<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>Advisory Reports Areas of activity The Health Council’s task is to advise ministers and parliament on issues in the field of public health. Most of the advisory reports that the Council produces every year are prepared at the request of one of the ministers. In addition, the Health Council issues unsolicited advice that has an ‘alerting’ function. In some cases, such an alerting report leads to a minister requesting further advice on the subject. Health Council of the Netherlands www.healthcouncil.nl Optimum healthcare What is the optimum result of cure and care in view of the risks and opportunities? Environmental health Which environmental influences could have a positive or negative effect on health? Prevention Which forms of prevention can help realise significant health benefits? Healthy working conditions How can employees be protected against working conditions that could harm their health? Healthy nutrition Which foods promote good health and which carry certain health risks? Innovation and the knowledge infrastructure Before we can harvest knowledge in the field of healthcare, we first need to ensure that the right seeds are sown. Health Council of the Netherlands Dimethyl sulphate Health-based calculated occupational cancer risk values 2014/27 2014/27 Dimethyl sulphate 627349_V23_OM_Paars_ENG.indd Alle pagina's 24-10-14 13:27</pre>

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<pre>Dimethyl sulphate
   Health-based calculated occupational cancer risk values
</pre>

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<pre></pre>

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<pre>Aan de minister van Sociale Zaken en Werkgelegenheid
Onderwerp              : Aanbieding advies Dimethyl sulphate
Uw kenmerk             : DGV/BMO U-932542
Ons kenmerk            : U-8223/BvdV/459-P70
Bijlagen               :1
Datum                  : 3 november 2014
Geachte minister,
Graag bied ik u hierbij aan het advies over de gevolgen van beroepsmatige blootstelling aan
dimethylsulfaat.
Dit advies maakt deel uit van een uitgebreide reeks, waarin concentratieniveaus in lucht
worden afgeleid die samenhangen met een extra kans op (overlijden aan) kanker van 4 per
1.000 en 4 per 100.000 door beroepsmatige blootstelling. De conclusies van het genoemde
advies zijn opgesteld door de Commissie Gezondheid en beroepsmatige blootstelling aan
stoffen (GBBS) van de Gezondheidsraad en beoordeeld door de Beraadsgroep Gezondheid
en omgeving.
In dit advies concludeert de commissie dat dimethylsulfaat een carcinogene stof is en
beveelt aan om deze stof te classificeren in categorie 1B (de stof moet beschouwd worden
als kankerverwekkend voor de mens). De commissie is echter van mening dat wegens
gebrek aan adequate humane en dierexperimentele gegevens het niet mogelijk is om de
extra kans op kanker na blootstelling aan dimethylsulfaat te berekenen.
Ik heb dit advies vandaag ter kennisname toegezonden aan de staatssecretaris van Infra-
structuur en Milieu en aan de minister van Volksgezondheid, Welzijn en Sport.
Met vriendelijke groet,
prof. dr. J.L. Severens,
vicevoorzitter
Bezoekadres                                                       Postadres
Rijnstraat 50                                                     Postbus 16052
2515 XP Den Haag                                                  2500 BB Den Haag
E - m a i l : b . v. d . v o e t @ g r. n l                       w w w. g r. n l
Te l e f o o n ( 0 7 0 ) 3 4 0 7 4 4 7
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<pre></pre>

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<pre>Dimethyl sulphate
Health-based calculated occupational cancer risk values
Dutch Expert Committee on Occupational Safety,
a Committee of the Health Council of the Netherlands
to:
the Minister of Social Affairs and Employment
No. 2014/27, The Hague, November 3, 2014
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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 and Sport, Infrastructure and the Environment, Social Affairs
and Employment, Economic Affairs, and Education, Culture and 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.
This report can be downloaded from www.healthcouncil.nl.
Preferred citation:
Health Council of the Netherlands. Dimethyl sulphate - Health-based calculated
occupational cancer risk values. The Hague: Health Council of the Netherlands,
2014; publication no. 2014/27.
all rights reserved
ISBN: 978-94-6281-015-0
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<pre>   Contents
   Samenvatting 9
   Executive summary 11
   Scope 13
.1 Background 13
.2 Committee and procedure 14
.3 Data 14
   Identity, toxicity profile and classification 15
.1 Identity and physical and chemical properties 15
.2 Classification as a carcinogenic substance 16
.3 Genotoxicity 16
.4 Non-carcinogenic effects 17
.5 Existing occupational exposure limits and classifications 18
   Carcinogenicity studies 21
.1 Observations in humans 21
.2 Carcinogenicity studies in animals 22
.3 Risk assessment 24
.4 Additional consideration 24
   Contents                                                     7
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<pre>  References 25
  Annexes 29
A Request for advice 31
B The Committee 33
C The submission letter (in English) 35
D Comments on the public review draft 37
E Animal studies 39
F Evaluation of the Subcommittee on the Classification of Carcinogenic Substances 43
G Carcinogenic classification of substances by the Committee 49
H Health-based calculated occupational risk values based on the rat study by Schlögel 51
  Dimethyl sulphate
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<pre>Samenvatting
Op verzoek van de Minister van Sociale zaken en Werkgelegenheid, schat de Commis-
sie Gezondheid en beroepsmatige blootstelling aan stoffen (GBBS) van de Gezond-
heidsraad, de concentraties van een stof in de lucht die overeenkomen met een vooraf
vastgesteld extra risico op kanker (4 per 1.000 en 4 per 100.000 individuen) door
beroepsmatige blootstelling gedurende het arbeidzame leven. Het gaat om kankerver-
wekkende stoffen die door de Gezondheidsraad of de Europese Unie geclassificeerd
zijn in categorie 1A of 1B en die kankerverwekkend zijn via een stochastisch geno-
toxisch mechanisme. Voor de schatting maakt de commissie gebruik van de Leidraad
Berekening risicogetallen voor carcinogene stoffen van de Gezondheidsraad.1 In dit
advies onderzoekt de commissie de mogelijkheid om zo’n schatting te maken voor
dimethylsulfaat. Dimethylsulfaat wordt gebruikt als methylerende stof bij de productie
van kleurstoffen, parfums, geneesmiddelen, voor de scheiding van minerale oliën, en
voor de analyse van motoroliën. Ook de sulfaterende eigenschappen worden toegepast
in de productie van verschillende producten (bv. kleurstoffen en textielverzachters).
De commissie concludeert dat dimethylsulfaat een carcinogene stof is met een sto-
chastisch genotoxisch werkingsmechanisme. De commissie beveelt aan om deze stof
onder te brengen in categorie 1B (stof moet beschouwd worden als kankerverwekkend
voor de mens).
    De commissie is echter van mening dat wegens gebrek aan adequate humane en
dierexperimentele gegevens het niet mogelijk is om de extra kans op kanker na
blootstelling aan dimethyl sulfaat exact te berekenen.
Samenvatting                                                                           9
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<pre>0 Dimethyl sulphate</pre>

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<pre>Executive summary
At the request of the Minister of Social Affairs and Employment, the Dutch Expert
Committee on Occupational Safety (DECOS), a committee of the Health Council of
the Netherlands, derives so-called health-based calculated - occupational cancer risk
values (HBC-OCRVs) associated with excess cancer risk levels of 4 per 1,000 and 4
per 100,000 as a result of working life exposure to substances. It concerns substances
which are classified by the Health Council or the European Union in category 1A or
1B, and which are considered stochastic genotoxic carcinogens. For the estimation,
the Committee uses the Guideline for the calculation of occupational cancer risk
values of the Health Council.1 In this report the Committee evaluates the possibility
to establish such estimates for dimethyl sulphate. Dimethyl sulphate is used as a
methylating agent in the manufacturing of dyes, perfumes, pharmaceuticals, for the
separation of mineral oils, and for the analysis of automobile fluids. Also its
sulphating properties are applied in the manufacturing of various products (e.g. dyes
and fabric softeners, etc.).
In this report, the Committee concludes that dimethyl sulphate is a carcinogenic
substance with a stochastic genotoxic mechanism. The Committee recommends
dimethyl sulphate to be classified in category 1B (substance presumed to be
carcinogenic to humans).
    The Committee is further of the opinion that due to a lack of adequate human and
animal data, it is not possible to exactly establish the health-based calculated
occupational cancer risk values for dimethyl sulphate.
