<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>    Health Council of the Netherlands
Potassium cyanide
    Evaluation of the carcinogenicity and genotoxicity
</pre>

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<pre>Gezondheidsraad
Health Council of the Netherlands
Aan de staatssecretaris van Sociale Zaken en Werkgelegenheid
Onderwerp              : aanbieding advies Potassium cyanide
Uw kenmerk             : DGV/MBO/U-932342
Ons kenmerk            : U-7041/BvdV/fs/246-Z15
Bijlagen               :1
Datum                  : 9 maart 2012
Geachte staatssecretaris,
Graag bied ik u hierbij het advies aan over de gevolgen van beroepsmatige blootstelling aan
kaliumcyanide.
Dit advies maakt deel uit van een uitgebreide reeks waarin kankerverwekkende stoffen
worden geclassificeerd volgens richtlijnen van de Europese Unie. Het gaat om stoffen
waaraan mensen tijdens de beroepsmatige uitoefening kunnen worden blootgesteld.
     Dit advies is opgesteld door een vaste subcommissie van de Commissie Gezondheid en
beroepsmatige blootstelling aan stoffen (GBBS), de Subcommissie Classificatie van
carcinogene stoffen. Daarbij heeft de subcommissie op verzoek van uw ministerie de
formulering van de categorie waarin kaliumcyanide valt, aangepast; niet een numerieke
aanduiding maar een standaardzin vormt de hoofdformulering. Het advies is getoetst door
de Beraadsgroep Gezondheid en omgeving van de Gezondheidsraad.
Ik heb het advies vandaag ter kennisname toegezonden aan de staatssecretaris van
Infrastructuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. L.J. Gunning-Schepers,
voorzitter
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 7 4 4 7                          w w w. g r. n l
E - m a i l : b . v. d . v o e t @ g r. n l
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<pre>Potassium cyanide
Evaluation of the carcinogenicity and genotoxicity
Subcommittee on the Classification of Carcinogenic Substances of
the Dutch Expert Committee on Occupational Safety,
a Committee of the Health Council of the Netherlands
to:
the State Secretary of Social Affairs and Employment
No. 2012/03, The Hague, March 9, 2012
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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 and health
(services) research...” (Section 22, Health Act).
     The Health Council receives most requests for advice from the Ministers of
Health, Welfare & Sport, Infrastructure & the Environment, Social Affairs &
Employment, Economic Affairs, Agriculture & Innovation, and Education, Cul-
ture & Science. 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 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 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. Potassium cyanide. Evaluation of the
carcinogenicity and genotoxicity. The Hague: Health Council of the Netherlands,
2012; publication no. 2012/03.
all rights reserved
ISBN: 978-90-5549-896-3
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<pre>    Contents
    Samenvatting 7
    Executive summary 8
1   Scope 9
1.1 Background 9
1.2 Committee and procedures 9
1.3 Data 10
2   General information 11
2.1 Identity and physico-chemical properties 12
2.2 IARC classification 12
3   Carcinogenicity 13
3.1 Observations in humans 13
3.2 Carcinogenicity studies in animals 13
4   Genotoxicity 14
4.1 In vitro assays 14
4.2 In vivo assays 16
    Contents                                    5
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<pre>5   Classification 18
5.1 Evaluation of data on carcinogenicity and genotoxicity 18
5.2 Recommendation for classification 19
    References 20
    Annexes 22
A   Request for advice 23
B   The Committee 25
C   The submission letter (in English) 27
D   Comments on the public review draft 29
E   Carcinogenic classification of substances by the Committee 30
    Contents                                                      6
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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 de beroepsmatige uitoefening 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 kaliumcyanide
  onder de loep.
  Kaliumcyanide is een stof die voornamelijk wordt gebruikt voor galvaniseren,
  het versterken van staal, de winning van goud en zilver uit erts en de ontsmetting
  van fruitbomen, schepen, treinwagons en warenhuizen. Daarnaast wordt deze
  stof breed gebruikt in de synthese van organische en anorganische chemicaliën
  (bv. cyanides, carboxylzuren, amides, esters, en amines, cyanides van zware met-
  alen) en tijdens de productie van chelerende verbindingen.
