<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>n-Butyl glycidyl ether
Evaluation of the carcinogenicity and genotoxicity
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<pre></pre>

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<pre>Gezondheidsraad                                          Vo o r z i t t e r
Health Council of the Netherlands
Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp               : Aanbieding advies n-Butyl glycidyl ether
Uw kenmerk              : DGV/MBO/U-932542
Ons kenmerk             : U-5132/JR/pg/246-E12
Bijlagen                :1
Datum                   : 1 april 2008
Geachte minister,
Graag bied ik u hierbij het advies aan over de kankerverwekkendheid van n-butyl glycidyl
ether. Het maakt deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen wor-
den geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen waaraan
mensen tijdens de beroepsmatige uitoefening kunnen worden blootgesteld.
     Het advies is opgesteld door een vaste subcommissie van de Commissie Gezondheid en
beroepsmatige blootstelling aan stoffen (GBBS), de Subcommissie Classificatie van carci-
nogene stoffen. Het advies is voorgelegd aan de Commissie GBBS en vervolgens getoetst
door de Beraadsgroep Gezondheid en omgeving van de Gezondheidsraad.
Ik heb dit advies vandaag ter kennisname toegezonden aan de minister van Volksgezond-
heid, Welzijn en Sport en de minister van Volkshuisvesting, Ruimtelijke Ordening en
Milieubeheer.
Hoogachtend,
prof. dr. J.A. Knottnerus
Bezoekadres                                                                 Postadres
Parnassusplein 5                                                            Postbus 16052
2 5 11 V X D e n          Haag                                              2500 BB Den            Haag
Te l e f o o n ( 0 7 0 ) 3 4 0 6 6 3 1                                      Te l e f a x ( 0 7 0 ) 3 4 0 7 5 2 3
E - m a i l : j o l a n d a . r i j n k e l s @ g r. n l                    w w w. g r. n l
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<pre></pre>

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<pre>n-Butyl glycidyl ether
Evaluation of the carcinogenicity and genotoxicity
Subcommittee on the classification of carcinogenic substances of the
Dutch Expert Committee on Occupational Standards,
a committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2008/07OSH, The Hague, April 1, 2008
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<pre>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
22, 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 & Food Quality. The Council
can publish advisory reports on its own initiative. It usually does this in order to
ask attention for developments or trends that are thought to be relevant to gov-
ernment policy.
     Most Health Council reports are prepared by multidisciplinary committees of
Dutch or, sometimes, foreign experts, appointed in a personal capacity. The
reports are available to the public.
                 The Health Council of the Netherlands is a member of the European
                 Science Advisory Network for Health (EuSANH), a network of science
                 advisory bodies in Europe.
                 The Health Council of the Netherlands is a member of the International Network
                 of Agencies for Health Technology Assessment (INAHTA), an international
                 collaboration of organisations engaged with health technology assessment.
 I NA HTA
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. n-Butyl glycidyl ether; Evaluation of the car-
cinogenicity and genotoxicity. The Hague: Health Council of the Netherlands,
2008; publication no. 2008/07OSH.
all rights reserved
ISBN: 978-90-5549-692-4
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<pre>    Contents
    Samenvatting 9
    Executive summary 11
1   Scope 13
1.1 Background 13
1.2 Committee and procedures 13
1.3 Data 14
2   General information 15
2.1 Identity and physico-chemical properties 15
2.2 IARC classification 16
3   Carcinogenicity studies 17
3.1 Observations in humans 17
3.2 Carcinogenicity studies in animals 17
4   Mutagenicity and genotoxicity 19
4.1 In vitro assays 19
4.2 In vivo assays 20
    Contents                                    7
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<pre>5   Classification 23
5.1 Evaluation of data on carcinogenicity and genotoxicity 23
5.2 Recommendation for classification 23
    References 25
    Annexes 27
A   Request for advice 29
B   The committee 31
C   Comments on the public review draft 33
D   IARC Monograph 35
E   Carcinogenic classification of substances by the committee 37
F   Guideline 93/21/EEG of the European Union 39
8   n-Butyl glycidyl ether
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<pre>Samenvatting
Op verzoek van de minister van Sociale Zaken en Werkgelegenheid evalueert en
beoordeelt de Gezondheidsraad de kankerverwekkende eigenschappen van stof-
fen waaraan mensen tijdens het uitoefenen van hun beroep kunnen worden bloot-
gesteld. De evaluatie en beoordeling worden verricht door de subcommissie
Classificatie van Carcinogene Stoffen van de Commissie Gezondheid en
Beroepsmatige Blootstelling aan Stoffen van de Raad, hierna kortweg aangeduid
als de commissie. In het voorliggende advies neemt de commissie n-butylglyci-
dylether onder de loep. n-Butylglycidylether wordt gebruikt voor vele doel-
einden, waaronder de productie van epoxyharsen.