Executive summary                                                                      11
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<pre>2 Dimethyl sulphate</pre>

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<pre> hapter 1
        Scope
1.1     Background
        In the Netherlands, occupational exposure limits for genotoxic chemical
        substances are set using a three-step procedure. In the first step, a scientific
        evaluation of the data on the toxicity of the substance is made by the Dutch
        Expert Committee on Occupational Safety (DECOS), a Committee of the Health
        Council of the Netherlands, at request of the Minister of Social Affairs and
        Employment (Annex A). This evaluation should lead, for genotoxic substances
        with a non stochastic mechanism, to a health-based recommended occupational
        exposure limit for the concentration of the substance in air. Such an exposure
        limit cannot be derived if the toxic action can not be evaluated using a threshold
        model, as is the case for substances with stochastic genotoxic carcinogenic
        properties. In that case, an exposure-response relationship is recommended for
        use in regulatory standard setting, i.e. the calculation of so-called health-based
        calculated occupational cancer risk values (HBC-OCRVs). The Committee
        calculates HBC-OCRVs for compounds, which are classified as stochastic
        genotoxic carcinogens by the European Union or by the Committee.
            For the establishment of the HBC-OCRV’s, the Committee generally uses a
        linear extrapolation method, as described in the Committee’s reports Calculating
        cancer risk and Guideline for the calculation of occupational cancer risk
        values.1,2 The linear model to calculate occupational cancer risk is used as a
        Scope                                                                              13
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<pre>    default method, unless scientific data would indicate that using this model is not
    appropriate.
        In the next phase of the three-step procedure, the Social and Economic
    Council advises the Minister of Social Affairs and Employment on the feasibility
    of using the HBC-OCRVs as regulatory occupational exposure limits. In the final
    step of the procedure the Minister determines the official occupational exposure
    limits.
1.2 Committee and procedure
    The present document contains the evaluation of the DECOS, hereafter called the
    Committee. The members of the Committee are listed in Annex B. The
    Committee requested the DECOS Subcommittee on the Classification of
    Carcinogenic Substances to evaluate the genotoxic mechanism of dimethyl
    sulphate (see Annex F and G). The recommendations of the Subcommittee were
    used by DECOS to decide on the appropriate approach to risk assessment. The
    submission letter (in English) to the Minister can be found in Annex C. In April
    2014, 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 D. The Committee has taken these comments into account in deciding
    on the final version of the advisory report. The received comments, and the
    replies by the Committee, can be found on the website of the Health Council.
1.3 Data
    The Committee’s recommendation has been based on scientific data, which are
    publicly available. Data were obtained from the online databases Chemical
    Abstracts, XToxline, and Medline, using ‘carcinogen’, ‘cancer’, ‘tumour’ or
    ‘neoplast’ and CAS registry number as keywords. In addition, in preparing this
    report reviews by IARC3, European Union4 and the Dutch Expert Committee on
    Occupational Standards (DECOS)5 were consulted. The last search was
    performed in September 2014.
 4  Dimethyl sulphate
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<pre> hapter 2
        Identity, toxicity profile and
        classification
2.1     Identity and physical and chemical properties
        Dimethyl sulphate is mainly used as a methylating agent in the manufacturing of
        dyes, perfumes, pharmaceuticals, for the separation of mineral oils, and for the
        analysis of automobile fluids. Also its sulphating properties are applied in the
        manufacturing of various products (e.g. dyes and fabric softeners, etc.).
        Formerly, dimethyl sulphate was used as a war gas.6
             The identity and some physicochemical properties of dimethyl sulphate are
        given below.4,7
        Chemical name                   : dimethyl sulphate
        CAS registry number             : 77-78-1
        EC number                       : 201-058-1
        RTECS number                    : WS82250007
        IUPAC name                      : dimethyl sulphate
        Synonyms                        : dimethyl monosulphate, DMS, methyl sulphate, sulphuric acid
                                          dimethyl ester
        Molecular formula               : C2H6O4S
        Physical description and colour : clear colourless, oily liquid with a very ‘faint’ or no odour
        Structure                       :
        Identity, toxicity profile and classification                                                   15
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<pre>    Molar mass                       : 126.13 g/mol
    Melting point                    : approximately -32 °C
    Boiling point                    : 188 °C (with decomposition) at 100 kPa
    Relative density (air = 1)       : 1.33 at 20 °C
    Solubility in water              : 28 g/L at 20 °C
    Solubility in organic solvents   : Miscible with many polar organic solvents and aromatic
                                       hydrocarbons but sparingly soluble in carbon disulphide and
                                       aliphatic hydrocarbons
    Log P (n-octanol/water)          : 0.16 (calc.)
    Vapour pressure                  : 65 Pa at 20 °C
    Relative vapour density (air = 1): 4.356
    Flash point (closed cup)         : 83 °C
    Odour threshold                  : Not available
    Conversion factor (20 °C,        : 1 ppm = 5.24 mg/m3 air at 20 °C; 1 mg/m3 = 0.19 ppm
    101.3 kPa)
2.2 Classification as a carcinogenic substance
    IARC concluded in 1999 that dimethyl sulphate is probably carcinogenic to
    humans (group 2A).3 In addition, dimethyl sulphate has been classified by the
    European Union as a substance which is presumed to have carcinogenic
    potential for humans (GHS category 1B).4,8 In the 12th NTP Report on
    Carcinogens dimethyl sulphate is reasonably anticipated to be a human
    carcinogen based on sufficient evidence of carcinogenicity from studies in
    experimental animals.6
         DECOS concluded in 1990 that there was insufficient evidence that dimethyl
    sulphate is carcinogenic to humans while the compound is carcinogenic to
    animals.5
         In the present evaluation (September 2014) the Committee (DECOS) follows
    the recommendation of the DECOS Subcommittee on the Classification of
    Carcinogenic Substances and classified dimethyl sulphate in category 1B
    (substance presumed to be carcinogenic to humans) (see Annex F and G).
2.3 Genotoxicity
    Dimethyl sulphate is a potent direct-acting genotoxicant in bacteria and
    mammalian cells both in vitro and in vivo.4 Dimethyl sulphate methylates DNA
    especially at the N7-guanine and the N3-adenine sites.3,5 It is positive in tests for
    primary DNA damage, gene mutations, and chromosome aberrations in vitro.
 6  Dimethyl sulphate
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<pre>    From the results of tests with mammals it is concluded that dimethyl sulphate has
    genotoxic activity in somatic cells in vivo.3-5
        The Committee concludes in accordance with the recommendation of the
    DECOS Subcommittee on the Classification of Carcinogenic Substances (see
    Annex F) that dimethyl sulphate is a stochastic genotoxic carcinogen.