  De commissie constateert dat de gegevens over kaliumcyanide niet voldoende
  zijn om de kankerverwekkende eigenschappen te evalueren (categorie 3).*
* Volgens het nieuwe classificatiesysteem van de Gezondheidsraad (zie bijlage E).
  Samenvatting                                                                       7
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<pre>  Executive summary
  At the request of the Minister of Social Affairs and Employment, the Health
  Council of the Netherlands evaluates and judges the carcinogenic properties of
  substances 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 Safety of the Health Council, hereaf-
  ter called the Committee. In this report, the Committee evaluates potassium cya-
  nide.
  Potassium cyanide is mainly used for electroplating, steel hardening, extraction
  of gold and silver from ores, fumigation of fruit trees, ships, railway cars and
  warehouses. They are also widely used in the synthesis of organic and inorganic
  chemicals (e.g., nitriles, carboxylic acids, amides, esters, and amines; heavy
  metal cyanides) and in the production of chelating agents.
  The Committee concludes that the available data are insufficient to evaluate the
  carcinogenic properties of potassium cyanide (category 3).*
* According to the new classification system of the Health Council (see Annex E).
  Executive summary                                                                8
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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). In addition to classifying substances, the Health Council also
        assesses the genotoxic properties of the substance in question. The assessment
        and the proposal for a classification are expressed in the form of standard sen-
        tences (see Annex E).
            This report contains the evaluation of the carcinogenicity and genotoxicity of
        potassium cyanide.
1.2     Committee and procedures
        The evaluation is performed by the Subcommittee on Classification of Carcino-
        genic Substances of the Dutch Expert Committee on Occupational Safety, here-
        after called the Committee. The members of the Committee are listed in Annex
        B. The submission letter (in English) to the State Secretary can be found in
        Annex C.
            In July 2011 the President of the Health Council released a draft of the report
        for public review. The individuals and organisations that commented on the draft
        Scope                                                                               9
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<pre>    are listed in Annex D. 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
    scientific data, which are publicly available. The starting points of the Commit-
    tees’ 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 Com-
    mittee when these are considered most relevant in assessing the carcinogenicity
    and genotoxicity of the substance in question. In the case of potassium cyanide
    such an IARC-monograph is not available. Published data were retrieved from
    the online databases Medline, Toxline, and Chemical Abstracts, using carcino*,
    cancer*, mutagen*, chromosom*, genotox* (*: wildcard character) and CAS no.
    151-50-8 as key words. The search covered publications till June 2011. The rele-
    vant data were included in this report.
    Scope                                                                             10
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<pre>Chapter 2
        General information
        The data have been retrieved from the European Substance Information System
        (ESIS)*, the Hazardous Substances Data Bank (HSDB)** and the INCHEM data-
        base of the International Programme on Chemical Safety (IPCS), which can be
        accesses via inchem-site***.
*       http://esis.jrc.ec.europa.eu/ (February 29, 2012).
**      http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?HSDB (February 29, 2012).
***     http://www.inchem.org/ (February 29, 2012).
        General information                                                         11
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<pre>2.1 Identity and physico-chemical properties
    Chemical name             :  Potassium cyanide
    CAS registry number       :  151-50-8
    EINECS number             :  205-792-3
                                 006-007-00-5 (group entry: hydrogen cyanide (Salts of ...)
                                 with the exception of complex cyanides such as ferrocyanides,
                                 ferricyanides and mercuric oxycyanide
    Synonyms                  :  Kaliumcyanide, KCN, hydrocyanic acid, potassium salt
    Appearance                :  White, granular or crystalline solid. Faint bitter almond-like
                                 odor or odor of hydrogen cyanide.
    Use                       :  Potassium cyanide is mainly used for electroplating, steel
                                 hardening, extraction of gold & silver from ores, fumigation of
                                 fruit trees, ships, railway cars and warehouses. They are also
                                 widely used in the synthesis of organic and inorganic chemi-
                                 cals (e.g., nitriles, carboxylic acids, amides, esters, and
                                 amines; heavy metal cyanides) and in the production of chelat-
                                 ing agents.