Op basis van de beschikbare gegevens leidt de commissie af dat n-butylglycidyl-
ether onvoldoende is onderzocht. Hoewel de gegevens het niet toelaten de stof te
classificeren als kankerverwekkend voor de mens of als moet beschouwd worden
als kankerverwekkend voor de mens, is waakzaamheid geboden. De commissie
adviseert daarom n-butylglycidylether te classificeren als verdacht kankerver-
wekkend voor de mens. Dit is vergelijkbaar met een classificatie in categorie 3
volgens de richtlijnen van de Europese Unie. Binnen deze categorie komt de situ-
atie het meest overeen met subcategorie b.
Samenvatting                                                                     9
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<pre>10 n-Butyl glycidyl ether</pre>

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<pre>Executive summary
At request of the Minister of Social Affairs and Employment, the Health Council
of the Netherlands evaluates and judges the carcinogenic properties of sub-
stances to which workers are occupationally exposed. The evaluation is per-
formed by the subcommittee on Classifying Carcinogenic Substances of the
Dutch Expert Committee on Occupational Standards of the Health Council, here-
after called the committee. In this report, the committee evaluated n-butyl gly-
cidyl ether. The agent has various uses, such as in the production of epoxy resins.
Based on the available information, the committee is of the opinion that n-butyl
glycidyl ether has been insufficiently investigated. While the available data do
not warrant a classification as carcinogenic to humans or as should be regarded
as carcinogenic to humans, they indicate that there is cause for concern. There-
fore, the committee recommends classifying n-butyl glycidyl ether as a sus-
pected human carcinogen. This recommendation is comparable to the EU
classification in category 3. The situation is, furthermore, comparable with sub-
category b of this category.
Executive summary                                                                   11
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<pre>12 n-Butyl glycidyl ether</pre>

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<pre>Chapter 1
        Scope
1.1     Background
        In the Netherlands a special policy is in force with respect to occupational use
        and exposure to carcinogenic substances. Regarding this policy, the Minister of
        Social Affairs and Employment has asked the Health Council of the Netherlands
        to evaluate the carcinogenic properties of substances, and to propose a classifica-
        tion (see Annex A). The assessment and the proposal for a classification are
        expressed in the form of standard sentences (see Annex E). The criteria used for
        classification are partly based on an EU-directive (see Annex F). In addition to
        classifying substances, the Health Council also assesses the genotoxic properties
        of the substance in question.
        This report contains the evaluation of the carcinogenicity of n-butyl glycidyl
        ether.
1.2     Committee and procedures
        The evaluation is performed by the subcommittee on Classifying Carcinogenic
        Substances of the Dutch Expert Committee on Occupational Standards of the
        Health Council, hereafter called the committee. The members of the committee
        are listed in Annex B. The first draft was prepared by I.A. van de Gevel and M.I.
        Willems, from the Department of Occupational Toxicology of the TNO Nutrition
        Scope                                                                               13
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<pre>    and Food Research, by contract with the Ministry of Social Affairs and Employ-
    ment.
         In 2007 the President of the Health Council released a draft of the report for
    public review. The individuals and organisations that commented on the draft are
    listed in Annex C. The committee has taken these comments into account in
    deciding on the final version of the report.
