyexplosiveaccordingtoMerck.
Inaddition,azidescanbetransformedtonitrenesbyuvlight.
Boundaries:MW100mg/L)tohightoxicity(i.
e.
,1000arenoexpectedtoshowtoxicityatsaturation.
Acutetoxicityforbenzotriazoleswhichareliquidsatroomtemperatureisknowntobelimitedbytheoctanol/waterpartitioncoefficient(Kow).
AbovealogKowvalueof5.
0,benzotriazolestypicallyshownoeffectsatsaturationduring96-hexposures(Clements1988).
BenzotriazoleswhicharesolidsatroomtemperaturemayshownotoxicityatsaturationatlowerKowvaluesdependingonthemeltingpoint,i.
e.
,thehigherthemeltingpointatagivenKow,thegreaterthelikelihoodthatnoacutetoxicitywillbeobservedatsaturation.
Forsolids,theno-effects-at-saturationpointforacutetoxicityhastobedeterminedonacase-by-casebasis.
ThelogKowlimitforchronictoxicityissetat8forliquidbenzotriazoles.
Forsolids,chronictoxicitytestingwilldeterminetheKowlimit.
Therefore,acutetoxicityisexpectedwhenlogKow≤5.
0andMW5.
0andMW5.
0and1000,noeffectsareexpectedatsaturationbecauseitisassumedthatbenzotriazoleshavetobeabsorbedtobetoxic.
Aerobicbiodegradationisexpectedtobethedominantrouteoftransformationintheenvironment.
40GeneralTestingStrategy.
I.
ReleasetoAquaticEcosystems:Tier1.
Theaquaticbasesetofenvironmentaltoxicitytestswillberecommendedforaquaticexposures.
Theacutetoxicitytestsforfish(HarmonizedTestGuideline850.
1075)anddaphnids(HarmonizedTestGuideline850.
1010)willbedoneusingtheflow-throughmethodwithmeasuredconcentrations;effectiveconcentrationswillbebasedon100%activeingredients(AI)andmeanmeasuredconcentrations;thehighesttreatmentconcentrationonanominal-basisshouldnotexceedtheaqueoussolubilitylimitofthetestedchemical;andsolventcanbeusedtoassistthechemicaltoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthechemicalbeyonditsaqueoussolubilitylimit.
Thealgaltoxicitytest(HarmonizedTestGuideline850.
5400)shouldbedonewiththestaticmethod;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsat24,48,72,and96hours;testmediumwithatleast0.
300mg/LEDTAasafinalconcentration;thehighesttreatmentconcentrationonanominal-basisshouldnotexceedtheaqueoussolubilitylimitofthechemical;andsolventcanbeusedtoassistthechemicaltoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthechemicalbeyonditsaqueoussolubilitylimit.
Ifthereisnosignificantriskfromthebenzotriazoleaftertheresultsoftheenvironmentalbasesethavebeenintegratedintotheriskassessment,thennofurthertestingisrecommended.
However,ifthereisasignificantrisk,thengotoTier2.
Tier2.
Aerobicbiodegradabilityaccordingtoeitherofthefollowingtestguidelines:-ReadyBiodegradability(sixmethods;chooseanyone)(HarmonizedTestGuideline835.
3110)-ReadyBiodegradability–CO2inSealedVessels(HeadspaceTest)(HarmonizedTestGuideline835.
3140)Ifthereisnosignificantriskfromthebenzotriazoleaftertheresultsoftheaerobicbiodegradationtestinghavebeenintegratedintotheriskassessment,thennofurthertestingisrecommended.
However,ifthereisasignificantrisk,thengotoTier3.
Tier3.
Fishchronictoxicitytesting,i.
e.
,fishearlylifestage(ELS)toxicitytesting(HarmonizedTestGuideline850.
1400),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,21,and28;thehighesttreatmentconcentrationonanominal-basisshouldnotexceedtheaqueoussolubilitylimitforthechemical;solventcanbeusedtoassistthechemicaltoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthechemicalbeyonditsaqueoussolubilitylimit;andthe7-dELSstagetoxicitytestcannotbesubstitutedfor41the28-dELStoxicitytestbecauseVanLeeuwenetal(1990)havedemonstratedthatthe7-dELStoxicitytestunderestimatedthechronictoxicityofanilinesmeasuredbythe28-dELStoxicitytestby>5.
3timeswhentheNOECswerecompared(seeTableVIIinVanLeeuwen).
Bothanilinesandbenzotriazoleswith-NHaremoretoxicthanpredictedbasedonnarcosisalone,i.
e.
,bothbenzotriazolesandanilineshaveexcesstoxicityduetoamorespecificmode(s)oftoxicaction.
Asevendayexposuremaynotallowenoughtimeforthisexcesstoxicitytobeexpressedeitherbecauseofnotenoughexposureand/ornotenoughtimeformetabolicactivation.
Daphnidchronictoxicitytesting(HarmonizedTestGuideline850.
1300),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,and21;thehighesttreatmentconcentrationonanominal-basisshouldnotexceedtheaqueoussolubilitylimitofthechemical;solventcanbeusedtoassistthechemicaltoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthechemicalaboveitsaqueoussolubilitylimit;andthe7-ddaphnidchronictoxicitytestcannotbesubstitutedforthe21-dtoxicitytest(VanLeeuwenetal1990).
II.
ReleasetoTerrestrialEcosystems:Theterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedlinggrowthtest[HarmonizedTestGuideline850.
4230],theearthwormtoxicitytest[HarmonizedTestGuideline850.
6200],theavianacuteoraltoxicitytest[HarmonizedTestGuideline850.
2100],andthesoilmicrobialcommunitybioassay[HarmonizedTestGuideline850.
5100])willberecommendedforterrestrialexposures.
Chronictoxicitytestingforterrestrialorganismsinclude:theplantwholelifecycletest(HarmonizedTestGuideline850.
4150),theplantuptaketest(HarmonizedTestGuideline850.
4800),theavianreproductivetoxicitytest(HarmonizedTestGuideline850.
2300),andthesoilmicrobialcommunitybioassay(HarmonizedTestGuideline850.
5100).
ReferencesClements,RG(editor).
1988.
Estimatingtoxicityofindustrialchemicalstoaquaticorganismsusingstructure-activityrelationships.
EPA-560-6-88-001.
Washington,DC:EnvironmentalEffectsBranch,HealthandEnvironmentalReviewDivision,OfficeofToxicSubstances(TS-796),UnitedStatesEnvironmentalProtectionAgency.
AvailablefromtheNationalTechnicalInformationService,Springfield,VA22161,PB89-117592.
VanLeeuwenCJ,AdemaDMM,andHermensJ.
1990.
Quantitativestructure-activityrelationshipsforfishearlylifestagetoxicity.
AquaticToxicology16:321-334.
March,1992;revisedJune201042Category:Benzotriazole-hinderedphenolsHumanHealthEnvironmentalToxicity(seePhenols)Definition.
Anymolecularstructurecontainingthefollowingsubstructureisconsideredtobeamemberofthecategory.
ThepredominantuseofmembersofthiscategoryisasaUVlightstabilizerincoatingorplasticformulations.
Note:Healtheffectsmayvarydependingonthenatureoftheringsubstituents.
HazardConcerns.
I.
HealthSystemictoxicitybasedon8(e)andPMNdataonanalogues.
Thesedataaregenerallyconsistentacrosscompounds,withthefollowingendpointsoccurringinsubacute,subchronic,andchronicoralfeedingstudiesinratsanddogsinwhichdosesrangedfrom5to15,000ppm.
Increasedorganweights(liverandkidney,withassociatedhistopathologyathigherdoses);hematologicaleffects(decreasedhemoglobin,packedcellvolume,anderythrocytes);andimmunesystemeffects(weightchangesinthymus,spleen,lymphnodes;decreasedleukocytes).
Generally,treatment-relatedeffectsaredose-related,increasinginfrequencyandseveritywithincreasingdose.
Malesappeartobemoresensitivethanfemales,andsimilartoxiceffectsoccurinbothratsanddogs.
ThelowestavailableNOAELforsystemiceffects,froma90-dayratstudy,is5ppm,or0.
25mg/kg/day.
Reproductivetoxicity-Concernisalsobasedon8(e)andPMNdataonanalogues.
Aswithsystemictoxiciy,thedataaregenerallyconsistentwiththefollowingendpointsoccurringinsubacuteandsubchronicoralfeedingstudiesinratsanddogsinwhichdosesrangedfrom5to4315,000ppm.
Atrophyoftheseminalvesicles,significantreductioninabsoluteandrelativetestesweight,significantreductioninabsoluteandrelativeprostateweight,andabnormalspermatogenesis.
Asubchronicdogstudyalsoprovidedevidenceoffemalereproductivetoxicity.
Generally,treatment-relatedeffectsaredose-related,increasinginbothfrequencyandseveritywithincreasingdose.
Malesappeartobemoresensitivethanfemales,andsimilartoxiceffectsoccurinbothratsanddogs.
ThelowestNOAELforreproductivetoxicity,froma90-daydogstudy,is15mg/kg/day.
Dermalsensitization-Dermalsensitizationtestdatawerepositivein3/4compoundstested.
Twoofthecompoundsshowedstrongsensitizingpotentialbasedonresultsobtainedfrommaximizationtestsinwhich70%and90%ofthetreatedguineapigsbecamesensitized,respectively.
II.
EnvironmentalTheenvironmentalconcernsforthesubstancesdescribedinthiscategoryhavealreadybeendescribedinthePhenolcategory.
Boundaries.
Notenoughisknownaboutthestructure-activityrelationshipsofthesecompoundstosetanyboundariesonmembersofthecategory;compoundswithboth"small"and"large"substituentshaveshowneffects,andtheeffectsaregenerallyconsistentfromcompoundtocompound.
GeneralTestingStrategyI.
HealthSystemicToxicityandReproductiveToxicity.
A90-daygavagestudyinratswithspecialattentiontohematology;weightandhistopathologyoflymphoidorgans(spleen,thymus,andbonemarrow);cellularityofthebonemarrow,thymus,andspleen;andhistopathologyoftheliver,kidney,heart,andallendocrineglandsforwhichweightchangesareobserved.
Particularattentionshouldbedirectedtowardachievingsatisfactoryqualityfromfixationandembeddingofthetestes,followingtherecommendationsofRusselletal.
[RussellLD,EttlinRA,SinhaHikimAP,CleggED.
1990.
Histologicalandhistopathologicalevaluationofthetestis.
CacheRiverPress,Clearwater,FL].
Agavagestudy,asopposedtoanoralfeedingstudy,isrecommendedbecausedecreasedbodyweightgain,finalbodyweight,and/orfoodconsumptionhavebeenreportedinsomeoralfeedingstudieswithanalogues.
44Ifimmunopathologyandhematologyinthe90-daystudysupporttheconcernforadverseeffectsofthePMNsubstancesontheimmunesystem,thenafurtherbatteryoftests,suchastheNTP'sImmunotoxicologyTierIIScreeningPanel,willberecommended.
DermalSensitization.
BecausedermalsensitizationisnotroutinelypursuedunderTSCA5(e)asaregulatoryendpoint,testingisnotrecommended.
AlettermaybesenttothePMNsubmitterexpressingtheAgency'sbeliefthatthecompoundsarelikelytobedermalsensitizersandthatprotectivemeasuresshouldbetakenforworkers.
II.
EnvironmentalToxicityIfexposuretotheaquaticenvironmentdemonstratesapotentialrisk,testingofthesubstancesdescribedinthiscategoryisthesameasthatprescribedforthePhenolscategory.
June,1993.
45Category:BoronCompoundsHumanHealthEnvironmentalToxicityDefinition.
Thiscategoryincludesborates,organoborates,borateesters,boronhydrides,boranes,andboroxines.
I.
HumanHealthHazardConcerns.
Reproductivetoxicity(males/females),bloodtoxicity,andneurotoxicity.
TheAgencyhasanoralRfDforboronof0.
09mg/kg/day(uncertaintyfactor100)basedonthefindingoftesticularatrophyandspermatogenicarrestindogsina2-yrfeedingstudy(WeirandFisher1972,assummarizedinIRIS1995).
[Alltoxicityinformationpresentedherearesummarizedinanassessmentofvariousaqueouscleanerchemicalspreparedin1990fortheOfficeofAirandRadiation.
ReproductivetoxicityinformationisalsosummarizedinIRIS1995.
]ReproductiveToxicity.
Themostsignificanteffectseeninanimalsisreproductivetoxicity(i.
e.
,sterilityinmalesandfemales,andtesticularatrophyinmales).
Athree-generationreproductivestudyinratsdemonstratedsterilityinmales(lackofspermatozoainatrophiedtestes)andfemales(decreasedovulation)afterexposureto58.
5mgboron/kginthediet.
NOAEL(rats)17.
5mgboron/kg.
Sterilitywasalsofoundinmales(at50or100mgboron/kg)inaserialmatingadjuncttoa60-dayfeedingstudy;NOAEL(rats)25mgboron/kg.
Datafromoralsubchronicandchronicstudiesinrats,dogs,andmicealsoprovideevidencethatboronproducesadverseeffectsonthemalereproductivesystem.
Astatisticallysignificantreductioninrelativeandabsolutetestesweightswasseenina2-yranda90-daydietarystudyinmaleratsat58.
5and26.
3mgboron/kg,respectively.
NOAEL=s(rats)17.
5and8.
8mgboron/kg,respectively.
Inmalerats,dietaryexposureto50mg/kgboronresultedinasignificantreductioninfertility,asignificantreductioninepididymalweight,andareductioninspermnumberafter30daysoftreatment.
Asignificantreductionintesticularweightandfurtherreductioninspermoccurredafter60daysoftreatment.
NOAEL(rats)25mgboron/kg.
Similarresultswereobservedinseveraldrinkingwaterstudiesinrats.
Inmaledogs,dietaryexposureto29.
4mgboron/kgfor2yrresultedinseveretesticularatrophyandspermatogenicarrest.
NOAEL(dogs)8.
8mgboron/kg.
Inmaleandfemaledogs,dietaryexposureto43.
8and4.
4mgboron/kgfor90daysdidnotaffectthefemalereproductivesystem,butproduceddecreasedtestesweights(statisticallysignificantat43.
8mgboron/kg).
NOAEL(dogs)0.
4mgboron/kg.
Inmalemice,dietaryexposureto131mgboron/kgfor103wk(onlydosetested)causedanincreasedincidenceoftesticularatrophyandinterstitialhyperplasia.
BloodToxicity.
Inachronicfeedingstudyinrats,packedcellvolumeandhemoglobinlevelsweresignificantlydecreasedinmalesandfemalesat58.
5mgboron/kg.
NOAEL(rats)17.
5mgboron/kg.
Inasubchronicdrinkingwaterstudyinrats,asignificantdecreaseinplasma46triglyceridelevelswasnotedat23.
7and47.
4mgboron/kg(onlydosestested).
LOAEL(rats)23.
7mgboron/kg.
Inasubchronicfeedingstudyindogs,43.
8mgboron/kgbutnot4.
4or0.