2.4 Non-carcinogenic effects
    Dimethyl sulphate can be absorbed by all routes (oral, respiratory and dermal)
    but data are limited. Rapid respiratory absorption is observed in rats exposed to
    dose levels up to 50.3 mg/m3. At higher dose levels uptake was decreased,
    probably due to a decreased minute volume. After inhalatory and dermal
    exposure dimethyl sulphate is hydrolysed to methanol, sulphuric acid and methyl
    sulphate, and metabolized to a lesser extent to formaldehyde and formate.4
        Dimethylsulphate is toxic after oral, dermal and inhalation exposure. The
    LD50 for oral administration is 106-440 mg/kg bw, for inhalation 45-168 mg/m3
    (4 hours), and for subcutaneous administration 100 mg/kg bw in rats.4
        Dimethyl sulphate is corrosive to skin, is considered an eye irritant with risk
    for serious damage to eyes and is irritating to the respiratory tract. Dimethyl
    sulphate was positive in the murine local lymph node assay. Although the
    positive response may be due to the corrosive properties, dimethyl sulphate is
    considered a potential skin sensitizer in the absence of further data.4,9
        No repeated-dose toxicity studies with dimethyl sulphate suitable for the
    establishment of a NOAEL (No Observed Adverse Effect Level) are reported. In
    a 2-week inhalation study with rats, a slightly increased proliferation of nasal
    epithelium cells was still seen at the lowest concentration examined, i.e. 0.5
    mg/m3.4
        No data on toxicity to fertility are available. From a prenatal developmental
    toxicity study in rats exposed to concentrations of 0.5 to 7.9 mg/m3, the NOAEL
    for maternal toxicity after inhalation was established to be 0.5 mg/m3 based on
    decreased food consumption and reduced weight gain. The NOAEL for
    developmental toxicity was determined to be 7.9 mg/m3.4 In another prenatal
    developmental toxicity study in mice exposed to 25 mg/kg bw once via the
    intraperitoneal route an increased incidence of resorptions, gestational deaths and
    increased incidence of live fetuses with malformations was noted following
    treatments at 1, 6 and 9 hours after mating.3 The substance is not classified as
    reprotoxic in the European Union.9
    Identity, toxicity profile and classification                                       17
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<pre>2.5          Existing occupational exposure limits and classifications
             An inventarisation of occupational exposure limits for dimethyl sulphate in
             various countries is given in Table 1. Only for the German TRK value it is
             reported that the critical effects of dimethyl sulphate are its respiratory irritation
             and genotoxic and carcinogenic effects. In Germany, dimethyl sulphate has been
             classified as a category A2 carcinogen.10 In the UK, dimethyl sulphate is listed as
             a carcinogen.11 In the US, ACGIH has classified the compound as an A3
             carcinogen, i.e. an animal carcinogen and OSHA as a potential occupational
             carcinogen.12 Dimethyl sulphate is not classified for reproduction toxic
             properties in any of the countries listed below. No information on biological limit
             values could be found. In most countries dimethyl sulphate has a skin notation
             (see Table 1). Following the decision tree for ‘skin notation’13, it is concluded
 able 1 Occupational exposure limits (OELs) of dimethyl sulphate.
  ountry (organization)                   OEL (ppm)         OEL (mg/m3) TWA                 Type of exposure limita
 he Netherlands  15                       -                 -
 uropean Union (SCOEL)15                  -                 -                               (skin)
Denmark15                                 0.01              0.05            8h              (skin)
 inland15                                 0.01              0.052           15min
 rance (INRS)15                           0.1               0.5             8h
United Kingdom (HSE) 11,15                0.05              0.26            8h              WEL (skin, carc*)
Germany (DFG)10                                                                             MAK (skin, carc A2**)
    production                            (0.02)            (0.1)           TRK
    use                                   (0.04)            (0.2)           TRK
Norway15                                  0.01              0.05            8h              (skin)
Austria15
    production                            0.02              0.1             8h              (skin)
    use                                   0.04              0.2             8h
    production                            0.08              0.4             15min
    use                                   0.16              0.8             15min
 witzerland15                             0.02              0.1             8h              (skin)
  elgium15                                0.1               0.53            8h              (skin)
 pain15                                   0.05              0.26            8h              (skin)
USA (ACGIH)12                             0.1               0.5             8h              TLV (skin, carc A3***)
USA (NIOSH)12                             0.1               0.5             10h             REL (skin, carco****)
USA (OSHA)12                              1                 5               8h              PEL (skin)
 WEL = workplace exposure limit; MAK = Maximum; TLV = threshold limit value; REL = recommended exposure limit;
 EL = permissible exposure limit; skin = skin notation.
  carc = capable of causing cancer and/or heritable genetic damage; ** carc A2 = DFG classifies dimethyl sulphate as a
 ategory A2 carcinogen, i.e., an animal carcinogen; DFG category A carcinogens are not assigned a health-based occupational
 xposure limit, but a so called TRK-value (TRK = Technische Richtkonzentrationen), a concentration feasible with currently
 vailable means. TRK-values are given in brackets; *** carc A3 = confirmed animal carcinogen with unknown relevance to
 umans; **** carco = potential occupational carcinogen.
 8           Dimethyl sulphate
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<pre>that in the EU the skin notation for dimethyl sulphate is based on human
experience indicating the importance of skin penetration.4,14
Identity, toxicity profile and classification                            19
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<pre> hapter 3
        Carcinogenicity studies
3.1     Observations in humans
        A very limited number of case reports and epidemiological studies concerning
        carcinogenicity of dimethyl sulphate is available in the older literature and has
        been reviewed repeatedly.3,4,6,9 The Committee did not identify data of a more
        recent date.
            Druckrey et al. (1966) reported a case of a 47-year-old male who died from
        bronchial cancer after 11 years of occupational exposure to dimethyl sulphate.
        Three out of ten co-workers also died from bronchial cancer.16 Bettendorf (1977)
        reported a case of lung cancer in a chemist exposed by inhalation to dimethyl
        sulphate for over 7 years; however, in this case, there was concomitant exposure
        to other alkylating agents (notably dichlorodimethyl ether) that were present at
        higher concentration.17 Albert and Puliafito (1977) reported a case of choroidal
        melanoma in a man exposed to dimethyl sulphate for 6 years.18
            In workers (n=145), who had been exposed to dimethyl sulphate for various
        periods between 1932 and 1972 (concentrations unknown), no significant
        increase in deaths from lung cancer was reported.3,5,9,19,20
            In two studies with workers (n=386 and 43,000 respectively) exposed to
        unknown concentrations of dimethyl sulphate, the number of cases with lung
        cancer was 4 and 257, respectively (Thiess & Goldman, 1968; Thiess et al.,
        1969). No information on concurrent control groups was available.21,22
        Carcinogenicity studies                                                           21
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<pre>        The Committee is of the opinion that the human epidemiological data on the
    carcinogenicity of dimethyl sulphate do not allow a qualitative or quantitative
    risk assessment . This conclusion is in agreement with the conclusions from HSE
    and IARC.3,23,24
3.2 Carcinogenicity studies in animals
    Animal carcinogenicity data are summarized in the Table 2 in Annex E. A
    number of animal studies concerning carcinogenicity of dimethyl sulphate is
    available in the older literature and has been reviewed repeatedly.3,4,6,9
        Inhalation studies in three species showed tumours of the nasal cavity,
    sometimes accompanied by lung tumours.25-27 Druckrey et al. (1970) exposed
    BD-rats (sex unspecified) for 130 days to 55 mg/m3 [10 ppm] and 17 mg/m3
    [3 ppm] (1 hr/d, 5 d/wk). At 55 mg/m3 5/15 of the rats developed malignant
    tumours (nasal cavity, cerebellum, thorax) . At 17 mg/m3 3/12 showed
    carcinomas (nasal cavity). Benign tumours were found in the cerebellum and the
    olfactory nerve. Several deaths due to inflammation of the nasal cavity or
    pneumonia were reported.25 However, this study was poorly reported (purity of
    dimethyl sulphate was unknown and no information on control animals, and on
    the observational and pathological examinations was reported).
        Key data were reported in a doctoral thesis by Schlögel (1970, 1972).26,27
    Male and female rats (Wistar), mice (NMRI) and hamsters (Syrian Golden) were
    exposed to 2.6-10.5 mg/m3 [0.5 ppm] dimethyl sulphate (6 hr/d, 2d/wk), to 10.5
    mg/m3 [2 ppm] (6hr/d, 1d/2wk) or to a sublethal concentration (4 times per year
    for 1 hour, 178 mg/m3 (rats), 252 mg/m3 (mice), 105 mg/m3 (hamsters)) for about
    15 months (Schlögel 1972).26 The animals were exposed for about 15 months
    and observed for at least 30 months. The Committee notes that in the first
    exposure month, animals of the 2.6-10.5 mg/m3 group were exposed to 10.5
    mg/m3 (5 d/wk, 6 hrs/d), during the second month they were exposed to 5.3 mg/
    m3 (3 d/wk, 6 hrs/d), and starting from the third month to 2.6 mg/m3 (2 d/wk,
    6 hrs/d).
        In general, survival in the groups exposed to dimethyl sulphate was lower
    than in controls, although the mean survival time varied considerably between
    the various exposure groups (see Annex E). The survival time in male and female
    rats of the 2.6 mg/m3 group was distinctly lower than the survival time in rats of
    the control or the 10.5 mg/m3 group. The same phenomenon was seen in mice
    although less pronounced. The lower survival time in the 2.6-10.5 mg/m3 group
    is probably due to the initially high exposure regimen applied to this exposure
    group (see also Annex E, footnote).
