<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>Genotoxiciteit van fytosterol(esters)
Genotoxicity of phytosterol(esters)
Aanvulling eerste beoordeling van de veiligheid voor de consument, volgens de
Europese verordening 258/97 betreffende nieuwe voedingsmiddelen
en nieuwe voedselingrediënten
Addition to the first assessment regarding consumer safety, in accordance with
European Regulation 258/97 concerning novel foods and novel food
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, Natuurbeheer en Visserij/
the Minister for Agriculture, Nature management and Fisheries
Nr 2001/02VNV, Den Haag, 13 december 2001
No. 2001/02VNV, The Hague, December 13, 2001
</pre>

====================================================================== Einde pagina 1 =================================================================

<br><br>====================================================================== Pagina 2 ======================================================================

<pre>Deze publicatie kan als volgt worden aangehaald:
Gezondheidsraad: Commissie Veiligheidsbeoordeling van nieuwe voedingsmiddelen.
Genotoxiciteit van fytosterol(esters). Den Haag: Gezondheidsraad, 2001; publicatie nr
2001/02VNV.
Preferred citation:
Health Council of the Netherlands: Committee on the Safety assessment of novel
foods. Genotoxicity of phytosterol(esters). The Hague: Health council of the
Netherlands, 2001; publication no. 2001/02VNV.
auteursrecht voorbehouden
all rights reserved
</pre>

====================================================================== Einde pagina 2 =================================================================

<br><br>====================================================================== Pagina 3 ======================================================================

<pre>  Inhoud/Contents
  Brief aan de Minister van Volksgezondheid, Welzijn en Sport 5
  Letter to the Minister of Health, Welfare and Sport 11
  Literatuur/Literature 15
  Bijlagen/Annexes 17
A De adviesaanvraag/Request for advice 19
B De commissie/The committee 21
C EU-procedure/EU-procedure 23
D Overzicht dossiergegevens/Overview of data in the dossier 27
E Aanvullende gegevens/additional data 29
3 Inhoud/Contents
</pre>

====================================================================== Einde pagina 3 =================================================================

<br><br>====================================================================== Pagina 4 ======================================================================

<pre>4 Genotoxiciteit fytosterol(esters)/Genotoxicity phytosterol(esters)</pre>

====================================================================== Einde pagina 4 =================================================================

<br><br>====================================================================== Pagina 5 ======================================================================

<pre>5 Inhoud/Contents</pre>

====================================================================== Einde pagina 5 =================================================================

<br><br>====================================================================== Pagina 6 ======================================================================

<pre>6 Genotoxiciteit fytosterol(esters)/Genotoxicity phytosterol(esters)</pre>

====================================================================== Einde pagina 6 =================================================================

<br><br>====================================================================== Pagina 7 ======================================================================

<pre>7 Brief aan de Minister van Volksgezondheid, Welzijn en Sport</pre>

====================================================================== Einde pagina 7 =================================================================

<br><br>====================================================================== Pagina 8 ======================================================================

<pre>8 Genotoxiciteit fytosterol(esters)/Genotoxicity phytosterol(esters)</pre>

====================================================================== Einde pagina 8 =================================================================

<br><br>====================================================================== Pagina 9 ======================================================================

<pre>9 Brief aan de Minister van Volksgezondheid, Welzijn en Sport</pre>

====================================================================== Einde pagina 9 =================================================================

<br><br>====================================================================== Pagina 10 ======================================================================

<pre>10 Genotoxiciteit fytosterol(esters)/Genotoxicity phytosterol(esters)</pre>

====================================================================== Einde pagina 10 =================================================================

<br><br>====================================================================== Pagina 11 ======================================================================