1.3 Data
    The evaluation and recommendation of the committee is standardly based on sci-
    entific data, which are publicly available. The starting points of the committees’
    reports are, if possible, the monographs of the International Agency for Research
    on Cancer (IARC). This means that the original sources of the studies, which are
    mentioned in the IARC-monograph, are reviewed only by the committee when
    these are considered most relevant in assessing the carcinogenicity and genotox-
    icity of the substance in question. In the case of n-butyl glycidyl ether, such an
    IARC-monograph is available, of which the summary and conclusion of IARC is
    inserted in Annex D.
         More recently published data were retrieved from the online databases Med-
    line, Toxline, Chemical Abstracts, and RTECS. The last updated online search
    was in June 2007. The new relevant data were included in this report.
14  n-Butyl glycidyl ether
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<pre>Chapter 2
        General information
2.1     Identity and physico-chemical properties
        n-Butyl glycidyl ether is used: as a reactive diluent in epoxy resins; as a viscos-
        ity-reducing agent for easier handling of conventional epoxy resins; as an acid
        acceptor for stabilizing chlorinated solvents; as a chemical intermediate; as a
        lubricant antioxidant; in electrical insulating, surface coating and lining, paint-
        ing, gluing, and fiberglass finishing; in the construction industry, for coating and
        impregnation of concretes, flooring, and repairing of cracks; and, also it is widely
        used in the household environment.1 Occupational exposure may occur during
        manufacturing and use of these substances.
            Below is given the identity and some of its physical and chemical properties.1
        Chemical name               :  n-butyl glycidyl ether
        CAS registry no.            :  2426-08-6
        EINECS no.                  :  219-376-4
        Synonyms                    :  oxirane, (butoxymethyl)-; 1-butoxy-2,3-epoxypropane; 3-
                                       butoxy-1,2-epoxypropane; butyloxymethyl-oxirane; butyl 2,3-
                                       epoxypropyl ether; 2,3-epoxypropyl butyl ether
        Description                 : colourless liquid with a slightly irritative odour
        Molecular formula           : C7H14O2
        General information                                                                        15
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<pre>    Structure                      :      C C C
                                         / \ / \ / \
                                       C C O C–C
                                                       \ /
                                                        O
    Molecular weight               : 130.21
    Flash point                    : 59 °C
    Boiling point                  : 163.8 °C
    Relative density (25°C/4°C)    : 0.908
    Vapour pressure (20°C)         : 0.4 kPa
    Partition coefficient (logKow) : 0.63
    Solubility                     : slightly soluble (20 g/L at 20°C)
    Conversion factors             : 1 ppm = 5.4 mg/m3
    (101.3 kPa; 20°C)                1 mg/m3 = 0.18 ppm
    Risk and safety phrases        : R10: flammable
                                     R20/22: Harmful by inhalation and if swallowed
                                     R37: irritating to respiratory system
                                     R40: limited evidence of a carcinogenic effect
                                     R52/53: harmful to aquatic organisms, may cause long-term
                                     adverse effects in the aquatic environment
                                     R68: possible risk for irreversible effects
                                     S2: keep out of reach of children
                                     S24/25: avoid contact with skin and eyes
                                     S36/37: wear suitable protective clothing and gloves
                                     S61: avoid release to the environment. Refer to special instruc-
                                     tions/safety data sheets
    EU classification              : carcinogenic category 3
                                     mutagenic category 3
2.2 IARC classification
    In 1989, the Working Group of IARC evaluated some glycidyl ethers.1 However,
    it did not classify n-butyl glycidyl ether, because of a lack of human and animal
    carcinogenicity data.
16  n-Butyl glycidyl ether
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<pre>Chapter 3
        Carcinogenicity studies
3.1     Observations in humans
        No data were available to evaluate the carcinogenicity of n-butyl glycidyl ether
        in humans.
3.2     Carcinogenicity studies in animals
        No data were available to evaluate the carcinogenicity of n-butyl glycidyl ether
        in animals.