    Chemical formula          :  C-K-N
    Structural formula
    Molecular weight          :  65.1
    Boiling point             :  1625°C
    Melting point             :  634°C
    Vapour pressure           :  -
    Vapour density (air = 1)  :  -
    Solubility                :  Soluble in 2 parts cold water and in 1 part boiling water
                                 71.6 g/100 ml
    Conversion factor         :  -
    EU Classification
    (100% solution)           :  Acute Tox. 1: H310 (Fatal in contact with skin)
                              :  Acute Tox. 2: H300 (Fatal if swallowed)
                              :  Acute Tox. 2: H330 (Fatal if inhaled)
                              :  EUH032 (Contact with acids liberates very toxic gas)
2.2 IARC classification
    Potassium cyanide has not been evaluated by IARC.
    General information                                                                          12
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<pre>Chapter 3
        Carcinogenicity
3.1     Observations in humans
        No human studies addressing the carcinogenicity of potassium cyanide have
        been retrieved from public literature.
3.2     Carcinogenicity studies in animals
        No in vivo animal studies addressing the carcinogenicity of potassium cyanide
        have been retrieved from public literature.
        Carcinogenicity                                                               13
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<pre>Chapter 4
        Genotoxicity
        No human studies addressing mutagenicity or genotoxicity of potassium cyanide
        have been retrieved from public literature.
4.1     In vitro assays
        In a study of De Flora et al. potassium cyanide was tested in the Ames reverse
        mutation assay with Salmonella typhimurium strains TA1535, TA1537, TA1538,
        TA98, TA100.1 Potassium cyanide was tested both with and without S9-mix (in
        duplicate or triplicate plates), and appeared negative in all strains.
        In another study of De Flora et al., potassium cyanide again was negative in the
        Ames test strains TA97 and TA102.2
        In a study of Kubo et al. potassium cyanide did not show any mutagenicity in the
        Ames test strains Salmonella typhimurium TA98 and TA100 without and with a
        metabolic activator (S9-mix).3
        Potassium cyanide was assayed in a liquid DNA-repair test with the 3 isogenic
        Escherichia coli strains WP2 (wild-type repair-proficient), WP67 (uvrA- polA-),
        and CM871 (uvrA- recA- lexA-) with or without S9-mix.1 The initial concentra-
        tions of potassium cyanide were governed either by its solubility or by its toxic-
        Genotoxicity                                                                       14
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<pre>ity for bacteria, as inferred from preliminary assays. Potassium cyanide was
positive with the E.coli strains without S9-mix, but negative with S9-mix.
In 3 studies potassium cyanide was used as test substance in studies aimed at
improving the discrimination between cytotoxins (like potassium cyanide) and
genotoxins.4-6
     In a study of Vock et al.to discriminate between direct genotoxicity and
cytotoxicity as cause of DNA double-strand breaks, genotoxic agents
(melphalan, etoposide and gamma-rays), potassium cyanide and Triton X100
were tested in cultured human lung epithelial cells (A549).6 DNA fragmentation
was assessed by pulsed-field gel electrophoresis and cell viability by measuring
the reduction of MTT dye (which can be accomplished by viable cells only). The
dose-response relationships for DNA fragmentation and for cell viability were
investigated at different times of incubation (8, 24 and 72 hours) in order to
discriminate between genotoxicity and cytotoxicity in the pathogenesis of DNA
double-strand breaks. Induction of double-strand breaks by potassium cyanide
was seen only after cell viability was reduced to less than about 60%, indicating
that double-strand breaks were the consequence of cytotoxic damage. For the
genotoxic agents double-strand breaks preceded decrease in cell viability. This
mechanistic distinction of genotoxins and cytotoxins was also supported by
DNA fragment length analysis. DNA fragments induced by potassium cyanide
and Triton X100 peaked below 0.5 Mbp, implicating activation of DNA-
degrading enzymes as a consequence of cell death. The authors conclude that this
study clearly demonstrates the cytotoxic nature of potassium cyanide induced
double-strand breaks.
