<b>Bijsluiter</b>. De hyperlink naar het originele document werkt niet meer. Daarom laat Woogle de tekst zien die in dat document stond. Deze tekst kan vreemde foutieve woorden of zinnen bevatten en de opmaak kan verdwenen of veranderd zijn. Dit komt door het zwartlakken van vertrouwelijke informatie of doordat de tekst niet digitaal beschikbaar was en dus ingescand en vervolgens via OCR weer ingelezen is. Voor het originele document, neem contact op met de Woo-contactpersoon van het bestuursorgaan.<br><br>====================================================================== Pagina 1 ======================================================================

<pre>Isomaltulose
Tweede beoordeling van de veiligheid voor de consument, volgens de
Europese verordening 258/97 betreffende nieuwe voedingsmiddelen en
nieuwe voedselingrediënten
Isomaltulose
Second opinion regarding consumer safety, in accordance with European
Regulation 258/97 concerning novel foods and novel ingredients
Gezondheidsraad:
Commissie Veiligheidsbeoordeling nieuwe voedingsmiddelen (VNV)
Health Council of the Netherlands
Committee on the Safety Assessment of Novel Foods
aan/to
de minister van Volksgezondheid, Welzijn en Sport/
the Minister of Health, Welfare and Sport
de minister van Landbouw, Natuur en Voedselkwaliteit/
the Minister of Agriculture, Nature and Food Quality
Nr 2004/01VNV, Den Haag, 15 juni 2004
No. 2004/01VNV, The Hague, June 15, 2004
</pre>

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<pre>De Gezondheidsraad, ingesteld in 1902, is een adviesorgaan met als taak de regering en
het parlement “voor te lichten over de stand der wetenschap ten aanzien van vraagstuk-
ken op het gebied van de volksgezondheid” (art. 21 Gezondheidswet).
     De Gezondheidsraad ontvangt de meeste adviesvragen van de bewindslieden van
Volksgezondheid, Welzijn & Sport; Volkshuisvesting, Ruimtelijke Ordening & Milieu-
beheer; Sociale Zaken & Werkgelegenheid en Landbouw, Natuur en Voedselkwaliteit.
De Raad kan ook eigener beweging adviezen uitbrengen. Het gaat dan als regel om het
signaleren van ontwikkelingen of trends die van belang kunnen zijn voor het overheids-
beleid.
     De adviezen van de Gezondheidsraad zijn openbaar en worden in bijna alle gevallen
opgesteld door multidisciplinaire commissies van – op persoonlijke titel benoemde –
Nederlandse en soms buitenlandse deskundigen.
The Health Council of the Netherlands, established in 1902, is an independent scientific
advisory body. Its remit is “to advise the government and Parliament on the current level
of knowledge with respect to public health issues...” (Section 21, Health Act).
     The Health Council receives most requests for advice from the Ministers of Health,
Welfare & Sport; Housing, Spatial Planning & the Environment; Social Affairs &
Employment, and Agriculture, Nature and Food Quality. The Council can publish advi-
sory reports on its own initiative. It usually does this in order to ask attention for devel-
opments or trends that are thought to be relevant to government policy.
     Most Health Council reports are prepared by multidisciplinary committees of Dutch
or, sometimes, foreign experts, appointed in a personal capacity. The reports are avail-
able to the public.
Deze publicatie kan als volgt worden aangehaald:
Gezondheidsraad. Commissie Veiligheidsbeoordeling nieuwe voedingsmiddelen. Iso-
maltulose. Den Haag: Gezondheidsraad, 2004; publicatie nr 2004/01VNV.
Preferred citation:
Health Council of the Netherlands. Committee on the Safety Assessment of Novel
Foods. Isomaltulose. The Hague: Health Council of the Netherlands, 2004; publication
no. 2004/01VNV.
auteursrecht voorbehouden/all rights reserved
U kunt het advies downloaden van www.gr.nl/
This report can be downloaded from www.healthcouncil.nl
</pre>

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<pre>  Inhoud/Contents
  Brief aan de Minister van Volksgezondheid, Welzijn en Sport 4
  Letter to the Dutch Minister of Health, Welfare and Sport 8
  Literatuur/Literature 11
  Bijlagen/Annexes 13
A De Adviesaanvraag/Request for advice 14
B De commissie/The committee 16
C EU-procedure/EU-procedure 18
D Samenvatting van het dossier/Executive summary of the dossier 21
E Eerste beoordeling/First assessment 31
  Inhoud/Contents                                                  3
</pre>

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<pre>Gezondheidsraad                                 Vice-voorzitter
Health Council of the Netherlands
Aan de Minister van Volksgezondheid,
Welzijn en Sport
Onderwerp          : Tweede beoordeling veiligheid Isomaltulose
Uw kenmerk         : VGB/VL 2483347
Ons kenmerk        : 2004/01VNV, U-865/MR/cv/622-CW
Datum              : 15 juni 2004
Mijnheer de minister,
Dit schrijven dient ter beantwoording van de adviesaanvraag over de veiligheid van nieuwe
voedingsmiddelen en nieuwe voedselingrediënten, die door u mede namens de Minister van
Landbouw, Natuur en Voedselkwaliteit aan de Gezondheidsraad is voorgelegd. Aan de orde is een
zogenoemde tweede beoordeling, conform de Europese verordening 258/97, van isomaltulose. Dit
nieuwe voedselingrediënt wordt gemaakt door enzymatische omvorming van sucrose (suiker). De
aanvrager is de firma Cargill die isomaltulose, geproduceerd door het dochterbedrijf Cerestar, op
de Europese markt wil brengen. Isomaltulose komt niet direct beschikbaar voor de consument,
maar zal worden verwerkt in verschillende categorieën levensmiddelen waaronder dranken,
bakkerijproducten, maaltijdvervangers en zoetwaren. De beoordeling is verricht door de
Commissie ‘Veiligheidsbeoordeling nieuwe voedingsmiddelen’ van de Gezondheidsraad
(Commissie VNV).
De eerste beoordeling van de aanvraag voor markttoelating is verricht door het Advisory
Committee on Novel Foods and Processes (ACNFP) van het Verenigd Koninkrijk. De ACNFP
heeft isomaltulose beoordeeld als veilig voor de toepassing als voedselingrediënt. Ten overvloede
wijst de ACNFP erop dat levensmiddelen die isomaltulose bevatten moeten voldoen aan bestaande
regelgeving en niet vergezeld mogen gaan van claims die de consument kunnen misleiden.
Volgens de ACNFP zou de aanvrager marktmonitoring moeten uitvoeren om het
consumptiepatroon van isomaltulose-houdende voedingsmiddelen vast te stellen en om na te gaan
of er bij de consument geen misvattingen zijn aangaande het energiegehalte van deze nieuwe
producten. De ACNFP is bezorgd dat de aan isomaltulose toegeschreven eigenschappen van
“verminderde zoetheid” en “vertraagde energieafgifte” verkeerd door consument geïnterpreteerd
Bezoekadres                                                            Postadres
Parnassusplein 5                                                       Postbus 16052
2511 VX     Den Haag                                                   2500 BB   Den Haag
Telefoon (070) 340 7520                                                Telefax (070) 340 7523
                                                                       www.gr.nl
</pre>

