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asthefreeacid;SCF1995).Atthattime,theSCFconsideredbothpreviousandnewexperimental
informationavailableandtheextensiveepidemiologicaldatawithnoevidenceofanyrelationship
betweensaccharinintakeandbladdercancerinhumans.Saccharinisnotgenotoxicbutisaurinary
bladdercarcinogeninmaleratswhengiveninverylargedoses. Althoughitisunlikelythatthis
carcinogeniceffectisrelevantinhumans,theADIhasbeenbasedontheNOELof500mg/kgbw/
dayformaleratsandasafetyfactorof100.
TheJECFAhasreviewedthesafetyofsaccharinonseveraloccasions.In1967and1974,the
reviewofthesafetyofthesweetenerresultedinanunconditionalADIof0-5mg/kgbw/dayanda
conditionalADIof0-15mg/kgbw/dayfordieteticpurposesonly(JECFA1967,1974).In1977,the
ADIwaschangedtoatemporaryADIof0-2.5mg/kgbw/day,andtheconditionalADIwasabol-
ished(JECFA1977).Thisactionwasbasedontheresultsofstudiesdemonstratingthathighdoses
ofsaccharininducedbladdertumorsinmalerats,butnosucheffecthasbeenfoundinotheranimal
species.Followingtheevaluationofnewdatain1980and1982,thetemporaryADIwasextended
(JECFA1980a,1982a,b).ThetemporaryADIwasconirmedin1984basedonano-effectlevelof
1%inthediet(equivalentto500mg/kgbw/dayinratsandasafetyfactorof200;JECFA1984a,b).
In1993,areviewofnewexperimentaldataandepidemiologicaldatathatprovidedevidenceofno
relationshipbetweensaccharinintakeandbladdercancerinhumansresultedinanADIof0-5mg/
kgbw/dayforsaccharinanditscalcium,potassium,andsodiumsaltsbasedontheNOAELof500
mg/kgbw/dayinatwo-generationlong-termfeedingstudyinratsandasafetyfactorof100(JECFA
1993a,b).
14.7.1.7 Steviol Glycosides (E960)
Steviolglycosides,acceptedintheEUasafoodadditive,aremixturesofsteviolglycosidesthat
comprisenotlessthan95%ofsteviosideand/orrebaudiosideA,whichcanbeextractedfromthe
leavesofthe
Stevia rebaudiana
Bertoniplant.Safetyevaluationofsteviolglycosideswasperformed
bytheEFSAin2010.TheANSPanelofEFSAestablishedanADIforsteviolglycosides,expressed
assteviolequivalents,of4mg/kgbw/daybasedontheapplicationofa100-folduncertaintyfactor
totheNOAELina2-yearcarcinogenicitystudyinrats(EFSA2010a).
Inthepast,stevioside,oneofthemajorglycosidesintheleavesofthe
S. rebaudiana
Bertoni
plant,wasevaluatedasasweetenerbytheSCFonseveraloccasions(SCF1985,1989,1999a).The
SCFconcludedthattheuseofsteviosidewastoxicologicallynotacceptableduetoinsuficientavail-
abledatatoassessitssafety.
TheJECFAevaluatedtoxicologicaldataonsteviolglycosides(steviosideandtheaglyconeste-
viol)in1998atits51stmeeting(JECFA1998),andtheneedforfurtherdatawasexpressed.Atthe
63rdmeeting,theJECFAreviewednewdataandinformationandestablishedtentativespeciica-
tionsforthematerialreferredtoas“steviolglycosides”(JECFA2004a,b).Theadditionalbiochemi-
calandtoxicologicaldataprovidedthebasisfortheallocationofatemporaryADIof0-2mg/kg
bw/day for steviol glycosides expressed as steviol. The temporary ADI was based on the NOEL
of2.5%steviosideinthediet,equalto970or383mg/kgbw/dayexpressedassteviol,ina2-year
studyinratsusinganuncertaintyfactorof200.Onthesameoccasion,theJECFAspeciiedthe
needforstudieswithrepeatedexposureofnormotensiveandhypotensiveindividualsandpatients
withinsulin-dependentandnoninsulin-dependentdiabetes.Onthe68thmeetingofthecommittee,
asubsequentreviewofadditionaldatadidnotraiseconcernsregardingthesafetyofsteviolglyco-
sides.However,thetemporaryADIwasmaintained,pendingsubmissionoftheresultsofongoing
clinicalstudies(JECFA2007).Thetentativespeciicationswererevised(JECFA2008a).Finally,
theresultsoftheinalizedclinicalstudieswerefoundbytheJECFAsuficienttoallowtheremoval
ofthetemporarystatus,andafullADIof0-4mg/kgbw/day,expressedassteviol,wasestablished
(JECFA2008b,c).
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