4mgboron/kgproduceddecreasedpackedcellvolumesandhemoglobinlevels.
NOAEL(dogs)4.
4mgboron/kg.
Inasubchronicfeedingstudyinmice,minimaltomildextramedullaryhematopoiesisofthespleenwasobservedinalldosedgroups(ca.
34,68,136,272,or544mgboron/kg).
LOAEL(mice)34mgboron/kg.
Thereisalsoacasestudyinwhichaninfantexposedto43mgboron/kg/dayfor12weeksdevelopedanemia.
Neurotoxicity.
Ingestionofboraxbyhumaninfantsresultsinneurotoxicity.
Casereportsofnineinfantswhowereexposedbysuckingpacifiersdippedinaborax-honeymixturedocumentsimilarfindingsofneurologicalsymptoms(notspecified)andseizures.
Forseveninfants,dosesarereportedas2to3gborax/wkfor4to10wk(ca.
4to16mgboron/kg/day).
Serumboronlevelsmeasuredinthreeoftheseveninfantswereelevated.
Fortheothertwoinfants,dosesarereportedas125mgborax/kgovera12-wkperiodand9gboraxovera5-wkperiod(ca.
43and8mgboron/kg/day,respectively).
Theeffectsappeartobereversibleuponcessationofexposure.
Neurotoxicitytestingisnotrecommendedbecauseanimalstudiesdonotappeartobepredictiveofthiseffect.
Boundaries.
Theboundariesofthiscategoryarenotyetwelldefinedforhealtheffects.
Allofthetoxicitydataareonboricacidorborax.
Amolecularweightcutoffof1,000isproposed,butthereisnoinformationfromavailabletoxicitydataonaproperwatersolubilitycutoff.
GeneralTestingStrategy.
TheOECDreproductivetoxicityscreen(OECD421)withspecialadditionalattentiontohematology.
Ifthisscreenispositiveforreproductivetoxicity,areproductivefertilitystudyinratsaccordingtoHarmonizedTestGuideline870.
3800isrecommended.
Incasesinwhichexposuresareexclusivelydermal,adermalabsorptionstudy(eitherinvivoorinvitro)couldbeconductedtorefinethedermalriskassessment.
Iftheinvivostudyisselected,thetestmaterialshouldnotbecorrosive.
Ifthereissomeuncertaintyastothecorrosivityoftheneattestmaterial,adermalirritationstudyshouldbeundertakenfirst.
Iftheneatmaterialiscorrosive,dilutiontoanoncorrosiveconcentrationwithavehiclesuchasacetoneorthealcoholusedtomaketheesterisrecommended.
II.
EnvironmentalToxicityMostofthetoxicityinformationforboroncompoundsisforboricacidandsodiumtetraborate.
Theseboroncompoundsshowlowacutetoxicitytowardsfish(250.
0mg/Lasameanacutetoxicityvalue)anddaphnids(70.
0mg/Lasameanacutetoxicityvalue),butmoderatetoxicitytowardsgreenalgae(20.
0mg/LasameanEC50value).
However,thesecompoundsexhibitlargeacutetochronicratios(ACR)towardsfish(125asameanACR)andthedifferencebetweentheEC50valueandthechronicvalue(ChV)ingreenalgaeislarge(about117asameandifference).
ThemeanACRfordaphnidsis8.
ThemeanChVsforfish,daphnids,and47greenalgaeare2.
0mg/L,9.
0mg/L,and0.
170mg/L,respectively.
Greenalgaeappearstobethemostsensitivegroupofspecieswithrespecttoboricacidandsodiumtetraborate.
Thereareonlyscreeningdataforfishforborateesters,specifically,onlyfortributylborate.
Thesescreeningdatashowednoeffectsat10.
0mg/Lfor24hourstowardsthreespeciesoffish.
However,thepurityofthetributylboratewasnotgiven.
Theonlydataforboranesarefortert-butylamineborane.
Thesedataare:fish96-hLC50=13.
0mg/L,daphnid96-hLC50=0.
700mg/L,greenalgal7-dEC50=3.
0mg/L,andalgalChV=0.
300mg/L.
Theonlytoxicityinformationforboronhydridesareformammals.
Thesedatashowthatallboronhydridesarehighlytoxicandmoretoxicthanborates.
Themajorenvironmentalhazardconcernsforthiscategoryareforchronictoxicitytowardsfishandtoxicitytowardsgreenalgae.
SincetherearenoSARsforboroncompounds,hazardprofilesaredevelopedusingthenearestanalog(s).
Boundaries.
Boroncompoundsmusthavewatersolubilitiesequaltoorgreaterthan1.
0μg/L(ppb)andmolecularweightsgenerallyneedtobenearorbelow1000.
EnvironmentalFate.
Certainboratesaresubjecttohydrolysisunderenvironmentallyrealisticconditions.
GeneralTestingStrategy.
Thefollowingtestingstrategywilladdressaquatictoxicityconcerns:I.
ReleasetoAquaticEcosystems:Tier1a.
Ifthehydrolysisrateforanymemberofthisclassispredictedtobeslow(t1/2>2days)orifhydrolysiswillresultinoneormoreproductswhichareexpectedtobejustastoxicastheparentborate,thenthefishanddaphnidacutetoxicitytestsfromtheaquaticbasesetofenvironmentaltoxicitytestswillberecommendedforaquaticexposures.
Theacutetoxicitytestsforfish(HarmonizedTestGuideline850.
1075)anddaphnids(HarmonizedTestGuideline850.
1010)willbedoneusingtheflow-throughmethodwithmeasuredconcentrations;effectiveconcentrationswillbebasedon100%activeingredients(AI)andmeanmeasuredconcentrations;measuredTOCofdilutionwaterinthecontrol;thehighesttreatmentconcentrationonanominal-basisshouldequaltheaqueoussolubilitylimit;andsolventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthePMNbeyonditsaqueoussolubilitylimit.
48Thealgaltoxicitytesting(HarmonizedTestGuideline850.
5400),shouldbedonewithstaticmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsat24,48,72,and96hours;testmediumwithatleast0.
300mg/LEDTAasafinalconcentration;thehighesttreatmentconcentrationonanominal-basisequaltotheaqueoussolubilitylimit;andsolventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthePMNbeyonditsaqueoussolubilitylimit.
IfthereisnosignificantriskfromthePMNaftertheresultsoftheenvironmentalbasesetoftestshavebeenintegratedintotheriskassessment,thennofurthertestingisrecommended.
However,ifthereisasignificantrisk,thengotoTier2.
Tier1b.
Ifthehydrolysisrateforanymemberofthisclassispredictedtoberapid(t1/22days,thentheenvironmentalbasesetwillberecommended.
IfthereisnosignificantriskfromthePMNaftertheresultsoftheenvironmentalbasesetoftestshavebeenintegratedintotheriskassessment,thennofurthertestingisrecommended.
However,ifthereisasignificantrisk,thengotoTier2.
Tier2.
Fishchronictoxicitytesting,i.
e.
,fishearlylifestage(ELS)toxicitytesting(HarmonizedTestGuideline850.
1400),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;andstatisticalanalysisofeffectiveconcentrationsatdays7,14,21,and28.
Daphnidchronictoxicitytesting(HarmonizedTestGuideline850.
1300),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,and21.
Aerobicbiodegradabilityaccordingtoeitherofthefollowingtestguidelines:-ReadyBiodegradability(sixmethods;chooseanyone)(HarmonizedTestGuideline835.
3110)-ReadyBiodegradability–CO2inSealedVessels(HeadspaceTest)(HarmonizedTestGuideline835.
3140)49II.
ReleasetoTerrestrialEcosystems:Theterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedlinggrowthtest[HarmonizedTestGuideline850.
4230],theearthwormtoxicitytest[HarmonizedTestGuideline850.
6200]andthesoilmicrobialcommunitybioassay[HarmonizedTestGuideline850.
5100])willberecommendedforterrestrialexposures.
Chronictoxicitytestingforterrestrialorganismsinclude:theplantwholelifecycletest(HarmonizedTestGuideline850.
4150),theplantuptaketest(HarmonizedTestGuideline850.
4800),andthesoilmicrobialcommunitybioassay(HarmonizedTestGuideline850.
5100).
July,1991;revisedAugust,1997;revisedJune2010.
50Category:CationicDyesEnvironmentalToxicityDefinition.
Anydyebearingoneormorenetpermanentpositivechargesisconsideredtobeamemberofthisclass.
A"typical"newchemicalofconcernisawatersolublemonoazodyewithasingledelocalizedpositivecharge.
HazardConcerns.
Watersolublecationicdyesaretoxictofish,daphnids,andalgae.
Poorlysolubledyestendtobetoxiconlytoalgae.
Norelationshipbetweenstructureandactivityhasbeenfoundforcationicdyes.
Boundaries.
Therearenoestablishedboundariesforcationicdyes.
Thereisnomolecularweightthreshold-onedyewithamolecularweightof3,000andbearingfourpositivechargeswasfoundtobetoxictofish.
Testing.
Toaddressenvironmentalconcerns,thebasesetofenvironmentaltoxicitytests(i.
e.
,thefishacutetoxicitytest,thedaphnidacutetoxicitytestandthegreenalgaltoxicitytest)isrecommended.
Thesetestsaretobedoneusingthestaticmethodandnominalconcentrations.
Inaddition,twoadditionalfishacutetoxicitytestsarerecommendedwithknownamountsofhumicacidaddedtothedilutionwater.
Thistestingisnecessarytomeasurethemitigatingeffectsofdissolvedorganiccarbon(DOC)onthetoxicityofthecationicdye.
Onetestwillbedonewith20mghumicacid/Lindilutionandthesecondtestwillhave10mghumicacid/Lindilutionwater.
Totalorganiccarbon(TOC)willbemeasuredthreetimesineachtestandtheTOCofthecleandilutionwaterwillalsobemeasuredatthebeginningofthetest.
IfDOCmitigatestheenvironmentalrisktowatercolumnorganisms,thentestingusingnaturalsedimentsandorganismsknowntoingestsedimentmayberecommended.
March,199051Category:Cationic(quaternaryammonium)surfactantsEnvironmentalToxicityDefinition.
Anycationicsurfactantisamemberofthiscategory,forexample:CH3|CH3-N+-(CH2-)15-CH3Br-|CH3HazardConcerns.
Cationicsurfactantsarebiocidaltoawidearrayofspeciesintheenvironment.
Toxicityincreasesexponentiallywithincreasingcarbonchainlengthupto16carbonsandthendecreaseswithincreasingchainlength.
QSAR(quantitativestructure-activityrelationships)havebeendevelopedtopredicttoxicity.
Boundaries.
Littletoxicityisobservedwhenthecarbonchainlengthexceeds22.
Tightionpairswillnotbesignificantlytoxic.
GeneralTestingStrategy.
Toaddressecotoxicityconcerns,basesetaquatictoxicitytestinginalgae,daphnids,andfish,plushumicacidtestinginfish(20mg/Land10mg/lhumicacidindilutionwater)isrecommended.
Alltestingusesstaticmethod,nominalconcentrations.
March,199052Category:CobaltEnvironmentalToxicityThiscategoryincludesbutisnotlimitedtoinorganicandorganiccompoundsofcobalt(Co),e.
g.
,solublecobaltcations,cobaltesters,andorganocobaltcompounds.
HazardConcerns.
Mostofthetoxicityinformationforinorganiccobaltcompoundsisforthesolublesalts:chloride,nitrate,andsulfate.
TherearenoknowndatafororganoCocompounds,organicacidchelateswithCo,orforCoesters.
ThebesttoxicitydataforCoarelistedbelowwithpredicted(P)andmeasured(M)toxicityvaluesindicatedandeffectiveconcentrationsinmgCo/L(ppm):fish(FHM)96-hLC50=48.
0MS,,H130,Cl(Ref.
E86)daphnid48-hLC50=1.
32MCl(Ref.
B&S74)daphnid48-hLC50=1.
11MS,N,H45,Cl(Ref.
B&C72)WQ2Eacutevalue=0.
195P(Ref.
S96)greenalgal7-dEC50=0.
160MS,NO3,Cl,SO4(Ref.
St81)RTELS28-dLC50=0.
470MSR12h,,H104,NO3(Ref.
B78)fishChEC20=0.
810M(Ref.
S96)fishChronicValue(ChV)=0.
290MS96fishACR=170.
0PdaphnidChEC20=0.
004M(Ref.
S96)daphnidChV=0.
010MS,N,H45,Cl(Ref.
B&C72)daphnidChV=0.
005M(Ref.
S96)daphnidACR=110.
0P(Ref.
B&C72)WQ2Echronicvalue=0.
003P(Ref.
S96)algalChV=0.
040PEC50)ChV=4Abbreviations:ACR=acute-to-chronicratio;Ch=chronic;ChV=chronicvalue;CC=concernconcentration;ELS=earlylifestage;FHM=fatheadminnow;H=hardnessasCaCO3;N=nominalconcentrations;=methodunknown;RT=rainbowtrout;S=staticmethod;53SR12h=staticrenewalmethodwithrenewalsevery12hours;andWQ=waterqualityvalue.
PredictionswerebasedonSARsforinorganicCocompounds;pH7;hardness1000havenoeffectsatsaturationtofishintheacutetoxicitytest.
Therefore,compoundswithMWn's>1000willbeexcludedfromthiscategoryregardlessofwatersolubility.
IntheNEATstate,diazoniumsaresolids,i.
e.
,salts,andaremostaresolubleinaqueousmedia.
Acutetoxicityfordiazoniumsisassumedtobelimitedbytheoctanol/waterpartitioncoefficient(Kow)andMW.
AbovealogKowvalueof8.
0and/orMW>1000,diazoniumsarenotexpectedtobetoxicatsaturationduring96-hexposures.
DiazoniumsareexpectedtobesimilartoanilineswithrespecttotheirKowcutoffvalueforacutetoxicity.
TheacutetoxicityofanilinesdiminishesataboutalogKow=7.
0(VeithandBroderius1987).
TherearenoknownKowlimitsforchronictoxicityatthistime,butitmaynotbemuchabovealogKow=10.
0fordiazoniums.
HazardConcerns.
OnlytheacutetoxicitytofishfordiazoniumshasbeendeterminedbyEPAthroughSARAnalysisusingECOSAR–ahazardestimationtoolthatuseschemicalstructuredescriptorstoestimatetheacuteandchronictoxicityofasubstancetoaquaticorganisms.
[LinkforECOSAR:http://www.
epa.
gov/opptintr/newchems/tools/21ecosar.
htm].
Daphnidsareassumedtohavesimilarsensitivitytofish,butgreenalgaeareexpectedtobemoresensitivebasedontheuseofdiazoniumsasfungicides.
EnvironmentalFate:Diazoniumfungicides,e.
g.
,Fenaminosulf,aresensitivetolightbutarestabilizedwithNasulphite.
Fenaminosulfisstableinalkalinemedia.
Diazoniumsarealsousedinphotography,e.
g.
,diazoreproductionpaperandfilm.
Therefore,diazoniumsareexpectedtobesubjecttorapiddirectandindirectphotolysisunderenvironmentallyrealisticconditions.