<pre>   Letter to the Dutch Minister of
   Health, Welfare and Sport
   On December 13, 2001, professor JGAJ Hautvast, Vice-president of the Health
   Council of the Netherlands wrote as follows to the Minister of Health, Welfare and
   Sport:
   This document has been prepared in response to your request for advice regarding the
   genotoxicity of sterol metabolites. Phytosterols in use as food ingredients, in particular
   -sitosterol, stigmasterol and campesterol, belong to the sterols group. The absorption
   of cholesterol in the intestine is inhibited by these phytosterols. Cholesterol itself also
   belongs to the sterols group. The assessment of the safety dossier for the phytosterols
   was carried out in 1998 by the Dutch Provisional Committee on Safety Assessment of
   Novel Foods within the context of European Regulation (EC) 258/97. The opinion of
   the European Scientific Committee on Food was published in April 2000.
   At the time of the application for marketing authorisation for phytosterol esters as a
   food ingredient, the documentation contained findings from in vitro genotoxicity
   studies on phytosterols and phytosterol esters. The genotoxicity studies yielded no
   evidence of a genotoxic action for phytosterols and their esters. The documentation
   also contained analytical data on intestinal content in humans, particularly primary and
   secondary bile acids, sterols and their oxidised and hydrogenated metabolites, in
   connection with consumption of 8600 mg phytosterols per person per day for 3-4
   weeks. The intake recommended by the applicant is 1600 mg per person per day. The
   daily intake for a consumer with an average dietary pattern is 160-360 mg per person
11 Letter to the Dutch Minister of Health, Welfare and Sport
</pre>

====================================================================== Einde pagina 11 =================================================================

<br><br>====================================================================== Pagina 12 ======================================================================

<pre>   per day. The change in the quantity of secondary bile acids was studied as these might
   stimulate the development of intestinal cancer. The change in the quantity of
   4-cholesten-3-one was investigated because it had been reported in some scientific
   publications that 4-cholesten-3-one, a metabolite of cholesterol, had a (geno)toxic
   effect on murine intestinal cells (Kau87, Suz84, Suz86). In the experimental group
   with high sterol consumption, the faecal secondary bile acid concentration was
   significantly reduced at the end of the test period compared with the start, so far as
   lithocholic acid and cholic acid are concerned. The concentration of lithocholic acid in
   the experimental group changed from 2.99 + 0.28 to 2.26 + 0.15 mg per g faeces (dry
   weight, mean + SEM). The concentration of cholic acid changed from 0.18 + 0.03 to
   0.07 + 0.02 mg per g faeces (dry weight). In the experimental group with high sterol
   consumption, excretion of cholesterol, phytosterols and their metabolites at the end of
   the test period was significantly elevated relative to the start. Excretion of
   4-cholesten-3-one was significant increased in the female volunteers from 0.05 + 0.05
   to 2.7 + 0.58 mg per g faeces (dry weight, mean + SEM) and increased in male
   volunteers from 0.06 + 0.04 to 1.1 + 0.46 mg per g faeces (dry weight, mean + SEM)
   (Wes99).
        Based on the dossier and the scientific literature, the provisional VNV Committee
   saw no grounds to ask further questions concerning the genotoxicity of phytosterols.
   Over the period that the Human Nutrition Scientific Committee assessed the safety of
   phytosterol esters, the dossier has been supplemented by the company with
   genotoxicity research on 4-cholesten-3-one, the aforementioned metabolite of
   cholesterol. This concerned a bacterial mutagenicity test and an in vitro test on
   chromosomal aberrations in human peripheral blood lymphocytes. The findings from
   these tests were negative, i.e. no evidence of genotoxicity. An important
   transformation product of 4-cholesten-3-one, 5-cholestan-3-one, was also tested in
   this way and proved likewise non-mutagenic. In addition, two in-vivo genotoxicity
   studies were conducted with phytosterol esters in rats. Excessive DNA reparative
   synthesis in the liver and the formation of micronuclei in bone marrow served as the
   indication parameters for genotoxicity. No genotoxic action for the phytosterol esters
   was found. The Scientific Committee on Food concluded that it had no doubt as to the
   safety of phytosterol mixtures on the basis of the documentation and the supplements.
   In 2000, the Minister for Health, Welfare and Sport asked the Committee on Safety
   Assessment of Novel Foods of the Health Council of the Netherlands to review all data
   critically. The Committee commented that a version of the in-vitro study on
   4-cholesten-3-one was lacking, namely the version in which liver enzymes are used. In
12 Genotoxiciteit fytosterol(esters)/Genotoxicity phytosterol(esters)
</pre>