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<pre>Gezondheidsraad                                Vice-voorzitter
Health Council of the Netherlands
Onderwerp          : Tweede beoordeling veiligheid Isomaltulose
Ons kenmerk        : 2004/01VNV, U-865/MR/vc/622-CW
Pagina             :2
Datum              : 15 juni 2004
kunnen worden, en daarom meent zij dat dergelijke uitspraken vergezeld moeten gaan van de
vermelding dat isomaltulose energetisch gelijkwaardig is aan suiker. De bevoegde autoriteit, de
Engelse Food Standards Agency, heeft het advies van de ACNFP overgenomen.
De Commissie VNV baseert haar oordeel op de informatie in het dossier (voor een samenvatting
zie Bijlage D), het rapport van de eerste beoordeling door de ACNFP (zie Bijlage E) en de
wetenschappelijke literatuur. De Commissie VNV stemt grotendeels in met de Engelse
beoordeling. De kwaliteit van het productieproces lijkt gewaarborgd. De zuiverheid van het
product is minstens 99 % en het bevat geen chemische of microbiologische verontreinigingen.
      Voor de productie van isomaltulose wordt een enzympreparaat gebruikt afkomstig van
Protaminobacter rubrum. Deze bacterie heeft geen ziekteverwekkende eigenschappen en kent een
geschiedenis van gebruik in de EU sinds 1984, toen de zoetstof isomalt werd toegelaten. Bij de
industriële bereiding van dit voedseladditief is isomaltulose een tussenproduct. De Commissie
VNV is het eens met de ACNFP dat dit een belangrijke ondersteuning is voor de veilige
toepassing van dit enzympreparaat.
      Vanuit voedingskundig oogpunt is er geen bezwaar tegen het gebruik van isomaltulose. Dit
komt van nature voor in geringe hoeveelheden in rietsuiker en honing. Isomaltulose is minder dan
half zo zoet als sucrose. Het bestaat net als sucrose uit één glucose- en één fructosemolecuul maar
verschilt van sucrose in de manier waarop deze beiden chemisch gekoppeld zijn. Alhoewel
isomaltulose langzamer wordt verteerd dan sucrose wordt het wel volledig opgenomen door het
lichaam. De voedingswaarde is dan ook gelijk aan die van sucrose.
      Bij het gebruik zoals de aanvrager voorstelt, komt de gemiddelde isomaltulose-inneming neer
op een vervanging van zo’n 10 % van de gewone suikerinneming. De Commissie VNV tekent aan
dat de voedselconsumptiegegevens die de aanvrager voor de Engelse consument afleidt, gezien de
aannames, slechts een globale indicatie zijn. Daarnaast is het onbekend in hoeverre deze resultaten
representatief zijn voor de Europese bevolking. De populatiegroep met de hoogste inneming uit
het door de aanvrager voorgestelde productassortiment zijn jongens van 11-18 jaar oud. Met het
scenario dat de aanvrager schetst zouden grootverbruikers onder hen (97,5 percentiel) bijna één
ons isomaltulose per dag consumeren. Dit is vergelijkbaar met een inneming van zo’n 42 % van de
totale suikerconsumptie in de vorm van isomaltulose. Uit de voedselconsumptiegegevens blijkt dat
Bezoekadres                                                               Postadres
Parnassusplein 5                                                          Postbus 16052
2511 VX    Den Haag                                                       2500 BB   Den Haag
Telefoon (070) 340 7520                                                   Telefax (070) 340 7523
                                                                          www.gr.nl
</pre>

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<pre>Gezondheidsraad                                         Vice-voorzitter
Health Council of the Netherlands
Onderwerp               : Tweede beoordeling veiligheid Isomaltulose
Ons kenmerk             : 2004/01VNV, U-865/MR/vc/622-CW
Pagina                  :3
Datum                   : 15 juni 2004
per kg lichaamsgewicht jonge kinderen het meeste isomaltulose binnen krijgen, en in het geval van
een worst case scenario bedraagt dit 4 gram per kg.
       Er zijn geen nadelige effecten waargenomen in de gebruikelijke onderzoeken naar
mutageniteit, teratogeniteit/embryotoxiciteit, subchronische toxiciteit en ook niet in 26-weken
onderzoeken. De toxicologische onderzoeken met isomaltulose bij proefdieren die in het dossier
zijn opgenomen betreffen allen producten van andere firma’s. De aanvrager heeft aanvullende
informatie verstrekt waaruit de ACNFP concludeert, dat het isomaltulose van deze aanvraag
voldoende vergelijkbaar is met de onderzochte producten. De Commissie VNV is het eens met de
ACNFP dat uit de resultaten van toxicologische testen blijkt dat isomaltulose een veilig product is.
       Aanvullend op de eerste beoordeling meldt de Commissie VNV dat in het dossier de
                                                                                        a
resultaten worden geëvalueerd van negen mensgebonden onderzoeken . Vier hiervan betreft het
product van de aanvrager en de hoogst geteste eenmalige dosering was bijna 80 gram. De
Commissie VNV stemt in met de aanvrager dat deze resultaten bevestigen dat isomaltulose bij het
voorgestelde gebruik goed wordt verdragen en dat er geen nadelige gezondheidseffecten optreden.
De Commissie tekent hierbij aan dat het dossier geen informatie bevat over twee zeldzame
                                                              b
erfelijke afwijkingen in het fructosemetabolisme , te weten fructose intolerantie (fructose–aldolase
deficiëntie, incidentie 1:20.000) en fructose 1,6-diphosphatase deficiëntie (incidentie onbekend).
Mensen met zo’n aangeboren stofwisselingstoornis kunnen géén of maar weinig fructose
verdragen. Voor deze groep consumenten is de door de aanvrager voorgestelde tekst op het etiket
dat isomaltulose een bron van glucose en fructose is net als suiker, belangrijk.
       Isomaltulose valt niet onder de categorie-aanduiding ’Suiker’ en moet apart worden vermeld
op de ingrediëntendeclaratie. Etikettering dient in overeenstemming te zijn met Richtlijn
2000/13/EG en artikel 8 van Verordening (EG) 258/97. De Commissie VNV onderkent het
probleem van mogelijke misleiding van de consument dat de ACNFP voorziet als bepaalde
kenmerken inzake de zoetheid en de snelheid van energieafgifte van isomaltulose op het etiket
a
  In één van de onderzoeken is de tolerantie bestudeerd van dagelijkse isomaltuloseconsumptie bij 60 gezonde
vrijwilligers waarbij de hoeveelheid over een periode van 12 weken toenam tot 48 gram per dag. Dit onderzoeksrapport
is niet in het dossier opgenomen, maar wordt wel besproken in een door derden gepubliceerd overzichtsartikel dat deel
uitmaakt van het dossier.
b
  Essentiële fructosuria (fructokinase deficiëntie, incidentie 1:130.000) is een onschuldige erfelijke stofwisselingstoornis
die niet als een ziekte wordt beschouwd.
Bezoekadres                                                                              Postadres
Parnassusplein 5                                                                         Postbus 16052
2511 VX        Den Haag                                                                  2500 BB       Den Haag
Telefoon (070) 340 7520                                                                  Telefax (070) 340 7523
                                                                                         www.gr.nl
</pre>

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<pre>Gezondheidsraad                             Vice-voorzitter
Health Council of the Netherlands
Onderwerp         : Tweede beoordeling veiligheid Isomaltulose
Ons kenmerk       : 2004/01VNV, U-865/MR/vc/622-CW
Pagina            :4
Datum             : 15 juni 2004
worden verwoord. Evenals de ACNFP vindt zij het belangrijk dat het etiket vermeldt dat
isomaltulose energetisch gelijkwaardig is aan suiker.
Ik onderschrijf de conclusies van de Commissie VNV.
Hoogachtend,
Prof. dr JGAJ Hautvast
Bezoekadres                                                         Postadres
Parnassusplein 5                                                    Postbus 16052
2511 VX    Den Haag                                                 2500 BB   Den Haag
Telefoon (070) 340 7520                                             Telefax (070) 340 7523
                                                                    www.gr.nl
</pre>