 2  Dimethyl sulphate
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<pre>    Annex E lists the observed incidence of benign and malignant lung tumours
and malignant tumours of the nose in animals surviving to the end of the study
period. Dimethyl sulphate exposure resulted generally in an increased incidence
of malignant tumours in the respiratory tract (nose and lungs) compared to the
respective control groups. Rats were most sensitive to the tumour inducing
activity of dimethyl sulphate, while hamsters were the least sensitive. In all three
animal species, females appeared more sensitive than males. Female rats
exposed to 10.5 mg/m3 showed a slightly higher incidence of lung adenomas
than the control females.
    The highest incidence of treatment-related malignant respiratory tract
tumours was found in rats exposed to 10.5 mg/m3 group. The incidence in the
2.6-10.5 mg/m3 group was distinctly lower although the total dose in the low
dose group was comparable to or higher than that in the 10.5 mg/m3 group. This
lower incidence might be related to the lower mean survival time in the 2.6
mg/m3 group, which in its turn may be a consequence of the initially high
exposure scheme applied to this group. Exposure to sublethal dimethyl sulphate
concentrations induced treatment-related tumours in rats only. In this context it is
important to realize that the exposure scheme applied for the sublethal
concentration (178 mg/m3) leads to a lower total dose than that used with the
2.6-10.5 and 10.5 mg/m3 groups, moreover most animals of the sublethal groups
have been exposed four times only.
    The Committee is aware that the study of Schlögel has shortcomings i.e.
small group size, for each concentration a different dosing regimen was used,
and poor survival, especially in the low dose (2.6-10.5 mg/m3) group.26
Moreover, it was not clear to the Committee which of the histologically assessed
animals actually died from cancer or from other causes.
    According to the study by van Duuren et al. (1974) dermal exposure of mice
did not result in skin papillomas or carcinomas (even not after challenge with a
tumour promotor) at a level beyond that of controls.28 In the offspring of 8 rats,
dosed intravenously with dimethyl sulphate (single dose 20 mg/kg bw), 7 out of
59 animals developed malignant tumours after one year. Duckrey et al. (1966,
1970) showed that subcutaneous injection of dimethyl sulphate caused local
sarcomas with metastases to the lung.16,25 There were no oral carcinogenicity
studies.
    The Committee is of the opinion that the data show that dimethyl sulphate is
carcinogenic to animals. There is species specificity of the carcinogenic response
and difference in target organs between species. All studies presented here have
shortcomings and deviate in one or more aspects from guideline studies (see also
Table 2 in Annex E).
Carcinogenicity studies                                                              23
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<pre>3.3 Risk assessment
    Epidemiological studies are not conclusive regarding carcinogenicity of
    dimethyl sulphate. However, sufficient evidence is available that dimethyl
    sulphate has carcinogenic potency to animals. The Committee classifies dimethyl
    sulphate in category 1B (substance presumed to be carcinogenic to humans) and
    concludes that a stochastic genotoxic mechanism underlies carcinogenicity.
        The logical approach to risk assessment would be the derivation of health-
    based calculated occupational cancer risk values (HBC-OCRVs). However, none
    of the animal studies is sufficiently adequate for quantitative risk assessment.
    Therefore the Committee concludes that due to a lack of adequate human and
    animal data, it is not possible to exactly establish the health-based calculated
    occupational cancer risk values for dimethyl sulphate.
3.4 Additional consideration
    In spite of this conclusion above (paragraph 3.3), the Committee emphasizes that
    dimethyl sulphate is a potent carcinogen and that performing no calculations at
    all may not be appropriate. Therefore, the Committee decided to use, by lack of
    more adequate studies, the data from Schlögel to speculate on exposure levels
    related to additional life-time cancer risk.26
        The Committee performed its calculations using the data from the 10.5
    mg/m3 treatment group (see calculations in Annex H). Being aware of the
    shortcomings of the Schlögel rat study [small group size, poor survival, no
    information on the cause of death (tumours or other causes)] the Committee
    decided not to include the data from the 2.6-10.5 and the 178 mg/m3 group in the
    calculations.
         From the data of the 10.5 mg/m3 group the Committee estimated an
    additional lifetime cancer risk of 4 cases per 1,000 at occupational exposure
    concentrations of 30 µg dimethyl sulphate/m3 during a working life (8 hr/day,
    40 yrs). The Committee is aware that this value is below any of the existing
    exposure limits (see Table 1). The Committee recommends that occupational
    exposures to dimethyl sulphate should be minimized.
        The non-carcinogenic toxicity data, as summarized in paragraph 2.4, do not
    allow to derive an exposure limit for toxicity below the concentration levels
    associated with additional lifetime cancer risk.
 4  Dimethyl sulphate
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<pre>  References
  Health Council of The Netherlands. Guideline for the calculation of occupational cancer risk values.
  The Hague: The Netherlands; 2012: publicationno. 2012/16E.
  Health Council of The Netherlands. Calculating cancer risk. The Hague, The Netherlands: 1995:
  publication no. 1995/06WGD.
  International Agency for Research on Cancer. Dimethyl sulfate. In: IARC monographs on the
  evaluation of carcinogenic risks to humans (volume 71): Re-evaluation of some organic chemicals,
  hydrazine and hydrogen peroxide (part 2). Lyon, France: 1999: 575-588.
  European Union Risk Assessment Report, Volume 12. Dimethyl sulphate. European Chemicals
  Bureau, European Commission; 2002.
  Werkgroep van Deskundigen (WGD). Rapport inzake grenswaarde dimethyl- en diethylsulfaat. The
  Hague, The Netherlands: Servicecentrum SDU Uitgevers; 1990: RA 12/90.
  Dimethyl sulphate. In: Report on Carcinogens (12th edition). National Toxicology Program,
  Department of Health and Human Services; 2011: 174-175.
  Dimethyl sulphate. In: Pohanish R, editor. Sittig’s Handbook of Toxic and Hazardous Chemicals.
  Oxford, UK: Elsevier; 2012: 1069-1070.
  Dimethyl sulphate (77-78-1). Annex VI to Regulation 1272/2008 of the European Parliament and of
  the Council. http://esis.jrc.ec.europa.eu/index.php?PGM=cla consulted: 1-10-2014.
  Recommendation from the Scientific Committee on Occupational Exposure Limits for dimethyl
  sulphate. European Commission; 2004: SCOEL/SUM/111.
0 Deckblatt zu Dimethylsulfat. The MAK Collection for Occupational Health and Safety. http://
  onlinelibrary.wiley.com/book/10.1002/3527600418 consulted: 1-10-2014.
1 EH40/2005 Workplace exposure limits. Health and Safety Executive (HSE), UK; 2011.
  References                                                                                           25
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<pre>2 Dimethyl sulphate. Hazardous Substances Data Bank. http://toxnet.nlm.nih.gov/cgi-bin/sis/
  htmlgen?HSDB consulted: 1-10-2014.
3 Strategy for assigning a ‘skin notation’. Brussels, Belgium: European Centre for Ecotoxicology and
  Toxicology of Chemicals; 1993: 31(revised).
4 Schettgen T, Broding HC, Angerer J, Drexler H. Dimethyl sulphate; a hidden problem in
  occupational medicine. Occup Environ Med 2004; 61(1): 73-75.
5 Dimethylsulfaat. SER: Databank Grenswaarden Stoffen op de Werkplek (GSW). http://www.ser.nl/
  nl/taken/adviserende/grenswaarden.aspx consulted: 1-10-2014.
6 Druckrey H, Preussmann R, Nashed N, Ivankovic S. [Carcinogenic alkylating substances.
  I. Dimethylsulfate, carcinogenic action in rats and probable cause of occupational cancer].
  Z Krebsforsch 1966; 68(1): 103-111.
7 Bettendorf U. [Occupational lung cancer after inhalation of alkylating compounds: dichlordimethyl
  ether, monochlordimethyl ether and dimethyl sulphate (author’s transl)]. Dtsch Med Wochenschr
  1977; 102(11): 396-398.
8 Albert DM, Puliafito CA. Choroidal melanoma: possible exposure to industrial toxins. N Engl J Med
  1977; 296(11): 634-635.
9 Pell S. Mortality of workers exposed to dimethyl sulphate, 1992-1974. Wilmington, Delaware, E I
  Dupont de Nemours & Co , Inc , 1976; 47pp.