====================================================================== Einde pagina 12 =================================================================

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

<pre>   2001, the company supplemented the documentation. The findings of these tests also
   yield no evidence of a genotoxic action for 4-cholesten-3-one.
   The Committee now considers that the applicant has, in a valid and reproducible
   manner, investigated the genotoxicity of mixtures of phytosterols that are
   representative of the consumer product and the most important metabolites of
   cholesterol. The choice of the tests is in accordance with a protocol for genotoxicity
   testing adopted in the European Union and within OECD member states.
   The significance of the exploratory genotoxicity and cytotoxicity research on the
   metabolite 4-cholesten-3-one described in the scientific literature is considered not to
   be great by the Committee (Kau87, Suz84, Suz86). The nuclear aberration test (NA) is
   an unvalidated test that has not been officially acknowledged. The parameters
   determined indicate a general toxic effect rather than a specific genotoxic effect. This
   finding can probably be induced with very many substances. The sister chromatid
   exchange test (SCE) is also not yet internationally accepted. The mechanism is
   unclear, and the biological relevance is debatable. In addition, 4-cholesten-3-one gives
   only a marginally positive response.
        The Committee considers the genotoxicity tests conducted in accordance with the
   international protocol to be decisive and regards the phytosterols and cholesterol
   metabolites tested as non-genotoxic.
   I endorse the conclusion of the Committee.
   (signed)
   professor JGAJ Hautvast
13 Letter to the Dutch Minister of Health, Welfare and Sport
</pre>

====================================================================== Einde pagina 13 =================================================================

<br><br>====================================================================== Pagina 14 ======================================================================

<pre>14 Genotoxiciteit fytosterol(esters)/Genotoxicity phytosterol(esters)</pre>

====================================================================== Einde pagina 14 =================================================================

<br><br>====================================================================== Pagina 15 ======================================================================

<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.
EG97a  Aanbeveling 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 1997; L253: 1-36.
FAO96  Biotechnology and Food Safety. Report of a joint FAO/WHO Consultation. Rome, FAO 1996
FAO01  Evalutation of allergenicity of genetically modified foods. Report of a joint FAO/WHO expert consultation
       on allergenicity of foods derived from biotechnology. Rome, FAO 2001.
GR92   Commissie Toxicologische aspecten van biotechnologisch bereide producten. Productveiligheid bij
       nieuwe biotechnologie. Den Haag, Gezondheidsraad 1992, publicatienummer 1992/03
Kau87  Kaul HK, Gouch DB, Gingerich JD, e.a. Genotoxicity of two fecal steroids in murine colonic epithelium
       assessed by the sister chromatid exchange technique. Mutagenesis 1987; 2(6): 441-4.
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.
OECD98 Report of the OECD workshop on the toxicological and nutritional testing of novel foods. Paris, OECD
       1998.
OECD00 Report of the task force for the safety of novel foods and feeds. Paris, OECD 2000.
15     Literatuur/Literature
</pre>

====================================================================== Einde pagina 15 =================================================================

<br><br>====================================================================== Pagina 16 ======================================================================