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<pre>Letter to the Dutch Minister of Health,
Welfare and Sport
On June 15, professor JGAJ Hautvast, Vice-president of the Health Council of the Neth-
erlands wrote as follows to the Minister of Health, Welfare and Sport:
This letter has been prepared in reply to your request for advice regarding the safety of
novel foods and food ingredients, also made on behalf of the Minister of Agriculture,
Nature and Food Quality. The subject in question is a so-called second opinion, in
accordance with European Regulation 258/97, concerning isomaltulose. This novel food
ingredient is produced via enzymatic conversion of sucrose (sugar). The applicant,
Cargill Incorporated, wishes to introduce isomaltulose (which is manufactured by its
business unit, Cerestar) to the European market. Isomaltulose will not be directly avail-
able for consumers, but will be incorporated in foods of various categories, such as bev-
erages, cereal products, instant meal replacements and confectionery products. This
assessment was carried out by the Health Council Committee on Safety Assessment of
Novel Foods (VNV Committee).
     The initial assessment of the application for market authorization was carried out by
the Advisory Committee on Novel Foods and Processes (ACNFP), in the United King-
dom. The ACNFP's assessment was that isomaltulose is safe for use as a food ingredi-
ent. Perhaps unnecessarily, the ACNFP points out that foodstuffs which contain
isomaltulose must comply with existing legislation and must not be associated with
claims that might mislead consumers. According to the ACNFP, the applicant must
carry out market monitoring to establish the pattern of consumption for isomaltulose-
containing foodstuffs and to determine whether consumers have mistaken ideas con-
Letter to the Dutch Minister of Health, Welfare and Sport                                  8
</pre>

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<pre>cerning the energy content of these products. The ACNFP is concerned that the charac-
teristics of ‘reduced sweetness’ and ‘delayed energy release’ could be misinterpreted by
consumers. Accordingly, it feels that any such claims should be accompanied by a state-
ment of the energy equivalence of the novel ingredient with other sugars. The competent
authority, the UK Food Standards Agency, has adopted the ACNFP’s recommendations.
     The VNV Committee based its views on the information contained in the dossier
(see Annex D for the summary), on the report of the initial assessment by the ACNFP
(see Annex E), and on the scientific literature. The VNV Committee is largely in agree-
ment with the British assessment. It appears that, in terms of quality, the production pro-
cess incorporates the necessary safeguards. The product is at least 99% pure, and is free
of chemical and microbiological contaminants.
     Isomaltulose is produced using an enzyme preparation derived from Protamino-
bacter rubrum. This non-pathogenic bacterium has been used in the EU since 1984,
when isomalt (a sweetener) was admitted to the European market. Isomaltulose is an
intermediate product in the industrial preparation of this food additive. The VNV Com-
mittee concurs with the ACNFP that this is important evidence of the safety of this
enzyme preparation.
     From the nutritional point of view, there is no objection to the use of isomaltulose.
This is a naturally occurring substance, which is present at low concentrations in cane
sugar and honey. Isomaltulose is less than half as sweet as sucrose. Like sucrose, it con-
sists of one molecule of glucose and one of fructose. It differs from sucrose with respect
to the type of glycosidic linkage between these two molecules. While it is digested more
slowly than sucrose, isomaltulose is nevertheless fully absorbed by the body. The nutri-
tional value is therefore equivalent to that of sucrose.
     When used in accordance with the applicant’s suggestion, average isomaltulose
intake amounts to a replacement of about 10 % of normal sugar intake. The VNV Com-
mittee notes that the food consumption data for British consumers is only a rough indi-
cation, given the assumptions made by the applicant when deriving this data.
Furthermore, it is not known to what extent these results are representative of the popu-
lation of Europe as a whole. The applicant has outlined a worst case scenario for the
population group with the highest intake figures from all proposed food categories.
These are male teenagers aged from 11 to 18, and the amount involved is almost one
hundred grams of isomaltulose per day. This is comparable to an intake of around 42 %
of total sugar consumption, in the form of isomaltulose, by ‘heavy users’ in this category
(97.5 percentile). The food consumption data reveals that, per kg of body weight, young
children ingest the largest amounts of isomaltulose. In the worst case scenario, this
would be four grams per kg.
     No adverse effects were observed in the course of the usual tests for mutagenicity,
teratogenicity/embryotoxicity, and subchronic toxicity, nor in 26-week studies. The tox-
Letter to the Dutch Minister of Health, Welfare and Sport                                   9
</pre>

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<pre>   icological tests described in the dossier, in which isomaltulose was administered to
   experimental animals, all used products manufactured by other companies. On the basis
   of additional information provided by the applicant, the ACNFP has concluded that the
   isomaltulose on which this application is based, is sufficiently similar with the products
   used in these tests. The VNV Committee concurs with the ACNFP that the toxicological
   data shows isomaltulose to be a safe product.
        In addition to the initial assessment, the VNV Committee reports that the dossier
   contains assessments of the results of nine studies on human subjects*. Four of these
   involved the applicant's own product, and the highest single dose tested was almost 80
   grams. The Committee concurs with the applicant that these results confirm that isoma-
   ltulose is well tolerated when used as described in the application dossier and that no
   adverse health effects occur. The Committee notes that the dossier does not contain
   information on two rare hereditary disorders of the fructose metabolism**. These are
   fructose intolerance (fructose-aldolase deficiency, incidence 1:20.000) and fructose1,6-
   diphosphatase deficiency (incidence unknown). People suffering from these inborn
   errors have no or a reduced tolerance for fructose. The information on the label that iso-
   maltulose is a source of glucose and fructose as proposed by the applicant is important
   for this group of consumers.
   Isomaltulose does not fall within the ‘Sugar’ category, and should therefore be listed
   separately on the ingredients declaration. Labelling should conform to Directive 2001/
   13/EC and Article 8 of European Regulation (EC) 258/97. The VNV Committee recog-
   nises the problem, foreseen by the ACNFP, that consumers could be misled as a result of
   statements referring to the sweetness or the rate of energy release. The Committee
   agrees with the ACNFP that the label should include information on the energy equiva-
   lence of the novel ingredient with sugar.
   I endorse the conclusions and recommendations of the VNV Committee,
   (signed) professor JGAJ Hautvast
*  One of the studies dealt with the tolerance of daily isomaltulose consumption in 60 healthy volunteers. Over a period of
   twelve weeks, the amount was increased to a final level of 48 grams per day. While the report of this study was not
   included in the dossier, it was discussed in a survey article published by other researchers, a copy of which was included
   in the dossier.
** Essential fructosuria (fructokinase deficiency, incidence 1:130.000) is considered a harmless metabolic abnormality and
   not a disease.
   Letter to the Dutch Minister of Health, Welfare and Sport                                                               10
</pre>

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<pre>      Literatuur/Literature
EG97  Verordening (EG) nr. 258/97 van het Europees Parlement en de Raad van 27 januari 1997 betreffende
      nieuwe voedingsmiddelen en nieuwe voedselingrediënten. Publikatieblad van de Europese
      Gemeenschappen 1997; L43: 1-6
      (Regulation (EC) No 258/97 of the European Parliament and of the Council of 27 January 1997 concerning
      novel foods and novel food ingredients. Official Journal of the European Communities 1997; L43: 1-6).
EG97a Aanbeveling (EG) nr. 97/618/EG van de Commissie van 29 juli 1997 betreffende de wetenschappelijke
      aspecten en de presentatie van de informatie die nodig is om aanvragen voor het in de handel brengen van
      nieuwe voedingsmiddelen en nieuwe voedselingrediënten te ondersteunen alsmede het opstellen van de
      verslagen van de eerste beoordeling uit hoofde van Verordening (EG) nr. 258/97 van het Europees
      Parlement en de Raad. Publicatieblad van de Europese Gemeenschappen 1997; L253: 1-36
      (97/618/EC: Commission Recommendation of 29 July 1997 concerning the scientific aspects and the
      presentation of information necessary to support applications for the placing on the market of novel foods
      and novel food ingredients and the preparation of initial assessment reports under Regulation (EC) No 258/
      97 of the European Parliament of the Council. Official Journal of the European Communities 1997; L253:
      1-36).
EG03  Verordening (EG) nr. 1829/2003 van het Europees Parlement en de Raad van 22 september 2003 inzake
      genetisch gemodificeerde levensmiddelen en diervoeders. Publikatieblad van de Europese
      Gemeenschappen 2003; L268: 1-23.
      (Regulation (EC) nr. 1829/2003 of the European Parliament and of the Council of 22 September 2003
      concerning genetically modified food and feed. Official Journal of the European Communities 2003; L268:
      1-23.)
FAO96 Biotechnology and Food Safety. Report of a joint FAO/WHO Consultation. Rome, FAO 1996.
      Literatuur/Literature                                                                                      11
</pre>