In the study of Henderson et al. potassium cyanide was tested in the alkaline
Comet assay in TK6 human lymphoblastoid cells.4 Potassium cyanide exerts its
toxic effect via the cell electron transfer chain. Potassium cyanide produced a
significant increase of DNA migration (increase in tail moments) at cell survival
levels of < 75% at a dose level of 5000 µg/ml. The wide distribution of damaged
cells indicated that cells at various stage of necrotic cell death were present.
Comparison of the results for cytotoxins and genotoxins showed that cytotoxins
are able to induce an increase in DNA migration only when cell viability was
< 75%.
Storer et al. performed a revalidation of the in vitro alkaline elution/rat hepato-
cyte assay for DNA damage.5 This assay is a sensitive assay for genotoxicity,
measured as DNA strand breaks induced in primary cultures of rat hepatocytes
Genotoxicity                                                                        15
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<pre>    after 3-h treatments with test compounds. Since DNA degradation can be rapid
    and extensive in dead and/or dying cells, the original criteria for a positive result
    in the assay were that a compound induce a 3.0-fold or greater increase in the
    elution slope (for the terminal phase of alkaline elution from 3 to 9 h) in the
    absence of significant cytotoxicity defined as relative cell viability of less than
    70% by trypan blue dye exclusion. Potassium cyanide produced no positive
    result by the proposed criteria. It shows significant increases in both cytotoxicity
    and in the induced elution slope.
    Fornace et al., studied the induction of DNA single strand breaks, and DNA
    cross-linking by various carcinogens and metabolic inhibitors (including potas-
    sium cyanide) in human or mouse fibroblasts in monolayer cultures.7 To deter-
    mine the degree of single-strand breaks or cross links induced a method was used
    of alkaline elution of the cells on polyvinyl chloride filters and measurement of
    the amount of (previously radiolabeled) DNA retained on the filters. Comparing
    the amount of DNA retained for cells only treated with the test substance with
    that of untreated control cells is a measure for the number of single strand breaks.
    The lower the retention of DNA in treated cells compared to untreated controls,
    the higher the number of single strand breaks induced.
        The difference between the amount of DNA retained on the filter after
    combined exposure to substance and X-rays compared to the amount of DNA
    retained after exposure to X-rays alone is a measure of the degree of cross-
    linking induced: a higher amount of DNA retained after concomitant treatment
    with the test substance and X-rays indicates cross-linking of DNA has taken
    place.
        No cross-link effects were seen following treatment with potassium cyanide.
    Also no DNA single-strand breaks were seen after a 1-h exposure to potassium
    cyanide. After 24-h exposure to potassium cyanide, when the cells showed
    marked lytic changes, i.e. less than 20% of the cells remained attached, the
    relative retention did decrease, but again no cross-linking effect was reported.
4.2 In vivo assays
    Schubert et al. studied the influence of potassium cyanide on the induction of
    chromosome aberrations in bone marrow cells of male mice as a control in a
    study that was designed to study the effect of potassium cyanide on induction of
    these genotoxic effects by single, whole-body 60Co irradiation in male mice.8
    The irradiation dose rate was 1.8 Gy/min, resulting in a total dose of 6.25 Gy
    (1 joule/kg or 100 rad), while potassium cyanide was injected intraperitoneally at
    Genotoxicity                                                                          16
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<pre>a non-toxic dose of 5.5 mg/kg bw, 2 min, respectively 20 min prior to irradiation.
Although potassium cyanide had a marked reduction in chromosome aberrations
2 min before irradiation, it induced by itself no chromosome aberrations.
Genotoxicity                                                                       17
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<pre>Chapter 5
        Classification
5.1     Evaluation of data on carcinogenicity and genotoxicity
        Potassium cyanide was not evaluated by IARC. In a recent (2010) toxicological
        review of hydrogen cyanide and cyanide salts the EPA reaffirms that there is
        ‘inadequate information to assess the carcinogenic potential’ of cyanide.9
        The public literature retrieved by the Committee provided no data on the possible
        carcinogenicity of potassium cyanide in humans and experimental animals.