        Carcinogenicity studies                                                          17
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<pre>18 n-Butyl glycidyl ether</pre>

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<pre>Chapter 4
        Mutagenicity and genotoxicity
4.1     In vitro assays
        Several mutagenicity studies have been performed using various strains of the
        bacteria Salmonella typhimurium.1,2 Overall, in the presence and absence of a
        metabolic activation system, positive outcomes were reported in strains TA97,
        TA100, TA1535, and TA1538. Negative outcomes were reported using strains
        TA98 and TA1537.1
            In the absence of a metabolic activation system, n-butyl glycidyl ether
        induced mutations in the Escherichia coli WP2uvrA strain.1
            Furthermore, a dose-related increase in mutation frequency was observed in
        the L5178Y mouse lymphoma mutagenicity assay.1,3 In that assay, the agent was
        tested at a concentration of up to 800 μg/mL, in the presence and absence of a
        metabolic activation system.
        n-Butyl glycidyl ether, at concentrations of 0.3 to 19 mmol/L, caused DNA dam-
        age in the SOS-Chromotest, using E. coli strain PQ37 and in the absence of met-
        abolic activation system.4 It also induced DNA damage in cultured human
        lymphocytes.1
            Furthermore, slight increases of unscheduled DNA synthesis were reported
        in human cell line WI38, which was exposed to n-butyl glycidyl ether (0.24 to
        8.0 μg/mL) for one hour plus metabolic activation.2,5 However, since there was
        no dose-related increase over at least 3 concentrations and since the highest
        Mutagenicity and genotoxicity                                                   19
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<pre>    response was less than twice the control response, the authors considered this to
    be a negative result. The committee agrees with this conclusion.
    At a concentration of 5 mmol/L, and in the absence of metabolic activation sys-
    tem, n-butyl glycidyl ether significantly increased the frequency of sister chro-
    matid exchanges in Chinese hamster V79 cells.6
4.2 In vivo assays
    Using the host-mediated assay, mice were given daily intraperitoneal injections
    of n-butyl glycidyl ether at a dose of 125 up to 1,000 mg/kg bw for five consecu-
    tive days.2 No mutations were observed in the various S. typhimurium indicator
    strains.
    n-Butyl glycidyl ether was tested in the mouse dominant lethal assay in three
    studies, resulting in mixed results. In the first, Pullin (1977) applied the agent at a
    dose of 1,500 mg/kg bw on the skin of at least 10 male B6D2F1 mice, three times
    per week for eight weeks.5 Each male was mated with three untreated virgin
    females per week, for two weeks. The agent decreased pregnancy rates,
    increased the number of fetal deaths (p=0.04), and decreased the proportion of
    implants per pregnant female compared to control animals (p=0.01). In a repeat
    study using the same study design, no effects were observed at the same dose
    level and at 750 mg/kg bw, but an increase in fetal deaths was observed at a dose
    level of 3,000 mg/kg bw.7
        In another study, Whorton et al. (1983) applied the agent at doses of 375,
    750, and 1,500 mg/kg bw on the skin of male BDF hybrid mice (n=15-24 ani-
    mals/group), three times per week for 8 weeks.7 Each male was mated with three
    untreated virgin females per week, for three weeks. No changes in pregnancy
    rates and number of implants per pregnant female were observed. However, the
    fetal death rates (7.75%) were significantly increased in the females, which were
    mated in the first post-treatment week with the highest-dosed males, compared to
    controls. However, since the increase was comparable to that of controls (death
    rate, 7.33%) for the same period of time in a second experiment, the results of
    this study are uncertain.