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<pre>GR92   Commissie Toxicologische aspecten van biotechnologisch bereide producten. Productveiligheid bij nieuwe
       biotechnologie. Den Haag, Gezondheidsraad 1992, publicatienummer 1992/03.
GR02   Commissie Veiligheidsbeoordeling nieuwe voedingsmiddelen. Veiligheidsbeoordeling van nieuwe
       voedingsmiddelen. Den Haag, Gezondheidsraad 2002, publicatienummer 2002/05VNV.
       Committee on the Safety Assessment of Novel Foods. Safety assessment of novel foods. The Hague, Health
       Council 2002, publicationnumber 2002/05VNV.
OECD93 Safety evaluation of foods derived by modern biotechnology. Concepts and principles. Paris, OECD 1993.
OECD96 OECD Workshop on Food Safety Evaluation. Paris, OECD 1996.
WHO91  Strategies for assessing the safety of foods produced by biotechnology. Report of a joint FAO/WHO
       Consultation. Geneva, WHO 1991.
       Literatuur/Literature                                                                                  12
</pre>

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<br><br>====================================================================== Pagina 13 ======================================================================

<pre>A De adviesaanvraag/Request for advice
B De commissie/The committee
C EU-procedure/EU-procedure
D Samenvatting van het dossier/Executive summary of the dossier
E Eerste beoordeling/First assessment
  Bijlagen/Annexes
                                                                13
</pre>

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<pre>Bijlage A
        De Adviesaanvraag/Request for advice
        Op 18 augustus 1999 schreef de Minister van Volksgezondheid, Welzijn en Sport aan de
        Voorzitter van de Gezondheidsraad (brief kenmerk GZB/VVB 993428):
        Sinds mei 1997 is in de Europese Unie de Verordening (EG) 258/97 van kracht inzake nieuwe voedingsmid-
        delen en nieuwe voedselingrediënten. Daarmee werd de veiligheidsbeoordeling onderdeel van een com-
        munautaire procedure.
             Met u is reeds de mogelijkheid besproken de beoordeling door de Gezondheidsraad te laten uitvoeren.
        Ik verzoek u dan ook mede namens de Staatssecretaris van Landbouw, Natuurbeheer en Visserij, in deze
        eerste fase van uitvoering van de Europese Verordening (EG) 258/97 gedurende een aantal jaren, de veilig-
        heidsbeoordeling gestalte te geven. Voor het onderbrengen bij de Gezondheidsraad pleit het experimentele
        karakter dat de beoordeling de eerste jaren zal hebben. Dit experimentele karakter komt voort uit het feit dat
        het een nieuw soort beoordeling betreft van deels nieuwe categorieën van voedingsmiddelen of voedse-
        lingrediënten. Het is namelijk een veiligheidsbeoordeling vóór het op de markt brengen van met name voe-
        dingsmiddelen van een genetisch gemodificeerde oorsprong en zogenaamd functional foods (nutriceutica).
        Daarnaast ga ik ervan uit dat de onafhankelijke wetenschappelijke advisering door de Gezondheidsraad het
        vertrouwen van de Europese Commissie en de andere lidstaten in het Nederlandse oordeel nog versterkt.
             Mijn beleid is erop gericht een zo groot mogelijke openheid en transparantie te realiseren van de
        gevolgde procedure en de beoordeling om de consument vertrouwen te geven in de veiligheid van de
        De Adviesaanvraag/Request for advice                                                                           14
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<br><br>====================================================================== Pagina 15 ======================================================================