Diazoniumsarealsoexpectedtoslowlyhydrolyzetophenols.
Boundaries.
:Therearenoknownlowerboundaries.
TheupperboundarieswillbebasedonKowandMW.
AcutetoxicityexpectedwithlogKow2days,gotoTier4.
Tier3a.
Ift1/25.
3timeswhentheNOECswerecompared(seeTableVIIinVanLeeuwen).
Daphnidchronictoxicitytesting(HarmonizedTestGuideline850.
1300),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,and21;measuredTOCofdilutionwaterinthecontrol;thehighesttreatmentconcentrationonanominal-basisshouldbesetattheaqueoussolubilitylimit;solventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthePMNbeyonditsaqueoussolubilitylimit;andthe7-ddaphnidchronictoxicitytestcannotbesubstitutedforthe21-dtoxicitytestbecauseVanLeeuwenetal(1990)havedemonstratedthatthefish7-dELStoxicitytestunderestimatedthechronictoxicityofanilinesmeasuredbythefish28-dELStoxicitytestby>5.
3timeswhentheNOECswerecompared(seeTableVIIinVanLeeuwen).
Aerobicbiodegradabilityaccordingtoeitherofthefollowingtestguidelines:-ReadyBiodegradability(sixmethods;chooseanyone)(HarmonizedTestGuideline835.
3110)-ReadyBiodegradability–CO2inSealedVessels(HeadspaceTest)(HarmonizedTestGuideline835.
3140)59II.
ReleasetoTerrestrialEcosystems:Theterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedlinggrowthtest[HarmonizedTestGuideline850.
4230],theearthwormtoxicitytest[HarmonizedTestGuideline850.
6200],theavianacuteoraltoxicitytest[HarmonizedTestGuideline850.
2100],andthesoilmicrobialcommunitybioassay[HarmonizedTestGuideline850.
5100])willberecommendedforterrestrialexposures.
Chronictoxicitytestingforterrestrialorganismsinclude:theplantwholelifecycletest(HarmonizedTestGuideline850.
4150),theplantuptaketest(HarmonizedTestGuideline850.
4800),avianreproductiontoxicitytest(HarmonizedTestGuideline850.
2300),andthesoilmicrobialcommunitybioassay(HarmonizedTestGuideline850.
5100).
References.
VanLeeuwenCJ,AdemaDMM,andHermensJ.
1990.
Quantitativestructure-activityrelationshipsforfishearlylifestagetoxicity.
AquaticToxicology16:321-334.
VeithGDandBroderiusSJ.
1987.
Structure-toxicityrelationshipsforindustrialchemicalscausingtype(II)narcosissyndrome.
InKaiserKLE(ed),QSARInEnvironmentalToxicology-II,pp.
385-391.
ReidelPublishingCompany.
November,1991;revisedJune201060Category:Dichlorobenzidine-basedPigmentsHumanHealthEnvironmentalToxicityOtherNames:DiarylidePigments,DCBPigments,PigmentYellowsDefinition:Anydiazopigmentcontainingthesubstructure,dichlorobenzidine,andcoupledwithacetoacetanilide.
HazardConcerns.
Thereareoncogenicity/mutagenicityconcernsfordichlorobenzidine-basedpigmentsbasedonthepotentialreleaseof3,3'-dichlorobenzidineandonthepresenceofresidual(unbound)dichlorobenzidine.
DCBisaknownanimalcarcinogenandasuspecthumancarcinogen.
Inaddition,DCBisknowntobioconcentrateinthetissuesofaquaticorganisms.
Boundaries.
Concernfortheintactpigmentisrestrictedtousesattemperaturesexceeding200oC.
DatasubmittedtotheAgencyunderTSCAsection8(e)showthatDCBpigmentsbreakdowntoreleaseDCBasavaporfromcoloredpolymerswhenheatedtoextrusiontemperatures(>200oC)and,fromsheetmetalcoatingsduringcuring.
Thoughlittleinformationexistsonthebiodegradationofpigmentsinsediments,dataonotherlowwatersolublecolorants,indicatethatbiodegradationmayoccuroveraperiodofmonths,possiblyresultinginthereleaseofDCB.
GeneralTestingStrategy.
EPA'sNewChemicalsProgramconsidersthefollowingteststobeappropriatetoaddressthepotentialforDCBpigmentstoposeasignificantrisktohealthortheenvironment:1.
MonitoringdatatodetectthepresenceofDCBunderactualconditionsofuse;temperature,dwelltime,%pigmentinpolymerorcoating,andtypeofpolymerorcoating.
2.
Iftherearereleasestowater,ananaerobicbiodegradationassay.
References:61AppletonHT,SikkaHC.
1980.
Accumulation,elimination,andmetabolismof3,3'-dichlorobenzidineinthebluegillsunfish.
EnvironSciTechnol14:50-54.
PlissGB.
1963.
Onsomeregularrelationshipbetweencarcinogenicityofaminobiphenylderivativesandthestructureofthesubstance.
ActaUnioIntCancrum19:499-501.
StulaEF,ShermanH,ReinhardtCF.
1975.
Experimentalneoplasiainratsfromoraladministrationof3,3'-dichlorobenzidine,4,4'-methylene-bis(2-chloroaniline),and4,4'-methylene-bis(2-methylaniline).
ToxicolApplPharmacol32:159-176.
StulaEF,BarnesJR,ShermanH.
1978.
Liverandurinarybladdertumorsindogsfrom3,3-dichlorobenzidine.
1978.
JEnvironPatholToxicol1:475-490.
TSCASection8(e)Documents:8EHQ-0490-0962INIT8EHQ-0590-0962SUPPL8EHQ-0690-0962FLWP8EHQ-0790-0962SUPPL8EHQ-0890-0962SUPPLMarch,199462Category:DithiocarbamatesEnvironmentalToxicityDefinition.
ThiscategoryincludesN,N-dialkyldithiocarbamates(DDC);ethylenebisdithiocarbamates(BDC);andtheirmetalsaltswhichincludebutarenotlimitedtozinc,sodium,iron,manganese,copper,lead,mercury,silverandselenium.
ThealkylgroupsoftheDDCsgenerallyinclude,methylthroughbutyl,butmaybelarger.
ThiscategoryalsoincludesthedegradationproductsofDDCandBDCwhichmayincludedisulfidemoieties,sulfidemoieties,thioureamoieties,ureamoieties,polymericsulfidemoieties,dithizaole-3-thiones,cyclicthioureasandcyclicureasasindicatedinthegenericenvironmentalhazardassessment.
HazardConcerns:Manymembersofthiscategoryarecommercialinsecticides,fungicides,disinfectants,rodenticides,antioxidants,slimicides,algalicides,bactericidesandheavymetalchelators.
Theirmodeoftoxicactionapparentlyresultsfrominterferencewithmetallo-enzymesinlivingcells;thetoxicityhasbeenattributedtoeitherDDCsandBDCsortheirdegradationproducts.
Alloftheknowndithiocarbamatesareacutelytoxictofish,algaeandbacteriaat19,notestingwillberequestedbecausenotoxiceffectsatsaturationwillbeexpected.
Generally,membersofthiscategorywillhaveMWsoflessthan1000.
63GeneralTestingStrategyTier1.
Theacuteaquaticbasesetofenvironmentaltoxicitytestswillberecommendedforaquaticexposuresandtheterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedinggrowthtest,theearthwormacutetoxicitytestandthesoilmicrobialcommunitybioassay)willberecommendedforterrestrialexposures.
Tier2.
Ifacutetoxicitytestingindicatesasignificantrisk,thenchronictoxicitywithfishandaquaticinvertebrateswillberecommendedaswellasaerobicbiodegradationtesting.
Aerobicbiodegradabilitycanbedeterminedusingeitherofthefollowingtestguidelines:-ReadyBiodegradability(sixmethods;chooseanyone)(HarmonizedTestGuideline835.
3110)-ReadyBiodegradability–CO2inSealedVessels(HeadspaceTest)(HarmonizedTestGuideline835.
3140)August1989;revisedNovember1995;revisedJune201064Category:EpoxidesHumanHealthEnvironmentalToxicityDefinition.
Anymolecularstructurecontainingoneormoreepoxygroupsisconsideredtobeamemberofthecategory:O/|-C-C-||HazardConcerns.
HumanHealth:concernsforepoxidesareforcancerandreproductiveeffectsbasedondataforseveralanalogouschemicals.
Thereisgreaterconcernforprimaryepoxides,thanforepoxideswithsubstitutionsonbothoftheepoxycarbonsEnvironmentalToxicity:isafunctionoftheoctanol-waterpartitioncoefficient.
CompoundswithlogKow's>5actasneutralorganicsproducingsimplenarcosis,butatlowerlogKow's,epoxidesdisplaytoxicitygreaterthanthatpredictedforsimplenarcotics.
TheaquatictoxicityforepoxidesandpolyepoxideshasbeendeterminedthroughSARanalysisbyEPAusingECOSAR–ahazardestimationtoolthatuseschemicalstructuredescriptorstoestimatetheacuteandchronictoxicityofasubstancetoaquaticorganisms.
[LinkforECOSAR:http://www.
epa.
gov/opptintr/newchems/tools/21ecosar.
htm].
Boundaries.
Structureswithepoxyequivalentweightsof>1,000arepresumednottoposeahazardunderanyconditions.
Concernsareconfinedtothosespecieswithmolecularweights1000willbeexcludedfromthiscategory.
Acutetoxicityforesterswhichareliquidsatroomtemperatureisknowntobelimitedbytheoctanol/waterpartitioncoefficient(Kow).
AbovealogKowvalueof≥5.
0,estersshownoeffectsatsaturationduring96-hexposures(Veithetal1984).
EsterswhicharesolidsatroomtemperaturemayshownotoxicityatsaturationatlowerKowvaluesdependingonthemeltingpoint,i.
e.
,thehigherthemeltingpointatagivenKow,thegreaterthelikelihoodthatnoacutetoxicitywillbeobservedatsaturation.
Forsolids,theno-effects-at-saturationpointhastobedeterminedonacase-by-casebasis.
TheKowlimitforchronictoxicityissetatalogKow=8forliquidesters.
Forsolidesters,chronictoxicitytestingwilldeterminethisKowlimit.
HazardConcerns.
ThetoxicityforsimpleestershasbeendeterminedthroughSARAnalysis(Clements1988).
Estersareknowntobemoretoxicthanneutralorganicchemicals,andthisexcesstoxicitydecreaseswithincreasingKow.
Thetoxicityforvinylesters,allylicesters,andpropargylicestersisexpectedtobegreaterthanforsimpleesters.
Again,theadditionalexcesstoxicityofthesevinylesters,allylicesters,andpropargylicestersisexpectedtodecreasewithincreasingKow.
Membersofthiscategoryexhibittoxicityrangingfromlowtoxicity(i.
e.
,>100mg/L)tohightoxicity(i.
e.
,5.
0.
Theupperboundaryforchronictoxicityis8.
0.
MWwillbe5.
0,chronictoxicitytestingwithfishanddaphnidswillberecommended.
Fate:Estersaresubjecttobothabioticandbiotichydrolysis,i.
e.
,esterhydrolysis,andaerobicbiodegradation.
Aerobicbiodegradationisexpectedtobethedominantrouteoftransformationintheenvironment.
GeneralTestingStrategy.
ReleasetoAquaticEcosystems:Tier1.
Theaquaticbasesetofenvironmentaltoxicitytestswillberecommendedforaquaticexposures.
Theacutetoxicitytestsforfish(HarmonizedTestGuideline850.
1075)anddaphnids(HarmonizedTestGuideline850.
1010)willbedoneusingtheflow-throughmethodwithmeasuredconcentrations;effectiveconcentrationswillbebasedon100%activeingredients(AI)andmeanmeasuredconcentrations;thehighesttreatmentconcentrationonanominal-basis66shouldnotexceedtheaqueoussolubilitylimit;andsolventcanbeusedtoassisttheestertoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityoftheesterbeyonditsaqueoussolubilitylimit.
Thealgaltoxicitytest(HarmonizedTestGuideline850.
5400)shouldbedonewiththestaticmethod;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsat24,48,72,and96hours;testmediumwithatleast0.
300mg/LEDTAasafinalconcentration;thehighesttreatmentconcentrationonanominal-basisshouldnotexceedtheaqueoussolubilitylimitoftheester;andsolventcanbeusedtoassisttheestertoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityoftheesterbeyonditsaqueoussolubilitylimit.
Ifthereisnosignificantriskfromtheesteraftertheresultsoftheenvironmentalbasesethavebeenintegratedintotheriskassessment,thennofurthertestingisrecommended.
However,ifthereisasignificantrisk,thengotoTier2.
Tier2.
Aerobicbiodegradabilityaccordingtoeitherofthefollowingtestguidelines:-ReadyBiodegradability(sixmethods;chooseanyone)(HarmonizedTestGuideline835.
3110)-ReadyBiodegradability–CO2inSealedVessels(HeadspaceTest)(HarmonizedTestGuideline835.
3140)Ifthereisnosignificantriskfromtheesteraftertheresultsoftheaerobicbiodegradationtestinghavebeenintegratedintotheriskassessment,thennofurthertestingisrecommended.
However,ifthereisasignificantrisk,thengotoTier3.
Tier3.
Fishchronictoxicitytesting,i.
e.
,fishearlylifestage(ELS)toxicitytesting(HarmonizedTestGuideline850.
1400),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,21,and28;thehighesttreatmentconcentrationonanominal-basisshouldnotexceedtheaqueoussolubilitylimitofthetestedchemical;solventcanbeusedtoassisttheestertoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityoftheesterbeyonditsaqueoussolubilitylimit;andthe7-dELSstagetoxicitytestcannotbesubstitutedforthe28-dELStoxicitytestbecauseVanLeeuwenetal(1990)havedemonstratedthatthe7-dELStoxicitytestunderestimatedthechronictoxicityofanilinesmeasuredbythe28-dELStoxicitytestby>5.
3timeswhentheNOECswerecompared(seeTableVIIinVanLeeuwen).
Bothanilinesandestersaremoretoxicthanpredictedbasedonnarcosisalone,i.
e.
,bothestersandanilineshaveexcesstoxicityduetoamorespecificmode(s)oftoxicaction.
Asevendayexposuremaynotallowenoughtimeforthisexcesstoxicitytobeexpressedeitherbecauseofnotenoughexposureand/ornotenoughtimeformetabolicactivation.
Daphnidchronictoxicitytesting(HarmonizedTestGuideline850.
1300),withflow-through67methods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,and21;thehighesttreatmentconcentrationonanominal-basisshouldnotexceedtheaqueoussolubilitylimitoftheester;solventcanbeusedtoassisttheestertoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityoftheesteraboveitsaqueoussolubilitylimit;andthe7-ddaphnidchronictoxicitytestcannotbesubstitutedforthe21-dtoxicitytest(VanLeeuwenetal1990).
II.
ReleasetoTerrestrialEcosystems:Theterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedlinggrowthtest[HarmonizedTestGuideline850.