    Regarding clastogenicity, intraperitoneal injections of 225 to 900 mg n-butyl gly-
    cidyl ether per kg bw increased the frequency of micronuclei in bone marrow
    cells of female BDF mice (n=5/group).1,2,8 However, no treatment-related
20  n-Butyl glycidyl ether
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<pre>increases of micronuclei in female B6D2F1 mice was observed after oral adminis-
tration for five days (200 mg/kg bw, by gavage).1,2,5,8
     Intraperitoneal administration of 31, 104, and 313 mg/kg bw per day for five
consecutive days to Sprague-Dawley rats (n=5/sex/dose) resulted in an increase
in the percentage of bone marrow cells with structural chromosomal aberrations
on day six.9 This effect was statistically significant at all dose levels. Comparison
with control groups did not show statistically significant differences in mean
chromosomal numbers and mean mitotic indices. No distinct adverse effects
attributable to n-butyl glycidyl ether were noted in evaluation of in-life animal
data (with the exception of one death in the high-dose group).
Mutagenicity and genotoxicity                                                         21
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<pre>22 n-Butyl glycidyl ether</pre>

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<pre>Chapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        No data on the genotoxicity and carcinogenicity of n-butyl glycidyl ether in
        humans were available, nor were there any carcinogenicity data available of ani-
        mals.
            The agent showed to be mutagenic and genotoxic in bacterial and mamma-
        lian cell systems. Furthermore, it acted as a clastogen when applied by intraperi-
        toneal injections in mice and rats. These findings are a cause for concern to the
        committee. The outcomes of the mouse dominant lethal assays were uncertain,
        due to contradictory results.
            The committee did not find indications that the observations in animals, and
        the proposed carcinogenic mechanism would not occur in humans.
5.2     Recommendation for classification
        Based on the available information, the committee is of the opinion that n-butyl
        glycidyl ether has been insufficiently investigated. While the available data do
        not warrant a classification as carcinogenic to humans or as should be regarded
        as carcinogenic to humans, they indicate that there is cause for concern. There-
        fore, the committee recommends classifying n-butyl glycidyl ether as a sus-
        pected human carcinogen. This recommendation is comparable to the EU
        Classification                                                                     23
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<pre>   classification in category 3. The situation is, furthermore, comparable with sub-
   category b of this category.
24 n-Butyl glycidyl ether
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<pre>  References
1 International Agency for Research on Cancer. Some glycidyl ethers. IARC Monograph
  Eval.Carcinog.Risks Hum., France, Volume 47: pp 237-261; 1989.
2 National Toxicology Program (NTP). n-Butyl glycidyl ether (BGE) [CAS No. 2426-08-6]. Review of
  toxicological literature. National Toxicology Program (NTP), NIEHS, Research Triangle Park, NC;
  2004.
3 Thompson ED, Coppinger WJ, Piper CE, McCarroll N, Oberly TJ, Robinson D. Mutagenicity of
  alkyl glycidyl ethers in three short-term assays. Mutat Res 1981; 90(3): 213-231.
4 von der Hude W., Seelbach A, Basler A. Epoxides: comparison of the induction of SOS repair in
  Escherichia coli PQ37 and the bacterial mutagenicity in the Ames test. Mutat Res 1990; 231(2): 205-
  218.
5 Pullin TG. Butyl glycidyl ether. Integrated mutagenicity testing program report with cover. Report of
  the Dow Chemical Company integrated mutagenicity testing program, Rhone-Poulenc Inc, and Shell
  Oil Company; 1977.
6 von der Hude W., Carstensen S, Obe G. Structure-activity relationships of epoxides: induction of
  sister-chromatid exchanges in Chinese hamster V79 cells. Mutat Res 1991; 249(1): 55-70.
7 Whorton EB, Jr., Pullin TG, Frost AF, Onofre A, Legator MS, Folse DS. Dominant lethal effects of n-
  butyl glycidyl ether in mice. Mutat Res 1983; 124(3-4): 225-233.
8 Connor TH, Pullin TG, Meyne J, Frost AF, Legator MS. Evaluation of the mutagenicity of n-BGE
  and t-BGE in a battery of shortterm assays. Environ Mutagen 1980; 2(2): 284.
9 Piper CE. In vivo bone marrow cytogenetics study in the rat R0065 in the rat. Vienna, Virginia:
  Hazleton Laboratories America; 1979: Project No. 297-323.