<pre>nieuwe voedingsmiddelen. Ik verzoek de Gezondheidsraad hieraan bij te dragen door bijvoorbeeld inzage te
geven in de dossiers waarvoor een aanvraag wordt ingediend, waarbij uiteraard bedrijfsvertrouwelijke gege-
vens worden beschermd en door de criteria, waarop de veiligheid zal worden beoordeeld, te publiceren.
De Minister van Volksgezondheid, Welzijn en Sport,
w.g. dr E Borst-Eilers
English translation
On 18 August 1999, the Minister of Health, Welfare and Sport wrote as follows to the
President of the Health Council of the Netherlands (under reference GZB/VVB
993428):
Since May 1997, Regulation (EC) 258/97 concerning novel foods and novel food ingredients has been in
force in the European Union. Under the Regulation, the safety of novel foods has to be assessed as part of a
community procedure.
      Following discussions regarding the possibility of the Health Council making such assessments, the
State Secretary for Agriculture, Nature Management and Fisheries and I wish the Council to take responsi-
bility for safety assessment for a period of several years during the fist phase of implementation of European
Regulation (EC) 258/97. It is considered appropriate that the Health Council should initially take on this
role because the assessment activities will be of an experimental nature, involving both a new form of asses-
sment (i.e. pre-marketing assessment) and, in many cases, new categories of foodstuff (primarily foodstuffs
with a genetically modified basis and functional foods or nutraceuticals). We also feel that if assessments
are made by a body with the Council's independent scientific status, this will support the validity of the
Netherlands' opinion in the eyes of the European Committee and other member states.
      My wish is to make the procedure and the assessment as open and transparent as possible, so as to
enhance consumer trust in the safety of novel foods. I would like the Health Council to support this objec-
tive by, for example, allowing perusal of the application dossier (insofar as consistent with the need to pro-
tect the confidentiality of commercially sensitive information) and publishing the criteria upon which safety
assessments are made.
The Minister of Health, Welfare and Sport,
(signed) dr E. Borst-Eilers
De Adviesaanvraag/Request for advice                                                                           15
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<pre>Bijlage B
        De commissie/The committee
        •  Prof. dr EG Schouten, voorzitter/chairman
           hoogleraar epidemiologie; Wageningen Universiteit and Researchcentrum/ profes-
           sor of epidemiology; Wageningen University and Research centre
        •  Prof. dr CAFM Bruijnzeel-Koomen
           hoogleraar dermatologie/allergologie; Academisch Ziekenhuis Utrecht/professor of
           dermatology/allergology; Academic Hospital Utrecht
        •  Ir EJ Kok
           toxicoloog; RIKILT-DLO Wageningen/toxicologist; State Institute for Quality Con-
           trol of Agricultural Products, Wageningen
        •  Dr CF van Kreijl
           moleculair-bioloog; RIVM Bilthoven/molecular biologist; National Institute of
           Public Health and the Environment, Bilthoven
        •  Prof. dr P van der Laan
           emeritus hoogleraar statistiek; Technische Universiteit Eindhoven/professor of sta-
           tistics; Technical University Eindhoven
        •  Dr FM Nagengast
           gastro-enteroloog; Academisch Ziekenhuis Nijmegen/gastro-enterologist; Acade-
           mic Hospital Nijmegen
        •  Dr ir JMA van Raaij
           voedingsfysioloog; Wageningen Universiteit and Researchcentrum/ food physiolo-
           gist; Wageningen University and Research centre
        De commissie/The committee                                                             16
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<pre>•   Prof. dr ir G Schaafsma
    hoogleraar voeding; TNO Voeding, Zeist/professor of nutrition; TNO Nutrition and
    Food Research, Zeist
•   Dr GJA Speijers
    toxicoloog; RIVM Bilthoven/toxicologist; National Institute of Public Health and
    the Environment, Bilthoven
•   Prof. dr WJ Stiekema
    hoogleraar bioinformatica; Wageningen Universiteit en Researchcentrum/ professor
    of bioinformatics; Wageningen University and Research centre
•   Ir R Top, adviseur/advisor
    Ministerie van VWS; Den Haag/Ministry of Health, Welfare and Sport; The Hague
•   Prof. dr WM de Vos
    hoogleraar microbiologie; Wageningen Universiteit en Researchcentrum/ professor
    of microbiology; Wageningen University and Research centre
•   Dr RA Woutersen
    toxicoloog, toxicologisch patholoog; TNO Voeding, Zeist/toxicologist, toxicologic
    pathologist; TNO Nutrition and Food Research, Zeist
•   Dr ir F van der Wilk, adviseur/advisor
    COGEM, Bilthoven/Committee on Genetic Modification, Bilthoven
•   Dr ir M Rutgers, secretaris/scientific staff member
    Gezondheidsraad, Den Haag/Health Council of the Netherlands, The Hague
Administratieve ondersteuning/Administrative assistance: CL Vuijst, MSc; Gezond-
heidsraad, Den Haag/Health Council of the Netherlands, The Hague.
Layout: J van Kan; Gezondheidsraad, Den Haag/Health Council of the Netherlands, The
Hague.
De commissie/The committee                                                            17
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<pre>Bijlage C
        EU-procedure/EU-procedure
        Als een fabrikant een nieuw voedingsmiddel op de markt brengt, dient de veiligheid
        voor de consument gewaarborgd te zijn. In 1997 werd de Europese verordening van
        kracht waarin de procedure is geregeld voor de goedkeuring voor marktintroductie van
        een nieuw voedingsmiddel (EG97). Bij deze procedure zijn verschillende actoren
        betrokken. De aanvrager moet beoordelen of het product werkelijk 'nieuw' is, dat wil
        zeggen dat het nog niet eerder in de Europese Unie in substantiële mate voor menselijke
        voeding is gebruikt en ook niet wezenlijk gelijkwaardig is aan een bestaand product.
        (Voor een wezenlijk gelijkwaardig product kan worden volstaan met een kennisgeving
        van de marktintroductie.) Ook moet het niet gaan om een levensmiddelenadditief, aroma
        of extractiemiddel, omdat deze producten op een andere wijze worden beoordeeld. Voor
        een nieuw voedingsmiddel in de zin van de Europese verordening moet de aanvrager
        een veiligheidsdossier overleggen volgens aanbevelingen van de Europese Commissie
        (EG97a). Deze aanbevelingen zijn gebaseerd op rapporten van verschillende instanties
        die zich met het onderwerp nieuwe voedingsmiddelen bezighouden, te weten de OECD
        (OECD93, OECD96) en de WHO/FAO (FAO96, WHO91). Ook de Gezondheidsraad
        heeft zich al eerder over dit onderwerp gebogen (GR92). Sinds het verschijnen van de
        aanbevelingen van de EU wordt in internationaal verband gewerkt aan explicitering en
        aanpassing aan de stand van de wetenschap (GR02).
            De fabrikant levert het volgens de richtlijnen samengestelde dossier in bij het land
        waar het product het eerst op de markt zal komen. Daarop komt de nationale veiligheids-
        beoordelingsautoriteit in actie. In Nederland is dat de Minister van Volksgezondheid,
        Welzijn en Sport. Zij heeft de Gezondheidsraad verzocht haar van advies te dienen. De
        EU-procedure/EU-procedure                                                                18
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<pre>Voorzitter van de Gezondheidsraad heeft hiertoe de commissie Veiligheidsbeoordeling
nieuwe voedingsmiddelen (commissie VNV) ingesteld.
     De commissie beoordeelt op basis van de huidige stand van de wetenschap of de
door de fabrikant geleverde gegevens juist en volledig zijn en of zij het eens is met diens
conclusies. Zij maakt een verslag van haar bevindingen — ook volgens de Europese
aanbevelingen (EG97a, deel III) — en biedt dat de minister aan. De minister formuleert
het Nederlandse oordeel over een voedingsmiddel en brengt dat in bij het Europese
overleg in het Permanent Comité voor de voedselketen en de diergezondheid. Alle Euro-
pese lidstaten worden uitgenodigd hun oordeel (de zogeheten tweede beoordeling) te
geven over het dossier en over de eerste beoordeling alvorens genoemd Comité een
eindoordeel velt. Als een dossier veel vragen oproept, gaat er een adviesvraag van de
Europese Autoriteit voor voedselveiligheid (EAV). Komt men dan nog niet tot overeen-
stemming dan beslist de Europese Ministerraad. Sinds 18 april 2004 moeten veiligheids-
dossiers van voedingsmiddelen van genetisch gemodificeerde oorsprong rechtstreeks
ingediend worden bij de EAV (EG03).
English translation
When manufacturers bring novel foodstuffs onto the market, consumer safety has to be
ensured. In 1997, a European Regulation (EG97) came into force, laying down the pro-
cedure for approving the market introduction of novel foodstuffs. The procedure recog-
nizes various actors. The applicant must decide whether a product is a novel foodstuff,
i.e. a substance that has not previously been available for human consumption to any
substantial extent within the European Union and is not substantially equivalent to any
existing product. (If a foodstuff is substantially equivalent to any existing product, it is
sufficient to inform the authorities of its market introduction). Food additives, aromas
and extracts are excluded from the provisions of the directive, since they fall within the
scope of an established assessment regime. Before marketing a novel foodstuff, the
applicant must compile a safety dossier that complies with the Recommendations of the
European Commission (EG97a). These Recommendations are based on reports by a
number of bodies that have studied the issue of novel foodstuffs, in particular the OECD
(OECD93, OECD96) and the WHO/FAO (FAO96, WHO91). The Health Council of the
Netherlands has also considered the question earlier (GR92). Since publication of the
EU recommendations, international efforts have been made to clarify and adapt the lat-
est scientific knowledge in the field (GR02).
     Having compiled a dossier in line with the guidelines, the manufacturer has to sub-
mit it to the competent authority in the country where the product is to be marketed first.
This dossier is assessed by the national safety assessment authority. In the Netherlands,
this is the Minister of Health, Welfare and Sport, who is advised by the Health Council.
EU-procedure/EU-procedure                                                                    19
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<pre>The President of the Health Council has created a Committee on the Safety Assessment
of Novel Foods (VNV Committee) to advise the minister on behalf of the Council.