4230],theearthwormtoxicitytest[HarmonizedTestGuideline850.
6200],theavianacuteoraltoxicitytest[HarmonizedTestGuideline850.
2100],andthesoilmicrobialcommunitybioassay[HarmonizedTestGuideline850.
5100])willberecommendedforterrestrialexposures.
Chronictoxicitytestingforterrestrialorganismsinclude:theplantwholelifecycletest(HarmonizedTestGuideline850.
4150),theplantuptaketest(HarmonizedTestGuideline850.
4800),avianreproductiontoxicitytest(HarmonizedTestGuideline850.
2300),andthesoilmicrobialcommunitybioassay(HarmonizedTestGuideline850.
5100).
References.
Clements,RG(editor).
1988.
Estimatingtoxicityofindustrialchemicalstoaquaticorganismsusingstructure-activityrelationships.
EPA-560-6-88-001.
Washington,DC:EnvironmentalEffectsBranch,HealthandEnvironmentalReviewDivision,OfficeofToxicSubstances(TS-796),UnitedStatesEnvironmentalProtectionAgency.
AvailablefromtheNationalTechnicalInformationService,Springfield,VA22161,PB89-117592.
VanLeeuwenCJ,AdemaDMM,andHermensJ.
1990.
Quantitativestructure-activityrelationshipsforfishearlylifestagetoxicity.
AquaticToxicology16:321-334.
VeithGD,DeFoeD,andKnuthM.
1984.
Structure-activityrelationshipsforscreeningorganicchemicalsforpotentialecotoxicityeffects.
DrugMetabolismReviews15(7):1295-1003.
November,1991;revisedJune201068Category:EthyleneGlycolEthersHumanHealthDefinition.
Theethyleneglycolethercategoryisdefinedasfollows:R-(OCH2CH2)n-OR'n=1,2,or3R=alkylC7orlessorphenyloralkylsubstitutedphenylR'=HoralkylC7orlessoranygroupthatcanbechemicallyormetabolicallyremovedtoyieldaglycoletherHazardConcerns.
Short-chainethyleneglycolethersareabsorbedbyallroutesofexposureandhavecausedirritationofskin,eyes,andmucousmembranes;hemolysis,bone-marrowdamage,andleukopeniaofbothlymphocytesandgranulocytes;directandindirectkidneydamage;liverdamage,immunotoxicity,andcentralnervoussystem(CNS)depression.
Short-chainethyleneglycolethersarealsodevelopmentalandreproductivetoxicants.
2-Phenoxyethanolisknowntocausehemolysisandeyeirritation.
Boundaries.
Thereisevidencethatdevelopmentaltoxicityisreducedgoingfromthemethyltothebutylether,andthatitisreducedgoingfromtheethyleneglycoltothetriethyleneglycol.
However,thereisstillaconcernformaternaltoxicityasreflectedindevelopmentalandsubchronictoxicitystudies.
Thesystemictoxicityoflonger-chainglycolethersandalkylphenylglycolethersisuncertainbecausedataarenotavailable.
ThealkylchainlengthofC7orlesswaschosenasaboundaryforshort-chainethyleneglycolethersbasedontheavailabledata.
GeneralTestingStrategyTheNewChemicalsProgramconsidersthefollowingteststobethemostappropriateforethyleneglycoletherswithsufficientexposuretopotentiallyposeanunreasonablerisk:Tier1.
CombinedRepeatedDoseToxicityStudywiththeReproduction/DevelopmentalToxicityScreenTest(OECDGuideline422).
Ifsignsofhematuriaareseen,redandwhitebloodcellcountsshouldbetaken2dayslaterexceptforfemaleanimalsduringpregnancyandlactation.
69Tier2.
TheneedforfurthertestingwouldbedeterminedbytheresultsofTier1.
Thiscouldincludeanyofthefollowingtests.
-PrenatalDevelopmentalToxicityviathemostappropriateroute(HarmonizedTestGuideline870.
3700)-2-GenerationReproductionStudyviathemostappropriateroute(HarmonizedTestGuideline3800)-90-DaySubchronicStudyviathemostappropriateroute(HarmonizedTestGuideline870.
3465–inhalationroute;870.
3250-dermalroute;870.
3150-oralroute)-ImmunotoxicityStudyviathemostappropriateroute(HarmonizedTestGuideline870.
7800)June1992,revisedDecember199770Category:HydrazinesandRelatedCompoundsHumanHealthEnvironmentalToxicityDefinition:Anystructurecontainingoneormoreofthefollowinggroupsisconsideredtobeamemberofthecategory:HazardConcerns:Concernsforcarcinogenicityandchroniceffectstoliver,kidney,andbloodarebasedondataforanumberofhydrazinesandrelatedchemicals.
Inhumans,hydrazine,itself,mayaffectthecentralnervoussystem,liver,andkidneys.
Thetoxiceffectsofhydrazineexposuretohumansmayrangefrommildskinandeyeirritation,andskinsensitization,tosevereirritationandburns,pulmonaryedema,CNSdepression,aswellasliverandkidneydamage,whichcanleadtodeath.
Hydrazinemayalsopresentaserioushazardtoplantlifeandaquaticorganisms.
Ecotoxicityconcernsarebasedonstructureactivityrelationships(SAR)usingdataforanumberofhydrazinesandhydrazides.
Hydrazineitself,(N2H4),isknowntobeacutelytoxictoaquaticorganismsatlowlevels,algaeat1000willbeexcludedfromthiscategory.
Acutetoxicityforimideswhichareliquidsatroomtemperatureisassumedtobelimitedbytheoctanol/waterpartitioncoefficient(Kow),andthelimitingKowvalueforacutetoxicityisassumedtobeabout5.
0.
Thelimitingvalueforchronictoxicityisassumedtobeabout8.
0.
ImideswhicharesolidsatroomtemperaturemayshownotoxicityatsaturationatlogKowvalues100.
0mg/L)tohightoxicity(i.
e.
,5.
3timeswhentheNOECswerecompared(seeTableVIIinVanLeeuwen);Daphnidchronictoxicitytesting(HarmonizedTestGuideline850.
1300),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,and21;measuredTOCofdilutionwaterinthecontrol;thehighesttreatmentconcentrationonanominal-basisshouldbesetattheaqueoussolubilitylimit;solventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubility;andthe7-ddaphnidchronictoxicitytestcannotbesubstitutedforthe21-dtoxicitytestbecauseVanLeeuwenetal(1990)havedemonstratedthatthefish7-dELStoxicitytestunderestimatedthechronictoxicityofanilinesmeasuredbythefish28-dELStoxicitytestby>5.
3timeswhentheNOECswerecompared(seeTableVIIinVanLeeuwen).
Theterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedlinggrowthtest(HarmonizedTestGuideline850.
4230],theearthwormacutetoxicitytest(HarmonizedTestGuideline850.
6200),andthesoilmicrobialcommunitybioassay(HarmonizedTestGuideline850.
5100)willberecommendedforterrestrialexposures.
Chronictoxicitytestingforterrestrialorganismsinclude:theplantwholelifecycletest(HarmonizedTestGuideline850.
4150),theplantuptaketest(HarmonizedTestGuideline850.
4800),andthesoilmicrobialcommunitybioassay(HarmonizedTestGuideline850.
5100).
76References.
VanLeeuwenCJ,AdemaDMM,andHermensJ.
1990.
Quantitativestructure-activityrelationshipsforfishearlylifestagetoxicity.
AquaticToxicology16:321-334.
April,1991;revisedJune201077Category:DiisocyanatesHumanHealthDefinition.
Anymolecularstructurecontainingtwoormoreisocyanategroupsisconsideredtobeamemberofthecategoryfornewchemicalpurposes:R-(N=C=O)>2Membersoftheclassincludenewisocyanatemonomersaswellasnewoligomers,polymers,prepolymers,orreactionproductsofexistingisocyanatemonomers.
Mostnewchemicaldiisocyanatesofconcernarepolymersoroligomerscontainingwell-knowndiisocyanatemonomerssuchastoluenediisocyanate(TDI)or4,4'-methylenediphenyldiisocyanate(MDI).
HazardConcerns.
Diisocyanatesareofconcernforpotentialdermalandrespiratorysensitization,andforpulmonarytoxicity.
Basedonconflictinganimalandhumandataforrespiratorysensitization,theAgencyhasdeterminedthatthereispresentlynotareliableanimalmodelfortestingdiisocyanatesforpotentialrespiratorysensitization.
Atthistime,itisassumedthatalldiisocyanatesmaybepotentialhumanrespiratorysensitizers.
Mostmembersofthediisocyanatecategoryhavenotbeentestedforcarcinogenicpotential.
Thoughthearomaticdiisocyanates[MDI,TDI,dianisidinediisocyanate(DADI)]testedpositiveandonealiphaticdiisocyanate[hexamethylenediisocyanate(HDI)]testednegativeinonespecies,itisprematuretomakeanygeneralizationsaboutthecarcinogenicpotentialofaromaticversusaliphaticdiisocyanates.
Boundaries.
Structureswithanisocyanateequivalentweightof>5,000arepresumednottoposeahazardunderanyconditions.
Typically,concernsareconfinedtothosespecieswithmolecularweights1000arenotexpectedtobeabsorbedbyaquaticorganismseveniftheyarewatersoluble.
Therefore,onlylanthaniderareearthmetal-compoundswithMWs8arenottoxicatwatersaturationevenafterprolongedexposure.
ThereareanumberofQSARs(quantitativestructure-activityrelationships)topredictthetoxicityofneutralorganics.
Boundaries.
NeutralorganicsofconcerngenerallyhaveMWslessthan1,000andLogKowvalues100mg/L)tohightoxicity(i.
e.
,1000areexpectedtohavelowtoxicitytoaquaticorganisms.
Likewise,iftheeffectivecross-sectionaldiameterisgreaterthan1.
5nanometers,thenabsorptionthrumembranesisexpectedtobenilandlowtoxicitytowardsaquaticorganismsisexpected.
Acutetoxicityforthesechemicalswhichareliquidsatroomtemperatureisknowntobelimitedbytheoctanol/waterpartitioncoefficient(Kow).
BelowalogKowvalueof5,thesecompoundsareexpectedtoshowacuteandchronictoxicitytoaquaticorganisms.
AbovealogKowvalueof5.
0,thesechemicalsareexpectedtoshowlowacutetoxicitytowardsfishandaquaticinvertebrates(daphnids),ornoeffectsatsaturationduring96-hexposurestofishand48-hexposurestodaphnids.
AbovealogKowof6.
4,thesechemicalsareexpectedtoshowlowtoxicitytowardsgreenalgaeintermsofinhibitionofbiomass,ornoobtainableEC50during72-hand96-hexposurestogreenalgae.
Allylic/vinylnitrileswhicharesolidsatroomtemperaturemayshownoacutetoxicityatsaturationatlowerKowvaluesdependingonthemeltingpoint,i.
e.
,thehigherthemeltingpointatagivenKow,thegreaterthelikelihoodthatnoacutetoxicitywillbeobservedatsaturation.
Forsolids,theno-effects-at-saturationpointforacutetoxicityhastobedeterminedonacase-by-casebasisbycomparingthepredictedLC50/EC50tothepredictedormeasuredwater91solubility.
ThesecompoundsshouldshowonlychronictoxicitytowardsfishanddaphnidswhenlogKowvaluesaregreaterthan5andlessthan8.
Forgreenalgae,onlychronicvaluesshouldbemeasurablebetweenlogKowvaluesof6.
4and8.
TheKowlimitforchronictoxicityissetatalogKow=8forliquidcompounds.
Allallylic/vinylnitrilesshouldshownotoxiceffectstofish,daphnids,andgreenalgaewhenthelogKowisgreaterthan8.
Forsolids,chronictoxicitytestingwillallowdeterminationofaKowlimit.
EnvironmentalFate:Aerobicbiodegradationisexpectedtobethedominantrouteoftransformationintheenvironment.
GeneralTestingStrategy:I.
ReleasetoAquaticEcosystems:Tier1.
Theaquaticbasesetofenvironmentaltoxicitytestswillberecommendedforaquaticexposures.
Theacutetoxicitytestsforfish(HarmonizedTestGuideline850.
1075)anddaphnids(HarmonizedTestGuideline850.
1010)willbedoneusingtheflow-throughmethodwithmeasuredconcentrations;effectiveconcentrationswillbebasedon100%activeingredients(ai)andmeanmeasuredconcentrations;dilutionwaterhardnesslessthan150mg/LasCaCO3;dilutionwatertotalorganiccarbon(TOC)lessthan2.
0mgTOC/L;thehighesttreatmentconcentrationonanominal-basisshouldnotexceedtheaqueoussolubilitylimitofthetestedchemical;andsolventcanbeusedtoassistthechemicaltoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthechemicalbeyonditsaqueoussolubilitylimit.
Thealgaltoxicitytest(HarmonizedTestGuideline850.
5400)shouldbedonewiththestaticmethod;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(ai)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsbasedon(1)cells/mL,(2)areaunderthegrowthcurve,and(3)growthrateat24,48,72,and96hours;testmediumwithatleast0.
300mg/LEDTA-Nasaltasafinalconcentration;thehighesttreatmentconcentrationonanominal-basisshouldnotexceedtheaqueoussolubilitylimitofthechemical;andsolventcanbeusedtoassistthechemicaltoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthechemicalbeyonditsaqueoussolubilitylimit.
Controlgrowthat72hshouldbegreaterthan16Xandat96hgreaterthan100X.
TheCoefficientofVariation(CV)betweencontrolreplicatesat72hand96hshouldbelessthan20percent.
Ifthereisnosignificantriskaftertheresultsoftheacutetoxicitytestinghavebeenintegratedintotheriskassessment,thennofurthertestingisrecommended.
However,ifthereisasignificantrisk,thengotoTier2.
Tier2.
Aerobicbiodegradabilityaccordingtoeitherofthefollowingtestguidelines:92-ReadyBiodegradability(sixmethods;chooseanyone)(HarmonizedTestGuideline835.
3110)-ReadyBiodegradability–CO2inSealedVessels(HeadspaceTest)(HarmonizedTestGuideline835.
3140)Ifthereisnosignificantriskaftertheresultsoftheaerobicbiodegradationtestinghavebeenintegratedintotheriskassessment,thennofurthertestingisrecommended.
However,ifthereisasignificantrisk,thengotoTier3.
Tier3.
Fishchronictoxicitytesting,i.
e.
,fishearlylifestage(ELS)toxicitytesting(HarmonizedTestGuideline850.
1400),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(ai)andmeanmeasuredconcentrations;dilutionwaterhardnesslessthan150mg/LasCaCO3;dilutionwatertotalorganiccarbon(TOC)lessthan2.
0mgTOC/L;statisticalanalysisofeffectiveconcentrationsatdays7,14,21,and28;thehighesttreatmentconcentrationonanominal-basisshouldnotexceedtheaqueoussolubilitylimitforthechemical;solventcanbeusedtoassistthechemicaltoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthechemicalbeyonditsaqueoussolubilitylimit;andthe7-dELSstagetoxicitytestcannotbesubstitutedforthe28-dELStoxicitytestbecauseVanLeeuwenetal(1990)havedemonstratedthatthe7-dELStoxicitytestunderestimatedthechronictoxicityofanilinesmeasuredbythe28-dELStoxicitytestby>5.