  References                                                                                            25
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<pre>26 n-Butyl glycidyl ether</pre>

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<pre>A Request for advice
B The committee
C Comments on the public review draft
D IARC Monograph
E Carcinogenic classification of substances by the committee
F Guideline 93/21/EEG of the European Union
  Annexes
                                                             27
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<pre>28 n-Butyl glycidyl ether</pre>

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<pre>Annex A
      Request for advice
      In a letter dated October 11, 1993, ref DGA/G/TOS/93/07732A, to, the State
      Secretary of Welfare, Health and Cultural Affairs, the Minister of Social Affairs
      and Employment wrote:
      Some time ago a policy proposal has been formulated, as part of the simplification of the governmen-
      tal advisory structure, to improve the integration of the development of recommendations for health
      based occupation standards and the development of comparable standards for the general population.
      A consequence of this policy proposal is the initiative to transfer the activities of the Dutch Expert
      Committee on Occupational Standards (DECOS) to the Health Council. DECOS has been established
      by ministerial decree of 2 June 1976. Its primary task is to recommend health based occupational
      exposure limits as the first step in the process of establishing Maximal Accepted Concentrations
      (MAC-values) for substances at the work place.
      In an addendum, the Minister detailed his request to the Health Council as fol-
      lows:
      The Health Council should advice the Minister of Social Affairs and Employment on the hygienic
      aspects of his policy to protect workers against exposure to chemicals. Primarily, the Council should
      report on health based recommended exposure limits as a basis for (regulatory) exposure limits for air
      quality at the work place. This implies:
      •    A scientific evaluation of all relevant data on the health effects of exposure to substances using a
           criteria-document that will be made available to the Health Council as part of a specific request
      Request for advice                                                                                        29
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<pre>       for advice. If possible this evaluation should lead to a health based recommended exposure limit,
       or, in the case of genotoxic carcinogens, a ‘exposure versus tumour incidence range’ and a calcu-
       lated concentration in air corresponding with reference tumour incidences of 10-4 and 10-6 per
       year.
   •   The evaluation of documents review the basis of occupational exposure limits that have been
       recently established in other countries.
   •   Recommending classifications for substances as part of the occupational hygiene policy of the
       government. In any case this regards the list of carcinogenic substances, for which the classifica-
       tion criteria of the Directive of the European Communities of 27 June 1967 (67/548/EEG) are
       used.
   •   Reporting on other subjects that will be specified at a later date.
   In his letter of 14 December 1993, ref U 6102/WP/MK/459, to the Minister of
   Social Affairs and Employment the President of the Health Council agreed to
   establish DECOS as a Committee of the Health Council.
30 n-Butyl glycidyl ether
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<pre>Annex B
      The committee
      •   G..J. Mulder, chairman
          emeritus professor of toxicology, Leiden University, Leiden
      •   P.J. Boogaard
          toxicologist, SHELL International BV, The Hague
      •   Ms. M.J.M. Nivard
          molecular biologist and genetic toxicologist, Leiden University Medical Cen-
          ter, Leiden
      •   G.M.H. Swaen
          epidemiologist, Dow Chemicals NV, Terneuzen
      •   R.A. Woutersen
          toxicologic pathologist, TNO Quality of Life, Zeist
      •   A.A. van Zeeland
          professor of molecular radiation dosimetry and radiation mutagenesis, Uni-
          versity Medical Center, Leiden
      •   E.J.J. van Zoelen
          professor of cell biology, Radboud University Nijmegen, Nijmegen
      •   J.M. Rijnkels, scientific secretary
          Health Council of the Netherlands, The Hague
      The committee consulted an additional expert, Prof. dr. G. Mohn, working at
      Department of Radiation Genetics and Chemical Mutagenesis of the University
      of Leiden, with respect to the genotoxic data.
      The committee                                                                    31
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<pre>   The Health Council and interests
   Members of Health Council Committees are appointed in a personal capacity
   because of their special expertise in the matters to be addressed. Nonetheless, it
   is precisely because of this expertise that they may also have interests. This in
   itself does not necessarily present an obstacle for membership of a Health Coun-
   cil Committee. Transparency regarding possible conflicts of interest is nonethe-
   less important, both for the President and members of a Committee and for the
   President of the Health Council. On being invited to join a Committee, members
   are asked to submit a form detailing the functions they hold and any other mate-
   rial and immaterial interests which could be relevant for the Committee’s work.