     On the basis of the scientific state of the art, the committee has to decide whether the
information provided by the manufacturer is accurate and complete and whether the
manufacturer's conclusions are sound. The committee then draws up a report on its find-
ings for the minister; this report must also comply with the European Recommendation
(EG97a, part III). After considering the report, the minister formulates the Netherlands’
opinion regarding the foodstuff in question, which is discussed at European level in the
Standing Committee on the Food Chain and Animal Health. All other European member
states are invited to express a ‘second opinion’ regarding the dossier and the first opin-
ion. The Standing Committee then arrives at a final judgement. If a dossier is particu-
larly contentious, the European Commission calls upon the European Food Safety
Authority (EFSA) for advice. If consensus still cannot be reached, the issue is referred to
the European Council of Ministers. From April 18th 2004 safety dossiers of food from
genetically modified origin have to be submitted to EFSA directly (EC03).
EU-procedure/EU-procedure                                                                     20
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<pre>Bijlage D
        Samenvatting van het dossier/
        Executive summary of the dossier
        Samenvatting van het dossier/ Executive summary of the dossier 21
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<pre>     APPLICATION FOR THE APPROVAL OF
                     ISOMALTULOSE
 Regulation (EC) No 258/97 of the European Parliament and
the Council of 27th January 1997 concerning novel foods and
                    novel food ingredients
                         SUMMARY
                Applicant:  Cargill, Incorporated,
                            a Delaware corporation,
                            with its principal place of business at
                            15407 McGinty Road West, Wayzata,
                            Minnesota 55391 (USA),
                            Acting through,
                            Cerestar Food & Pharmaceutical Specialties,
                            one of its Business Units,
                            c/o Cerestar Research and Development Centre
                            Havenstraat 84
                            B-1800 Vilvoorde (Belgium)
                            October 22, 2003
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<pre>  APPLICATION FOR THE APPROVAL OF ISOMALTULOSE:
          USE AS A NOVEL FOOD INGREDIENT IN EUROPE
                                                  CONTENTS
1.0      ADMINISTRATIVE DATA .............................................................................................. 1
2.0      APPLICATION .................................................................................................................. 2
3.0      IDENTIFICATION OF ESSENTIAL INFORMATION REQUIREMENTS ................... 3
4.0      SUMMARY........................................................................................................................ 4
Cerestar                                                                                                            October 22, 2003
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<pre>1.0      ADMINISTRATIVE DATA
The application is submitted by:
Applicant:            Cargill, Incorporated, a Delaware corporation, with its principal place of
                      business at 15407 McGinty Road West, Wayzata, Minnesota 55391
                      (USA),
                      Acting through,
                      Cerestar Food & Pharmaceutical Specialties, one of its Business Units,
                      c/o Cerestar Research and Development Centre
                      Havenstraat 84
                      B-1800 Vilvoorde (Belgium)
                      Hereinafter referred to as Cerestar
Contact person:       Yves Le Bail-Collet
                      Manager Food and Feed Law
                      Cerestar Research and Development Centre
                      Havenstraat 84
                      B-1800 Vilvoorde
                      Belgium
                      Tel: 32(0)22 57 06 11
                      Fax: 32(0)22 57 07 81
                      yves_le-bail-collet@cargill.com
Cerestar                                     1                                      October 22, 2003
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<pre>2.0      APPLICATION
This application seeks approval for the use of isomaltulose, obtained by enzymatic
rearrangement of sucrose, as a novel food ingredient in Europe. Approval is sought under
Regulation (EC) No 258/97 of the European Parliament and of the Council of 27th January 1997
concerning novel foods and novel food ingredients (hereafter referred to as EC 258/97).
Article 1(2) of EC 258/97 states that the regulation “…shall apply to the placing on the market
within the Community of foods and food ingredients which have not hitherto been used for
human consumption to a significant degree within the Community…” and which fall under one
of six categories of novel foods and novel food ingredients. The lack of a significant prior
history of human consumption in the European Community dictates that isomaltulose will be
considered under category (c), pertaining to “foods and food ingredients with a new or
intentionally modified primary molecular structure”. Isomaltulose is thus considered a novel
food/food ingredient.
Cerestar                                     2                                      October 22, 2003
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<pre>3.0      IDENTIFICATION OF ESSENTIAL INFORMATION REQUIREMENTS
The application dossier (“Application for the Approval of Isomaltulose”) was prepared pursuant
to the Commission Recommendation of 29 July 1997 concerning the scientific aspects and the
presentation of information necessary to support applications for the placing on the market of
novel foods and novel food ingredients (hereafter referred to as the Commission
Recommendation of 1997).
Section 4 of the Commission Recommendation of 1997 outlines recommendations made by the
Scientific Committee on Food (SCF) pertaining to the “Scientific Classification of Novel Foods
for the Assessment of Wholesomeness”, which facilitates the safety and nutritional evaluation of
a given novel food/food ingredient. Of the six classes identified, isomaltulose would be
allocated a Class 1 designation (pure chemicals or simple mixtures from non-GM sources), since
it is manufactured by conventional methods as a pure chemical, with no use of genetic
modification. Isomaltulose is further classified under sub-class 1.2 (the source of the NF has no
history of food use in the Community) of the SCF categorization. However, isomaltulose does
occur as an intermediate product in the production of isomalt (E953), an additive permitted for
use in food since 1984, which is manufactured by both Cerestar and Südzucker and involves the
use of the same microorganism as that used in the preparation of isomaltulose.
Pursuant to Table II, Part I, under the Commission Recommendation of 1997, the essential
information requirements corresponding with this classification are outlined as follows:
               I.       Specification of the novel food
               II.      Effect of the production process applied to the novel food
               III.     History of the organism used as the source of the novel food
               IX.      Anticipated intake/extent of use of the novel food
               XI.      Nutritional information on the novel food
               XII.     Microbiological information on the novel food
               XIII.    Toxicological information on the novel food
For each category (I through XIII), structured schemes have been developed (Part I of the
Commission Recommendation of 1997), which consist of a decision-tree-like set of questions
designed to elicit sufficient data for a comprehensive safety and nutritional evaluation of the
novel food. This data is provided in the application dossier (“Application for the Approval of
Isomaltulose”).
Cerestar                                      3                                      October 22, 2003
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<pre>4.0      EXECUTIVE SUMMARY
Under Regulation (EC) No 258/97 on Novel Foods and Food Ingredients, Cerestar seeks
approval to market isomaltulose, obtained by enzymatic rearrangement of sucrose, for use as a
novel food ingredient in Europe. Cerestar submitted an application in accordance with
Commission Recommendation 97/618/EC, concerning the scientific aspects of information
necessary for the placing on the market of novel foods and novel food ingredients.
Specifications and Manufacturing
Isomaltulose is a naturally occurring reducing dissacharide, composed of a glucose and fructose
molecule, linked by a 1,6-glycosidic bond. Its sweetness is approximately 42% that of sugar.
The production of isomaltulose by Cerestar is initiated by dissolving food-grade sucrose in water
and subsequently treating the resulting solution with a biocatalyst obtained from a non-viable,
non-pathogenic strain of Protaminobacter rubrum (Porter et al., 1991). Once the enzymatic
rearrangement is complete, the residual biomass material is removed by filtration. The crude
isomaltulose product is then sequentially subjected to several stages of purification, including
demineralisation, crystallisation, and washing. Drying and cooling of isomaltulose complete the
production process, resulting typically in a product of 99% or greater purity. Results of analysis
for representative batches of isomaltulose demonstrate compliance with final product
specifications.
Previous Human Exposure
Isomaltulose has been identified to occur naturally in honey at levels of up to 1% as well as in
sugar cane extract at low levels. Moreover, in Japan, isomaltulose has been used in yoghurt,
chewing gum, and candy since 1985.
Estimated Intake of the Novel Food
The individual proposed food-uses and their maximum usage levels for isomaltulose in the E.U.
are summarized in the following Table:
Cerestar                                      4                                      October 22, 2003
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<pre>Table 4-1         Summary of the Individual Proposed Food-Uses and Use-Levels for
                  Isomaltulose in the E.U.
         Food Category                            Proposed Food-Use                   Use-Levels for
                                                                                         IM (%)
Beverages                       Dilutable Soft Drinks                                      20.0
                                Energy Drinks                                               5.5