0 Dimethyl Sulfate, Environmental Health Criteria 48, International Programme on Chemical Safety.
  http://www.inchem.org/documents/ehc/ehc/ehc/48.htm consulted: 1-10-2014.
1 Thiess AM, Goldmann PJ. [Industrial medical problems in connexion with dimethylsulfate
  poisoning. Observations over 30 years in the BASF]. Zentralbl Arbeitsmed 1968; 18(7): 195-204.
2 Thiess AM, Oettel H, Uhl C. [Contribution to the problems of lung cancer due to occupation. Long
  term observations from the Badischen Anilin- und Soda-Fabrik AG in Ludwigshafen on the Rhine].
  Zentralbl Arbeitsmed 1969; 19(4): 97-113.
3 International Agency for Research on Cancer. Dimethyl sulphate (Group 2A). In: IARC monographs
  on the evaluation of carcinogenic risks to humans (Suppl 7): Overall evaluations of carcinogenicity:
  An updating of IARC monographs volumes 1 to 42. Lyon, France: 1987: 200-201.
4 Cartlidge G, Cain J, Brown R. Dimethyl and diethyl sulphates. In: Criteria document for an
  occupational exposure limit. Sudbury, UK: HSE Books; 1996:
5 Druckrey H, Kruse H, Preussmann R, Ivankovic S, Landschuetz C. [Cancerogenic alkylating
  substances. 3. Alkyl-halogenides,-sulfates,-sulfonates and strained heterocyclic compounds].
  Zeitschr Krebsforsch 1970; 74(3): 241-270.
6 Schlögel F. Cancerogenität und chronische Toxicität inhalierten Dimethylsulfats. Dissertation,
  Wurzburg: 1972.
7 Schlögel F, Bannash P. [Toxicity and carcinogenic properties of inhaled dimethyl sulfate]. Naunyn
  Schmiedebergs Arch Pharmacol 1970; 266(4): 441.
8 Van Duuren B, Goldschmidt B, Katz C, Seidman I, Paul J. Carcinogenic activity of alkylating agents.
  J Natl Cancer Inst 1974; 53(3): 695-700.
6 Dimethyl sulphate
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<pre>9 Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The
  Hague, The Netherlands: 2010: publication no. A10/07E.
  References                                                                                        27
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<pre>8 Dimethyl sulphate</pre>

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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 Animal studies
F Evaluation of the Subcommittee on the Classification of Carcinogenic
  Substances
G Carcinogenic classification of substances by the Committee
H Health-based calculated occupational risk values based on the rat study
  by Schlögel
  Annexes
                                                                          29
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<pre>0 Dimethyl sulphate</pre>

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<pre>nnex 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
     governmental 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                                                                                        31
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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
      calculated 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
      classification 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.
2 Dimethyl sulphate
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<pre>nnex B
     The Committee
     •  RA Woutersen, chairman
        Toxicologic Pathologist, TNO Innovation for Life; and Professor of
        Translational Toxicology, Wageningen University and Research Centre,
        Wageningen
     •  P.J. Boogaard
        Toxicologist, Shell International BV, The Hague
     •  D.J.J. Heederik
        Professor of Risk Assessment in Occupational Epidemiology, Institute for
        Risk Assessment Sciences, Utrecht University, Utrecht
     •  R. Houba
        Occupational Hygienist, Netherlands Expertise Centre for Occupational
        Respiratory Disorders (NECORD), Utrecht
     •  H. van Loveren
        Professor of Immunotoxicology, Maastricht University, Maastricht; and
        National Institute for Public Health and the Environment, Bilthoven
     •  T.M. Pal
        Occupational Physician, Netherlands Center for Occupational Diseases,
        Amsterdam
     •  A.H. Piersma
        Professor of Reproductive Toxicology, National Institute for Public Health
        and the Environment, Bilthoven
     The Committee                                                                 33
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<pre>  •   H.P.J. te Riele
      Professor of Molecular Biology, VU University Amsterdam; and Netherlands
      Cancer Institute, Amsterdam
  •   I.M.C.M. Rietjens
      Professor of Toxicology, Wageningen University and Research Centre,
      Wageningen
  •   F.G.M. Russel
      Professor of Molecular Farmacology and Toxicology, Radboud University,
      Nijmegen
  •   G.M.H. Swaen
      Epidemiologist, Maastricht University, Maastricht
  •   R.C.H. Vermeulen
      Epidemiologist, Institute for Risk Assessment Sciences, Utrecht
  •   P.B. Wulp
      Occupational Physician, Labour Inspectorate, Groningen
  •   B.P.F.D. Hendrikx, advisor
      Social and Economic Council, The Hague
  •   G.B. van der Voet, scientific secretary
      Toxicologist, Health Council of the Netherlands, The Hague
  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
  Council Committee. Transparency regarding possible conflicts of interest is
  nonetheless 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 material 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.
4 Dimethyl sulphate
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<pre>nnex C
     The submission letter (in English)
     Subject         : Submission of the advisory report dimethyl sulphate
     Your Reference: DGV/MBO/U-932342
     Our reference : U-8223/BvdV/459-P70
     Enclosed        :1
     Date            : November 3, 2014
     Dear Minister,
     I hereby submit the advisory report on the effects of occupational exposure to
     dimethyl sulphate.
     This advisory report is part of an extensive series in which carcinogenic
     substances are evaluated for the possibility to establish health-based
     occupational cancer risk values in accordance with European Union guidelines.
     This involves substances to which people can be exposed while pursuing their
     occupation.
     The advisory report was prepared by the Dutch Expert Committee on
     Occupational Safety (DECOS) of the Health Council. The advisory report has
     been assessed by the Health Council’s Standing Committee on Health and the
     Environment.
     The submission letter (in English)                                             35
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<pre>      In this report, the Committee concludes that dimethyl sulphate is a
  carcinogenic substance (category 1B, substance presumed to be carcinogenic to
  humans).
      The Committee is of the opinion that due to a lack of adequate data, it is not
  possible to estimate the additional lifetime cancer risk for dimethyl sulphate.
  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 J.L. Severens,
  Vice President
6 Dimethyl sulphate
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<pre>nnex D
     Comments on the public review draft
     A draft of the present report was released in April 2014 for public review. The
     following organization and persons have commented on the draft document:
     • T. Lentz, PhD, P. Erdely, PhD, A. Rengasamy, PhD, R. Streicher, Ph.D,
         National Institute for Occupational Safety and Health (NIOSH), Cincinnati
         OH, USA.
     Comments on the public review draft                                             37
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<pre>8 Dimethyl sulphate</pre>

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<pre> nnex        E
             Animal studies
able 2 All studies presented here are non-guideline studies and deviate in one or more aspects from a guideline study.
