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areportallegingaconnectionbetweenaspartameandincreasesintheincidenceofbraintumors
intheU.S.(Olneyetal.1996)andconcludedthattherewasnonewevidencetojustifyareevalu-
ationofaspartame(SCF1997).In2002,SCFcarriedoutafurtherreviewofalltheoriginaland
morerecentdataonaspartameandconcludedthattherewasnoneedtorevisethepreviouslyestab-
lished ADI (SCF 2002). The EFSA AFC and ANS Panels have evaluated, on the request of the
EuropeanCommission,twolong-termcarcinogenicitystudiesinratsonaspartameconductedby
the European Rammazzini Foundation of Oncology and Environmental Sciences (ERF; Soffritti
etal.2005,2006,2007).Inbothcases,thePanelsconcludedthat,onthebasisofalltheevidence
availablefromtheERFstudies,othernewdataemergedsince2002onaspectsotherthancarcino-
genicity,aswellaspreviousevaluationsthattherewasnoreasontorevisethepreviouslyestablished
ADIforaspartame(EFSA2006b,2009a,b).In2010,acarcinogenicitystudyinmiceonaspartame
(Soffrittietal.2010)andanepidemiologicalstudyontheassociationbetweenintakesofartiicially
sweetenedsoftdrinksandincreasedincidenceofpretermdelivery(Halldorssonetal.2010)were
published.Althoughtheepidemiologicalstudydidnotspeciicallyaddressaspartame,asintense
sweeteners other than aspartame are also used in soft drinks, the authors speculated that expo-
suretoaspartameoritsmetabolitemethanolcouldbeacausativefactorforprematuredeliveries.
Subsequently, EFSA, in its statement from 2011, concluded that these studies gave no reason to
reconsiderpreviousevaluationsofaspartameorofothersweetenerscurrentlyauthorizedforfood
useintheEU(EFSA2011).
TheJECFAevaluatedaspartamein1980andallocatedanADIof0-40mg/kgbw/daybased
ontheestimatedlevelcausingnotoxicologicaleffectsinrats(JECFA1980a,b).In1981,theJECFA
evaluatedanadditionallong-termstudyinratsonaspartameandthediketopiperazineimpurityand
furtherbiochemicalstudiesofaspartameinhumans.TheADIof40mg/kgbw/daywasconirmed
(JECFA1981a,b).
14.7.1.3 Cyclamate (E952)
Themixtureof10partsofcyclamateandonepartofsaccharinewaswidelyusedinfoodsand
beveragesduringthe1960s.In1969,however,cyclamatewasprohibitedinmanycountries,because
bladdertumorswerefoundinratsfedwiththe10:1cyclamate-saccharinmixture(Priceetal.1970).
Sincethen,severaladditionaltoxicityandcarcinogenicitystudieswereconductedwithcyclamate,
the cyclamate-saccharin mixture, and the cyclamate metabolite cyclohexylamine (CHA). These
studieswereconsiderednegativewithregardtothecarcinogeniceffectofbothcyclamateandCHA
(Boppetal.1986).
TheSCFexpresseditsopiniononcyclamateanditstwometabolites(CHAanddicyclohexyl-
amine)in1984andestablishedatemporaryADIof0-11mg/kgbw/dayexpressedascyclamicacid,
forcyclamicacid,anditscalciumandsodiumsalts(SCF1985).TheADIwasbasedonaNOAEL
of100mg/kgbw/dayforCHA,ametaboliteproducedbytheintestinalmicrolora,withrespectto
testiculartoxicityina90-daytoxicitystudyinrats.Anuncertaintyfactorof100wasusedforCHA,
andaconversionfactorof11wasappliedtoaccountfortheamountofCHAformedfromcyclamate.
The ADI was made temporary because of uncertainties relating to the relevance for man of the
testiculardamagefoundinratstreatedwithCHA.Thereafter,thecommitteereviewedcyclamate
onseveraloccasions,whenadditionaldatabecameavailable(SCF1989,1992,1997).Eachtime,
thetemporaryADIof0-11mg/kgbw/daywasmaintained.Finally,in2000,theSCFremovedthe
temporary status and established an ADI of 0-7 mg/kg bw/day, expressed as cyclamic acid, for
cyclamicacid,anditscalciumandsodiumsalts(SCF2000b).
TheJECFAestablishedatemporaryADIforcyclamateof0-4mg/kgbw/daybasedonano-effect
levelforCHA(freebase)of74mg/kgbw/daywithrespecttotesticularatrophyin1977(JECFA
1977).TheJECFAusedanuncertaintyfactorof200toestablishatemporaryADIforCHA,afactor
of2toconverttheADIforCHAtoanADIforcyclamicacidifallcyclamicacidwasconvertedinto
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