   It is the responsibility of the President of the Health Council to assess whether
   the interests indicated constitute grounds for non-appointment. An advisorship
   will then sometimes make it possible to exploit the expertise of the specialist
   involved. During the establishment meeting the declarations issued are dis-
   cussed, so that all members of the Committee are aware of each other’s possible
   interests.
32 n-Butyl glycidyl ether
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<pre>Annex C
      Comments on the public review draft
      A draft of the present report was released in 2007 for public review. The follow-
      ing organisations and persons have commented on the draft document:
      • E. González-Fernández, Ministerio de Trabajo y Asuntos Sociales, Spain;
      • R.D. Zumwalde, National Institute for Occupational Safety and Health, the
          USA.
      Comments on the public review draft                                               33
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<pre>Annex D
      IARC Monograph
      Some glycidyl ethers
      Vol.: 47 (1989) (p. 237)1
      Summary of Data Reported and Evaluation
      Exposures
      Glycidyl ethers are basic components of epoxy resins which have been commer-
      cially available since the late 1940s.
      Experimental carcinogenicity data
      -
      Human data
      No data were available to the Working Group.
      Other relevant data
      Some glycidyl ethers have been shown to cause allergic contact dermatitis in
      humans. Glycidyl ethers generally cause skin sensitization in experimental ani-
      IARC Monograph                                                                  35
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<pre>   mals. Necrosis of the mucous membranes of the nasal cavities was induced in
   mice exposed to allyl glycidyl ether. Phenyl glycidyl ether, but not n-butyl gly-
   cidyl ether, induced morphological transformation in mammalian cells in vitro.
   n-Butyl glycidyl ether induced micronuclei in mice in vivo following intraperito-
   neal but not oral administration.
   Evaluation
   No data were available from studies in humans on the carcinogenicity of glycidyl
   ethers.
   Overall evaluation
   -
36 n-Butyl glycidyl ether
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<pre>Annex         E
              Carcinogenic classification of sub-
              stances by the committee
The committee expresses its conclusions in the form of standard phrases:
Judgment of the committee                                                                       Comparable with EU class
This compound is known to be carcinogenic to humans                                             1
•   It is stochastic or non-stochastic genotoxic
•   It is non-genotoxic
•   Its potential genotoxicity has been insufficiently investigated. Therefore, it is unclear
    whether it is genotoxic
This compound should be regarded as carcinogenic to humans                                      2
•   It is stochastic or non-stochastic genotoxic
•   It is non-genotoxic
•   Its potential genotoxicity has been insufficiently investigated. Therefore, it is unclear
    whether it is genotoxic
This compound is a suspected human carcinogen.                                                  3
•   This compound has been extensively investigated. Although there is insufficient evidence    (A)
    for a carcinogenic effect to warrant a classification as ‘known to be carcinogenic to
    humans’ or as ‘should be regarded as carcinogenic to humans’, they indicate that there is
    cause for concern.
•   This compound has been insufficiently investigated. While the available data do not war-    (B)
    rant a classification as ‘known to be carcinogenic to humans’ or as ‘should be regarded as
    carcinogenic to humans’, they indicate that there is a cause for concern.
This compound cannot be classified                                                              not classifiable
•   There is a lack of carcinogenicity and genotoxicity data.
•   Its carcinogenicity is extensively investigated. The data indicate sufficient evidence sug-
    gesting lack of carcinogenicity.
              Carcinogenic classification of substances by the committee                                             37
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<pre>Annex F
      Guideline 93/21/EEG of the European
      Union
      4.2            Criteria for classification, indication of danger, choice of risk phrases
      4.2.1          Carcinogenic substances
      For the purpose of classification and labelling, and having regard to the current state of knowledge,
      such substances are divided into three categories:
      Category 1:
      Substances known to be carcinogenic to man.