<pre>SCF99 Opinion concerning the scientific basis for determining whether food products, derived from genetically
      modified maize, could be included in a list of food products which do not require labelling because they
      do not contain (detectable) traces of DNA or protein. Brussels, Scientific Committee on Food of the EU
      1999.
SSC99 Opinion of the Scientific Steering Committee on microbial resistance, Brussels, Scientific Steering
      Committee of the EU 1999.
Suz84 Suzuki K, Bruce WR. Human fecal fractions can produce nuclear damage in the colonic epithelial cells of
      mice. Mut Res 1984; 141: 35-9.
Suz86 Suzuki K, Bruce WR, Baptista J, e.a. Characterization of cytotoxic steroids in human faeces and their
      putative role in the etiology of human colonic cancer. Canc Let 1986; 33: 307-16.
Wes99 Weststrate JA, Ayesh R, Bauer-Plank C. Safety evaluation of phytosterol esters. Part 4. Faecal
      concentrations of bile acids and neutral sterols in healthy normolipidaemic volunteers consuming a
      controlled diet either with or without a phytosterol ester-enriched margarine. Food chem Tox 1999; 37:
      1063-71.
WHO91 Strategies for assessing the safety of foods produced by biotechnology. Report of a joint FAO/WHO
      Consultation. Geneva, WHO 1991.
WHO00 Safety aspects of genetically modified foods of plant origin. Report of a joint FAO/WHo expert
      consultation on foods derived from biotechnology. Geneva, WHO 2000.
16    Genotoxiciteit fytosterol(esters)/Genotoxicity phytosterol(esters)
</pre>

====================================================================== Einde pagina 16 =================================================================

<br><br>====================================================================== Pagina 17 ======================================================================

<pre>A  De adviesaanvraag/Request for advice
B  De commissie/The committee
C  EU-procedure/EU-procedure
D  Overzicht dossiergegevens/Overview of data in the dossier
E  Aanvullende gegevens/additional data
   Bijlagen/Annexes
17
</pre>

====================================================================== Einde pagina 17 =================================================================

<br><br>====================================================================== Pagina 18 ======================================================================

<pre>18 Genotoxiciteit fytosterol(esters)/Genotoxicity phytosterol(esters)</pre>

====================================================================== Einde pagina 18 =================================================================

<br><br>====================================================================== Pagina 19 ======================================================================

<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
        voedingsmiddelen en nieuwe voedselingrediënten. Daarmee werd de veiligheidsbeoordeling onderdeel van
        een communautaire 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
        veiligheidsbeoordeling 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 voedselingrediënten. Het is namelijk een veiligheidsbeoordeling vóór het op de
        markt brengen van met name voedingsmiddelen 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
        nieuwe
19      De adviesaanvraag/Request for advice
</pre>

====================================================================== Einde pagina 19 =================================================================

<br><br>====================================================================== Pagina 20 ======================================================================

<pre>   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 gegevens
   worden beschermd en door de criteria, waarop de veiligheid zal worden beoordeeld, te publiceren.
   De Minister van Volksgezondheid, Welzijn en Sport,
   (wg) 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 (under reference GZB/VVB 993428):
   Since May 1977, 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
   reponsibility 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 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
   assessment (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
   objective by, for example, allowing perusal of applicants (insofar as consistent with the need to protect the
   conficentiality 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
20 Genotoxiciteit fytosterol(esters)/Genotoxicity phytosterol(esters)
</pre>

====================================================================== Einde pagina 20 =================================================================

<br><br>====================================================================== Pagina 21 ======================================================================

<pre>Bijlage B
        De commissie/The committee
           Prof. dr LM Schoonhoven, voorzitter/chairman
           emeritus hoogleraar entomologie; Wageningen Universiteit en Researchcentrum/
           emeritus professor of entomology; 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
           Control 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
           hoogleraar statistiek; Technische Universiteit Eindhoven/professor of statistics;
           Technical University Eindhoven
           Dr B Loos, adviseur/advisor
           COGEM, Den Haag/Committee on Genetic Modification, The Hague
           Prof. dr FM Nagengast
           gastro-enteroloog; Academisch Ziekenhuis Nijmegen/ gastro enterologist;
           Academic Hospital Nijmegen
21      De commissie/The committee
</pre>

====================================================================== Einde pagina 21 =================================================================

<br><br>====================================================================== Pagina 22 ======================================================================