3timeswhentheNOECswerecompared(seeTableVIIinVanLeeuwen).
Bothanilinesandallylic/vinyl/propargylnitrilesaremoretoxicthanpredictedbasedonnarcosisalone,i.
e.
,bothclasseshaveexcesstoxicityduetoamorespecificmode(s)oftoxicaction.
Asevendayexposuremaynotallowenoughtimeforthisexcesstoxicitytobeexpressedeitherbecauseofnotenoughexposureand/ornotenoughtimeformetabolicactivation.
Daphnidchronictoxicitytesting(HarmonizedTestGuideline850.
1300),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(ai)andmeanmeasuredconcentrations;dilutionwaterhardnesslessthan150mg/LasCaCO3;dilutionwatertotalorganiccarbon(TOC)lessthan2.
0mgTOC/L;statisticalanalysisofeffectiveconcentrationsatdays7,14,and21;thehighesttreatmentconcentrationonanominal-basisshouldnotexceedtheaqueoussolubilitylimitofthechemical;solventcanbeusedtoassistthechemicaltoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthechemicalaboveitsaqueoussolubilitylimit;andthe7-ddaphnidchronictoxicitytestcannotbesubstitutedforthe21-dtoxicitytest(VanLeeuwenetal1990).
Ifthereisnosignificantriskaftertheresultsofthechronictoxicitytestinghavebeenintegratedintotheriskassessment,thennofurthertestingisrecommended.
However,ifthereisasignificantrisk,thengotoTier3.
93II.
ReleasetoTerrestrialEcosystems:Theterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedlinggrowthtest[HarmonizedTestGuideline850.
4230],theearthwormacutetoxicitytest[HarmonizedTestGuideline850.
6200],theavianacuteoraltoxicitytest[HarmonizedTestGuideline850.
2100),andthesoilmicrobialcommunitybioassay[HarmonizedTestGuideline850.
5100])willberecommendedforterrestrialexposures.
Chronictoxicitytestingforterrestrialorganismsinclude:theplantwholelifecycletest(HarmonizedTestGuideline850.
4150),theplantuptaketest(HarmonizedTestGuideline850.
4800),theavianreproductivetoxicitytest(HarmonizedTestGuideline850.
2300),andthesoilmicrobialcommunitybioassay(HarmonizedTestGuideline850.
5100).
Inaddition,afatetestforbiodegradabilityinsoil(HarmonizedTestGuideline835.
4100)mayberecommended.
References:VanLeeuwenCJ,AdemaDMM,andHermensJ.
1990.
Quantitativestructure-activityrelationshipsforfishearlylifestagetoxicity.
AquaticToxicology16:321-334.
December2007;revisedJune201094Category:NonionicSurfactantsEnvironmentalToxicityDefinition.
Anyneutralstructurehavingsurfactantactivityisconsideredamemberofthiscategory.
Manyofthesesurfactantshavethefollowingtypesofstructure:Ethoxylategroupsmaybemixedwithorbereplacedbyalcoholgroups.
Otherneutralgroupse.
g.
propoxylates,esters,halogens,mayalsobepresent.
HazardConcerns.
Acuteaquatictoxicityincreasesexponentiallywithincreasesinthehydrophobicchainlengthwhenthenumberofethoxygroupsorthehydrophiliccomponentisheldconstant.
Inaddition,whenthenumberofcarbonsinthehydrophobeisconstant,toxicitydecreaseswithanincreasingnumberofethoxylategroups.
Theaquatictoxicityofmembersofthecategorycanbepredictedbystructure-activityrelationship(SAR).
Boundaries.
Therearenoestablishedmolecularweightboundariesforthiscategory.
LimitsonchainlengthareinherentintheSARs.
Testing.
Toaddressecotoxicityconcerns,basesetacuteaquatictoxicitytesting(algae:staticmethod,daphnidandfish:flow-throughmethod,allmeasuredconcentrations).
Tier1.
Theacuteaquaticbasesetofenvironmentaltoxicitytestswillberecommendedforaquaticexposuresandtheterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedinggrowthtest,theearthwormacutetoxicitytestandthesoilmicrobialcommunitybioassay)willberecommendedforanyterrestrialexposures.
AcutefishtoxicitytestHarmonizedTestGuideline850.
1075AcutedaphnidtoxicitytestHarmonizedTestGuideline850.
1010GreenalgaetoxicitytestHarmonizedTestGuideline850.
5400EarlyseedlinggrowthtestHarmonizedTestGuideline850.
4230EarthwormacutetoxicitytestHarmonizedTestGuideline850.
6200SoilmicrobialcommunitybioassayHarmonizedTestGuideline850.
5100Tier2.
Ifacutetoxicitytestingindicatesasignificantrisk,thenenvironmentalfate95testingintheformofaerobicbiodegradationtestingisrecommended.
Aerobicbiodegradationtestingmaybeconductedusingeitherofthefollowingtestguidelines:-ReadyBiodegradability(sixmethods;chooseanyone)(HarmonizedTestGuideline835.
3110)-ReadyBiodegradability–CO2inSealedVessels(HeadspaceTest)(HarmonizedTestGuideline835.
3140)Tier3.
Inaddition,ifacutetoxicitytestingindicatesasignificantrisk,thenchronicaquatictoxicitytestingwithfishandaquaticinvertebrateswillberecommended.
FishearlylifestagetestHarmonizedTestGuideline850.
1400DaphnidchronictoxicitytestingHarmonizedTestGuideline850.
1300September1988,revisedSeptember1996;revisedJune201096Category:OrganotinsHumanHealthEnvironmentalToxicityDefinition.
Thiscategoryincludesallmono-,di-,tri-andtetra-alkylorphenylorganotincompounds,includingorganotinesters/oxides.
Themodeoftoxicactionoforganotinsinhumansisunknown,buttheyareknowntoaffectcarbonatemetabolismandothermetabolicprocessesinthebrain,liver,andmuscle,aswellasseveralenzymesandtheoxidativeactivityofmitochondria.
Ithasbeensuggestedthatgeneralsulfhydrylbindingmayberesponsiblefortheeffectsseeninmammals.
Itisassumedthatthesecompoundsneedtobeabsorbedtobetoxic,therefore,compoundswithMWs>1000andwhichdonottransformtoorganotincompoundswithMWs10mg/L)tohightoxicity(i.
e.
,13.
7.
MWwillbe5.
3timeswhentheNOECswerecompared(see99TableVIIinVanLeeuwen).
ChronicAquaticToxicityFishearlylifestagetestHarmonizedTestGuideline850.
1400DaphnidchronictoxicitytestingHarmonizedTestGuideline850.
1300References.
8E-594.
Tributyltinoxide.
Bis-(tri-n-butyltin)-oxide.
(1988,December).
GesellschaftDeutscherChemiker-AdvisoryCommitteeonExistingChemicalofEnvironmentalRelevance(BUA).
BUAReport36.
USEPA1996.
UnitedStatesEnvironmentalProtectionAgency(1996).
TheOfficeofPollutionPreventionandToxics(OPPT)premanufacturenotification(PMN)ECOTOXdatabase:aconfidentialbusinessinformation(CBI)collectionofenvironmentaltoxicitydatafromnewchemicalsubmissionsunderSec.
5oftheToxicSubstancesControlAct(TSCA).
Washington,DC:EnvironmentalEffectsBranch,HealthandEnvironmentalReviewDivision(7403),OPPT,USEPA.
OPPTcontactisV.
Nabholz,202-260-1271.
VanLeeuwen,C.
J.
,Adema,D.
M.
M.
,&Hermens,J.
(1990).
Quantitativestructure-activityrelationshipsforfishearlylifestagetoxicity.
AquaticToxicology,16,321-334.
Vighi,M.
,&Calamari,D.
(1985).
QSARsfororganotincompoundsonDaphniamagna.
Chemosphere,14,1925-1932.
WHO1980.
WorldHealthOrganizationEnvironmentalHealthCriteria15.
Tinandorganotincompounds:Apreliminaryreview.
Geneva:WHO,pp.
59-62.
Wong,P.
T.
S.
,Chau,Y.
K.
,Kramar,O.
,&Bengert,G.
A.
(1982).
Structure-toxicityrelationshipoftincompoundsonalgae.
CanadianJournalofFisheriesandAquaticSciences,39,483-488.
April1991,revisedSeptember1996.
100Category:PeroxidesHumanHealth(case-by-case)EnvironmentalToxicityDefinition.
Anymolecularstructurecontainingoneormoreofthefollowingfunctionalgroupsisconsideredtobeamemberoftheclass:||-C-O-O-C-dialkylperoxide|||-C-O-O-Halkylhydroperoxide|O|-C-O-O-C-peroxyester|OO-C-O-O-C-diacylperoxideO-C-O-O-HperoxyacidThe"typical"peroxideinthenewchemicalprogramisadiscrete(classI)chemicalwithamolecularweightof2months>6monthsBioaccumulation*(FishBCForBAF)>1000>5000ToxicityDeveloptoxicitydatawherenecessary,baseduponvariousfactors,includingconcernsforP,B,otherphysical/chemicalfactors,andtoxicity.
*ChemicalsmustalsomeetcriteriaforMW(60daysandmeasuredBCFis>1000,tier3testingwillberequired.
Ifonlyoneconditionismet,releasesandexposurearefurtherconsideredtodetermineifadditionaltestingisrequired.
Tier3.
Toxicity/advancedenvironmentalfatetesting.
HumanhealthtoxicityCombinedrepeateddoseoraltoxicitywiththereproductive/developmentaltoxicityscreeningtest(OECDNo.
422)inrats.
Otherhealthtestingwillbeconsideredwhereappropriate.
EnvironmentalfateSediment/watermicrocosmbiodegradationtest(HarmonizedtestGuideline835.
3180)orAerobic/anaerobicaquaticmetabolism(HarmonizedtestGuideline835.
4300/835.
4400ChronicenvironmentaltoxicityFish(rainbowtrout)anddaphnidsshouldbetestedaccordingtoHarmonizedTestGuideline850.
1400(sameasOECD210)andHarmonizedTestGuideline850.
1300(sameasOECD202),respectively.
Additionaltestingtoevaluateotherbiota(e.
g.
,avian,sedimentdwellingorganisms)orothereffects(e.
g.
,endocrinedisruptingpotential)willbeconsideredwhereappropriate.
November,1999105Category:PhenolphthaleinsHumanHealthDefinition.
Anychemicalcontainingthephenolphthaleinstructureisconsideredtobeamemberofthecategory.
HazardConcerns.
ThehealthconcernforphenolphthaleinandderivativesofphenolphthaleinisforcancerbasedontheNTPcancerstudy(NTPreportTR-465,November1996)forphenolphthaleinwithadministrationviathediet.
TherewasclearevidenceofcarcinogenicactivityinmaleF344/Nratsbasedonmarkedlyincreasedincidencesofbenignpheochromocytomasoftheadrenalmedullaandofrenaltubuleadenomasandadenomasorcarcinomas(combined).
TherewassomeevidenceofcarcinogenicactivityinfemaleF344/Nratsbasedontheincreasedincidencesofbenignpheochromocytomasoftheadrenalmedullainthe12,000ppmgroupandofbenignormalignantpheochromocytomas(combined)inthe12,000and25,000ppmgroups.
TherewasclearevidenceofcarcinogenicactivityinmaleB6C3F1micebasedonincreasedincidencesofhistiocyticsarcomasandofmalignantlymphomasofthymicorigin.
TherewasclearevidenceofcarcinogenicactivityinfemaleB6C3F1micebasedonincreasedincidencesofhistiocyticsarcomas,malignantlymphomasofalltypes,lymphomasofthymicorigin,andbenignsex-cordstromaltumorsoftheovary.
Boundaries.
Noboundariescurrentlydefined.
Testing.
EPAconsidersthefollowingteststobethemostappropriateforphenolphthalein106derivativesfoundtoposeanunreasonablerisktohumanhealth:Tier1.
Comparativedermalandoralabsorptionstudyinrats(HarmonizedTestGuideline,870.
7485)InvitroChromosomeaberrationsstudyinChinesehamsterovarycellswithphenolphthaleinasanadditionalpositivecontrol(HarmonizedTestGuideline870.
5375)LogKowtest(HarmonizedTestGuideline830.
7550,830.
7560,or830.
7570;orOECD123,PartitionCoefficient(1-Octanol/Water):Slow-StirringMethod)Watersolublilityforbothlactoneandacidform(HarmonizedTestGuideline830.
7840or830.
7860)Readybiodegradability(HarmonizedTestGuideline835.
3110)Tier2.
2-yearcarcinogenicitystudyinmice(HarmonizedTestGuideline870.
4200)April,1998107Category:PhenolsEnvironmentalToxicityDefinition.
Thiscategoryincludesphenols(i.
e.
,monophenols),polyhydroxyphenols,andpolyphenols.
Itisassumedthatthesecompoundsneedtobeabsorbedtobetoxic;therefore,compoundswithMWs>1000willbeexcludedfromthiscategory.
Acutetoxicityforphenolswhichareliquidsatroomtemperatureisknowntobelimitedbytheoctanol/waterpartitioncoefficient(Kow).
AbovealogKowvalueofabout7.
38,phenolsareexpectedtoshownoeffectsatsaturationduring96-hexposures(VeithandBroderius1987).
PhenolswhicharesolidsatroomtemperaturemayshownotoxicityatsaturationatlowerKowvaluesdependingonthemeltingpoint,i.
e.
,thehigherthemeltingpointatagivenKow,thegreaterthelikelihoodthatnotoxicitywillbeobservedatsaturation.
Forsolids,noeffectsatsaturationhastobedemonstratedonacase-by-casebasis.
TherearenoknownKowlimitsforchronictoxicityatthistime,butitmaynotbemuchabovealogKow=9.
0forliquidphenols.
FuturetestingwilldeterminethisKowlimit.
HazardConcerns.
TheaquatictoxicityforphenolshasbeendeterminedthroughSARanalysisbyEPAusingECOSAR–ahazardestimationtoolthatuseschemicalstructuredescriptorstoestimatetheacuteandchronictoxicityofasubstancetoaquaticorganisms.
[LinkforECOSAR:http://www.
epa.
gov/opptintr/newchems/tools/21ecosar.
htm].
Membersofthiscategoryexhibittoxicityrangingfromlowtoxicity(i.
e.
,>100mg/L)tohightoxicity(i.
e.
,=7.
38.
ChronictoxicityhasnoknownupperboundforlogKow,butitisprobablynear9.
MWwillbe=7.
38,chronictoxicitytestingwithfish,daphnids,andgreenalgaewillberecommended.
GeneralTestingStrategyI.
ReleasetoAquaticEcosystems:Tier1.
Theaquaticbasesetofenvironmentaltoxicitytestswillberecommendedforaquaticexposures.
Theacutetoxicitytestsforfish(HarmonizedTestGuideline850.