      There is sufficient evidence to establish a causal association between human exposure to a substance
      and the development of cancer.
      Category 2:
      Substances which should be regarded as if they are carcinogenic to man.
      There is sufficient evidence to provide a strong presumption that human exposure to a substance may
      result in the development of cancer, generally on the basis of:
      •    appropriate long-term animal studies
      •    other relevant information.
      Guideline 93/21/EEG of the European Union                                                             39
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<pre>   Category 3:
   Substances which cause concern for man owing to possible carcinogenic effects but in
   respect of which the available information is not adequate for making a satisfactory assess-
   ment.
   There is some evidence from appropriate animal studies, but this is insufficient to place the substance
   in Category 2.
   4.2.1.1       The following symbols and specific risk phrases apply:
   Category 1 and 2:
   T; R45 May cause cancer
   However for substances and preparations which present a carcinogenic risk only when inhaled, for
   example, as dust, vapour or fumes, (other routes of exposure e.g. by swallowing or in contact with
   skin do not present any carcinogenic risk), the following symbol and specific risk phrase should be
   used:
   T; R49 May cause cancer by inhalation
   Category 3:
   Xn; R40 Possible risk of irreversible effects
   4.2.1.2       Comments regarding the categorisation of carcinogenic substances
   The placing of a substance into Category 1 is done on the basis of epidemiological data; placing into
   Categories 2 and 3 is based primarily on animal experiments.
   For classification as a Category 2 carcinogen either positive results in two animal species should be
   available or clear positive evidence in one species; together with supporting evidence such as geno-
   toxicity data, metabolic or biochemical studies, induction of benign tumours, structural relationship
   with other known carcinogens, or data from epidemiological studies suggesting an association.
40 n-Butyl glycidyl ether
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<pre>Category 3 actually comprises 2 sub-categories:
a    substances which are well investigated but for which the evidence of a tumour-inducing effect is
     insufficient for classification in Category 2. Additional experiments would not be expected to
     yield further relevant information with respect to classification.
b    substances which are insufficiently investigated. The available data are inadequate, but they
     raise concern for man. This classification is provisional; further experiments are necessary
     before a final decision can be made.
For a distinction between Categories 2 and 3 the arguments listed below are relevant which reduce
the significance of experimental tumour induction in view of possible human exposure. These argu-
ments, especially in combination, would lead in most cases to classification in Category 3, even
though tumours have been induced in animals:
•    carcinogenic effects only at very high levels exceeding the 'maximal tolerated dose'. The maxi-
     mal tolerated dose is characterized by toxic effects which, although not yet reducing lifespan, go
     along with physical changes such as about 10% retardation in weight gain;
•    appearance of tumours, especially at high dose levels, only in particular organs of certain species
     is known to be susceptible to a high spontaneous tumour formation;
•    appearance of tumours, only at the site of application, in very sensitive test systems (e.g. i.p. or
     s.c. application of certain locally active compounds);
•    if the particular target is not relevant to man;
•    lack of genotoxicity in short-term tests in vivo and in vitro;
•    existence of a secondary mechanism of action with the implication of a practical threshold above
     a certain dose level (e.g. hormonal effects on target organs or on mechanisms of physiological
     regulation, chronic stimulation of cell proliferation;
•    existence of a species - specific mechanism of tumour formation (e.g. by specific metabolic
     pathways) irrelevant for man.
For a distinction between Category 3 and no classification arguments are relevant which exclude a
concern for man:
•    a substance should not be classified in any of the categories if the mechanism of experimental
     tumour formation is clearly identified, with good evidence that this process cannot be extrapo-
     lated to man;
•    if the only available tumour data are liver tumours in certain sensitive strains of mice, without
     any other supplementary evidence, the substance may not be classified in any of the categories;
•    particular attention should be paid to cases where the only available tumour data are the occur-
     rence of neoplasms at sites and in strains where they are well known to occur spontaneously with
     a high incidence.
Guideline 93/21/EEG of the European Union                                                                 41
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<br><br>