<pre>      Dr ir JMA van Raaij
      voedingsfysioloog; Wageningen Universiteit and Researchcentrum/ food
      physiologist; Wageningen University and Research centre
      Prof. dr G Schaafsma
      hoogleraar voeding; TNO voeding, Zeist/prodessor of nutrition; TNO Nutrition
      and Food Research, Zeist
      Prof. dr EG Schouten
      hoogleraar epidemiologie; Wageningen Universiteit and Researchcentrum/
      professor of epidemiology; Wageningen University and Research centre
      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; TNO Voeding, Zeist/toxicologist; TNO Nutrition and Food Research
      Dr JAG van de Wiel, wetenschappelijk stafmedewerker/scientific staff member
      Gezondheidsraad, Den Haag/ Health Council of the Netherlands, The Hague
   Administratieve ondersteuning: C Nederpelt-Brussee; Gezondheidsraad, Den Haag/
   Administrative assistance: C Nederpelt-Brussee; Health Council of the Netherlands,
   The Hague.
22 Genotoxiciteit fytosterol(esters)/Genotoxicity phytosterol(esters)
</pre>

====================================================================== Einde pagina 22 =================================================================

<br><br>====================================================================== Pagina 23 ======================================================================

<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 (WHO91, FAO96). 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 (FAO01, SCF99, SSC99, OECD98, OECD00,
        WHO00) gewerkt aan explicitering en aanpassing aan de stand van de wetenschap.
            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
23      Europese procedure/EU-procedure
</pre>

====================================================================== Einde pagina 23 =================================================================

<br><br>====================================================================== Pagina 24 ======================================================================

<pre>   veiligheidsbeoordelingsautoriteit in actie. In Nederland is dat de Minister van
   Volksgezondheid, Welzijn en Sport. Zij heeft de Gezondheidsraad verzocht haar van
   advies te die-nen. De 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 levensmiddelen. Alle Europese
   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 Commissie naar het Wetenschappelijk Comité voor de menselijke voeding.
   Komt men dan nog niet tot overeenstemming dan beslist de Europese Ministerraad.
   English translation
   When manufacturers bring novel foodstuffs onto the market, consumer safety has to be
   assured. In 1997, a European Regulation (EC97) came into force, laying down the
   procedure for approving the market introduction of novel foodstuffs. The procedure
   recognises 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
   substiantially equivalent to any existing product. (If a foodstuff is substiantially
   equivalent to any existing product, it is sufficient to inform the authorities of its market
   introduction). Foodstuff 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 (WHO91, FAO96). 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
   latest scientific knowledge in the field (FAO01, SSC99, SCF99, OECD98, OECD00,
   WHO00).
   Having compiled a dossier in line with the guidelines, the manufacturer has to submit
   it to the competent authority in the country where the product is to be marketed first.
24 Genotoxiciteit fytosterol(esters)/Genotoxicity phytosterol(esters)
</pre>

====================================================================== Einde pagina 24 =================================================================

<br><br>====================================================================== Pagina 25 ======================================================================

<pre>   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. The President of the Health Council has created a Committee on the Safety
   assessment of novel foods (VNV) 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
   findings for the minister; this report must also comply with the European
   Recommendation (EC97a, 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 Foodstuffs. All other
   European member states are invited to express a ‘second opinion’ regarding the dossier
   and the first opinion. The Standing Committee then arrives at a final judgement. If a
   dossier is particularly contentious, the European Commission calls upon the Scientific
   Committee on Food for advice. If consensus still cannot be reached, the issue is
   referred to the European Council of Ministers.
25 Europese procedure/EU-procedure
</pre>

====================================================================== Einde pagina 25 =================================================================

<br><br>====================================================================== Pagina 26 ======================================================================

<pre>26 Genotoxiciteit fytosterol(esters)/Genotoxicity phytosterol(esters)</pre>

====================================================================== Einde pagina 26 =================================================================

<br><br>====================================================================== Pagina 27 ======================================================================