        From in vitro tests that tried to identify genotoxic or mutagenic effects it was
        found that potassium cyanide was essentially negative. Only in DNA-repair tests
        with E-coli strains potassium cyanide appeared to be positive, though only with-
        out S9-mix. However, a couple of more mechanistic studies with mammalian cell
        cultures showed that DNA damaging effects by potassium cyanide are induced
        only after it has become cytotoxic.
        Only one in vivo study was retrieved from the literature. In mice no cytotoxic
        effects of potassium cyanide were demonstrated.
        Classification                                                                    18
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<pre>5.2 Recommendation for classification
    The Committee concludes that the available data are insufficient to evaluate the
    carcinogenic properties of potassium cyanide (category 3).*
*   According to the new classification system of the Health Council (see Annex E).
    Classification                                                                   19
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<pre>  References
1 De Flora S., Zanacchi P, Camoirano A, Bennicelli C, Badolati GS. Genotoxic activity and potency of
  135 compounds in the Ames reversion test and in a bacterial DNA-repair test. Mutat Res 1984;
  133(3): 161-198.
2 De Flora S., Camoirano A, Zanacchi P, Bennicelli C. Mutagenicity testing with TA97 and TA102 of
  30 DNA-damaging compounds, negative with other Salmonella strains. Mutat Res 1984; 134(2-3):
  159-165.
3 Kubo T, Urano K, Utsumi H. Mutagenicity characteristics of 255 environmental chemicals. J Health
  Sci 2002; 48(6): 545-554.
4 Henderson L, Wolfreys A, Fedyk J, Bourner C, Windebank S. The ability of the Comet assay to
  discriminate between genotoxins and cytotoxins. Mutagenesis 1998; 13(1): 89-94.
5 Storer RD, McKelvey TW, Kraynak AR, Elia MC, Barnum JE, Harmon LS et al. Revalidation of the
  in vitro alkaline elution/rat hepatocyte assay for DNA damage: improved criteria for assessment of
  cytotoxicity and genotoxicity and results for 81 compounds. Mutat Res 1996; 368(2): 59-101.
6 Vock EH, Lutz WK, Hormes P, Hoffmann HD, Vamvakas S. Discrimination between genotoxicity
  and cytotoxicity in the induction of DNA double-strand breaks in cells treated with etoposide,
  melphalan, cisplatin, potassium cyanide, Triton X-100, and gamma-irradiation. Mutat Res 1998;
  413(1): 83-94.
7 Fornace AJ, Jr., Little JB. DNA-protein cross-linking by chemical carcinogens in mammalian cells.
  Cancer Res 1979; 39(3): 704-710.
8 Schubert J, Pan SF, Wald N. Chromosome aberrations reduced in whole-body irradiated mice by
  pretreatment with cyanide. Mutat Res 1992; 282(2): 107-111.
  References                                                                                         20
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<pre>9  Toxicological review of hydrogen cyanide and cyanide salts. US Environmental Protection Agency
   (EPA), Washington DC: 2010.
10 Health Council of The Netherlands. Guideline for the classification of carcinogenic compounds.
   Health Council of The Netherlands, The Hague, The Netherlands: 2010: publication no. A10/07E.
   References                                                                                     21
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<pre>A Request for advice
B The Committee
C The submission letter (in English)
D Comments on the public review draft
E Carcinogenic classification of substances by the Committee
  Annexes
                                                             22
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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
      follows:
      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                                                                                        23
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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. The membership of the
Committee is given in Annex B.