tudy design and       Data on exposure and effect Results                                          Remarks
nimal species         endpoints
 chlögel, 197226      Inhalation;                   TBA (tumor bearing animals)                    mean survival in days ± SD
arcinogenicity study;                                                                              for M and F, respectively
at, Wistar;           1) 0 (30 M, 20 F)             1 lung adenomas M 2/25, F 0/11                 1) 839 ± 26; 617 ± 87
ontrol: 30 M, 20 F                                    malignant lung tumours M 0/25, F 0/11
5-30 F                                                malignant nasal tumours M 0/25, F 0/11
                      2) 2.6 mg/m3 *, 6 hr/d, 2     2 lung adenomas M 0/21, F 0/16                 2) 226 ± 27; 301 ± 56
                          d/wk (35 M, 30 F)           malignant lung tumours M 0/21, F 1/16            (initially high exposure)
                                                      malignant nasal tumours M 0/21, F 2/16
                      3) 10.5 mg/m3, 6 hr/d, 1      3 lung adenomas M 1/14, F 3/13                 3) 590 ± 62; 637 ± 61
                         d/2 wks (15 M, 15 F)         malignant lung tumours M 0/14, F 0/13
                                                      malignant nasal tumours M 3/14, F 3/13
                      4) 178 mg/m3, 4 times per     4 lung adenoma M 1/14, F 0/15                  4) 605 ± 84; 279 ± 72
                         year for 1 hr (15 M, 15 F) malignant lung tumours M 0/14, F 0/15
                         Xpo = 15 months, Xpe =       malignant nasal tumours M 1/14, F 1/15
                         30 months
             Animal studies                                                                                                  39
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<pre> chlögel, 197226       Inhalation;                   TBA                                          mean survival in days ± SD
 arcinogenicity study;                                                                            for M and F, respectively
mouse, NMRI;           1) 0 (25 M, 25 F)             1 lung adenomas M 1/8, F 2/11                1) 304 ± 59; 540 ± 35
 ontrol: 25/sex;                                       malignant lung tumours M 0/8, F 0/11
reated: 15-25/sex      2) 2.6 mg/m3 *, 6 hr/d,       2 lung adenomas M 1/14, F 3/18               2) 287 ± 39; 371 ± 38
                           2 d/wk (25 M, 25 F)         malignant lung tumours M 0/14, F 1/18         (initially high exposure)
                       3) 10.5 mg/m3, 6 hr/d,        3 lung adenomas M 4/11, F 2/14               3) 308 ± 34; 393 ± 62
                           1 d/2 wks (15 M, 15 F)      malignant lung tumours M 0/11, F 3/14
                       4) 252 mg/m3, 4 times per     4 lung adenomas M 0/6, F 3/11                4) 249 ± 33; 325 ± 23
                           year for 1 hr (15 M, 15     malignant lung tumours M 0/6, 0/11
                          F)Xpo = 15 months, Xpe
                          = 30 months
 chlögel, 197226       Inhalation;                   TBA                                          mean survival in days ± SD
 arcinogenicity study;                                                                            for males and females,
 amster, Syrian                                                                                   respectively
 olden; control:       1) 0 (16 M, 16 F)             1 lung adenomas M 0/5, F 0/10                1) 247 ± 54; 303 ± 49
 6/sex; treated:                                         malignant lung tumours M 0/5, F0/10
 5-31/sex              2) 2.6 mg/m3 *, 6 hr/d,       2 lung adenomas M 0/16, F 0/12               2) 262 ± 34; 244 ± 44
                          2 d/wk (20 M, 16 F)            malignant lung tumours M 0/16, 0/12
                       3) 10.5 mg/m3, 6 hr/d,        3 lung adenomas M 0/11, F 1/11               3) 148 ± 25; 171 ± 32
                           1 d/2 wks (15 M, 15 F)        malignant lung tumours M 0/11, F 1/11
                       4) 105 mg/m3, 4 times per     4 lung adenomas M 1/25, F 0/26               4) 253 ± 29; 144 ± 19
                          year for 1 hr (31 M, 31 F)     malignant lung tumours M 0/25, F 0/26
                          Xpo = 15 months,
                          Xpe = 30 months
Druckrey, 197025       inhalation                    Death: 8/20, 12/27 with inflammation of the  purity: ?; no concurrent
at, BD;                                              nasal cavity,                                control group; sex
 =20,                  1) 17 mg/m3, 1 h/d,           1 3/12 survivors with treatment related      unspecified; observations
                           5 d/wk,                     tumours: one rat with squamous cell        and pathological
                                                       carcinoma of the nasal cavity, one with    examination were reported
                                                       brain neuroma and a third with an          limitedly
 =27                                                   esthesioneuroepithelioma of the olfactory
                                                       nerve;
                       2) 55 mg/m3, 1 h/d,           2 5/15 survivors with treatment related
                           5 d/wk                      tumours: 3 squamous cell carcinomas of the
                                                       nasal cavity, one cerebellum tumour, and
                                                       one lymphosarcoma of the thorax with lung
                       Xpo = 130d                      metastases.
                       Xpe = until life end
 an Duuren, 197428 dermal; 3 times per week,         Medium survival 437 days. No papillomas or purity: ?; no information on
 arcinogenicity study; 475 days, 0.1 mg/0.1 ml       carcinomas found                             controls; numbers too
mouse, ICR/Ha          acetone                                                                    limited
 wiss; n=20 F
 an Duuren, 197428     dermal; challenge with        2 papillomas                                 purity: ? (DMS was
wo stage               single dose 0.1 mg/0.1 ml     0 in controls (challenge with acetone only   distilled at
 arcinogenesis study;  acetone, followed by phorbol (n=50) or untreated (n=100)                   93 °C at 50 mm Hg)
mouse, ICR/Ha          myristate acetate 3 times a
 wiss; n=20 F          week 14 days after challenge
 0            Dimethyl sulphate
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<pre>Druckrey, 197025       intravenous; single dose, 20 7 tumours in brain, liver, uterus, and thyroid purity: ?; no information on
 evelopmental          mg/kg bw at day 15 of         gland in F1 animals after 1 year              controls; no information on
oxicity study; rat,    gestation; examination of F1                                                observational and
  D;                   (n=59) at 1 year                                                            pathological examinations
  pregnant F
Druckrey, 197025       subcutaneous; single dose, 7 deaths with sarcomas at the injection site, 3 purity: ?; limited report; no
 arcinogenicity study; 50 mg/kg bw, observation for of these animals had multiple lung metastases information on controls; no
at, BD; n=15           740 days                                                                    information on
                                                                                                   observational and
                                                                                                   pathological examinations
Druckrey, 196616       subcutaneous; once a week                                                   purity: ?; no information on
 arcinogenicity study;                                                                             controls; no information on
at, BD;                                                                                            observational and
 ) n=12                1) 8 mg/kg bw                 1 one death with liver carcinoma with spleen pathological examination
                                                        and lung metastases, 7 animals with
                                                        injection site tumours (3 of these
                                                        accompanied with metastases in lungs and
                                                        lymph-nodes and kidneys).
 ) n=15                2) 16 mg/kg bw                2 two deaths due to pneumonia, all survivors
                                                        with tumours at the injection site (2 of
                                                        these accompanied with metastases in the
                       Xpo=56 wks                       lung)
                       Xpe=until natural death
  In first exposure month, animals of the 2.6 mg/m3 group were exposed to 10.5 mg/m3 (5 d/wk, 6 hrs/d), during the second
month they were exposed to 5.3 mg/m3 (3 d/wk, 6 hrs/d), and starting from the third month to 2.6 mg/m3 (2 d/wk, 6 hrs/d).
Xpo exposure period; Xpe total experimental/observation period
              Animal studies                                                                                                 41
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<pre>2 Dimethyl sulphate</pre>

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<pre>nnex F
     Evaluation of the Subcommittee on
     the Classification of Carcinogenic
     Substances
     IARC concluded in its most recent evaluation (1999) that dimethyl sulphate is
     probably carcinogenic to humans (group 2A).1 In addition, dimethyl sulphate has
     been classified by the European Union as a substance which is presumed to have
     carcinogenic potential for humans (GHS category 1B).2 [In the 12th NTP Report
     on Carcinogens dimethyl sulfate is reasonably anticipated to be a human
     carcinogen based on sufficient evidence of carcinogenicity from studies in
     experimental animals.3]
         DECOS concluded in 1990 that there was insufficient evidence that dimethyl
     sulphate was carcinogenic to humans, while the compound was carcinogenic to
     animals.4 Dimethyl sulphate was classified by DECOS in 1990 as a genotoxic
     carcinogen.4
         In the present evaluation (November 2013) the DECOS Subcommittee on the
     Classification of Carcinogenic Substances evaluated the existing and new
     information regarding human, animal and in vitro studies on carcinogicity and
     genotoxicity of dimethyl sulphate.
     Human studies
     A very limited number of case reports and epidemiological studies concerning
     carcinogenicity of dimethyl sulphate is available in the older literature and
     repeatedly reviewed (IARC, 1999; EU-RAR, 2002; SCOEL, 2004; NTP-RoC,
     2011).1,3,5,6 The Subcommittee did not identify human data of a more recent date.