1075)anddaphnids(HarmonizedTestGuideline850.
1010)willbedoneusingtheflow-throughmethodwith108measuredconcentrations;effectiveconcentrationswillbebasedon100%activeingredients(AI)andmeanmeasuredconcentrations;measuredTOCofdilutionwaterinthecontrol;thehighesttreatmentconcentrationonanominal-basisshouldequaltheaqueoussolubilitylimit;andsolventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthePMNbeyonditsaqueoussolubilitylimit.
Thealgaltoxicitytesting(HarmonizedTestGuideline850.
5400),shouldbedonewithstaticmethods;measuredconcentrations;effectiveconcentrationsbasedon100%AIandmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsat24,48,72,and96hours;testmediumwithatleast0.
300mg/LEDTAasafinalconcentration;thehighesttreatmentconcentrationonanominal-basisequaltotheaqueoussolubilitylimit;andsolventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthePMNbeyonditsaqueoussolubilitylimit.
IfthereisnosignificantriskfromthePMNaftertheresultsoftheenvironmentalbasesethavebeenintegratedintotheriskassessment,thennofurthertestingisrecommended.
However,ifthereisasignificantrisk,thengotoTier2.
Tier2.
PhototransformationofChemicalsinWater—IndirectPhotolysisScreeningTest(HarmonizedTestGuideline835.
5270).
Ift1/22days,gotoTier4.
Tier3a.
Ift1/25.
3timeswhentheNOECswerecompared(seeTableVIIinVanLeeuwen);Daphnidchronictoxicitytesting(HarmonizedTestGuideline850.
1300),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%AIandmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,and21;measuredTOCofdilutionwaterinthecontrol;thehighesttreatmentconcentrationonanominal-basisshouldbesetattheaqueoussolubilitylimit;solventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthePMNbeyonditsaqueoussolubilitylimit;andthe7-ddaphnidchronictoxicitytestcannotbesubstitutedforthe21-dtoxicitytestbecauseVanLeeuwenetal(1990)havedemonstratedthatthefish7-dELStoxicitytestunderestimatedthechronictoxicityofanilinesmeasuredbythefish28-dELStoxicitytestby>5.
3timeswhentheNOECswerecompared(seeTableVIIinVanLeeuwen).
Aerobicbiodegradabilityaccordingtoeitherofthefollowingtestguidelines:-ReadyBiodegradability(sixmethods;chooseanyone)(HarmonizedTestGuideline835.
3110)-ReadyBiodegradability–CO2inSealedVessels(HeadspaceTest)(HarmonizedTestGuideline835.
3140)II.
ReleasetoTerrestrialEcosystems:Theterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedlinggrowthtest[HarmonizedTestGuideline850.
4230],theearthwormtoxicitytest[HarmonizedTestGuideline850.
6200]andthesoilmicrobialcommunitybioassay[HarmonizedTestGuideline850.
5100])willberecommendedforterrestrialexposures.
Chronictoxicitytestingforterrestrialorganismsinclude:theplantwholelifecycletest(HarmonizedTestGuideline850.
4150),theplantuptaketest(HarmonizedTestGuideline850.
4800),andthesoilmicrobialcommunitybioassay(HarmonizedTestGuideline850.
5100).
References.
VanLeeuwenCJ,AdemaDMM,andHermensJ.
1990.
Quantitativestructure-activityrelationshipsforfishearlylifestagetoxicity.
AquaticToxicology16:321-334.
VeithGDandBroderiusSJ.
1987.
Structure-toxicityrelationshipsforindustrialchemicalscausingtype(II)narcosissyndrome.
InKaiserKLE(ed),QSARInEnvironmentalToxicology-II,pp.
385-391.
ReidelPublishingCompany.
July,1991;revisedJune2010110Category:Phosphates,InorganicDefinition.
Thiscategoryincludesallinorganicsolubleformsofphosphates,suchas,phosphoricacid[PO4H3orOP(=O)(O)O]anditssaltsorphosphatesalts,pyrophosphates,polyphosphates,andorganicandinorganicformsofphosphorousthatcanbeoxidizedtophosphatesrapidly.
Inorganicformsofphosphonicacid(H2PO3orOP(=O)O)arenotincludedinthiscategorybecausemonopotassiumphosphonicacid[13977-65-6]hasbeenshownnottobeanalgalnutrient,nottobeareplacementforphosphateinalgalgrowthmedium,andnottocauseexponentialgrowthofgreenalgae.
HazardConcerns.
ThestandardenvironmentaltoxicityprofileforinorganicphosphatesasPinmgP/Lis:ECOTOX:Predicted(P)andmeasured(M)toxicityvaluesinmg/L(ppm)are:fish96-hLC50>100.
0Pdaphnid48-hLC50>100.
0Pgreenalgal96-hEC50b10.
0PdaphnidChV>10.
0PalgalChV=0.
010M,Hutchinson1957PredictionsarebasedonSAR-nearestanaloganalysisforsolubleformsofinorganicphosphates(PO4);SARchemicalclass=P-O4;MWofP=31,PO4=95,PO4H3=98;pH7;effectiveconcentrationsbasedon100%activeingredientsandnominalconcentrationsofP;hardness1000willbeexcludedfromthiscategory.
Acutetoxicityforphosphinateestersisknowntobecorrelatedandlimitedbytheoctanol/waterpartitioncoefficient(Kow).
AbovealogKowvalueof>5.
0,phosphinateestersshownoeffectsatsaturationduring96-hrexposurestofish.
PhosphinateesterswhicharesolidsatroomtemperaturemayshownotoxicityatsaturationatlowerKowvaluesdependingonthemeltingpoint,i.
e.
,thehigherthemeltingpointatagivenKow,thegreaterthelikelihoodthatnotoxicitywillbeobservedatsaturation.
Forsolids,thenoeffectsatsaturationhastobedeterminedonacase-by-casebasis.
TherearenomeasuredupperKowlimitsforchronictoxicityatthistime,butitmaynotbemuchabovealogKow=8.
HazardConcerns.
TheaquatictoxicityforphosphonateestershasbeendeterminedthroughSARanalysisbyEPAusingECOSAR–ahazardestimationtoolthatuseschemicalstructuredescriptorstoestimatetheacuteandchronictoxicityofasubstancetoaquaticorganisms.
[LinkforECOSAR:http://www.
epa.
gov/opptintr/newchems/tools/21ecosar.
htm].
EnvironmentalFate.
PhosphinateestershydrolyzeinwaterandtheirrateofhydrolysisiscorrelatedwithpH.
Themorealkaline,thefasterthehydrolysis.
TheSARforhydrolysisis:Loghydrolysist1/2(d)=4.
325-0.
497pHwheren=2,R2=1.
0.
AtpH7.
1,thehydrolysist1/2=6.
3daysor150hours.
Boundaries.
MW1000.
HazardConcerns.
Polyaromaticsulfonatesaremoderatelytoxictofish,daphnids,andalgae.
Thepolyacrylatesaretoxictoalgaeonly.
Polyanionicmonomers(assalts,e.
g.
,NaorKsalts)aremoderatelytoxictogreenalgae,butshowlowtoxicitytofishanddaphnids.
Itisassumedthatthetoxicityofthesecompoundsisduetoover-chelationofnutrientelementsneededforalgalgrowthandthatthistoxicitywillbemitigatedinthepresenceofCa++eitheraddedtothecompoundbeforetestingorpresentinthegrowth/testmediumatahardnessofabout150mg/LasCaCO3.
Boundaries.
Polymersmustbewater-soluble.
Molecularweightsaregenerally>1,000.
GeneralTestingStrategyToaddressecotoxicityconcerns,forpolycarboxylicacids(polyacrylates)andpolyanionicmonomers,algaltesting(staticmethods,nominalconcentrations)isrecommended,in3separatetests:1)thetestsubstanceasis,2)withequivalentofcalciumion,and3)withgrowthmediumat150mg/Lhardness,asCaCO3).
Forpolyaromaticsulfonates,basesetaquatictoxicitytesting(flowthroughmethods,measuredconcentrations)inalgae,daphnids,andfishisrecommended.
September,1988;revisedApril,1991117Category:PolycationicPolymersEnvironmentalToxicityDefinition.
Anypolymerthatexistsintheenvironmentwithmultiplepositivechargesisamemberofthisclass.
Suchstructuresincludepolyamines,polyquaternaryammonium,polysulfonium,andpolyphosphoniumcompounds.
HazardConcerns.
Membersofthecategoryaretoxictofish,invertebrates,andalgae.
Algaearesix-foldmoresensitivethanfishanddaphnids.
Itispresumedthatthesecompoundsactonthesurfaceoforganismsandneednotbeabsorbed.
Toxicityincreasesexponentiallywithincreasingchargedensityatcationicequivalentweightsof>400.
Atlowerchargeequivalentweights,toxicitydoesnotincrease.
AnumberofQSARs(quantitativestructure-activityrelationships)havebeendevelopedtopredictthetoxicityofpolycationicpolymers.
Boundaries.
Polymersmustbewater-solubleorwater-dispersible.
Molecularweightsare>300althoughthetypicalnewchemicalpolycationicpolymerhasamolecularweightinexcessof1000.
EPAhasbeenengagedindiscussionswiththeCationicFlocculantProducersAssociationinanattempttoidentifyanddevelopasetoftestsonrepresentativepolycationicpolymerswhichcouldbetterdefinethelimitsofthecategory.
GeneralTestingStrategyToaddressecotoxicityconcerns,forpolymerswith%aminenitrogen0.
1%:basesetacuteaquatictoxicitytestinginalgae,daphnids,andfish,plushumicacidtestinginfish(20mg/Lhumicacidindilutionwaterand10mg/L)isrecommended.
Alltestingusesstaticmethod,nominalconcentrations.
Forsomemembersoftheclass,atestofsorbedchemicalusingabenthicorganismmayalsoberecommended.
September,1988;periodicallyrevised.
118Category:PolynitroaromaticsEnvironmentalToxicityDefinition.
Thiscategoryincludesalldinitroaromaticsandtrinitroaromaticcompounds,forexample,dinitrobenzenes,dinitroanilines,dinitrophenols,anddinitropyridines.
Polynitroaromaticsprobablyactbyuncouplingofoxidativephosphorylation(Doulletal1980).
Itisassumedthatthesecompoundsneedtobeabsorbedtobetoxic;therefore,compoundswithMWs>1000willbeexcludedfromthiscategory.
Acutetoxicityforpolynitroaromaticswhichareliquidsatroomtemperatureisassumedtobelimitedbytheoctanol/waterpartitioncoefficient(Kow).
AbovealogKowvalueof≥7.
00(basedontestdataforanilinesreportedVeithandBroderius1987),polynitroaromaticsarenotexpectedtoshowtoxiceffectsatsaturationduring96-hexposures.
PolynitroaromaticswhicharesolidsatroomtemperaturemayshownotoxicityatsaturationatlowerKowvaluesdependingonthemeltingpoint,i.
e.
,thehigherthemeltingpointatagivenKow,thegreaterthelikelihoodthatnotoxicitywillbeobservedatsaturation.
Forsolids,thenoeffectsatsaturationhastobedeterminedonacase-by-casebasis.
TherearenoknownKowlimitsforchronictoxicityatthistime,butitmaynotbemuchabovealogKow=10forliquidpolynitroaromatics.
HazardConcerns.
TheaquatictoxicityforseveralclassesofpolynitroaromaticshavebeendeterminedthroughSARanalysisbyEPAusingECOSAR–ahazardestimationtoolthatuseschemicalstructuredescriptorstoestimatetheacuteandchronictoxicityofasubstancetoaquaticorganisms.
[LinkforECOSAR:http://www.
epa.
gov/opptintr/newchems/tools/21ecosar.
htm].
Membersofthiscategoryexhibittoxicityrangingfromlowtoxicity(i.
e.
,>100mg/L)tohightoxicity(i.
e.
,2days,gotoTier4.
Tier3a.
Ift1/25.
3timeswhentheNOECswerecompared(seeTableVIIinVan120Leeuwen);Daphnidchronictoxicitytesting(HarmonizedTestGuideline850.
1300),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,and21;measuredTOCofdilutionwaterinthecontrol;thehighesttreatmentconcentrationonanominal-basisshouldbesetattheaqueoussolubilitylimit;solventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthePMNbeyonditsaqueoussolubilitylimit;andthe7-ddaphnidchronictoxicitytestcannotbesubstitutedforthe21-dtoxicitytestbecauseVanLeeuwenetal(1990)havedemonstratedthatthefish7-dELStoxicitytestunderestimatedthechronictoxicityofanilinesmeasuredbythefish28-dELStoxicitytestby>5.
3timeswhentheNOECswerecompared(seeTableVIIinVanLeeuwen).
Aerobicbiodegradabilityaccordingtoeitherofthefollowingtestguidelines:-ReadyBiodegradability(sixmethods;chooseanyone)(HarmonizedTestGuideline835.
3110)-ReadyBiodegradability–CO2inSealedVessels(HeadspaceTest)(HarmonizedTestGuideline835.
3140)II.
ReleasetoTerrestrialEcosystems:Theterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedlinggrowthtest[HarmonizedTestGuideline850.
4230],theearthwormtoxicitytest[HarmonizedTestGuideline850.
6200],andthesoilmicrobialcommunitybioassay[HarmonizedTestGuideline850.
5100])willberecommendedforterrestrialexposures.
Chronictoxicitytestingforterrestrialorganismsinclude:theplantwholelifecycletestHarmonizedTestGuideline850.
4150),theplantuptaketestHarmonizedTestGuideline850.
4800),andthesoilmicrobialcommunitybioassay(HarmonizedTestGuideline850.
5100).
References.
DoullJ,KlaassenCD,andAmdurMO.
1980.
CasarettandDoull'sToxicology.
TheBasicScienceofPoisons.
SecondEd.
NewYork,NY:MacmillanPub.
Co.
,Inc.
VanLeeuwenCJ,AdemaDMM,andHermensJ.
1990.
Quantitativestructure-activityrelationshipsforfishearlylifestagetoxicity.
AquaticToxicology16:321-334.
VeithGDandBroderiusSJ.
1987.
Structure-toxicityrelationshipsforindustrialchemicalscausingtype(II)narcosissyndrome.
InKaiserKLE(ed),QSARInEnvironmentalToxicology-II,pp.
385-391.
Boston,MA:D.
ReidelPublishingCompany.
May,1991;revisedJune2010121Category:Respirable,PoorlySolubleParticulatesHealthOnlyDefinition.
Thiscategoryincludesavarietyofinorganic,poorlysoluble(asdesignatedinILSI2000)particulates.
Typically,theyareoxidesofvariousmetalsornonmetals(i.
e.
,silicon)Boundaries.
Thereisapotentialforrespirabilityifthereareanyparticles≤10μindiameterinthematerialbeinghandledbyworkers.
Summarizedbelowarecurrentlyavailabletestdataonfivedifferentpoorlysolubleparticulates:silica,talc,titaniumdioxide,PMN96-175(lithiummanganeseoxide),andcarbonblack.