                                Energy Reduced Soft Drinks                                  7.0
                                Regular Soft Drinks                                         5.5
                                Sports and Isotonic Drinks                                  7.0
Cereals and Cereal Products     Biscuits, Sandwich-Type with Filling                       20.0
                                Cereal Bars                                                10.0
                                Coated Ready-to-Eat Breakfast Cereals                      30.0
                                Energy and Diet Meal Bars                                  15.0
Miscellaneous Beverages         Meal Replacements, Dry Weight                              20.0
                                Milk Based Meal Replacements, Dry Weight                   20.0
Sugar, Preserves, and           Candy and Chocolate Bars                                   25.0
Confectionery
                                Energy Tablets                                             97.0
Isomaltulose is proposed for use as a nutritive sweetener, in a variety of food products including
soft drinks, fillings in baked goods, grain and meal replacement products. Under the conditions
of intended use, male teenagers were estimated to have the highest intake of isomaltulose on an
all-user basis by the U.K. population, from all-proposed food-uses, with mean and 97.5th
percentile intakes of 37.8 and 97.8 g/day, respectively. On a body weight basis, children were
identified as having the highest intakes, with mean and 97.5th percentile all-user isomaltulose
intakes of 1.6 and 4.0 g/kg body weight/day, respectively. These intake levels represent a “worst
case” exposure estimate.
Labelling
The designation 'isomaltulose' shall be displayed on the labelling of the product as such or in the
list of ingredients of foodstuffs containing it.
In a prominently displayed footnote related to the designation isomaltulose by means of an
asterisk (*) the words “Isomaltulose, like sugar, is a source of glucose and fructose which
undergoes slower digestion and absorption” shall be displayed.
The words of the footnote shall have a typeface of at least the same size as the list of ingredients
itself.
Cerestar                                         5                                    October 22, 2003
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<pre>Safety of the Novel Food
Metabolic data in animals and humans, toxicity data in rats, and clinical studies, have been used
to support the safety of isomaltulose. Metabolism studies have indicated that prior to absorption
isomaltulose is almost completely hydrolyzed in the small intestine to the simple sugars, fructose
and glucose. Both metabolites are subsequently utilized in well-characterized carbohydrate
pathways. The metabolic fate of isomaltulose is equivalent to that of sucrose, which also is
metabolized to glucose and fructose.
Results of subchronic and chronic studies, as well as human data, have consistently demonstrated
a lack of any toxicologically significant effects relevant to the conditions of the intended uses in
foods. No treatment-related adverse effects were observed in a 13-week study in rats
administered dietary levels of isomaltulose up to a maximum of 10% (approximately 7,000 and
8,100 mg/kg body weight, for males and females, respectively) or in a 26-week oral gavage
study in which rats were administered a maximum isomaltulose dose of 4,500 mg/kg body
weight/day. Furthermore, isomaltulose provided in the diet at concentrations of up to 10%
(approximately 7 g isomaltulose/kg body weight/day), the highest dose tested, demonstrated no
evidence of developmental toxicity in rats. The safety of isomaltulose was further verified in
several clinical trials involving administration of oral bolus doses of isomaltulose as high as
1 g/kg body weight (approximately 70 g isomaltulose) to healthy as well as diabetic individuals
and ileostomy patients. No physiological or adverse effects were observed in these studies.
Tolerance studies conducted with sucrose or combinations of glucose and fructose demonstrated
that bolus doses of up to 100 g were well tolerated without incidence of gastrointestinal effects.
Since, isomaltulose, like sucrose, is metabolized to equal parts of glucose and fructose, these
studies provide additional support that intake of up to 100 g isomaltulose, throughout the day,
would be well tolerated. Furthermore, the absorption of fructose is facilitated by the presence of
glucose, especially when both are ingested in equal amounts. Therefore, the gastrointestinal
effects apparent following consumption of fructose alone would not be expected with
isomaltulose.
Safety of the Microorganism Protaminobacter rubrum
The safety of the microorganism utilized in the production of isomaltulose has been confirmed in
a 14-day toxicity study in which mice and rabbits received intravenous administrations
consisting of viable cells as well as the growth medium. Study results demonstrated
Protaminobacter rubrum to be non-pathogenic and possessing only a low order of toxigenicity.
The production of isomaltulose and isomalt, however, involves the use of non-viable cells only.
Furthermore, the microorganism has an established history of use in the production of isomalt
Cerestar                                       6                                       October 22, 2003
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<pre>(E953), which was approved for use in food by the SCF in 1984. In fact, isomaltulose is an
intermediate in the manufacturing process of isomalt.
Conclusion
In conclusion, there is a substantial body of evidence to support the safety of isomaltulose, which
meets the criteria of a novel food ingredient based on its lack of prior history of use in the
European Community. On the basis of the available toxicology data, its nutritional equivalence
to sucrose, and the established use of the microorganism Protaminobacter rubrum in the
production of isomalt, it is concluded that isomaltulose does not present a significant risk for
human health at the levels of intake, which would result from its intended uses in food.
Cerestar                                      7                                        October 22, 2003
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<pre>Bijlage E
        Eerste beoordeling/First assessment
        Eerste beoordeling/First assessment 31
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<pre>                                                                                 19 Mar 2004
ADVISORY COMMITTEE FOR NOVEL FOODS AND PROCESSES
OPINION ON AN APPLICATION UNDER THE NOVEL FOODS REGULATION FOR THE
APPROVAL OF ISOMALTULOSE AS A FOOD INGREDIENT
Applicant:                      Cerestar (Cargill Cerestar BVBA)
Responsible Person:             Yves Le-Bail Collet
Novel Food: I                   somaltulose
EC Classification:              1.2
INTRODUCTION
1. An application has been submitted by Cerestar to the UK Competent Authority on 30th
    October 2003 for approval of isomaltulose for use in a range of food products. A copy of
    the Application dossier was placed on the FSA web-site at the same time.
2. The present application for authorisation of isomaltulose was prepared pursuant to
    Commission Recommendation (97/618/EC) of 29 July 1997 concerning the scientific
    aspects and presentation of information necessary to support applications for the placing
    on the market of novel foods and novel food ingredients. Isomaltulose has been
    classified as a pure chemical or simple mixture from a non-GM source (class 1.2). The
    information presented in the dossier is structured accordingly and is considered below
    under the schemes outlined in this Commission Recommendation.
I. Specification of the novel food
     Application Dossier, p 4-7
3. Certificates and methods for most analyses are to be found in the application dossier in
    appendix A. These analyses show isomaltulose to be a stable product under normal
    conditions and when subjected to heat treatments and of high purity containing low levels
    of arsenic and mercury. The certificates of analysis for the raw materials can be found in
           Eerste beoordeling/First assessment                                             32
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<pre>     appendix B. Batch on batch variation was assessed by testing five non-consecutive
     batches for composition. The results of these analyses on the samples indicate a narrow
     range of variation in composition and contaminants. Isomaltulose is produced via
     enzymatic conversion of sucrose using the non-pathogenic bacteria Protaminobacter
     rubrum.
Discussion. The Committee requested further analyses on heavy metals to be carried out
on the final product. Members accepted the additional data offered reassurance of the heavy
metal content of the novel food. Otherwise, Members were satisfied that the analyses
carried out by the applicant on the raw materials, the final product and the bacteria, P.
rubrum demonstrated the safety of the novel food. The applicants’ response is tabulated
below.
  Summary of Metal Analysis Results
  Specification                                  Manufacturing Lot
  Parameter           (Batch 1)        (Batch 2)   (Batch 3)     (Batch 4)    (Batch 5)
  Arsenic (ppb)       <100             <100        <100          <100         <100
  Cadmium             <10              <10         <10           <10          <10
  (ppb)
  Lead (ppb)          <20              <20         <20           21           <20
  Mercury (ppb) <5                     <5          <5            <5           <5
  Nickel (ppb)        <50              <50         <50           <50          <50
II. Effect of the production process applied to the novel food
      Application dossier, p 8-19
4. The production process uses food-grade sucrose dissolved in water that is treated with a
     crude enzyme preparation consisting of P. rubrum cell mass killed using formaldehyde.
     After the enzymatic conversion the cells are removed by filtration. The product is then
     purified by demineralisation, crystallisation, washing, drying and cooling, producing a
     final isomaltulose product of at least 99% purity. Formaldehyde is not detectable in the
     final product.
Discussion. The Committee was content that the production process is controlled and that
the in-process monitoring steps were sufficient to ensure a safe and consistent product. The
Committee was also reassured that the micro-organism P. rubrum is used in the commercial
production of isomalt in the EU.
            Eerste beoordeling/First assessment                                            33