<pre>Bijlage D
        Overzicht dossiergegevens/
        Overview of data in the dossier
        Study number: KA960254
        Study title: Phytosterols: Bacterial mutation assay
        Study results: Two independent mutation tests were performed, in the presence and
        absence of liver preparations from Arochlor 1254-induced rats. Dose levels of
        phytosterols (tested in tetrahydrofuran) of 5000, 1500, 500, 150 and 50 g per plate
        showed no evidence of mutagenic activity in this bacterial system (TA98, TA100,
        TA1535, TA1537).
        Study number: KA960256
        Study title: Phytosterol-esters: Bacterial mutation assay
        Study results: Two independent mutation tests were performed, in the presence and
        absence of liver preparations from Arochlor 1254-induced rats. Dose levels of
        phytosterol-esters (tested in acetone) of 5000, 1500, 500, 150 and 50 g per plate
        showed no evidence of mutagenic activity in this bacterial system (TA98, TA100,
        TA1535, TA1537).
        Study number: KC960255
        Study title: Phytosterols: Metaphase chromosome analysis of human lymphocytes
        cultured in vitro.
        Study results: Two tests were performed, in the presence and in the absence of liver
        preparations. Dose levels of phytosterols of 40, 80 and 160 g per ml culture, after 21
27      Overzicht dossiergegevens/Overview of data in the dossier
</pre>

====================================================================== Einde pagina 27 =================================================================

<br><br>====================================================================== Pagina 28 ======================================================================

<pre>   hours of incubation, showed no evidence of clastogenic activity in this in vitro
   cytogenetic test system. Dose levels of phytosterols of 160 g per ml culture, after 45
   hours of incubation, showed no evidence of clastogenic activity in this in vitro
   cytogenetic test system.
   Study number: KC960257
   Study title: Phytosterol-esters: Metaphase chromosome analysis of human lymphocytes
   cultured in vitro.
   Study results: Two tests were performed, in the presence and in the absence of liver
   preparations. Dose levels of phytosterol-esters of 25, 50 and 100 g per ml culture,
   after 21 hours of incubation, showed no evidence of clastogenic activity in this in vitro
   cytogenetic test system. Dose levels of phytosterols of 100 g per ml culture, after 45
   hours of incubation, showed no evidence of clastogenic activity in this in vitro
   cytogenetic test system.
   Study number: 97037-E
   Study title: Faecal bile acids and sterols in subjects fed controlled diets with or without
   added vegetable oil sterols.
   Study results: Consumption of vegetable oil phytosterols slightly but significantly
   increased the faecal concentration of 4-cholesten-3-one. This concentration increased
   in females from 0.05 + 0.05 to 2.7 + 0.58 mg/g dry weight faeces. In males from 0.06 +
   0.04 to 1.1 + 0.46 mg/g dry weight faeces. These values are still in line with values
   reported in the literature for subjects fed high or low fat diets. There was no increase in
   faecal secondary bile acids and sterol oxides could not be detected. The authors of the
   study mention that all tree compounds are studied in the ongoing scientific research on
   the causal factors of large bowel cancer.
28 Genotoxiciteit fytosterol(esters)/Genotoxicity phytosterol(esters)
</pre>

====================================================================== Einde pagina 28 =================================================================

<br><br>====================================================================== Pagina 29 ======================================================================

<pre>Bijlage E
        Aanvullende gegevens/additional data
        Study number: KA980008
        Study title: Plant sterols: bacterial mutation assay.
        Study results: It was concluded that plant sterols (in acetone) did not induce mutation
        in four strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537) and one
        strain of Escherichia coli (CM891) under the conditions employed, which included
        treatments at concentrations up to 5000 g per plate, in the absence and in the presence
        of a metabolic activation system (S9).
        Study number: KC980009
        Study title: Plant sterols: in vitro mammalian chromosome aberration test in human
        lymphocytes.
        Study results: Two tests were performed, in the presence and in the absence of liver
        preparations. Dose levels of phytosterols of 50, 100 and 200 g/ml culture, after 3
        hours of incubation, in the presence and in the absence of liver preparations, showed
        no evidence of clastogenic activity in this in vitro cytogenetic test system. Dose levels
        of phytosterols of 50, 100 and 200 g per ml culture, after 21 hours of incubation, in
        the absence of liver preparations, showed no evidence of clastogenic activity in this in
        vitro cytogenetic test system.
        Study number: KA980261
        Study title: 4-Cholesten-3-one: reverse mutation in five histidine requiring strains of
29      Aanvullende gegevens/additional data
</pre>