ThesuitabilityofoneormoreoftheseanaloguesforaparticularPMNparticulatemustbedeterminedonacase-by-casebasis.
Riskistobeassessedbythemarginofexposuremethodforthereasonstatedinthenextparagraph.
HazardConcerns.
Thecategoryconcernsdiscussedherearelimitedtoeffectsonthelungasaresultofinhalingtheparticles.
Broadly,asshowninratinhalationstudies,theseeffectsrangefrominflammationtofibrosisto,potentially,cancer.
Becauseitisstillnotknownwithcertaintywhetherhighlungburdensofpoorlysolubleparticulatescanleadtolungcancerinhumansviamechanismssimilartothoseoftherat,intheabsenceofmechanisticdatatothecontrary,itmustbeassumedthattheratmodelcanidentifypotentialcarcinogenichazardstohumans.
Sincetheapparentresponsivenessoftheratmodelatoverloadisdependentoncoexistentchronicactiveinflammationandcellproliferation,atlowerlungdosesinwhichchronicactiveinflammationandcellproliferationarenotpresent,nolungcancerhazardisanticipated(ILSI2000).
Someoftheparticulatesmaycontainmetals,forexample,chromium,thatmaypresentotherandmoreimminenttoxicities,dependingonthebioavailabilityofthemetalions.
Thus,thetoxicitiesofthemetalcomponentsoftheparticulatesmustalsobeassessed,andonacase-by-casebasis.
LungToxicityofFivePoorlySolubleParticulates1.
Fibrogenicity/CarcinogenicityofCrystallineSilicaHumans.
Basedonsufficientevidenceforthecarcinogenicityofinhaledcrystallinesilicafromoccupationalsources,theInternationalAgencyforResearchonCancer(IARC,1997)hasclassifiedcrystallinesilicaasaGroup1carcinogeninhumans.
AccordingtoIARC,studiesofthefollowingpopulationsprovidedtheleast-confoundedexaminationsofanassociationbetweensilicaexposureandcancerrisk:goldminers,stoneindustryworkers,graniteshedandquarryworkers,crushedstoneindustryworkers,diatomaceousearthindustryworkers,refractorybrickworkers,potteryworkers,andcohortsofregisteredsilicotics.
Notallofthesestudiesdemonstratedexcesscancerrisks;but,inviewofthelargenumberofepidemiologicalstudiesundertakenandthewiderangeofpopulationsandexposurecircumstances,somenonuniformityofresultswouldbeexpected.
Insomestudies,increasingriskgradientshavebeenobservedinrelationtodosesurrogates--cumulativeexposure,durationofexposure,orthepresenceofradiographicallydefinedsilicosis--and,inoneinstance,topeakintensityexposure.
Forthese122reasons,theIARCWorkingGroupconcludedthatoverall,theepidemiologicalfindingssupportincreasedlungcancerrisksfrominhaledcrystallinesilicaresultingfromoccupationalexposure.
Animals.
IARC(1997)hasconcludedthatthereisAsufficientevidenceinexperimentalanimalsforthecarcinogenicityofcrystallinesilica.
Anumberofstudies(rev.
in:IARC,1997;Wooetal.
,1988;Holland,1990)havedemonstratedthat,inadditiontosilicosis/fibrosis,pulmonarytumorsareinducedinratsexposedtoquartz(Mini-U-Sil;acommonformofcrystallinesilica)byinhalation,singleintrapleural,intraperitoneal,and/orintratrachealadministration.
Ina24-monthinhalationstudyinrats,thelowesttesteddoseofrespirablecrystallinesilicaparticlestoinducelungtumors(LowestObservedAdverseEffectLevel,orLOAEL)was0.
74mg/m3.
*NoteforCasesUsingSilicaasPrimaryAnalogue:ForLOAELdoses,theAgencyconsidersamarginofexposure(MOE)of1,000orgreaterasrepresentingaloworderoftoxicityforhealthendpointsforwhichathresholddoseisdeemedappropriate.
Inthisinstance,exposureswouldhavetobereducedto0.
0007mg/m3toachieveaMOEof1,000,aconcentrationthatispracticallyimpossibletoachieve.
BecausetheLOAELof0.
74mg/m3isbasedontestdataonpuresilicaandbecausesilicaisconsideredtobeamuchmorepotentlungtoxicantthancrystallineparticulatescontainingsilica,theAgencyhasadoptedtheNIOSHREL(RecommendedExposureLimit)forsilica,0.
05mg/m3,asaNCEL(NewChemicalExposureLimit)-seehttp://www.
epa.
gov/opptintr/newchems/pubs/ncelmain.
htmformoreinformation)concentrationthatwouldadequatelyprotectworkersfromcrystallineparticulatescontainingsilica.
ThisNCELreplacestheformeronebasedontheOSHAPermissibleExposureLimit(PEL)forsilica,0.
1mg/m3.
2.
Fibrogenicity/CarcinogenicityofTalcHumans.
Epidemiologystudiessuggestanassociationbetweennonfibroustalc(afinelypowderedhydrousmagnesiumsilicate)andlungcancerrisk.
TheOSHAPELfortalcis20mppcf(millionparticlespercubicfoot),andtheNIOSH-recommended8-hrTWAconcentrationis2mg/m3.
Animals.
InanNTPinhalationstudy(NTPTR421,1993),maleandfemaleF344ratswereexposedto0,6,or18mg/m3talcfor113and122weeks,respectively.
Therewasclearevidenceofthecarcinogenicityoftalcinfemaleratsbasedontheincreasedincidenceofalveolar/bronchiolaradenomasandcarcinomasofthelunginthe18-mg/m3group(LOAEL).
TheNoObservedAdverseEffectLevel(NOAEL)fromthisstudyis6mg/m3.
TheNCELforanalogousparticulateswouldbe0.
06mg/m3.
3.
Fibrogenicity/CarcinogenicityofTitaniumDioxide(TI)Humans.
AccordingtoIARC(ACGIH1993),thereisinadequateevidenceforthecarcinogenicityofTIinhumans.
[ThereislimitedevidenceforthecarcinogenicityofTIinexperimentalanimals.
]Overallevaluation:TIisnotclassifiableastoitscarcinogenicitytohumans.
TheOSHAPEL=sfornuisancedust(inwhichTIisincluded)are15mg/m3totalparticulatesand5mg/m3respirablefraction.
TheACGIHTLV-TWAis10mg/m3oftotaldust123containingnoasbestosand1000willbeexcludedfromthiscategory.
Itisalsoassumedthatthesecompoundsneedtobewatersolubletobetoxic,therefore,compoundswithwatersolubilities(WS)1000forstablecompounds.
Theenvironmentalbasesetoftestswillberequestedforaquaticreleasesandtheterrestrialbasesetoftestswillberecommendedforterrestrialexposures.
GeneralTestingStrategy.
Theaquaticbasesetofenvironmentaltoxicitytestswillberecommendedforaquaticexposures.
Theacutetoxicitytestsforfish(HarmonizedTestGuideline850.
1075)anddaphnids(HarmonizedTestGuideline850.
1010)willbedoneusingtheflow-throughmethodwithmeasuredconcentrations;effectiveconcentrationswillbebasedon100%activeingredients(AI)andmeanmeasuredconcentrations;measuredTOCofdilutionwaterinthecontrol;thehighesttreatmentconcentrationonanominal-basisshouldequaltheaqueoussolubilitylimit;andsolventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubility.
Thealgaltoxicitytesting(HarmonizedTestGuideline850.
5400),shouldbedonewithstaticmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsat24,48,72,and96hours;testmediumwithatleast0.
300mg/LEDTAasafinalconcentration;thehighesttreatmentconcentrationonanominal-basisequaltotheaqueoussolubilitylimit;andsolventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubility.
Fishchronictoxicitytesting,i.
e.
,fishearlylifestage(ELS)toxicitytesting(HarmonizedTestGuideline850.
1400),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,21,and28;measuredTOCofdilutionwaterinthecontrol;thehighesttreatmentconcentrationonanominal-basisshouldbesetattheaqueoussolubilitylimit;solventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubility;andthe1277-dELSstagetoxicitytestcannotbesubstitutedforthe28-dELStoxicitytestbecauseVanLeeuwenetal(1990)havedemonstratedthatthe7-dELStoxicitytestunderestimatedthechronictoxicityofanilinesmeasuredbythe28-dELStoxicitytestby>5.
3timeswhentheNOECswerecompared(seeTableVIIinVanLeeuwen);Daphnidchronictoxicitytesting(HarmonizedTestGuideline850.
1300),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,and21;measuredTOCofdilutionwaterinthecontrol;thehighesttreatmentconcentrationonanominal-basisshouldbesetattheaqueoussolubilitylimit;solventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubility;andthe7-ddaphnidchronictoxicitytestcannotbesubstitutedforthe21-dtoxicitytestbecauseVanLeeuwenetal(1990)havedemonstratedthatthefish7-dELStoxicitytestunderestimatedthechronictoxicityofanilinesmeasuredbythefish28-dELStoxicitytestby>5.
3timeswhentheNOECswerecompared(seeTableVIIinVanLeeuwen).
Theterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedinggrowthtest,HarmonizedTestGuideline850.
4230),theearthwormacutetoxicitytest(HarmonizedTestGuideline850.
6200),andthesoilmicrobialcommunitybioassay(TestGuideline850.
5100)willberecommendedforterrestrialexposures.
Chronictoxicitytestingforterrestrialorganismsinclude:theplantwholelifecycletest(TestGuideline850.
4150),theplantuptaketest(TestGuideline850.
4800),andthesoilmicrobialcommunitybioassay(TestGuideline850.
5100).
References.
Leach,J.
M.
andThakore,A.
N.
,1976.
Toxicconstituentinmechanicalpulpingeffluents.
Tappi,59:129.
Leach,J.
M.
andThakore,A.
N.
,1978.
Compoundstoxictofishinpulpmillwastestreams.
Progr.
WaterTechnol.
(G.
B.
)9:787.
VanLeeuwenCJ,AdemaDMM,andHermensJ.
1990.
Quantitativestructure-activityrelationshipsforfishearlylifestagetoxicity.
AquaticToxicology16:321-334.
January,1994;revisedJune2010128Category:Stilbene,derivativesof4,4-bis(triazin-2-ylamino)-HumanHealth(case-by-case)Definition.
Anywatersoluble(sulfonated)derivativeof4,4-bis(triazin-2-ylamino)stilbeneisconsideredtobeamemberofthiscategory.
HazardConcerns.
EPApreviouslyidentifiedhazardconcernsforthepossibledevelopmental/reproductivetoxicityofnewchemicalsfallingintothisstilbene,derivativesof4,4-bis(triazin-2-ylamino)-categorybasedonpublishedtestresultsforamemberofthecategory.
EPAhasreviewedtestdatadevelopedbytheStilbeneWhiteningAgentTaskForceoftheEcologicalandToxicologicalAssociationofDyesandOrganicPigmentsManufacturers(ETAD).
Thesestudiesconsistedofarange-findinganddefinitive2-generationratstudy(gavage)andrange-findinganddefinitivedevelopmentaltoxicitystudiesinratsandrabbits(gavage)forC.
I.
FluorescentBrightener220(CASNo.
16470-24-9).
Basedontheresultsfromthesestudies,EPAhasconcludedthatavailableinformationdoesnotsupportcontinuedidentificationofstilbenesasanewchemicalcategorypresentingconcernsforpossibledevelopmental/reproductivetoxicity.
EPAwillcontinuetoevaluatethepotentialhealthconcernsfornewchemicalstilbenesthatarenotifiedbut,withthischange,willnotapplyacategoryunderstandingasregardspotentialdevelopmental/reproductivetoxicity.
References.
Breslin,WJ.
ApilotprenataldevelopmentaltoxicitystudyofC.
I.
FluorescentBrightener220andC.
I.
FluorescentBrightener339administeredviaoralgavagetorats.
MPIResearchLaboratoryStudyIdentification795-001,August18,1998a.
Breslin,WJ.
ApilotprenataldevelopmentaltoxicitystudyofC.
I.
FluorescentBrightener220andC.
I.
FluorescentBrightener339administeredviaoralgavagetoNewZealandWhiterabbits.
MPIResearchLaboratoryStudyIdentification795-002,August18,1998b.
129Turck,PA.
PrenataldevelopmentaltoxicitystudyofC.
I.
FluorescentBrightener220administeredviaoralgavagetorats.
MPIResearchLaboratoryStudyIdentification795-003,December2,1999.
Turck,PA.
Range-findingreproductionstudyofC.
I.
FluorescentBrightener220administeredviaoralgavagetorats.
MPIResearchLaboratoryStudyIdentification795-005,June8,2000a.
Turck,PA.
PrenataldevelopmentaltoxicitystudyofC.
I.
FluorescentBrightener220administeredviaoralgavagetoNewZealandWhiterabbits.
MPIResearchLaboratoryStudyIdentification795-004,January27,2000b.
Turck,PA.
TwogenerationreproductionandfertilitystudyofC.
I.
FluorescentBrightener220administeredviaoralgavageinrats.
MPIResearchLaboratoryStudyIdentificationNo.
795-006,August24,2001.
PreviousCategoryStatementReferences.
Burg,AW,Rohovsky,MW&Kensler,CJ(1977).
CurrentstatusofhumansafetyandenvironmentalaspectsoffluorescentwhiteningagentsusedindetergentsintheUnitedStates.
CriticalReview&EnvironmentalControl,7,91-120.
Gloxhuber,CH&Bloching,H(1978).
Toxicologicpropertiesoffluorescentwhiteningagents.
ClinicalToxicology,13,(2),171-203.
Keplinger,ML,Fancher,OE,Lyman,FL&Calandra,JC(1974).
Toxicologicstudiesoffourfluorescentwhiteningagents.
Toxicology&AppliedPharmacology,27,494-506.
Keplinger,ML,Lyman,FL&Calandra,JC(1975).
Three-generationreproductionstudieswithFWAs.
In:FlourescentWhiteningAgents.
R.
Anliker&G.
Muller(Eds.
).
Stuttgart,Germany:GeorgThiemePublishers.
Kramer,JB(1992).
Fluorescentwhiteningagents.
In:TheHandbookofEnvironmentalChemistry,3,(partF),351-366.
O.
Hutzinger(Ed.
).
Heidelberg,Germany:Springer-VerlagBerlin.
Lorke,D(1975).
Studiesofembryotoxicityinrats&rabbits.
In:FlourescentWhiteningAgents.
R.
Anliker&G.
Muller(Eds.
).
Stuttgart,Germany:GeorgThiemePublishers.
Lyman,FL,Schulze,J,Ganz,CR,Stensby,PS,Keplinger,ML&Calandra,JC(1975).
Long-termtoxicityoffourfluorescentwhiteningagents.
Food,Cosmetics&Toxicology,13,521-527.
Poiger,T&Giger,W(1991).
Determinationoffluorescentwhiteningagentsinsewageandsewagesludgebyhighperformanceliquidchromatography.
ReprintofaposterpresentedatthemeetingoftheSwissChemicalSocietyinBern,Switzerland.
October18,1991.