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<pre>III. History of the organism used as a source of the novel food
     Application dossier, p 20
5. No information is supplied under this heading, as isomaltulose is not sourced from an
     organism but from food grade sucrose.
IX. Anticipated intake/extent of use of the novel food
      Application dossier, p 21-27
6. The applicant intends to use their isomaltulose product as an ingredient in beverages
     and a variety of other products where it would partly replace other sugars as a source of
     energy. The availability of these products will not be restricted geographically and there
     are no plans to target these products at a particular consumer group.
7. The applicant has stated that the highest intake figures from all proposed food categories
     when related to body weight were found amongst children with mean and 97.5th
     percentile intakes of 1.6 and 4.0g /kg body weight/day respectively. The lowest intake
     figures were found amongst the female adults group with a mean intake of 0.2g/kg body
     weight/day and a 97.5th percentile intake of 0.6g/kg body weight/day.
Discussion. The Committee had concerns over the intended market and were concerned
that the use of isomaltulose could result in an overall increase in energy intake due to the
misinterpretation of any claims made for reduced sweetness or delayed energy release.
This issue is addressed in the labelling section below.
XI. Nutritional information on the novel food
     Application dossier, p 28-29
8. Isomaltulose is hydrolysed to equal amounts of fructose and glucose and absorbed
     almost completely in the small intestine in a similar way to sucrose.
9. Isomaltulose is metabolised at a rate of one-fifth to one quarter that of sucrose, but the
     final calorific value is the same as sucrose because both disaccharides are cleaved to
     form glucose and fructose. Isomaltulose is also characterised by a reduced sweetness
     when compared to sucrose. These functional properties will not be used to target
     products containing isomaltulose at specific consumer groups but they will be used to
     alter the organoleptic and physical properties of the products in which it is used.
Discussion. The Committee had a concern over the study using 8 ileostomy patients
outlined on page 48 of the dossier. Members were concerned over the possibility of a
            Eerste beoordeling/First assessment                                              34
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<pre>polymorphism in the population for isomaltulose metabolism that may cause problems. The
applicant is of the opinion that there is no such polymorphism in the population as
isomaltulose is metabolised by the same route as sucrose. The applicant has provided an
expert confirming this view.
The Committee were otherwise content with the nutritional properties of isomaltulose, but
had concerns over the vagueness of the target market and possibility for misinterpretation
by the public. These concerns are addressed in the response from the applicant that can be
found in section IX.
XII. Microbiological information on the novel food
     Application dossier, p 30
10. Microbiological information is presented under schemes XII and XIII in the application
    dossier.
11. The purity of the stock suspension of P. rubrum is verified at the time of its preparation
    and the absence of mycotoxins and contaminating micro-organisms is also routinely
    demonstrated. P. rubrum has also been demonstrated to be non-pathogenic and has a
    low order of toxicity (Application dossier, p. 32-34)
12. Specifications for most raw materials including micro-organism screens were reproduced
    in the application.
Discussion. The Committee was satisfied with the information supplied by the applicant
and considered the production process, quality control measures and the nature of the final
product to be sufficient to ensure no unintentional microbiological contamination of the
product. They were also satisfied that the P. rubrum was suitable for food use and would
cause no safety concerns.
XIII. Toxicological information on the novel food
     Application dossier, p 31-63
13. A number of toxicological studies have been provided to demonstrate the safety of
    isomaltulose including chronic and sub-chronic animal studies, developmental studies
    and various human studies. The toxicological tests described in the dossier have
    primarily been carried out on isomaltulose products from the applicant and two other
    manufacturers.
           Eerste beoordeling/First assessment                                              35
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<pre>Discussion. The Committee was satisfied that the isomaltulose products produced by other
manufacturers of isomaltulose were sufficiently similar to the product produced by the
applicant for the toxicological studies to be relevant. The Committee was content that the
toxicological data provided by the applicant were sufficient to demonstrate the safety of
isomaltulose.
Allergenicity
Application dossier, p 54
14. The applicant has addressed the possibility that protein from the P. rubrum may be
    released during the production process, or protein from other raw materials may pass
    into the final product. The presence of protein in the final product has been estimated to
    be 5.2ppm, based on a measured nitrogen concentration of 0.8ppm and a standard
    conversion factor of 6.25. The protein figure may be an overestimate, since the
    calculation assumes that all nitrogen is in the form of protein.
Discussion. The Committee considered this level of protein to be sufficiently low to cause
no problems with allergenicity, taking into account the quantities that might be consumed.
Labelling
15. The applicant provided the following labelling suggestion:
      "The designation 'isomaltulose' shall be displayed on the labelling of the product in the list
      of ingredients of foodstuffs containing it. In a prominently displayed footnote related to the
      designation isomaltulose by means of an asterisk (*), the words 'isomaltulose is like sugar,
      a source in equal parts of glucose and fructose, but has a slower rate of digestion and
      absorption' or 'Isomaltulose, like sugar, is a source of glucose and fructose which
      undergoes slower digestion and absorption' shall be displayed. The words of the footnote
      shall have a typeface of at least the same size as the list of ingredients itself.”
Discussion. The Committee was content that the labelling was sufficiently clear so that
diabetics in particular would be aware that products containing isomaltulose were a source
of glucose. In response to the Committee’s earlier concern over the possibility of increasing
calorific intake because of reduced sweetness and to clarify the exact role of isomaltulose as
an ingredient the applicant has provided the following revised labelling suggestion:
            Eerste beoordeling/First assessment                                                      36
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<pre>      “Isomaltulose, like sugar, is a source of glucose and fructose, which undergoes slower
      digestion and absorption. A gram of isomaltulose provides as much total energy/calories as
      a gram of sugar, but over a prolonged period of time”.
The Committee noted the inclusion of a statement about the energy content, but was
concerned that the final part of the statement could lead to this information being
misunderstood by consumers. The Committee concluded that any claims referring either to
reduced sweetness of isomaltulose or to the rate of energy release should be accompanied
by a statement of the energy equivalence of the novel ingredient with other sugars,
presented in a way that cannot be construed as misleading to consumers".
OVERALL DISCUSSION
16. The Applicant has provided a clear specification of the proposed novel food and
    indicated, on the basis of analysis from a number of non-consecutive batches that the
    specification is achievable. The production process differs very little from that used in the
    production of isomalt, an approved sweetener in the EU.
17. Given that isomaltulose is an isomer of sucrose and is broken down to glucose and
    fructose in the GI tract in a similar way to sucrose, no additional nutritional concerns were
    raised from the consumption of the novel food. The information supplied by the applicant
    offers sufficient reassurance that consumption of the novel food does not give rise to any
    toxicological concerns.
18. The applicant has demonstrated that the novel food is stable under normal conditions
    and also when subject to raised temperatures. The applicant has also demonstrated that
    the novel food is microbiologically safe.
19. The proposed labelling of the product is acceptable, nevertheless the applicant should
    be reminded of the need to comply with food labelling legislation and ensure that the
    labelling and presentation of the products does not mislead the consumer, particularly in
    relation to their energy content.
20. While the projected levels of isomaltulose intake do not give rise to any toxicological
    concern, the effect of substitution for sucrose on the overall pattern of extrinsic sugar
    consumption is unknown. The Committee noted concerns that the consumption of
    extrinsic sugars is already undesirably high and recommended that the applicant
    undertakes post-market monitoring to demonstrate the pattern of consumption of
           Eerste beoordeling/First assessment                                                   37
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<pre>   isomaltulose-containing products and to establish whether consumers correctly
   understand the energy content of such products compared with their existing
   counterparts
Conclusion
The Advisory Committee on Novel Foods and Processes is satisfied by the evidence
provided by Cerestar that the range of uses for isomaltulose is acceptable, subject to the
applicants’ adherence to the specification and production parameters described in the
application dossier. Isomaltulose containing foods should comply with existing legislation
and should not make claims that are likely to mislead consumers. The applicant should
establish a post-launch monitoring scheme to determine the patterns of consumption and to
ascertain whether the use of isomaltulose leads to any misunderstanding of the energy
content of foods in which it is used.
                                                                             March 2004
          Eerste beoordeling/First assessment                                           38
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