====================================================================== Einde pagina 29 =================================================================

<br><br>====================================================================== Pagina 30 ======================================================================

<pre>   Salmonella typhimurium.
   Study results: It was concluded that 4-cholesten-3-one (in acetone) did not induce
   mutation in five strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537
   and TA102) under the conditions employed, which included treatments at
   concentrations up to 2500 g per plate (a precipitating dose), in the absence of a
   metabolic activation system (S9).
   Study number: KC980260
   Study title: 4-Cholesten-3-one: induction of chromosome aberrations in cultured
   human peripheral blood lymphocytes.
   Study results: Treatment of cultures with 4-cholesten-3-one in the absence of S9 for 3
   or 20 hours resulted in frequencies of cells with structural aberrations that were similar
   to those seen in concurrent solvent control cultures. Frequencies of aberrant cells in the
   majority of 4-cholen-3-one treated cultures fell within the historical negative control
   range.
   Study number: KA980259
   Study title: 5-Cholestan-3-one: reverse mutation in five histidine-requiring strains of
   Salmonella typhimurium.
   Study results: It was concluded that 5-cholestan-3-one (in acetone) did not induce
   mutation in five strains of Salmonella typhimurium (TA98, TA100, TA1535, TA1537
   and TA102) under the conditions employed, which included treatments at
   concentrations up to 5000 g per plate (a precipitating dose), in the absence of a
   metabolic activation system (S9).
   Study number: KC980258
   Study title: 5-Cholestan-3-one: induction of chromosome aberrations in cultured
   human peripheral blood lymphocytes.
   Study results: Treatment of cultures with 5-Cholestan-3-one in the absence of S9 for
   3 or 20 hours resulted in frequencies of cells with structural aberrations that were
   similar to those seen in concurrent solvent control cultures. Frequencies of aberrant
   cells in all 5-Cholestan-3-one treated cultures fell within the historical negative
   control range.
   Study number: KU990111
   Study title: Plant sterol ester SSE26698-02: measurement of unscheduled DNA
   synthesis in rat liver using an in vivo/in vitro procedure.
   Study results: Treatment with 800 or 2000 mg/kg plant sterol ester did not produce a
30 Genotoxiciteit fytosterol(esters)/Genotoxicity phytosterol(esters)
</pre>

====================================================================== Einde pagina 30 =================================================================

<br><br>====================================================================== Pagina 31 ======================================================================

<pre>   group mean NNG (net grain count) value greater than -0.4 nor were any more than
   2.7% cells found in repair at either dose. The sterol ester did not induce UDS.
   Study number: KC990110
   Study title: Plant sterol ester SSE26698-02: induction of micronucleï in the bone
   marrow of treated rats.
   Study results: It is conluded that plant sterol ester SSE26698-02 did not induce
   micronucleï in the polychromatic erythrocytes of the bone marrow of male rats treated
   up to 2000 mg/kg/day.
   Study number: KA010009
   Study title: 4-cholesten-3-one: reverse mutation in five histidine-requiring strains of
   Salmonella typhimurium.
   Study results: No evidence of mutagenic activity was obtained with 4-cholesten-3-one
   in either the presence or absence of metabolic activation in the bacterial mutation
   assay. Concentrations were up to precipitating test doses (625 and/or 2500 g per
   plate)
   Study number: KC010008
   Study title: 4-cholesten-3-one: induction of chromosome aberrations in cultured human
   peripheral blood lymphocytes.
   Study results: The results of the study indicate that 4-cholesten-3-one showed no
   evidence of mutagenic activity in vitro, either the presence or absence of metabolic
   activation in the in vitro chromosome aberration assay in human lmphocytes. Dose
   levels were up to 1000 g per ml.
31 Aanvullende gegevens/additional data
</pre>

====================================================================== Einde pagina 31 =================================================================

<br><br>