130EAWAG/ETH,CH-8600Dubendorf,Switzerland.
Zinkernagel,R(1975).
Fluorescentwhiteningagentsintheenvironment.
In:FlourescentWhiteningAgents.
R.
Anliker&G.
Muller(Eds.
).
Stuttgart,Germany:GeorgThiemePublishers.
8E-CAP-0024.
ReporttoCiba-GeigyCorporation.
TeratogenicstudywithFA-15inAlbinorabbits,May23,1972.
SubmittedtoUSEPAonOctober9,1992.
PB81-148819.
InformationHazardProfilesonPotentialOccupationalHazards.
Vol.
2.
ChemicalClassesFluorescentWhiteningAgent(FWA's).
NationalInstituteforOccupationalSafetyandHazard,Rockville,Maryland.
December1979.
January,1992;revisedDecember,1994;revisedAugust,2002.
131Category:ThiolsEnvironmentalToxicityDefinition.
Thiscategoryincludesallthiolsormercaptans.
Itisassumedthatthiolshavetobeabsorbedtobetoxic,therefore,compoundswithMWs>1000willbeexcludedfromthiscategory.
Acutetoxicityforthiolswhichareliquidsatroomtemperatureisknowntobelimitedbytheoctanol/waterpartitioncoefficient(Kow).
AbovealogKowvalue≥6.
5,thiolsshownoeffectsatsaturationduring96-hexposuresforfish.
ThelogKowcut-offsforotherorganismsforacuteeffectsaregenerallylower.
ThiolswhicharesolidsatroomtemperaturemayshownotoxicityatsaturationatlowerKowvaluesdependingonthemeltingpoint,i.
e.
,thehigherthemeltingpointatagivenKow,thegreaterthelikelihoodthatnotoxicitywillbeobservedatsaturation.
Forsolids,thenoeffectsatsaturationhastobedeterminedonacase-by-casebasis.
TherearenoknownKowlimitsforchronictoxicityatthistime,butitmaynotbemuchabovealogKowof8to9forliquidthiols.
HazardConcerns.
TheaquatictoxicityforthiolsandmercaptanshasbeendeterminedthroughSARanalysisbyEPAusingECOSAR–ahazardestimationtoolthatuseschemicalstructuredescriptorstoestimatetheacuteandchronictoxicityofasubstancetoaquaticorganisms.
[LinkforECOSAR:http://www.
epa.
gov/opptintr/newchems/tools/21ecosar.
htm].
Thiolswhicharesubstitutedwithacarboxylicacidwillbeabout10timeslesstoxicthanpredictedbythisSARatpH7.
UsetheKowforthefreeacid.
Membersofthiscategoryexhibittoxicityrangingfromlowtoxicity(i.
e.
,>100mg/L)tohightoxicity(i.
e.
,6.
5forfish.
ChronictoxicityhasnoknownupperboundforlogKow,butitisprobablynear9.
MWwillbe6.
5,chronictoxicitytestingwillberecommended.
GeneralTestingStrategyI.
ReleasetoAquaticEcosystemsTier1.
Theaquaticbasesetofenvironmentaltoxicitytestswillberecommendedforaquaticexposures.
Theacutetoxicitytestsforfish(HarmonizedTestGuideline850.
1075)anddaphnids(HarmonizedTestGuideline850.
1010)willbedoneusingtheflow-throughmethodwithmeasuredconcentrations;effectiveconcentrationswillbebasedon100%activeingredients(AI)andmeanmeasuredconcentrations;measuredTOCofdilutionwaterinthecontrol;thehighesttreatmentconcentrationonanominal-basisshouldequaltheaqueoussolubilitylimit;andsolventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthePMNbeyonditsaqueoussolubilitylimit.
Thealgaltoxicitytesting(HarmonizedTestGuideline850.
5400),shouldbedonewith132staticmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsat24,48,72,and96hours;testmediumwithatleast0.
300mg/LEDTAasafinalconcentration;thehighesttreatmentconcentrationonanominal-basisequaltotheaqueoussolubilitylimit;andsolventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthePMNbeyonditsaqueoussolubilitylimit.
IfthereisnosignificantriskfromthePMNaftertheresultsoftheenvironmentalbasesethavebeenintegratedintotheriskassessment,thennofurthertestingisrecommended.
However,ifthereisasignificantrisk,thengotoTier2.
Tier2.
Aerobicbiodegradabilityaccordingtoeitherofthefollowingtestguidelines:-ReadyBiodegradability(sixmethods;chooseanyone)(HarmonizedTestGuideline835.
3110)-ReadyBiodegradability–CO2inSealedVessels(HeadspaceTest)(HarmonizedTestGuideline835.
3140)IfthereisnosignificantriskfromthePMNaftertheresultsoftheaerobicbiodegradationhavebeenintegratedintotheriskassessment,thennofurthertestingisrecommended.
However,ifthereisasignificantrisk,thengotoTier3.
Tier3.
Fishchronictoxicitytesting,i.
e.
,fishearlylifestage(ELS)toxicitytesting(HarmonizedTestGuideline850.
1400),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,21,and28;measuredTOCofdilutionwaterinthecontrol;thehighesttreatmentconcentrationonanominal-basisshouldbesetattheaqueoussolubilitylimit;solventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthePMNbeyonditsaqueoussolubilitylimit;andthe7-dELSstagetoxicitytestcannotbesubstitutedforthe28-dELStoxicitytest.
Daphnidchronictoxicitytesting(HarmonizedTestGuideline850.
1300),withflow-throughmethods;measuredconcentrations;effectiveconcentrationsbasedon100%activeingredients(AI)andmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,and21;measuredTOCofdilutionwaterinthecontrol;thehighesttreatmentconcentrationonanominal-basisshouldbesetattheaqueoussolubilitylimit;solventcanbeusedtoassistthePMNtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthePMNbeyonditsaqueoussolubilitylimit;andthe7-ddaphnidchronictoxicitytestcannotbesubstitutedforthe21-dtoxicitytest.
II.
ReleasetoTerrestrialEcosystemsTheterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedinggrowthtest,HarmonizedTestGuideline850.
4230),theearthwormacutetoxicitytest(HarmonizedTest133Guideline850.
6200),andthesoilmicrobialcommunitybioassay(TestGuideline850.
5100)willberecommendedforterrestrialexposures.
Chronictoxicitytestingforterrestrialorganismsinclude:theplantwholelifecycletest(TestGuideline850.
4150),theplantuptaketest(TestGuideline850.
4800),andthesoilmicrobialcommunitybioassay(TestGuideline850.
5100).
December,1994;revisedJune2010134Category:SubstitutedTriazinesEnvironmentalToxicityDefinition.
Thiscategoryincludessubstitutedtriazineswhichcanbearomatic,partiallyaromatic(orpartiallysaturated)andunsaturated.
Thenitrogensinthetriazineringmaybesymmetricalorasymmetrical.
Substitutionsonthecarbonsmayincludebutnotbelimitedto:aliphaticalcohols;ketones;benzeneandsubstitutedbenzenes;aliphatichydrocarbons,alkyenesandalkynes;freeaminesandsubstitutedamines;cyclicaliphatichydrocarbons;halogens;amides;cyanides;ethers;methoxygroups;sulfides;azidogroups;andcarboxylicacidesters.
Substitutionsonthenitrogensmayincludebutnotbelimitedto:freeaminesandsubstitutedamines;-N=CH;aliphatichydrocarbons,alkyenesandalkynes;andbenzeneandsubstitutedbenzenes.
HazardConcerns.
Manymembersofthiscategoryarecommercialherbicideswhichareusedtocontrolbothaquaticplantsandterrestrialplants.
Theirmodeoftoxicactionisgenerallyconsideredtobeinhibitionofphotosynthesis.
Manymembersofthisclassaretoxictoalgaeat8,notestingwillberequestedbecausenotoxiceffectsatsaturationwillbeexpected.
Generally,membersofthiscategorywillhaveMWsoflessthan1000.
GeneralTestingStrategyTheaquaticbasesetofenvironmentaltoxicitytestswillberecommendedforaquaticexposuresandtheterrestrialbasesetofenvironmentaltoxicitytests(i.
e.
,theearlyseedlinggrowthtest,theearthwormacutetoxicitytestandthesoilmicrobialcommunitybioassay)willberecommendedforterrestrialexposures.
August,1989;revisedJune2010135Category:TriarylmethanePigments/DyeswithNon-solubilizingGroupsHumanHealthEnvironmentalToxicityOtherNames:TriphenylmethanePigments/Dyes,Diphenylnaphthyl-methanePigments/DyesDefinition.
Structurally,triarylmethanepigments/dyesarederivativesoftriphenylmethaneordiphenylnaphthylmethane.
Inordertoachievetherequiredspectralabsorptionpropertiesthatcharacterizethesedyes,aminegroups(primary,secondary,ortertiary)orhydroxylgroupsmustbepresentonthearomaticringpositionsparatothemethanecarbon.
Aminesubstitutionsaremoreprevalentthanhydroxysubstitutions(C.
I.
42000-42175fordiaminoderivatives,C.
I.
42500-42800fortriaminoderivatives,C.
I.
43800-43875forhydroxyderivatives,and43500-43570foraminohydroxyderivatives.
HazardConcerns.
Thereareoncogenicityconcernsforthetriarylmethanepigments/dyesbasedonanalogytoGentianVioletandC.
I.
BasicRed9.
Inaddition,therearedevelopmentalandreproductivetoxicityconcernsforthesecompoundsbasedonanalogytoGentianVioletandMalachiteGreen.
EcotoxicityconcernsarebasedonQSARpredictionsfordelocalizedcationicdyes.
Cationicdyesareanestablishedecotoxicitycategory.
136Boundaries.
Pigments/Dyesincludedinthiscategoryarethedi-andtri-aminosubstitutedtriphenylmethaneanddiphenylnaphthyl-methanederivatives.
Dyessubstitutedwithsolubilizinggroupssuchascarboxylicacid,sulfonicacid,orhalogens,arenotincluded.
Pigmentsthathaveessentiallynegligiblewatersolubility(2days,thenintegratetheresultsintotheriskassessment.
IfthereisnosignificantriskfromthePMN,thennofurthertestingisrecommended.
However,ifthereremainsasignificantrisk,thengotoTier4.
Tier3a.
Ift1/22days,gotoTier3.
Tier2a.
Ift1/21000arenotexpectedtobeabsorbedbyaquaticorganismseveniftheyarewatersoluble.
Therefore,onlyZrcompoundswithMWs<1000areexpectedtobetoxic.
GeneralTestingStrategyI.
ReleasetoAquaticEcosystemsTier1.
Theaquaticbasesetofenvironmentaltoxicitytestswillberecommendedforaquaticexposures.
Theacutetoxicitytestsforfish(HarmonizedTestGuideline850.
1075)anddaphnids(HarmonizedTestGuideline850.
1010)willbedoneusingtheflow-throughmethod;effectiveconcentrationswillbebasedon100%activeingredients(AI)andmeanmeasuredconcentrations;thetotalorganiccarbon(TOC)concentrationofdilutionwaterinthecontrolmustbelessthan2.
0mgTOC/L;TOCmustbemeasuredinthecontroljustpriortothestartofthetest;thehighesttreatmentconcentrationonanominal-basisshouldnotexceedtheaqueoussolubilitylimitofthetestedcompound;solventcanbeusedtoassistthecompoundtoreachits148aqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthecompoundbeyonditsaqueoussolubilitylimit;andhardnessofdilutionwaterhastobelessthan180.
0mg/LasCaCO3.
Iftoxicitymitigationtestingisdonewithhumicacid,thenthestaticmethodwithnominalconcentrationswillberecommended.
Thealgaltoxicitytesting(HarmonizedTestGuideline850.
5400),shouldbedonewiththestaticmethod;effectiveconcentrationsbasedon100%AIandmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsat24,48,72,and96hours;testmediumwithnomorethan0.
300mg/LEDTAasafinalconcentration;theTOCofthetest/growthmediumshouldbelessthan2.
0mgTOC/L;TOCshouldbemeasuredjustpriortothestartofthetest;thehighesttreatmentconcentrationonanominal-basisshouldnotexceedtheaqueoussolubilitylimitofthetestedcompound;andsolventcanbeusedtoassistthecompoundtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthecompoundbeyonditsaqueoussolubilitylimit.
Iftoxicitymitigationtestingisdonewithhumicacid,thennominalconcentrationswillberecommended.
IfthereisnosignificantriskfromtheZrcompoundaftertheresultsoftheenvironmentalbasesethavebeenintegratedintotheriskassessment,thennofurthertestingwillberecommended.
However,ifthereisasignificantrisk,thengotoTier2.
Tier2.
Fishchronictoxicitytesting,i.
e.
,fishearlylifestage(ELS)toxicitytesting(HarmonizedTestGuideline850.
1400),withtheflow-throughmethod;effectiveconcentrationsbasedon100%AIandmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,21,and28;theTOCofdilutionwaterinthecontrolshouldbelessthan2.
0mgTOC/L;TOCshouldbemeasuredinthecontrolsjustpriortoandduringthetest;thehighesttreatmentconcentrationonanominal-basisshouldnotexceedtheaqueoussolubilitylimitofthetestedcompound;solventcanbeusedtoassistthecompoundtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthecompoundbeyonditsaqueoussolubilitylimit;andhardnessofdilutionwaterhastobelessthan180.
0mg/LasCaCO3.
Daphnidchronictoxicitytesting(HarmonizedTestGuideline850.
1300),withtheflow-throughmethod;effectiveconcentrationsbasedon100%AIandmeanmeasuredconcentrations;statisticalanalysisofeffectiveconcentrationsatdays7,14,and21;theTOCofdilutionwaterinthecontrolshouldnotexceed2.
0mgTOC/L;TOCmustbemeasuredinthecontrolsjustpriortoandduringthetest;thehighesttreatmentconcentrationonanominal-basisshouldnotexceedtheaqueoussolubilitylimitofthetestedcompound;solventcanbeusedtoassistthecompoundtoreachitsaqueoussolubilitylimitquicker,butcannotbeusedtoartificiallyenhancethewatersolubilityofthecompoundbeyonditsaqueoussolubilitylimit;andhardnessofdilutionwaterhastobelessthan180.
0mg/LasCaCO3.
II.
ReleasetoTerrestrialEcosystems:Theterrestrialbasesetofenvironmentaltoxicitytestswillberecommendedforterrestrialexposures.
Theterrestrialbasesetincludes:theearlyseedinggrowthtest(HarmonizedTestGuideline850.
4230),theearthwormtoxicitytest(HarmonizedTestGuideline850.
6200),thesoilmicrobialcommunitybioassay(HarmonizedTestGuideline850.
5100),andtheavianacuteoraltoxicitytest(HarmonizedTestGuideline850.
2100).
Chronictoxicitytestingforterrestrialorganismsinclude:theplantwholelifecycletest(HarmonizedTestGuideline850.
4150),theplantuptaketest(HarmonizedTestGuideline149850.
4800)andtheavianreproductiontest(HarmonizedTestGuideline850.
2300).
June,1992;revisedJune2010