     Evaluation of the Subcommittee on the Classification of Carcinogenic Substances   43
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<pre>      Druckrey et al. (1966) reported a case of a 47-year-old male who died from
  bronchial cancer after 11 years of occupational exposure to dimethylsulphate.7
  Three out of ten co-workers also died from bronchial cancer. Bettendorf (1977)
  reported a case of lung cancer in a chemist exposed by inhalation to dimethyl
  sulphate for over 7 years; however, in this case, there was concomitant exposure
  to other alkylating agents (notably dichlorodimethyl ether) that were present at
  higher concentrations.8 Albert and Puliafito (1977) reported a case of choroidal
  melanoma has been reported in a man exposed to dimethyl sulphate for 6 years.9
      In workers (n=145), who had been exposed to dimethyl sulphate for various
  periods between 1932 and 1972 (concentrations unknown), no significant
  increase in deaths from lung cancer was reported (Pell, 1972).1,4,6,10,11
      In two studies (Thiess & Goldman 1968; Thiess et al. 1969) with workers
  (n=386 or 43,000) exposed to unknown concentrations of dimethyl sulphate, the
  number of cases with lung cancer was 4 and 257, respectively. 12,13 No
  information on concurrent control groups was available.
      The Subcommittee agrees with IARC that the data available from
  epidemiological studies are inadequate to evaluate the relationship between
  human cancer and exposure specifically to dimethyl sulfate.
  Animal studies (see Table 2 in Annex E)
  A number of animal studies concerning carcinogenicity of dimethyl sulphate is
  available in the older literature and repeatedly reviewed (IARC, 1999; EU-RAR,
  2002; SCOEL, 2004; NTP-RoC, 2011).1,3,5,6 The Subcommittee did not identify
  animal data of a more recent date. Although these older studies were not
  designed to fulfil the requirements of the OECD the Subcommittee decided not
  to exclude these studies from her evaluation.
      Inhalation studies in three species showed tumours of the nasal cavity,
  sometimes accompanied by lung tumours.14-16 Druckrey et al. (1970) showed in a
  study with BD-rats (sex unspecified) for 130 days (55 mg/m3 [10 ppm] and 17
  mg/m3 [3 ppm], 1 hr/d, 5 d/wk) 5/15 that rats developed malignant tumours
  (nasal cavity, cerebellum, thorax) at 55 mg/m3. At 17 mg/m3 3/12 showed
  carcinomas (nasal cavity). Benign tumours were found in the cerebellum and the
  olfactory nerve. Several deaths due to inflammation of the nasal cavity or
  pneumonia were reported.14 However, this study was poorly reported (purity of
  dimethyl sulphate was unknown and no information on control animals, and on
  the observational and pathological examinations was reported).
      Key data were reported in a doctoral thesis by Schlögel (1970, 1972).15,16
  Male and female rats (Wistar), mice (NMRI) and hamsters (Syrian Golden) were
4 Dimethyl sulphate
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<pre>exposed to 2.6 mg/m3 [0.5 ppm] dimethyl sulphate (6 hr/d, 2d/wk), to 10.5
mg/m3 [2 ppm] (6hr/d, 1d/2wk) or to a sublethal concentration (4 times per year
for 1 hour, 178 mg/m3 (rats), 252 mg/m3 (mice), 105 mg/m3 (hamsters)) for about
15 months. The animals were exposed for about 15 months and observed for at
least 30 months after the start of exposure provided they survived. DMS
exposure resulted in an increased incidence of malignant tumours in the
respiratory tract (nose and lungs) of rats and mice. Rats were most sensitive to
the tumour-inducing activity of dimethyl sulphate, while hamsters were the least
sensitive (only one tumour at 10.5 mg/m3 [2 ppm] dimethyl sulphate). In all three
animal species females appeared more sensitive than males. In female rats of the
10.5 mg/m3 group, the incidence of lung adenomas was slightly higher than in
control females.
    Dermal exposure of mice did not result in skin papillomas or carcinomas
(even not after challenge with a tumour promotor) at a level beyond that of
controls (van Duuren et al., 1974).17 In the offspring of 8 rats, dosed
intravenously with dimethyl sulphate (single dose 20 mg/kg bw), 7 out of 59
animals developed malignant tumours after one year. Druckrey et al.(1966, 1970)
showed that subcutaneous injection of dimethyl sulphate caused local sarcomas
with metastases to the lung.7,14 There were no oral carcinogenicity studies.
    The Subcommittee agrees with IARC that sufficient evidence exists that
dimethyl sulphate is carcinogenic to animals.
Mechanism of genotoxicity
Dimethyl sulphate is a potent direct-acting alkylating genotoxic substance in
bacteria, and mammalian cells in vitro and in vivo.5 Dimethyl sulphate
methylates DNA especially at the N7-guanine and the N3-adenine sites.1,4 It is
positive in tests for primary DNA damage, gene mutations, and chromosome
aberrations in vitro. From the results of the tests with mammals it is concluded
that dimethyl sulphate has genotoxic activity in somatic cells in vivo.1,4,5
    DECOS Subcommittee is of the opinion that a stochastic genotoxic
mechanism may underly the carcinogenicity of dimethyl sulphate.
Recommendation
Epidemological studies are not conclusive regarding carcinogenicity of dimethyl
sulphate. However, sufficient evidence is available that dimethyl sulphate is
carcinogenic to animals. Therefore, the Subcommittee recommends to classify
dimethyl sulphate in category 1B (substance presumed to be carcinogenic to
Evaluation of the Subcommittee on the Classification of Carcinogenic Substances   45
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<br><br>====================================================================== Pagina 47 ======================================================================

<pre>  humans). Moreover, the Subcommittee is of the opinion that a stochastic
  genotoxic mechanism may underly carcinogenicity. The Subcommittee
  recommends health-based calculated occupational cancer risk values (HBC-
  OCRVs) to be calculated for regulatory standard setting.
  References
  International Agency for Research on Cancer. Dimethyl sulfate. In: IARC monographs on the
  evaluation of carcinogenic risks to humans (volume 71): Re-evaluation of some organic chemicals,
  hydrazine and hydrogen peroxide (part 2). Lyon, France, 1999: 575-588.
  Dimethyl sulphate (77-78-1). Annex VI to Regulation 1272/2008 of the European Parliament and of
  the Council. http://esis.jrc.ec.europa.eu/index.php?PGM=cla consulted: 1-10-2014.
  Dimethyl sulphate. In: Report on Carcinogens (12th edition). National Toxicology Program,
  Department of Health and Human Services, 2011:174-175.
  Werkgroep van Deskundigen (WGD). Rapport inzake grenswaarde dimethyl- en diethylsulfaat. The
  Hague, The Netherlands: Servicecentrum SDU Uitgevers, 1990: RA12/90.
  European Union Risk Assessment Report, Volume 12. Dimethyl sulphate. European Chemicals
  Bureau, European Commission, 2002
  Recommendation from the Scientific Committee on Occupational Exposure Limits for dimethyl
  sulphate. European Commission, 2004: SCOEL/SUM/111.
  Druckrey H, Preussmann R, Nashed N, Ivankovic S. [Carcinogenic alkylating substances. I.
  Dimethylsulfate, carcinogenic action in rats and probable cause of occupational cancer]. Z
  Krebsforsch 1966; 68(1): 103-111.
  Bettendorf U. [Occupational lung cancer after inhalation of alkylating compounds: dichlordimethyl
  ether, monochlordimethyl ether and dimethyl sulphate (author's transl)]. Dtsch Med Wochenschr
  1977; 102(11): 396-398.
  Albert DM, Puliafito CA. Choroidal melanoma: possible exposure to industrial toxins. N Engl J Med
  1977; 296(11): 634-635.
0 Pell S. Mortality of workers exposed to dimethyl sulphate, 1992-1974. Wilmington, Delaware, E I
  Dupont de Nemours & Co, Inc, 1976, 47pp.
1 Dimethyl sulfate, Environmental Health Criteria 48, International Programme on Chemical Safety,
  1985. http://www.inchem.org/documents/ehc/ehc/ehc48.htm consulted 1-10-2014.
2 Thiess AM, Goldmann PJ. [Industrial medical problems in connexion with dimethylsulfate
  poisoning. Observations over 30 years in the BASF]. Zentralbl Arbeitsmed 1968; 18(7): 195-204.
3 Thiess AM, Oettel H, Uhl C. [Contribution to the problems of lung cancer due to occupation. Long
  term observations from the Badischen Anilin- und Soda-Fabrik AG in Ludwigshafen on the Rhine].
  Zentralbl Arbeitsmed 1969; 19(4): 97-113.