Request for advice                                                                                      24
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<pre>Annex B
      The Committee
      •  R.A. Woutersen, chairman
         Toxicologic Pathologist, TNO Innovation for Life, Zeist; Professor of
         Translational Toxicology, Wageningen University and Research Centre,
         Wageningen
      •  J. van Benthem
         Genetic Toxicologist, National Institute for Public Health and the
         Environment, Bilthoven
      •  P.J. Boogaard
         Toxicologist, SHELL International BV, The Hague
      •  G.J. Mulder
         Emeritus Professor of Toxicology, Leiden University, Leiden
      •  Ms M.J.M. Nivard
         Molecular Biologist and Genetic Toxicologist, Leiden University Medical
         Center, Leiden
      •  G.M.H. Swaen
         Epidemiologist, Dow Chemicals NV, Terneuzen
      •  E.J.J. van Zoelen
         Professor of Cell Biology, Radboud University Nijmegen, Nijmegen
      •  G.B. van der Voet, scientific secretary
         Toxicologist, Health Council of the Netherlands, The Hague
      The Committee                                                              25
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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 chairperson 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 inaugural meeting the declarations issued are discussed, so
that all members of the Committee are aware of each other’s possible interests.
The Committee                                                                      26
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<pre>Annex C
      The submission letter (in English)
      Subject         : Submission of the advisory report Potassium cyanide
      Our reference : DGV/MBO/U-932342
      Your Reference: U-7041/BvdV/fs/246-Z15/E
      Enclosed        :1
      Date            : March 9, 2012
      Dear State Secretary,
      I hereby submit the advisory report on the effects of occupational exposure to
      Potassium cyanide.
      This advisory report is part of an extensive series in which carcinogenic sub-
      stances are classified in accordance with European Union guidelines. This
      involves substances to which people can be exposed while pursuing their occu-
      pation.
          The advisory report was prepared by the Subcommittee on Classifying
      Carcinogenic Substances, a permanent subcommittee of the Health Council’s
      Dutch Expert Committee on Occupational Safety (DECOS). In addition, at your
      Ministry’s request, the Subcommittee has modified the formulation of the cate-
      gory into which Potassium cyanide has been placed; the main formulation is a
      standard phrase rather than a numerical designation. The advisory report has
      The submission letter (in English)                                             27
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<pre>been assessed by the Health Council’s Standing Committee on Health and the
Environment.
I have today sent copies of this advisory report to the State Secretary of
Infrastructure and the Environment and to the Minister of Health, Welfare
and Sport, for their consideration.
Yours sincerely,
(signed)
Professor L.J. Gunning-Schepers,
President
The submission letter (in English)                                         28
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<pre>Annex D
      Comments on the public review draft
      A draft of the present report was released in July 2011 for public review. The fol-
      lowing organisation has commented on the draft document:
      • National Institute for Occupational Safety and Health, Cincinnati, USA.
      Comments on the public review draft                                                 29
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<pre>Annex        E
             Carcinogenic classification of
             substances by the Committee
             The Committee expresses its conclusions in the form of standard phrases:
Category      Judgement of the Committee (GRGHS)                                 Comparable with EU Category
                                                                                 67/548/EEC            EC No 1272/2008
                                                                                 before                as from
                                                                                 12/16/2008            12/16/2008
1A            The compound is known to be carcinogenic to humans.                1                     1A
              It acts by a stochastic genotoxic mechanism.
              It acts by a non-stochastic genotoxic mechanism.
              It acts by a non-genotoxic mechanism.
              Its potential genotoxicity has been insufficiently investigated.
              Therefore, it is unclear whether the compound is genotoxic.
1B            The compound is presumed to be as carcinogenic to humans.          2                     1B
              It acts by a stochastic genotoxic mechanism.
              It acts by a non-stochastic genotoxic mechanism.
              It acts by a non-genotoxic mechanism.
              Its potential genotoxicity has been insufficiently investigated.
              Therefore, it is unclear whether the compound is genotoxic.
2             The compound is suspected to be carcinogenic to man.               3                     2
(3)           The available data are insufficient to evaluate the carcinogenic   not applicable        not applicable
              properties of the compound.
(4)           The compound is probably not carcinogenic to man.                  not applicable        not applicable
Source: Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The Hague: Health
Council of the Netherlands, 2010; publication no. A10/07E.10
             Carcinogenic classification of substances by the Committee                                                 30
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