6 Dimethyl sulphate
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<pre>4 Druckrey H, Kruse H, Preussmann R, Ivankovic S, Landschuetz C. Carcinogene alkylierende
  Substanzen, III. Alkyl-halogenide-sulfate-sulfonate and ringgespannte Heterocyclen. Zeitschr
  Krebsforsch 1970; 74(3): 241-270.
5 Schlὂgel F, Bannash P. Toxicity and carcinogenic properties of inhaled dimethyl sulfate. Naunyn
  Schmiedebergs Arch Pharmacol 1970; 266(4): 441.
6 Schlὂgel F. Cancerogenität und chronische Toxicität inhalierten Dimethylsulfats. Dissertation,
  Wurzburg, 1972.
7 Duuren B van, Goldschmidt B, Katz C, Seidman I, Paul J. Carcinogenic activity of alkylating agents.
  J Natl Cancer Inst 1974; 53(3): 695-700.
  The Subcommittee
  •   R.A. Woutersen, chairman
      Toxicologic Pathologist, TNO Innovation for Life, Zeist; and 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
  •   M.J.M. Nivard
      Molecular Biologist and Genetic Toxicologist, Leiden University Medical
      Center, Leiden
  •   G.M.H. Swaen
      Epidemiologist, Exponent, Menlo Park, USA
  •   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
  Date meeting: November 11, 2013
  Evaluation of the Subcommittee on the Classification of Carcinogenic Substances                     47
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<pre>8 Dimethyl sulphate</pre>

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<pre> nnex        G
             Carcinogenic classification of
             substances by the Committee
             The Committee expresses its conclusions in the form of standard phrases:
 ategory     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
A            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.
B            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.
             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
ource: Health Council of the Netherlands. Guideline to the classification of carcinogenic compounds. The Hague: Health
 ouncil of the Netherlands, 2010; publication no. A10/07E.29
             Carcinogenic classification of substances by the Committee                                                49
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<pre>0 Dimethyl sulphate</pre>

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<pre>nnex H
     Health-based calculated occupational
     risk values based on the rat study by
     Schlögel
     Data
     Epidemiological studies are not conclusive regarding carcinogenicity of
     dimethyl sulphate. However, sufficient evidence is available that dimethyl
     sulphate is a potent carcinogen for experimental animals. A stochastic genotoxic
     mechanism underlies carcinogenicity. The proper approach to risk assessment
     would be the derivation of health-based occupational risk values. However, all
     animal studies presented are non-guideline studies and deviate in one or more
     aspects from a guideline study (see also Table 2 in Annex E). The Committee is
     aware that none of the studies is sufficiently adequate for quantitative risk
     assessment.
         That being said, the Committee emphasizes that dimethyl sulphate is a potent
     carcinogen and that performing no calculations at all may not be appropriate.
     Therefore, the Committee decides to use the data from the study by Schlögel to
     speculate on the exposure levels related to additional life-time cancer risk.26
     In the study by Schlögel, groups of male and female rats, mice and hamsters
     were exposed to 0, 2.6-10.5 mg/m3 (6 hr/day, 2 days/week), 10.5 mg/m3 once
     every two weeks (6 hr/day), or 178 mg/m3 dimethyl sulphate (a sublethal
     concentration), 4 times per year for 1 hour. Animals were exposed for about 15
     months and observed for at least 30 months. The three concentration groups had
     different exposure regimens and survival was more affected in 2.6-10.5 mg/m3
     Health-based calculated occupational risk values based on the rat study by Schlögel 51
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<pre>  group than in 10.5 or 178 mg/m3 group. This might be explained by the initial
  higher dosage regimens, i.e. in the first exposure month, animals of the 2.6 mg/
  m3 group were exposed to 10.5 mg/m3 (5 d/wk, 6 hrs/d), during the second
  month they were exposed to 5.3 mg/m3 (3 d/wk, 6 hrs/d), and starting from the
  third month to 2.6 mg/m3 (2 d/wk, 6 hrs/d).
       The incidence of rats with malignant respiratory tract tumours amounted to 0/
  36, 3/37, 6/27 and 2/29 in the 0, 2.6, 10.5 and 178 mg/m3 groups.
  Being aware of the shortcomings of the Schlögel rat study (small group size,
  poor survival no information on cause of death (tumours or other causes) the
  Committee decided not to use the data from both the 2.6-10.5 mg/m3 and the 178
  mg/m3 group in the calculations.
       The Committee calculated the occupational exposure related to additional
  life-time respiratory cancer risk based on the data from the 10.5 mg/m3 group.
  Procedure
  First, the incidence per µg/m3 per day (lifespan conditions, assuming a linear
  dose-response relationship) is calculated as follows:
                                                      Ie – Ic
  Iconcentration =
                   C x (Xpo/L) x (Xpe/L) x hours exposure per day/24 x days exposure per week/7
  Where:
  • Iconcentration is the carcinogenic activity attributable to the exposure to the
       substance per unit daily dose under lifespan conditions, assuming a linear
       dose response relationship, usually expressed per mg/m3 or per mg/kg bw/
       day.
  • Ie and Ic are the incidence of tumour bearing animals or tumours in exposed
       and control animals, respectively.
  • Xpo and Xpe (see Table 2 in Schlögel) are the exposure and experimental
       periods, respectively.
  • L is the standard lifespan for the animals in question (L rat in this experiment
       is 728 days, equal to the mean survival time found in the controls).
  Furthermore, it is assumed that the average man lives 75 years, weighs 70 kg,
  and is exposed 24 hours per day 7 days/week, 52 weeks per year for lifetime.
2 Dimethyl sulphate
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<pre>To estimate the additional lifetime risk of cancer in humans under workplace
exposure conditions, it is assumed that the average man lives 75 years, is
exposed 8 hours per day, 5 days per week, 48 weeks per year for 40 years and
inhales 10 m3 per 8-hour-working day.
Using as starting point the estimated incidence, Iconcentration, the additional life-
time cancer risk per µg/m3 under occupational exposure conditions (= HBC-
OCRV) amounts to:
                              40 years 48 weeks 5 days 8 hours 10 m3/day
HBC-OCRV = Iconcentration x            x            x        x          x
                              75 years 52 weeks 7 days 24 hours 18 m3/day
Calculations for the 10.5 mg/m3 exposure group
                                    6/27 - 0/36
Iconcentration =                                                           =
                 (10.5x103 µg/m3) x (456/728) x (613/728) x 6/24 x 1/14
     = 2.2x10-3 [µg/m3]-1
                              40 years   48 weeks     5 days    8 hours   10 m3/day
HBC-OCRV = 2.2x10-3 x                  x           x         x          x           =
                              75 years   52 weeks     7 days   24 hours 18 m3/day
     = 1.4 x 10-4 [µg/m3]-1
Based on the HBC-OCRV of 1.4 x 10-4 per µg/m3 the additional life-time cancer
risk amounts to:
• 4 per 1,000 (4 x 10-3), for 40 years of exposure to 29 µg/m3
• 4 per 100,000 (4 x 10-5), for 40 years of exposure 0.29 µg/m3.
Health-based calculated occupational risk values based on the rat study by Schlögel   53
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<pre>4 Dimethyl sulphate</pre>

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<pre>Health Council of the Netherlands
Advisory Reports
The Health Council’s task is to       In addition, the Health Council
advise ministers and parliament on    issues unsolicited advice that
issues in the field of public health. has an ‘alerting’ function. In some
Most of the advisory reports that     cases, such an alerting report
the Council produces every year       leads to a minister requesting
are prepared at the request of one    further advice on the subject.
of the ministers.
Areas of activity
Optimum healthcare                    Prevention                          Healthy nutrition
What is the optimum                   Which forms of                      Which foods promote
result of cure and care               prevention can help                 good health and
in view of the risks and              realise significant                 which carry certain
opportunities?                        health benefits?                    health risks?
Environmental health                  Healthy working                     Innovation and
Which environmental                   conditions                          the knowledge
influences could have                 How can employees                   infrastructure
a positive or negative                be protected against                Before we can harvest
effect on health?                     working conditions                  knowledge in the
                                      that could harm their               field of healthcare,
                                      health?                             we first need to
                                                                          ensure that the right
                                                                          seeds are sown.
www.healthcouncil.nl
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<br><br>